1-substituted tetrahydroisoquinoline compound

CONTINUING DATA

This application is a 371 of PCT/JP08/59287 filed May 20, 2008.

TECHNICAL FIELD

The present invention relates to a medicament, and specifically to a 1-substituted tetrahydroisoquinoline compound which is useful as an active ingredient of a pharmaceutical composition for preventing and/or treating pain, abdominal symptoms, spastic constipation, and irritable bowel syndrome.

BACKGROUND ART

Pain is an important biological defense mechanism which reflects the addition of any invasion to organisms. When pain or dysesthesia still lasts even after tissue damage or diseases responsible for the onset of pain have been cured, such a condition is recognized as a disease. Pain is broadly classified into nociceptive pain and neuropathic pain. Nociceptive pain includes pain caused by tissue inflammation, cancer-induced nerve compression, or the like (inflammatory pain, cancer pain, etc.). Non-steroidal anti-inflammatory drugs (NSAIDs) or opioids are therapeutically effective for the treatment of nociceptive pain.

On the other hand, neuropathic pain is chronic pain caused by nerve tissue damage or compression, or the like. Symptoms of neuropathic pain include unpleasant dysesthesia such as continuous or sudden spontaneous pain, numbness, burning sensation, the pain of being cut into small pieces, and stabbing pain; a condition which is a painful response to a usually non-painful weak stimulus (hyperalgesia); pain due to a stimulus that does not normally provoke pain (allodynia), such as caused by contact with clothing or changes in temperatures; and the like. Specific diseases of neuropathic pain include trigeminal neuralgia, complex regional pain syndrome, post spinal surgery syndrome, phantom limb pain, pain after brachial plexus injury, post-spinal cord injury pain, post-stroke pain, painful diabetic neuropathy, postherpetic neuralgia, HIV-induced neuropathy, and further some cases of cancer pain and low back pain on which analgesic effects of opioids are not sufficiently exerted, in addition to anticancer drug- and anti-HIV drug-induced neuropathy.

Neuropathic pain is known as pain on which NSAIDs or opioids which are effective on nociceptive pain exhibit difficulty in being therapeutically effective. In practical medication therapy, alleviation of pain is effected by hemp, capsaicin cream, or intraspinal administration of opioids, as well as by administration of antidepressants (duloxetine, amitriptylin, etc.), antiepileptic drugs (pregabalin, carbamazepine, etc.), or local analgesics (mexiletine, etc.). Unfortunately, effects of these drugs are limited since many neuropathic pains are developed by an overlap of multiple pathogenic causes and individual patients have different disease backgrounds. Further, there are also problems associated with inherent side effects of individual drugs. To this end, there is a strong need for an anti-neuropathic pain agent which has more potent and broader analgesic spectrum and lower side effects.

Irritable bowel syndrome (IBS) is a syndrome which brings about abdominal symptoms such as abdominal pain and abdominal distension and stool abnormalities such as diarrhea or defecation urgency and constipation or difficulty in defecation, due to the dysfunction of the lower digestive tract around the large intestine, despite no occurrence of organic alteration such as inflammation and tumor. Depending on predominant bowel habits, IBS is broadly subclassified into diarrhea type IBS (IBS-D), constipation type IBS (IBS-C), and mix type IBS (IBS-M) with alternating diarrhea and constipation (Gastroenterology 130: 1377-90, 1480-91 (2006)). As a medication therapy for IBS, there may be mentioned anticholinergic drugs for abdominal pain, tricyclic antidepressants (TCAs) for improving decreased pain threshold of the digestive tract, and in the case of bowel movement disturbance, antidiarrheals or intestinal remedies for diarrhea and cathartic salts for constipation, which are merely allopathic therapies and are also uncertain in their effects (Irritable bowel syndrome.about.Communication between the brain and the intestines (ISBN4-521-67671-5, 2006)).

As drugs which are recently attracting attention, alosetron which is a 5-HT.sub.3 receptor antagonist and tegaserod which is a 5-HT.sub.4 receptor agonist are used for IBS-D and IBS-C, respectively. However, use of alosetron is limited due to the incidence of constipation in 30% to 35% of patients, in conjunction with serious side effects of ischemic colitis (including death), even though it exhibits a comparatively high improvement rate of 40% to 60% for abdominal symptoms and diarrhea (Drug Today 36: 595-607 (2000), FDA information about lotronex, GlaxoSmithKline press release). In addition, it is said that tegaserod has little effect on abdominal symptoms due to poor constipation-alleviating effects, which may result in the risk of tachyphylaxis (phenomenon of producing resistance to a drug after repeated doses over a short period of time) (Clinical Therapeutics 25: 1952-1974 (2003)). In addition, an application of tegaserod is also strongly limited in terms of side effects, due to having adverse effects on the circulatory system (FDA information about zelnorm, Novartis press release).

Opioids, such as morphine, which have been commonly used as pain-relieving drugs, are known to cause severe dysfunction of the digestive tract including constipation, which is called opioid bowel dysfunction (OBD). Among symptoms of OBD, the onset of constipation is very high without creating drug resistance unlike other opioid-induced central nervous system side-effects, so it is necessary to take appropriate measures to deal with the situation (American J. Surgery 182: 11S-18S (2001), Jpn. Cancer Chemother. 32: 1377-1383 (2005)). For these reasons, in opioid treatment particularly on cancer pain patients, a combined prophylactic treatment with a laxative agent is essential from the beginning of administering an opioid drug, but it is not easy to control defecation by means of the laxative agent (Drugs 63: 649-671 (2003), Pharmacotherapy 22: 240-250 (2002)).

The digestive tract is provided with an independent nerve network, called the enteric nervous system. Various kinds of neurons are present in the enteric nervous system and are responsible for governing respective digestive tract functions. Among those neurons, Intrinsic Primary Afferent Neutrons (IPANs) are neurons that primarily receive changes in the digestive tract lumen. IPANs detect physical or chemical changes in the digestive tract lumen and transmit the information to motor neurons or sensory neurons. Therefore, drugs altering the activity of IPANs bring about changes in the digestive tract function, called peristaltic motion or visceral perception (Progress in Neurobiol. 54: 1-18 (1998)). Further, from the fact that the N-type Ca.sup.2+ channel is expressed in IPANs and contributes to the activity of IPANs (J. Comp. Neurol. 409: 85-104 (1999)), it can be considered that a compound blocking the N-type Ca.sup.2+ channel would be useful for functional digestive tract diseases by altering digestive tract functions.

In addition, it is known that abdominal pain signals, like somatic pain, travel to the brain via the dorsal root ganglion (DRG) and the spinal cord (Neurogastroentel. Motil. 16: 113-124 (2004)). This signaling pathway is hypersensitized in IBS patients, suggesting significant occurrences of abdominal symptoms (Gut 53: 1465-1470 (2004)). Therefore, it is anticipated that a blocker of the N-type Ca.sup.2+ channel involved in this pain-signaling pathway would be an effective therapeutic agent against abdominal symptoms of IBS. In fact, it has been reported that gabapentin or pregabalin, which is a ligand for the Ca.sup.2+ channel .alpha.2.delta. subunit, exerts analgesic effects in animal models of abdominal pain hypersensitization (J. Pharmacol. Exp. Ther. 295: 162-167 (2000), Anesthesiology 98: 729-733 (2003)).

There are many kinds of Ca.sup.2+-dependent functional proteins in cells, and changes in the intracellular Ca.sup.2+ concentration play an important role in the expression or regulation of various physiological functions such as neuronal viability, synaptic plasticity, and gene expression. Among Ca.sup.2+ channels present on the cell membrane, a channel using a membrane potential as a trigger in the opening of the channel is called a voltage-dependent Ca.sup.2+ channel (VDCC), which consists mainly of an .alpha.1 subunit forming the channel body, a .beta. subunit controlling an expression level of the .alpha.1 subunit or functions of the channel, and an .alpha.2.delta. subunit (Trends Neurosci. 21 148-154 (1998)). The Ca.sup.2+ channels are classified into high-threshold Ca.sup.2+ channels such as L-type (.alpha.1S, C, D, and F), P/Q-type (.alpha.1A), N-type (.alpha.1B), and R-type (.alpha.1E); and low-threshold Ca.sup.2+ channels such as T-type (.alpha.1G, H, I), depending on .alpha.1 subunit type and activation threshold potential (Rev. Physiol. Biochem. Pharmacol. 139: 33-87 (1999)).

Among the high-threshold Ca.sup.2+ channels, the P/Q-, N-, and R-type Ca.sup.2+ channels are present in neuron synaptic terminals and serve as a trigger of the neurotransmitter release. In particular, the N-type Ca.sup.2+ channel is highly expressed in the dorsal root ganglion (DRG) (J. Neurosci. 15: 4315-4327 (1995)) which is a collection of cell bodies of the sensory neurons or the spinal dorsal horn (J. Neurosci. 18: 6319-6330 (1998)) which is a synaptic projection region of sensory neurons. Further, the spinal dorsal horn of neuropathic pain model rats exhibited an increased expression of the N-type Ca.sup.2+ channel in synchronization with the progression of hyperalgesia (Exp. Brain Res. 147: 456-463 (2002)). From these facts, it is believed that the N-type Ca.sup.2+ channel plays a role as a trigger that transmits an excess of pain signals to the brain.

With recent observations showing that a selective N-type Ca.sup.2+ channel-blocking peptide, .omega.-conotoxin (.omega.-CTx) exhibits broad analgesic effects in animal models of nociceptive, inflammatory and neuropathic pain, respectively (J. Pharmacol. Exp. Ther. 279: 1243-1249 (1996), J. Pharmacol. Exp. Ther. 287: 232-237 (1998), J. Pharmacol. Exp. Ther. 269: 1117-1123 (1994)), and no neuropathic pain occurs in .alpha.1B-deficient mice (EMBO J. 20: 2349-2356 (2001)), it has been suggested that the N-type Ca.sup.2+ channel is deeply implicated in the pathogenesis of neuropathic pain. In fact, it has been reported that chronic spinal administration of ziconotide (.omega.-conotoxin MVIIA:.omega.-CTxMVIIA) by means of an implantable pump improves hyperalgesia and allodynia in morphine non-responsive neuropathic pain patients (Clin. J. Pain 13: 256-259 (1997)). Further, it has been demonstrated that gabapentin or pregabalin, frequently used as an anti-neuropathic pain agent, binds with a high affinity to the Ca.sup.2+ channel .alpha.2.delta. subunit to exert thereby analgesic effects (J. Pharm. Sci. 100: 471-486 (2006)). Based on the above-mentioned findings, the N-type Ca.sup.2+ channel blocker is expected to be an excellent therapeutic agent for pain, particularly neuropathic pain. Further, from the fact that the N-type Ca.sup.2+ channel is involved in hyperactivity of neurons, cellular death and the like, the N-type Ca.sup.2+ channel blocker is consequently expected to be useful for the prevention or treatment of conditions or diseases associated with activation of the N-type Ca.sup.2+ channel, in addition to the above-mentioned pain. Taken altogether, it is believed that a compound having the N-type Ca.sup.2+ channel-blocking action would be useful for various pains such as neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, central nervous system diseases such as anxiety, depression, epilepsy, cerebral stroke and restless legs syndrome, digestive system diseases such as abdominal pain and irritable bowel syndrome, and urinary system diseases such as overactive bladder and interstitial cystitis.

N-type Ca.sup.2+ channel-blocking compounds have been hitherto reported. For example, it has been described that the following benzazepine derivatives have an action of blocking N-type Ca.sup.2+ channels and are useful as an agent for preventing and/or treating cerebral infarction, transient cerebral ischemic attack, encephalomyelopathy after cardiac surgery, spinal cord vascular disorders, stress-induced hypertension, neurosis, epilepsy, asthma, frequent micturition, and ophthalmic diseases, or as anti-pain drugs (Patent Document 1).

##STR00001##

(See the above-referenced document for symbols in the formula)

However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.

Further, it has been described that the following diarylalkene or diarylalkane derivatives have an action of blocking N-type Ca.sup.2+ channels and are useful for treating pain, brain infarction, cerebral disorders caused by acute ischemia after the onset of cerebral hemorrhage, Alzheimer's disease, AIDS-associated dementia, Parkinson's disease, progressive degenerative diseases of the brain, neurological disorders caused by head injury, bronchial asthma, unstable angina, irritable colon inflammatory diseases, and withdrawal symptoms of drug addiction (Patent Document 2).

##STR00002##

(See the above-referenced document for symbols in the formula)

However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.

Further, it has been described that the following tricyclic heteroaromatic compounds have an action of blocking N-type Ca.sup.2+ channels and are useful as a medicament, particularly an analgesic agent (Patent Document 3).

##STR00003##

(See the above-referenced document for symbols in the formula)

However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.

Further, it has been described that the following substituted piperazine compounds have an action of blocking N-type Ca.sup.2+ channels and are useful for treating cerebral stroke, pain, anxiety, depression, gastrointestinal disorders, genitourinary disturbance, cardiovascular disturbance, epilepsy, diabetes, and cancer (Patent Document 4).

##STR00004##

(See the above-referenced document for symbols in the formula)

However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.

Further, it has been reported that the following azacyclo compounds are useful for treating or preventing diseases associated with a flow of sodium ions of the sensory neuron channel, for example, pain such as chronic and acute pain, hypersensitivity diseases such as bladder diseases and irritable bowel syndrome, and demyelinating diseases (Patent Document 5).

##STR00005##

(See the above-referenced document for symbols in the formula)

However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.

Further, it has been reported that the following compounds have a farnesyl protein transferase inhibitory activity and are useful as an anticancer drug (Patent Document 6).

##STR00006##

(See the above-referenced document for symbols in the formula)

However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. In addition, there is no disclosure or suggestion of their effects on N-type Ca.sup.2+ channel-blocking action, pain including neuropathic pain, and digestive system diseases including irritable bowel syndrome.

Further, it has been reported that the following compounds have an anti-arrhythmic action (Non-Patent Document 1).

##STR00007##

(See the above-referenced document for symbols in the formula)

However, an English Abstract attached to the above-referenced Document contains no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. In addition, there is no disclosure or suggestion of their effects on N-type Ca.sup.2+ channel-blocking action, pain including neuropathic pain, and digestive system diseases including irritable bowel syndrome.

Further, it has been reported that the following compounds have an anti-arrhythmic action (Non-Patent Document 2).

##STR00008##

(See the above-referenced document for symbols in the formula)

However, an English Abstract attached to the above-referenced Document contains no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. In addition, there is no disclosure or suggestion of their effects on N-type Ca.sup.2+ channel-blocking action, pain including neuropathic pain, and digestive system diseases including irritable bowel syndrome.

Further, it has been reported that the following compounds have an action of blocking Ca.sup.2+ channels and are useful as a hypotensive agent and an anti-arrhythmic agent (Non-Patent Document 3).

##STR00009##

(See the above-referenced document for symbols in the formula)

However, an English Abstract attached to the above-referenced Document contains no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. In addition, there is no disclosure or suggestion of their effects on N-type Ca.sup.2+ channel-blocking action, pain including neuropathic pain, and digestive system diseases including irritable bowel syndrome.

Further, it has been reported that the following compounds have a Ca.sup.2+ channel-blocking action, a Na.sup.+ channel-blocking action and a calmodulin inhibitory activity and are possibly useful in neuroprotective therapy (Non-Patent Documents 4 and 5).

##STR00010##

(See the above-referenced document for symbols in the formula)

However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.

Further, the following compounds have been reported as an Orexin-2 receptor antagonist (Non-Patent Document 6). Additionally, it has also been suggested that an Orexin-2 receptor is involved in the transmission of nociceptive stimuli.

##STR00011##

(Me in the formula represents methyl)

However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.

As other references which disclose compounds having a tetrahydroisoquinoline skeleton, there are Patent Documents 7 to 9. However, these documents contain no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. [Patent Document 1] JP-A-2002-363163 [Patent Document 2] Pamphlet of International Publication No. WO 03/018538 [Patent Document 3] Pamphlet of International Publication No. WO 2004/089950 [Patent Document 4] Pamphlet of International Publication No. WO 2005/021523 [Patent Document 5] Pamphlet of International Publication No. WO 2005/005392 [Patent Document 6] European Patent Application Laid-open Publication No. EP 0 696 593 [Patent Document 7] Pamphlet of International Publication No. WO 01/85693 [Patent Document 8] Pamphlet of International Publication No. WO 02/079189 [Patent Document 9] Pamphlet of International Publication No. WO 03/082828 [Non-Patent Document 1] Fudan University Journal of Medical Science, 1987, 14 (1), 15-20 [Non-Patent Document 2] Fudan University Journal of Medical Science, 1989, 16 (1), 71-74 [Non-Patent Document 3] Journal of China Pharmaceutical University, 1993, 24 (4), 193-201 [Non-Patent Document 4] Biological & Pharmaceutical Bulletin, 2000, 23 (3), 375-378 [Non-Patent Document 5] Neurochemical Research, 2003, 28 (12), 1813-1818 [Non-Patent Document 6] Bioorganic & Medicinal Chemistry Letters, 2003, 13 (24), 4497-4499

DISCLOSURE OF THE INVENTION

Problem that the Invention is to Solve

It is an object of the present invention to provide a medicament having a selective blocking action on N-type Ca.sup.2+ channels, and specifically a compound useful as an active ingredient of a pharmaceutical composition for preventing and/or treating pain and irritable bowel syndrome.

The compound of the present invention has a structural characteristic in that in the formula (I), at least one of R.sup.1a and R.sup.1b is a substituent other than --H, and R.sup.22 is a hydroxyl-containing substituent. Further, the compound of the present invention has pharmacological properties in that it has an N-type Ca.sup.2+ channel-blocking action, an antinociceptive pain action, an antineuropathic pain action, an abdominal pain-inhibitory action and an opioid-induced constipation-improving action.

Means for Solving the Problem

As a result of intensive studies on compounds having a selective blocking action on N-type Ca.sup.2+ channels, the present inventors found that a 1-substituted tetrahydroisoquinoline compound of the present invention has a selective N-type Ca.sup.2+ channel-blocking action, an antinociceptive pain action, an antineuropathic pain action, an abdominal pain-inhibitory action and an opioid-induced constipation-improving action. The present invention has been completed based on these findings.

That is, the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[1]

A compound of the formula (I):

##STR00012## wherein the symbols in the formula have the following meanings:

R.sup.1a and R.sup.1b: the same or different and --H, C.sub.1-6 alkyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, or an aromatic hetero ring which may be substituted, provided that both of R.sup.1a and R.sup.1b cannot be --H, and R.sup.1a and R.sup.1b, taken together with the carbon atom to which they are attached, may represent cycloalkyl which may be substituted,

R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b: the same or different and --H, or C.sub.1-6 alkyl,

R.sup.5, R.sup.6, R.sup.7 and R.sup.8: the same or different and --H, C.sub.1-6 alkyl which may be substituted, --O--(C.sub.1-6 alkyl) which may be substituted, cyano, carbamoyl which may be substituted with one or two C.sub.1-6 alkyl, or halogen, and any two adjacent groups of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 taken together may form --O--CH.sub.2--O-- or --O--(CH.sub.2).sub.2--O--,

R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16: the same or different and --H or C.sub.1-6 alkyl,

R.sup.21: --H, C.sub.1-6 alkyl which may be substituted, or cycloalkyl which may be substituted,

R.sup.22:

(1) cycloalkyl which is substituted with one or more groups selected from the group consisting of --OH and --CH.sub.2OH and which may be further substituted;

(2) C.sub.1-8 alkyl substituted with one or two --OH, wherein the C.sub.1-8 alkyl may further have a substituent, and one or two methylene groups (--CH.sub.2--) contained in this alkyl chain may be replaced with --O--; or

(3) C.sub.1-6 alkyl substituted with cycloalkyl which is substituted with one or more groups selected from the group consisting of --OH and --CH.sub.2OH and which may be further substituted, wherein the C.sub.1-6 alkyl may be substituted with --OH, and one or two methylene groups (--CH.sub.2--) contained in this alkyl chain may be replaced with --O--;

n and m: the same or different and are 0 or 1,

R.sup.12 and R.sup.21 taken together may form methylene, ethylene, or trimethylene, and in this case, R.sup.11 may represent --OH, or

R.sup.21 and R.sup.22, taken together with the nitrogen atom to which they are attached, may form azetidine, pyrrolidine, piperidine, azepane, azocane, morpholine, tetrahydroisoquinoline or thiomorpholine which are substituted with --OH or C.sub.1-6 alkyl substituted with --OH; or a pharmaceutically acceptable salt thereof.

[2]

The compound according to [1], wherein m is 0, n is 0, and R.sup.1a, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.11, R.sup.12 and R.sup.21 are each --H; or a pharmaceutically acceptable salt thereof.

[3]

The compound according to [2], wherein R.sup.1b is isopropyl, methoxymethyl, phenyl, 2-(trifluoromethyl)benzyl, or cyclohexyl; or a pharmaceutically acceptable salt thereof.

[4]

The compound according to [2] or [3], wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are the same or different and are independently selected from the group consisting of --H, methyl, ethyl, methoxy, and fluoro; or a pharmaceutically acceptable salt thereof.

[5]

The compound according to [2], [3] or [4], wherein R.sup.22 is 2-hydroxypropan-1-yl, 2-hydroxy-3-methoxypropan-1-yl, or (1-hydroxycyclohexyl)methyl; or a pharmaceutically acceptable salt thereof.

[6]

The compound according to [1], which is 1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}ami- no)methyl]cyclohexanol, (2S)-1-({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl- }amino)-3-methoxy propan-2-ol, 1-({[2-(1(1S)-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoe- thyl]amino}methyl)cyclohexanol, (2R)-1-({2-[(1S)-8-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-ox- oethyl}amino)propan-2-ol, 1-[({2-[(1R)-7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2- -oxoethyl}amino)methyl]cyclohexanol, (2S)-1-methoxy-3-[(2-oxo-2-{1(1S)-[2-(trifluoromethyl)benzyl]-3,4-dihydro- isoquinolin-2(1H)-yl}ethyl)amino]propan-2-ol, 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxo propyl]amino}methyl)cyclohexanol, (2R)-1-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amin- o}propan-2-ol, (2R)-1-[(2-oxo-2-{1-[2-(trifluoromethyl)phenyl]-3,4-dihydroisoquinolin-2(- 1H)-yl}ethyl)amino]propan-2-ol, (2S)-1-{[2-(1-cyclohexyl-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoe- thyl]amino}-3-methoxy propan-2-ol, (2R)-1-({2-oxo-2-[(1S)-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}ami- no)propan-2-ol, 1-[({2-[7-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxo- ethyl}amino)methyl]cyclohexanol, 1-[({2-[7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoe- thyl}amino)methyl]cyclohexanol, 1-({[2-(1-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl- ]amino}methyl)cyclohexanol, 1-[({2-[5-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-ox- oethyl}amino)methyl]cyclohexanol, 1-[({2-[1-(methoxymethyl)-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxo- ethyl}amino)methyl]cyclohexanol, (1S,2S)-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]a- mino}-1-phenyl propane-1,3-diol, 1-({(2R)-2-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]pyrrol- idin-1-yl}methyl)cyclohexanol, (2R)-1-{[2-(1-cyclohexyl-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoe- thyl]amino}propan-2-ol, 1-({[2-(3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-2'-yl)-2-ox- oethyl]amino}methyl)cyclohexanol, (2R)-1-[(2-oxo-2-{1-[2-(trifluoromethoxy)phenyl]-3,4-dihydroisoquinolin-2- (1H)-yl}ethyl)amino]propan-2-ol, (2R)-1-{[2-(1-cyclohexyl-7-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoet- hyl]amino}propan-2-ol, 1-({[2-(6-fluoro-1-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]- amino}methyl)cyclohexanol, 1,1-dicyclopropyl-2-({2-[6-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoli- n-2(1H)-yl]-2-oxoethyl}amino)ethanol, 1-({[2-(1-tert-butyl-8-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethy- l]amino}methyl)cyclohexanol, 1-({[2-(1-isopropyl-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]- amino}methyl)cyclohexanol, 1-({[2-(6-fluoro-1-propyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]ami- no}methyl)cyclohexanol, 1-[({2-[1-(methoxymethyl)-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxo- ethyl}amino)methyl]cyclohexanol, 1-({[2-(5-fluoro-1-propyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]ami- no}methyl)cyclohexanol, 1-[({2-[5-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxo- ethyl}amino)methyl]cyclohexanol, 1-[({2-[8-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-ox- oethyl}amino)methyl]cyclohexanol, 1-[({2-[1-(ethoxymethyl)-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoe- thyl}amino)methyl]cyclohexanol, or (1R,2S)-2-({2-[(1R)-1-(2-methoxyphenyl)-3,4-dihydroisoquinolin-2(1H)-yl]-- 2-oxoethyl}amino)cyclopentanol; or a pharmaceutically acceptable salt thereof.

[7]

A pharmaceutical composition comprising a compound of [1] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[8]

An N-type Ca.sup.2+ channel blocker comprising a compound of [1] or a pharmaceutically acceptable salt thereof.

[9]

A pharmaceutical composition for preventing or treating pain, neuropathic pain, abdominal symptom, spastic constipation, opioid-induced constipation, irritable bowel syndrome, or constipation-type irritable bowel syndrome, comprising a compound of [1] or a pharmaceutically acceptable salt thereof.

[10]

The pharmaceutical composition according to [9], which is a pharmaceutical composition for preventing or treating pain.

[11]

The pharmaceutical composition according to [10], which is a pharmaceutical composition for preventing or treating neuropathic pain.

[12]

The pharmaceutical composition according to [9], which is a pharmaceutical composition for preventing or treating abdominal symptom.

[13]

The pharmaceutical composition according to [9], which is a pharmaceutical composition for preventing or treating spastic constipation.

[14]

The pharmaceutical composition according to [13], which is a pharmaceutical composition for preventing or treating opioid-induced constipation.

[15]

The pharmaceutical composition according to [9], which is a pharmaceutical composition for preventing or treating irritable bowel syndrome.

[16]

The pharmaceutical composition according to [15], which is a pharmaceutical composition for preventing or treating constipation-type irritable bowel syndrome.

[17]

A pharmaceutical composition comprising a compound of [1] or a pharmaceutically acceptable salt thereof and an opioid as active ingredients.

[18]

A pharmaceutical composition comprising a compound of [1] or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the composition is used in combination with an opioid.

[19]

Use of a compound of [1] or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing or treating pain, neuropathic pain, abdominal symptom, spastic constipation, opioid-induced constipation, irritable bowel syndrome, or constipation-type irritable bowel syndrome.

[20]

A compound of [1] for use as an active ingredient of a pharmaceutical composition for preventing or treating pain, neuropathic pain, abdominal symptom, spastic constipation, opioid-induced constipation, irritable bowel syndrome, or constipation-type irritable bowel syndrome.

[21]

A method for preventing or treating pain, neuropathic pain, abdominal symptom, spastic constipation, opioid-induced constipation, irritable bowel syndrome, or constipation-type irritable bowel syndrome, comprising administering to a patient an effective amount of a compound of [1] or a pharmaceutically acceptable salt thereof.

Further, the present invention relates to a pharmaceutical composition for treating pain, in a certain embodiment neuropathic pain; abdominal symptoms; spastic constipation, in a certain embodiment opioid-induced constipation; or irritable bowel syndrome, in a certain embodiment constipation-type irritable bowel syndrome, comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, that is, a pharmaceutical composition for preventing and/or treating pain, in a certain embodiment neuropathic pain; abdominal symptoms; spastic constipation, in a certain embodiment opioid-induced constipation; or irritable bowel syndrome, in a certain embodiment constipation-type irritable bowel syndrome, comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

Further, the present invention relates to use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating pain, in a certain embodiment neuropathic pain; abdominal symptoms; spastic constipation, in a certain embodiment opioid-induced constipation; or irritable bowel syndrome, in a certain embodiment constipation-type irritable bowel syndrome, and a method for treating pain, in a certain embodiment neuropathic pain; abdominal symptoms; spastic constipation, in a certain embodiment opioid-induced constipation; or irritable bowel syndrome, in a certain embodiment constipation-type irritable bowel syndrome, comprising administering to a patient an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

Effect of the Invention

The compound of the present invention can be used as a pharmaceutical composition for preventing and/or treating various pains such as neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, central nervous system diseases such as anxiety, depression, epilepsy, cerebral stroke and restless legs syndrome, abdominal symptoms such as abdominal pain and abdominal distension, stool abnormalities such as diarrhea and constipation, digestive system diseases such as irritable bowel syndrome, urinary system diseases such as overactive bladder and interstitial cystitis, etc.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

In the definitions of this specification, the "C.sub.1-6 alkyl" means a linear or branched alkyl having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. The "C.sub.1-8 alkyl" means a linear or branched alkyl having 1 to 8 carbon atoms, and examples thereof include n-heptyl, n-octyl, diisopropyl ethyl, and the like, in addition to the above-described C.sub.1-6 alkyls.

The "halogen" means F, Cl, Br, or I.

The "cycloalkyl" is a C.sub.3-10 saturated hydrocarbon ring group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like. It also includes cyclohexenyl, cyclooctadienyl, and the like, which contain a partially unsaturated bond. Further, it also includes groups wherein one or two methylene groups on the ring are replaced with --O--, for example, tetrahydropyranyl, tetrahydrofuranyl, and the like. Further, its ring may be condensed with a benzene ring, and examples thereof include indenyl, indanyl, dihydronaphthyl, and tetrahydronaphthyl.

The "aryl" is a C.sub.6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and examples thereof include phenyl, naphthyl, and the like.

The "aromatic hetero ring" is a 5- to 6-membered monocyclic hetero ring group containing 1 to 3 hetero atoms selected from oxygen, sulfur, and nitrogen, and examples thereof include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, triazinyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and the like.

The "which may be substituted" means that it is "not substituted" or "substituted with 1 to 5 substituents which are the same or different". Further, if it has multiple substituents, the substituents may be the same or different from each other.

Examples of the substituent for the "C.sub.1-6 alkyl which may be substituted" in the definition of R.sup.1a and R.sup.1b include --OH; --OR.sup.z; or phenyl which may be substituted with one or more same or different groups selected from the group consisting of halogen, R.sup.Y, and --OR.sup.Y. R.sup.Y represents C.sub.1-6 alkyl which may be substituted with 1 to 5 halogens, and R.sup.z represents C.sub.1-6 alkyl which may be substituted with one or more same or different groups selected from the group consisting of --O--(C.sub.1-6 alkyl) and --OR.sup.Y (the same shall apply hereinafter).

Examples of the substituent for the "cycloalkyl which may be substituted" in the definition of R.sup.1a and R.sup.1b include --OH, halogen, R.sup.Y, and --OR.sup.Y.

Examples of the substituent for the "aryl which may be substituted" and the "aromatic hetero ring which may be substituted" in the definition of R.sup.1a and R.sup.1b include --OH, halogen, R.sup.Y, --OR.sup.Y, --SR.sup.Y, cyano, and cycloalkyl.

Examples of the substituent for the "C.sub.1-6 alkyl which may be substituted" and the "--O--(C.sub.1-6 alkyl) which may be substituted" in the definition of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 include --OH, halogen, --OR.sup.Y, and --NHCO--(C.sub.1-6 alkyl).

Examples of the substituent for the "C.sub.1-6 alkyl which may be substituted" in the definition of R.sup.21 include --OH, halogen, --OR.sup.Y, and cycloalkyl.

Examples of the substituent for the "cycloalkyl which may be substituted" in the definition of R.sup.21 include --OH, halogen, R.sup.Y, and --OR.sup.Y.

The "cycloalkyl which is substituted by one or more groups selected from the group consisting of --OH and --CH.sub.2OH and which may be further substituted" in the definition of R.sup.22 means that the cycloalkyl has at least one or more same or different groups selected from the group consisting of --OH and --CH.sub.2OH, as substituents, and may be further substituted with other substituents. Examples of the acceptable additional substituents include halogen, R.sup.Y, --OR.sup.Y, oxo (.dbd.O), and oxo protected with ethylene glycol.

The "C.sub.1-8 alkyl substituted with one or two --OH, wherein the C.sub.1-8 alkyl may further have a substituent, and one or two methylene groups (--CH.sub.2--) contained in this alkyl chain may be replaced with --O--" in the definition of R.sup.22 means that methylene group(s) on the alkyl chain of the C.sub.1-8 alkyl may be replaced with --O--, and the C.sub.1-8 alkyl has at least one or two --OH as substituents and may be further substituted with other substituents. Examples of the acceptable additional substituent include halogen; --OR.sup.Y; cycloalkyl; or aryl that may be substituted with one or more same or different groups selected from the group consisting of --OH, halogen, R.sup.Y, and --OR.sup.Y.

The "C.sub.1-6 alkyl substituted with cycloalkyl which is substituted with one or more groups selected from the group consisting of --OH and --CH.sub.2OH and which may be further substituted, wherein the C.sub.1-6 alkyl may be substituted with --OH, and one or two methylene groups (--CH.sub.2--) contained in this alkyl chain may be replaced with --O--" in the definition of R.sup.22 means that the C.sub.1-6 alkyl may be substituted with --OH, methylene group(s) on the alkyl chain may be replaced with --O--, and the C.sub.1-6 alkyl has at least cycloalkyl which may be substituted, as a substituent. Cycloalkyl as a substituent of the C.sub.1-6 alkyl has at least one or more same or different groups selected from the group consisting of --OH and --CH.sub.2OH, as substituents, and may be further substituted with other substituents. Examples of the acceptable additional substituents include halogen, R.sup.Y, --OR.sup.Y, oxo (.dbd.O), and oxo protected with ethylene glycol.

The "pain" means a variety of pains including nociceptive pain and neuropathic pain.

The "nociceptive pain" is a pain which is caused by the addition of nociceptive stimuli through nociceptors and examples thereof include pain caused by tissue damage, pain caused by tissue inflammation (inflammatory pain), pain caused by cancer-induced nerve compression (cancer pain).

The "neuropathic pain" is chronic pain which is caused by nerve tissue damage or compression or the like and examples thereof include trigeminal neuralgia, complex regional pain syndrome, post spinal surgery syndrome, phantom limb pain, pain after brachial plexus injury, post-spinal cord injury pain, post-stroke pain, painful diabetic neuropathy, postherpetic neuralgia, HIV-induced neuropathy, and further some cases of cancer pain and low back pain on which analgesic effects of opioids are not sufficiently, in addition to anticancer drug- and anti-HIV drug-induced neuropathy.

The "abdominal symptom" means abdominal discomfort such as abdominal pain and abdominal distension.

The "spastic constipation" is constipation caused by spastic dysmotility of the digestive tract, and examples thereof include opioid-induced constipation, and constipation found in constipation-type irritable bowel syndrome (IBS-C).

The "opioid-induced constipation" means constipation caused by opioids such as morphine.

The "irritable bowel syndrome" is a disease which brings about abdominal symptoms such as abdominal pain and abdominal distension and stool abnormalities such as diarrhea or defecation urgency and constipation or difficulty in defecation, due to the dysfunction of the lower digestive tract around the large intestine, despite no occurrence of organic alterations such as inflammation and tumor and the like, and is a disease which is classified into diarrhea type IBS (IBS-D), constipation type IBS (IBS-C), and mix type IBS (IBS-M) with alternating diarrhea and constipation, depending on bowel conditions.

Hereinafter, some embodiments of the present invention will be described.

(1) In the formula (I), a compound wherein R.sup.1a is --H or C.sub.1-6 alkyl which may be substituted. In another embodiment, a compound wherein R.sup.1a is --H or methyl. In yet another embodiment, a compound wherein R.sup.1a is --H.

(2) In the formula (I), a compound wherein R.sup.1b is C.sub.1-6 alkyl which may be substituted, cycloalkyl which may be substituted, or aryl which may be substituted. In another embodiment, a compound wherein R.sup.1b is n-propyl, isopropyl, tert-butyl, methoxymethyl, ethoxymethyl, phenyl, 2-methoxyphenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-(trifluoromethyl)benzyl, or cyclohexyl. In yet another embodiment, a compound wherein R.sup.1b is isopropyl, methoxymethyl, phenyl, 2-(trifluoromethyl)benzyl, or cyclohexyl.

(3) In the formula (I), a compound wherein R.sup.1a and R.sup.1b, together with the carbon atom to which they are attached, represent cycloalkyl which may be substituted. In another embodiment, a compound wherein R.sup.1a and R.sup.1b, together with the carbon atom to which they are attached, represent cyclohexyl.

(4) In the formula (I), a compound wherein R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are each --H.

(5) In the formula (I), a compound wherein m is 0, and n is 0 or 1. In another embodiment, a compound wherein m is 0, and n is 0.

(6) In the formula (I), a compound wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are the same or different and are independently selected from the group consisting of --H, C.sub.1-6 alkyl, --O--(C.sub.1-6 alkyl), and halogen. In another embodiment, a compound wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are the same or different and are selected from the group consisting of --H, methyl, ethyl, methoxy, and fluoro.

(7) In the formula (I), a compound wherein R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each --H.

(8) In the formula (I), a compound wherein m is 0, n is 0, R.sup.11 is --H, and R.sup.12 and R.sup.21 taken together represent methylene, ethylene or trimethylene. In another embodiment, a compound wherein m is 0, n is 0, R.sup.11 is --H, and R.sup.12 and R.sup.21 taken together represent trimethylene.

(9) A compound wherein R.sup.21 is --H.

(10) In an embodiment, a compound wherein R.sup.22 is cycloalkyl substituted with one or more groups selected from the group consisting of --OH and --CH.sub.2OH. In another embodiment, a compound wherein R.sup.22 is cyclopentyl or cyclohexyl substituted with one or more groups selected from the group consisting of --OH and --CH.sub.2OH. In yet another embodiment, a compound wherein R.sup.22 is 2-hydroxycyclopentyl.

(11) In an embodiment, a compound wherein R.sup.22 is C.sub.1-8 alkyl which is substituted with one or two --OH and is further substituted with one or more the same or different groups selected from the group consisting of --O--(C.sub.1-6 alkyl), cycloalkyl, and aryl. In another embodiment, a compound wherein R.sup.22 is C.sub.1-8 alkyl which is substituted with one or two --OH and is further substituted with one or more the same or different groups selected from the group consisting of methoxy, cyclopropyl, and phenyl. In a further embodiment, a compound wherein R.sup.22 is ethyl or propyl which is substituted with one or two --OH and is further substituted with one or more same or different groups selected from the group consisting of methoxy, cyclopropyl, and phenyl. In a still further embodiment, a compound wherein R.sup.22 is 2-hydroxypropan-1-yl, 2-hydroxy-3-methoxypropan-1-yl, 1,3-dihydroxy-1-phenylpropan-2-yl, or 2-hydroxy-2,2-dicyclopropylethyl. In yet another embodiment, a compound wherein R.sup.22 is 2-hydroxypropan-1-yl or 2-hydroxy-3-methoxypropan-1-yl.

(12) In an embodiment, a compound wherein R.sup.22 is C.sub.1-6 alkyl substituted with cycloalkyl which is substituted with one or more groups selected from the group consisting of --OH and --CH.sub.2OH. In another embodiment, a compound wherein R.sup.22 is cyclohexylmethyl substituted with --OH. In yet another embodiment, a compound wherein R.sup.22 is (1-hydroxycyclohexyl)methyl.

(13) In an embodiment, a compound as set forth in (10), (11), or (12). In another embodiment, a compound as set forth in (11) or (12).

(14) A compound which is a combination of any two or more selected from the group consisting of (1), (2), (4), (5), (6), (7), (9), and (13).

(15) A compound which is a combination of any two or more selected from the group consisting of (3), (4), (5), (6), (7), (9), and (13).

(16) A compound which is a combination of any two or more selected from the group consisting of (1), (2), (4), (6), (8), and (13).

(17) A compound which is a combination of any two or more selected from the group consisting of (3), (4), (6), (8), and (13).

(18) In an embodiment, a compound which is any one of (14) to (17). In another embodiment, a compound as set forth in (14).

(19) A compound which is a combination of any two or more of (1) to (12) which are not inconsistent with each other.

Examples of the compounds encompassed by the present invention include the following compounds. 1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}ami- no)methyl]cyclohexanol, (2S)-1-({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl- }amino)-3-methoxy propan-2-ol, 1-({[2-(1(1S)-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoe- thyl]amino}methyl)cyclohexanol, (2R)-1-({2-[(1S)-8-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-ox- oethyl}amino)propan-2-ol, 1-[({2-[(1R)-7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2- -oxoethyl}amino)methyl]cyclohexanol, (2S)-1-methoxy-3-[(2-oxo-2-{1(1S)-[2-(trifluoromethyl)benzyl]-3,4-dihydro- isoquinolin-2(1H)-yl}ethyl)amino]propan-2-ol.

As another embodiment of compounds that are encompassed in the present invention, the following compounds may be mentioned. 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]amino}m- ethyl)cyclohexanol, (2R)-1-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amin- o}propan-2-ol, (2R)-1-[(2-oxo-2-{1-[2-(trifluoromethyl)phenyl]-3,4-dihydroisoquinolin-2(- 1H)-yl}ethyl)amino]propan-2-ol, (2S)-1-{[2-(1-cyclohexyl-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoe- thyl]amino}-3-methoxy propan-2-ol, (2R)-1-({2-oxo-2-[(1S)-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}ami- no)propan-2-ol, 1-[({2-[7-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxo- ethyl}amino)methyl]cyclohexanol, 1-[({2-[7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoe- thyl}amino)methyl]cyclohexanol, 1-({[2-(1-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl- ]amino}methyl)cyclohexanol, 1-[({2-[5-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-ox- oethyl}amino)methyl]cyclohexanol, 1-[({2-[1-(methoxymethyl)-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxo- ethyl}amino)methyl]cyclohexanol, (1S,2S)-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]a- mino}-1-phenylpropane-1,3-diol, 1-({(2R)-2-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]pyrrol- idin-1-yl}methyl)cyclohexanol, (2R)-1-{[2-(1-cyclohexyl-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoe- thyl]amino}propan-2-ol, 1-({[2-(3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-2'-yl)-2-ox- oethyl]amino}methyl)cyclohexanol, (2R)-1-[(2-oxo-2-{1-[2-(trifluoromethoxy)phenyl]-3,4-dihydroisoquinolin-2- (1H)-yl}ethyl)amino]propan-2-ol, (2R)-1-{[2-(1-cyclohexyl-7-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoet- hyl]amino}propan-2-ol, 1-({[2-(6-fluoro-1-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]- amino}methyl)cyclohexanol, 1,1-dicyclopropyl-2-({2-[6-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoli- n-2(1H)-yl]-2-oxoethyl}amino)ethanol, 1-({[2-(1-tert-butyl-8-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethy- l]amino}methyl)cyclohexanol, 1-({[2-(1-isopropyl-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]- amino}methyl)cyclohexanol, 1-({[2-(6-fluoro-1-propyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]ami- no}methyl)cyclohexanol, 1-[({2-[1-(methoxymethyl)-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxo- ethyl}amino)methyl]cyclohexanol, 1-({[2-(5-fluoro-1-propyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]ami- no}methyl)cyclohexanol, 1-[({2-[5-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxo- ethyl}amino)methyl]cyclohexanol, 1-[({2-[8-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-ox- oethyl}amino)methyl]cyclohexanol, 1-[({2-[1-(ethoxymethyl)-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoe- thyl}amino)methyl]cyclohexanol, (1R,2S)-2-({2-[(1R)-1-(2-methoxyphenyl)-3,4-dihydroisoquinolin-2(1H)-yl]-- 2-oxoethyl}amino)cyclopentanol.

The compound of the present invention may in some cases exist in the form of other tautomers or geometrical isomers, depending on the kind of the substituents. In the present specification, the compound may be described only in one form of isomers, and the present invention includes these isomers as well as isolated forms or mixtures thereof.

Further, the compound of the formula (I) may have asymmetric carbon atoms or axial asymmetries in some cases, and correspondingly, it may exist in the form of optical isomers such as R- and S-forms. All of the mixtures and isolates of these optical isomers are included in the present invention.

Further, a pharmaceutically acceptable prodrug of the compound of the formula (I) is also included in the present invention. The "pharmaceutically acceptable prodrug" is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group or the like of the present invention by solvolysis or under a physiological condition. Examples of the group for forming a prodrug include those as described for example in Prog. Med., 5, 2157-2161 (1985) or "Iyakuhin no Kaihatsu (Development of Pharmaceuticals)" (Hirokawa Shoten Ltd., 1990), Vol. 7, "Bunshi Sekkei (Molecular Design)", pp. 163-198.

Further, the compound of the present invention may form an acid addition salt or a salt with a base, depending on the kind of substituents, and this salt is included in the present invention, as long as it is a pharmaceutically acceptable salt. Specifically, examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, or with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine, ammonium salts, and the like.

In addition, the present invention also includes various hydrates or solvates, and crystalline polymorphs of the compound of the present invention and a pharmaceutically acceptable salt thereof. Further, compounds labeled with various radioactive or non-radioactive isotopes are also included in the present invention.

(Production Methods)

The compound of the present invention and a pharmaceutically acceptable salt thereof can be prepared by applying various known synthetic methods, making use of the characteristics based on its basic skeleton or type of substituents. In that case, depending on the kind of functional groups, there is an effective case from the production technology point of view to replace the functional group with an appropriate protecting group (a group which can be easily converted into the functional group), at the stage of starting materials to intermediates. Examples of such a protecting group include those described for example in "Protective Groups in Organic Synthesis (3.sup.rd edition, 1999)", edited by Greene and Wuts, and the like, which may be appropriately selected and used depending on the reaction conditions. According to such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group, if desired.

In addition, the prodrug of the compound (I) can be produced in the same manner as the case of the above-mentioned protecting groups, by carrying out the reaction after introducing a specific group at the stage of starting materials to intermediates or using the obtained compound of the present invention. The reaction can be carried out by employing methods known to those skilled in the art, such as usual esterification, amidation, dehydration and the like.

Hereinafter, the representative production processes for the compound of the present invention will be described. Each of the production processes may also be carried out with reference to References appended to the corresponding description. Further, the production processes of the present invention are not limited to the examples as shown below.

(Production Process 1)

##STR00013##

(In the formula, X represents a leaving group, and other symbols are as defined above. The same shall apply hereinafter)

This production process is a method in which the compound (I) of the present invention is produced by reacting a compound (1a) having a leaving group with an amine derivative (1b).

In this case, examples of the leaving group include halogen, methanesulfonyloxy, and p-toluenesulfonyloxy.

The reaction can be carried out using the compound (1a) and the compound (1b) in equivalent amounts or one of them in an excess amount, from under cooling to under heating, for example, at 0.degree. C. to 80.degree. C. usually stirring for 0.1 hour to 5 days, in a reaction-inert solvent or without a solvent. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxyethane (DME); halogenated hydrocarbons such as dichloromethane (DCM), 1,2-dichloroethane (DCE), and chloroform; N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetonitrile, and a mixture thereof. It may be advantageous in some cases for smooth progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene, or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, or potassium hydroxide, or otherwise in the co-presence of a phase-transfer catalyst such as tetrabutylammonium iodide or 18-crown-6-ether.

REFERENCE LITERATURE

S. R. Sandler and W. Karo, Editors, Organic Functional Group Preparations, 2.sup.nd edition. Vol. 1, Academic Press Inc., 1991 Courses in Experiment Chemisty, 5.sup.th edition, edited by The Chemical Society of Japan, Vol. 14 (2005), Maruzen Co., Ltd.

(Production Process 2)

##STR00014##

(the symbols in the formula are as defined above)

This production process is a method in which the compound (I-2) of the present invention is produced by reacting an acrylic derivative (2a) with the amine derivative (1b).

The reaction can be carried out using the compound (2a) and the compound (1b) in equivalent amounts or one of them in an excess amount, from under cooling to under heating, for example, at 0.degree. C. to 120.degree. C. usually stirring for 0.1 hour to 5 days, in a reaction-inert solvent or without a solvent. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as methanol, ethanol, and 2-propanol, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetonitrile, and a mixture thereof. When the amine derivative is in the form of a salt, it may be advantageous in some cases for smooth progress of the reaction to carry out desalination in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[4.5.0]-7-undecene, or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide.

(Production Process 3)

##STR00015##

(the symbols in the formula are as defined above)

This production process is a method in which the compound (I) of the present invention is produced by reacting a tetrahydroisoquinoline derivative (3a) with an amino acid derivative (3b).

The reaction can be carried out using the compound (3a) and the compound (3b) in equivalent amounts or one of them in an excess amount in the presence of a condensing agent, from under cooling to under heating, for example, at -20.degree. C. to 60.degree. C. usually stirring for 0.1 hour to 5 days, in a reaction-inert solvent. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include aromatic hydrocarbons, halogenated hydrocarbons, ethers, N,N-dimethylformamide (DMF), N-methylpyrrolidone, ethyl acetate, acetonitrile, water, and a mixture thereof. Examples of the condensing agent include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphoryl azide, and phosphorus oxychloride. It may be advantageous in some cases for smooth progress of the reaction to carry out the reaction using, for example, an additive such as 1-hydroxybenzotriazole (HOBt).

Further, a method can also be used in which the amino acid derivative (3b) (with respect to a carboxyl group serving as a reaction site) is converted into a reactive derivative thereof, and then the reactive derivative is reacted with the tetrahydroisoquinoline derivative (3a). In this case, examples of the reactive derivative include acid halides obtained by reaction with a halogenating agent such as phosphorus oxychloride or thionyl chloride, mixed acid anhydrides obtained by reaction with isobutyl chloroformate or the like, and active esters obtained by condensation with HOBt or the like. The reaction between the reactive derivative of the compound (3b) and the compound (3a) can be carried out from under cooling to under heating, for example at -20.degree. C. to 60.degree. C., in a reaction-inert solvent such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers.

REFERENCE LITERATURE

S. R. Sandler and W. Karo, Editors, Organic Functional Group Preparations, 2.sup.nd edition. Vol. 1, Academic Press Inc., 1991 Courses in Experimental Chemistry, 5.sup.th edition, edited by The Chemical Society of Japan, Vol. 16 (2005), Maruzen Co., Ltd.

(Production Process 4)

##STR00016##

(In the formula, Y represents a leaving group, and other symbols are as defined above. The same shall apply hereinafter).

This production process is a method in which the compound (I) of the present invention is produced by reacting an amine derivative (4a) with a compound (4b) and/or (4c) having a leaving group.

The reaction can be carried out in the same manner as in Production Process 1. When R.sup.21 represents --H, Step A using the compound (4b) may be omitted. Further, the order of performing Step A using the compound (4b) and Step B using the compound (4c) is not critical.

In addition to N-alkylation using the compound (4b) or (4c) having a leaving group, this production process may also employ N-alkylation using an epoxy derivative corresponding to the compound (4b) or (4c), and reductive amination using an aldehyde derivative corresponding to the compound (4b) or (4c).

The N-alkylation using the epoxy derivative corresponding to the compound (4b) or (4c) can be carried out in the same manner as in Production Process 1.

The reductive amination using the aldehyde derivative corresponding to the compound (4b) or (4c) can be carried out using the compound (4a) and the aldehyde derivative corresponding to the compound (4b) or (4c) in equivalent amounts or one of them in an excess amount, at -45.degree. C. to heating under reflux in the presence of a reducing agent in a reaction-inert solvent, for example, at 0.degree. C. to room temperature, usually stirring for 0.1 hour to 5 days. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include alcohols, ethers, and a mixture thereof. Examples of the reducing agent include sodium cyanoborohydride, triacetoxy sodium borohydride, sodium borohydride, and the like. It may be advantageous in some cases for smooth progress of the reaction to carry out the reaction in the presence of a dehydrating agent such as molecular sieves or an acid such as acetic acid, hydrochloric acid, or titanium (IV) isopropoxide complex. Depending on the reaction, there is a case where an imine compound may be formed by condensation of the compound (4a) with the aldehyde derivative corresponding to the compound (4b) or (4c) and then may be isolated as a stable intermediate. Further, the reaction may be carried out in a solvent such as alcohols or ethyl acetate, in the presence or absence of an acid such as acetic acid or hydrochloric acid, using a reduction catalyst (such as Pd-supported carbon (Pd/C), palladium hydroxide, or Raney nickel), instead of treatment with the reducing agent. In this case, the reaction can be carried out from under cooling to under heating, under a hydrogen atmosphere at normal pressure to 50 atmospheres.

REFERENCE LITERATURE

A. R. Katritzky and R. J. K. Taylor, Editors, Comprehensive Organic Functional Group Transformation II, Vol. 2, Elsevier Pergamon, 2005 Courses in Experimental Chemistry, 5.sup.th edition, edited by The Chemical Society of Japan, Vol. 14 (2005), Maruzen Co., Ltd.

Further, the starting compound (4a) of this production process can be prepared by deprotection of the amine through the reaction of the compound (1a) with the protected amine derivative in the same manner as in Production Process 1, or by deprotection of the amino group through the reaction of the compound (3a) with the amino-protected amino acid derivative in the same manner as in Production Process 3.

(Starting Material Synthesis)

(1) Production of Compounds (1a) and (2a)

##STR00017##

(In the formula, Hal represents halogen, and other symbols are as defined above. The same shall apply hereinafter).

This production process is a method in which the compound (2a) or (1a) is produced by reacting the tetrahydroisoquinoline derivative (3a) with an acid halide (5a) or (5b).

The reaction can be carried out using the compound (3a) and the compound (5a) or (5b) in equivalent amounts or one of them in an excess amount, from under cooling to under heating, for example, at 0.degree. C. to 80.degree. C. usually stirring for 0.1 hour to 5 days, in a reaction-inert solvent or without a solvent. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include aromatic hydrocarbons, ethers, halogenated hydrocarbons, ethyl acetate, acetonitrile, and a mixture thereof. It may be advantageous in some cases for smooth progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, or potassium hydroxide, or an aqueous solution thereof, or in the presence of 0.01 to 0.2 equivalent amounts, preferably 0.05 to 0.15 equivalent amounts of a catalyst such as N,N-dimethylaminopyridine.

(2) Production of Compound (3a)-1

##STR00018##

(In the formula, M is an alkali metal or alkaline earth metal and represents an anionic metal salt of R.sup.1b showing nucleophilicity in the form of R.sup.1b-M, and other symbols are as defined above. The same shall apply hereinafter.)

This production process is a method in which the compound (3a) is produced by subjecting a phenethylamide derivative (6b) obtained by amidation of a phenethylamine derivative (6a) to a ring closure reaction using a phosphoric acid derivative, or to a condensation reaction using oxalyl chloride, followed by acid-catalyzed ring cleavage to obtain a dihydroisoquinoline derivative (6d), and reduction of the compound (6d) or addition of a nucleophilic reagent to the compound (6d).

The amidation step of the compound (6a) can be carried out in the same manner as in Production Process 3.

The ring closure step of the compound (6b) can be carried out by stirring the compound (6b) in a reaction-inert solvent or without a solvent, in the presence of a phosphoric acid derivative, usually for 1 hour to 5 days. The reaction is typically carried out from under cooling to under heating, for example, from room temperature to heating under reflux. It may be advantageous in some cases to carry out the reaction in the absence of a solvent. The solvent, if used, is not particularly limited, but examples thereof include high-boiling aromatic hydrocarbons such as toluene, and xylene. Examples of the phosphoric acid derivative include diphosphorus pentoxide, a mixture of diphosphorus pentoxide and phosphorus oxychloride, polyphosphoric acid, ethyl polyphosphate, and the like.

Alternatively, this step can be carried out in such a manner that an oxalyl chloride is reacted with the amide (6b) to construct a 2-chlorooxazolone ring, the resulting product is subjected to ring-closure condensation in the presence of a Lewis acid catalyst such as iron chloride to obtain a 6,10b-dihydro-5H-[1,3]isoxazolo[2,3-a]isoquinoline-2,3-dione derivative (6c), followed by solvolysis of the derivative (6c) in the presence of a strong acid such as sulfuric acid or using an alkali metal alkoxide such as sodium methoxide to result in a compound (6d).

When R.sup.1b is hydrogen, the compound (3a) wherein R.sup.1b is hydrogen can be obtained by reduction of the compound (6d). The reaction is carried out by treating the compound (6d) with an equivalent or excess amount of a reducing agent, from under cooling to under heating, for example, at -20.degree. C. to 80.degree. C. usually for 0.1 hour to 3 days, in a reaction-inert solvent. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include ethers, alcohols, aromatic hydrocarbons, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, and a mixture thereof. Examples of the reducing agent include hydride reducing agents such as sodium borohydride, diisobutylaluminum hydride, and lithium aluminum hydride, metal reducing agents such as sodium, zinc, and iron, and other reducing agents as described in the following literature.

REFERENCE LITERATURE

M. Hulicky, Reductions in Organic Chemistry, 2.sup.nd ed (ACS Monograph: 188), ACS, 1996 R. C. Larock, Comprehensive Organic Transformations, 2.sup.nd ed, VCH Publishers, Inc., 1999 T. J. Donohoe, Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6), Oxford Science Publications, 2000 Courses in Experimental Chemistry, 5.sup.th edition, edited by The Chemical Society of Japan, Vol. 14 (2005), Maruzen Co., Ltd.

When R.sup.1b represents a group other than hydrogen, it is possible to make use of anionic addition by means of a nucleophilic reagent (6e) for the compound (6d). The reaction can be carried out using the compound (6d) and the compound (6e) in equivalent amounts or one of them in an excess amount, from under cooling to under heating, for example, at -78.degree. C. to 0.degree. C. usually stirring for 0.1 hour to 5 days, in a reaction-inert solvent. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include ethers, aromatic hydrocarbons, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), and a mixture thereof. For adjustment of the compound (6e), R.sup.1b-magnesium halide, R.sup.1b-lithium produced by the reaction of the corresponding halide with magnesium is appropriately used.

In addition, positions of R.sup.1a and R.sup.1b in the formula may be changed to each other.

(3) Production of Compound (3a)-2

##STR00019##

(the symbols in the formula are as defined above)

This production process is a method in which the compound (3a-2) is produced by reducing an acetonitrile derivative (7a).

The reaction can be carried out by stirring the compound (7a) in a reaction-inert solvent under a hydrogen atmosphere, in the presence of a metal catalyst, usually for 1 hour to 5 days. The reaction is typically carried out from under cooling to under heating, for example at room temperature. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include alcohols, ethers, water, ethyl acetate, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and a mixture thereof. Examples of the metal catalyst that can be preferably used include palladium catalysts such as Pd-supported carbon (Pd/C), palladium black, and palladium hydroxide, platinum catalysts such as platinum oxide, rhodium catalysts such as tetrakis triphenylphosphine chloro rhodium, Raney nickel, iron catalysts such as reduced iron, and the like. Instead of using hydrogen gas, an equivalent or excess amount of formic acid or ammonium formate with regard to the compound (7a) may also be used as a hydrogen source.

REFERENCE LITERATURE

M. Hudlicky, Reductions in Organic Chemistry, 2nd ed (ACS Monograph:188), ACS, 1996 Courses in Experimental Chemistry, 5.sup.th edition, edited by The Chemical Society of Japan, Vol. 19 (2005), Maruzen Co., Ltd.

Further, R.sup.1a in the formula may also be R.sup.1b.

(4) Production of Compound (3a)-3

##STR00020##

(the symbols in the formula are as defined above)

This production process is a method in which the compound (3a) is produced by condensation of the amine derivative (6a) with a ketone (8a).

The reaction can be carried out using the compound (6a) and the compound (8a) in equivalent amounts or one of them in an excess amount, in a reaction-inert solvent or without a solvent, in the presence of a dehydrating agent or a Lewis acid catalyst, from under cooling to under heating, for example, from room temperature to heating under reflux, usually stirring for 0.1 hour to 5 days. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include halogenated hydrocarbons, ethers, and the like. It may be advantageous in some cases for smooth progress of the reaction to carry out the reaction in the presence of a strong acid such as formic acid-acetic anhydride, and trifluoroacetic acid. Examples of the dehydrating agent include acid anhydrides such as polyphosphoric acid, acetic anhydride, and trifluoroacetic anhydride. Examples of the Lewis acid catalyst include titanium tetraisopropoxide and the like.

The compound of the present invention is isolated and purified as its free compound, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorph thereof. The pharmaceutically acceptable salt of the compound of the formula (I) can also be prepared in accordance with a conventional method for a salt formation reaction.

Isolation and purification are carried out by employing common chemical operations such as extraction, fractional crystallization, and various types of fraction chromatography.

Various isomers can be prepared by selecting an appropriate starting compound, or can be separated by making use of the difference in the physicochemical properties between isomers. For example, the optical isomer can be derived into an optically pure isomer by means of general optical resolution methods (for example, fractional crystallization for inducing diastereomers with optically active bases or acids, chromatography using a chiral column, etc., and the like). In addition, the isomers can also be prepared from an appropriate optically active starting compound.

The pharmacological activity of the compound of the present invention was confirmed by the following tests.

Test Example 1

Test of Compounds on Blockade of N-Type Ca.sup.2+ Channel

Culture of human fibroblasts (IMR-32 cells), and induction of differentiation were carried out by a modification of the method described in the literature [Carbone et al., Pflugers Arch. Eur. J. Physiol., 416, 170-179 (1990)]. IMR-32 cells were subcultured in a MEM (Invitrogen Corporation, USA) containing 10% fetal bovine serum (FBS), 1% non-essential amino acids, 1% sodium pyruvate, 100 .mu.g/mL streptomycin, and 100 U/mL penicillin. Upon induction of cellular differentiation, 1 mM dibutyryl cyclic adenine monophosphate (dbcAMP) and 2.5 .mu.M 5-bromodeoxyuridine (BrdU) were added to the culture medium, and the cells were cultured for 10 to 11 days to result in expression of the human N-type Ca.sup.2+ channel.

The 10-11 day differentiation-induced IMR-32 cells were seeded at a density of 6.times.10.sup.5 cells/well in a 96-well plate coated with poly-D-lysine. After the cells were cultured in the culture medium for 3 hours or more, Fluo-3 AM was added thereto, followed by incubation at 37.degree. C. for 60 minutes. The culture was washed in assay buffer (HBSS, 20 mM HEPES, 2.5 mM probenecid, pH 7.4), to which a test compound solution was then added in the presence of 1 .mu.M nitrendipine. After 10 minutes, elevation of an intracellular Ca.sup.2+ concentration induced by high K.sup.+ stimulation with a 50 mM KCl solution was assayed using a FLIPR Calcium Assay Kit (Molecular Devices Corporation, USA). The blocking activity of a test compound on the N-type Ca.sup.2+ channel was calculated as a relative value, by taking a maximum increase of an intracellular Ca.sup.2+ concentration in the control group as 100%. Next, a concentration of the compound (IC.sub.50 value) which is required for 50% inhibition of an increase in the intracellular Ca.sup.2+ concentration was calculated by nonlinear regression analysis.

As a result, the compounds of the present invention exhibited a blocking action on the N-type Ca.sup.2+ channel. IC.sub.50 values for several compounds of the present invention are given in Table 1 below. Abbreviation "Ex" in the table represents Example No.

TABLE-US-00001 TABLE 1 Ex IC.sub.50(.mu.M) 1 1.0 2 0.75 117 1.4 121 0.87 134 2.0 157 2.1 174 2.1 199 1.1 202 0.78 236 2.0 274 1.5 292 0.89 296 2.4 316 0.89 319 1.3 330 1.4 379 1.2 386 1.9 409 1.3 415 2.1 429 1.1 433 2.0 435 1.4 436 1.4 449 0.85 461 1.2 473 1.9 474 1.6 476 1.0 478 2.0 480 2.0 490 1.0 504 0.62

Test Example 2

Effects of Compounds on Nociceptive Pain Model (Formalin Test)

A mouse formalin test was carried out by a modification of the method as described in the literature [Murakami et al., Eur. J. Pharmacol. 419: 175-181 (2001)]. When 20 .mu.L of 2.0% formalin was subcutaneously administered to the paw pads of mice (ddY, male, 5 weeks old), pain behaviors (limb withdrawal and licking behaviors) were induced in the treated animal limbs. From 15 to 25 minutes after the administration of formalin, the time taken for the onset of pain behaviors was measured to thereby evaluate the inhibitory action of the test compound on pain behaviors of animals. The test compound was orally given 30 minutes prior to the administration of formalin. The evaluation of the test compound was made from calculation of an inhibition rate (%) in the test compound-treated group, by taking the time taken for the onset of pain behaviors in the vehicle-treated group as 100%. Inhibition rate(%)=100-(mean onset time of pain behaviors in test compound-treated group)/(mean onset time of pain behaviors in vehicle-treated group).times.100

As a result, the compounds of the present invention exhibited an analgesic action on formalin-induced pain. Inhibition rates (%) of several compounds of the present invention at a dose of 100 mg/kg are given in Table 2 below.

TABLE-US-00002 TABLE 2 Inhibition rate Ex (%) 1 52 157 52 415 95 433 60 436 55 575 77

Test Example 3

Effects of Compounds on Neuropathic Pain Model (Antiallodynic Effects in L5/L6 Spinal Nerve-Ligated Rats)

One of the major symptoms in neuropathic pain is a significantly reduced threshold of response to tactile stimulation (allodynia). The antiallodynic effects of the compounds of the present invention were confirmed by assessing the analgesic action in L5/L6 spinal nerve-ligated rats. The assessment was carried out by the method of Kim and Chung (Pain 50, 355-363, 1992) with some modifications.

Under pentobarbital anesthesia, the left L5 and L6 spinal nerves of male SD rats (5-6 weeks old) were tightly ligated with silk thread. For the assessment of analgesic action, the von Frey hair test was adopted. That is, the animal's hind paw pad was pricked with hair and the lowest strength of hair for limb withdrawal response was designated as a response threshold (log gram) to mechanical stimulation. Since it was confirmed in preliminary tests that the response threshold of the animal's hind paw ipsilateral to the side of ligation surgery was significantly low during days 7 to 14 after the surgery (in the state of mechanical allodynia), the antiallodynic effects of the test compound were assessed on any day between days 7 and 14 after the surgery. On the day before the assessment of the test compound, the response threshold before administration of the test compound was measured. The animals were divided into 4 to 5 groups such that mean value differences of response thresholds between groups before administration of the test compound and within-group variation become small. In the assessment of the test compound, the response threshold after administration of the test compound was measured. The test compound was orally administered 30 to 60 minutes before the measurement of the response threshold. The antiallodynic potency of the test compound was assessed as a recovery rate (%) in the test compound-treated group, by taking the response thresholds of ipsilateral and contralateral paws in the vehicle-treated group as 0% and 100%, respectively. Recovery rate(%)={(mean of response threshold in test compound-treated group)-(mean of response threshold of ipsilateral paw in vehicle-treated group)}/{(mean of response threshold of contralateral paw in the vehicle-treated group)-(mean of response threshold of ipsilateral paw in the vehicle-treated group)}.times.100

As a result, the compounds of the present invention exhibited an analgesic action on mechanical allodynia in the neuropathic pain model. Recovery rates (%) for groups with administration of several compounds of the present invention are given in Table 3 below.

TABLE-US-00003 TABLE 3 Recovery rate (%) Ex (dose) 1 95 (30 mg/kg) 157 97 (30 mg/kg) 415 100 (10 mg/kg) 433 80 (10 mg/kg) 436 156 (10 mg/kg) 575 83 (10 mg/kg)

Test Example 4

Effects of Compounds on Abdominal Pain Model (Assay of CRD-Induced Abdominal Pain in Rats)

In response to pressure stimulation caused by colorectal distension (CRD), IBS patients are known to exhibit a reduction of digestive perception threshold (allodynia) which gives rise to discomfort against weak stimulus that is not perceived by a normal person and hyperalgesia which leads to stronger subjective response to digestive perception than in a normal person (Gastroenterol. 130: 1377-1390 (2006)), and such conditions are believed to be responsible for abdominal symptoms. Improving effects of the compounds of the present invention on digestive tract pain were confirmed by assay of CRD-induced abdominal pain in rats. The rat CRD-induced abdominal pain assay was carried out by a modification of the method described in the literature [Neurogastroenterol. Motil. 15: 363-369 (2003)]. When stimulation of constant internal pressure is applied to the colorectum of an animal by inflation of a 6-cm long balloon inserted into the anus of the rat (Wistar, male, 250-350 g), abdominal flexion reflex behaviors are induced due to abdominal pain. A frequency of reflex behaviors occurring during distension stimulation of 5 minutes was counted to estimate an abdominal pain-inhibitory action of the test compound. The test compound was orally administered 30 minutes before the initiation of distension stimulation. Estimation of the test compound was made by calculating an inhibition rate (%) of abdominal flexion reflex behaviors on the vehicle-treated group.

As a result, the compounds of the present invention exhibited an abdominal pain-inhibitory action. For several compounds of the present invention at a dose of 10 mg/kg, inhibition rates (%) of abdominal flexion reflex behaviors upon distension at an internal pressure of 45 mmHg are given in Table 4 below.

TABLE-US-00004 TABLE 4 Inhibition rate Ex (%) 157 59 415 60 433 43 435 46 436 56 568 61

Test Example 5

Effects of Compounds on Spastic Constipation Model (Loperamide-Induced Colon Bead Transport Delay Test)

Generally, it is known that the onset of constipation in IBS-C is caused by spastic dysmotility of the digestive tract and is similar to opioid-induced constipation in terms of pathophysiology of the disease (Eur. J. Pharmacol. 75: 239-245 (1981), American J. Physiol. 96: 667-676 (1931), Nippon Rinsho 64: 1461-1466 (2006)). An improving action of the compounds of the present invention on spastic constipation was confirmed by a loperamide-induced colorectal bead transit delay test in mice. The mouse loperamide-induced colorectal bead transit delay test was carried out by a modification of the method described in the literature [J. Smooth Muscle Res. 29:47-53 (1993)]. A 3-mm diameter glass bead is deeply inserted at a depth of 2 cm into the anus of the mouse (ddY, male, 6 weeks old), and the time taken for excretion of the bead is measured. When 0.3 mg/kg of loperamide is subcutaneously administered 30 minutes before the insertion of the bead, delay of bead excretion is induced. With improving effects on the loperamide-induced bead transit delay, a bowel movement-improving action of the test compound on spastic constipation was evaluated. The test compound was orally administered concurrently with administration of loperamide (30 minutes before the insertion of the bead). The assessment of the test compound was made from calculation of an improvement rate in the bead excretion time of the test compound-treated/loperamide-treated group, by taking the bead excretion time of the non-test compound treated/non-loperamide treated (vehicle-treated/vehicle-treated) group as 100%, and by taking the bead excretion time of the non-test compound treated/loperamide-treated (vehicle-treated/loperamide-treated) group as 0%.

As a result, the compounds of the present invention exhibited an opioid-induced constipation-improving action. For several compounds of the present invention at a dose of 3 mg/kg, improvement rates (%) in the bead excretion time are given in Table 5 below.

TABLE-US-00005 TABLE 5 Inhibition rate Ex (%) 157 40 415 88 433 73 435 67 436 59 568 83

Test Example 6

Effects of Compounds in Combined Use with Morphine (1)

Morphine has potent analgesic effects on nociceptive pain through .mu. opioid receptors. For example, morphine exhibits dose-dependent analgesic effects in a formalin test which is a nociceptive pain model (Pharmacol. Biochem. Behav. 84: 479-486 (2006)). Meanwhile, it is known that a selective N-type Ca.sup.2+ channel-blocking peptide, .omega.-conotoxin (.omega.-CTx) also independently exhibits dose-dependent analgesic effects in the formalin test, and its combined use with morphine enhances analgesic effects over those obtained by single use of morphine (add-on effects) (Pain 84: 271-281 (2000)). Therefore, it can be confirmed that when the compounds of the present invention having an N-type Ca.sup.2+ channel-blocking action were used in combination with morphine in the formalin test, a potent antinociceptive pain action comparable to or higher than single administration of morphine or single administration of the compound of the present invention is achieved.

Test Example 7

Effects of Compounds in Combined Use with Morphine (2)

It is known that mechanical allodynia observed in L5/L6 spinal nerve-ligated rats exhibits only a partial recovery with treatment of morphine. On the other hand, as described hereinbefore, the compounds of the present invention exhibit almost 100% recovery effects on mechanical allodynia in L5/L6 spinal nerve-ligated rats. Therefore, when the compounds of the present invention were used in combination with morphine, a potent antineuropathic pain action comparable to or higher than single administration of morphine or single administration of the compounds of the present invention can be confirmed by testing their antiallodynic effects in L5/L6 spinal nerve-ligated rats.

Test Example 8

Effects of Compounds in Combined Use with Morphine (3)

Morphine is a .mu. opioid receptor agonist having the same action mechanism as loperamide, and has a delay action on colon bead transport in mice, similar to loperamide. Upon administering a dose of morphine which exhibits an abdominal pain-inhibitory action in the rat CRD-induced abdominal pain assay and exhibits a transit delay action in the mouse colorectal bead transit test, and a dose of the test compound which improves the bead transit delay caused by the above-defined dose of morphine, it can be confirmed that such combined use exhibits a potent abdominal pain-inhibitory action comparable to or higher than single administration of morphine in the rat CRD-induced abdominal pain assay, and also has an inhibitory action on morphine-induced transit delay in the bead transit test.

Alternatively, upon administering the test compound with a low dose of morphine at which an abdominal pain-inhibitory action is insufficient in the rat CRD-induced abdominal pain assay, but a delay action is not recognized in the mouse colon bead transit test, a sufficient abdominal pain-inhibitory action which was not obtained by a low dose of morphine alone can be confirmed.

From the experimental results as described above, it was confirmed that the compounds of the present invention have an N-type Ca.sup.2+ channel-blocking action. Therefore, it is clear that the compounds of the present invention are useful as an active ingredient of a pharmaceutical composition for preventing and/or treating various pains such as neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, central nervous system diseases such as anxiety, depression, epilepsy, cerebral stroke and restless legs syndrome, digestive system diseases such as abdominal pain and irritable bowel syndrome, and urinary system diseases such as overactive bladder and interstitial cystitis.

From the results of the formalin test as described above, it was confirmed that the compounds of the present invention have an antinociceptive pain action. In addition, from the test results of antiallodynic effects in L5/L6 spinal nerve-ligated rats, it was confirmed that the compounds of the present invention have an antineuropathic pain action. Upon considering these facts, it is clear that the compounds of the present invention are useful as an active ingredient of a pharmaceutical composition for preventing and/or treating various pains including neuropathic pain and nociceptive pain. Further, it is clinically demonstrated that pregabalin, which is a Ca.sup.2+ channel .alpha.2.delta. subunit ligand and is used as an antineuropathic pain agent, exhibits therapeutic effects on fibromyalgia syndrome having a lot in common with neuropathic pain, in terms of clinical condition. Based on this point, it can be considered that the compounds of the present invention are also useful as an active ingredient of a pharmaceutical composition for preventing and/or treating fibromyalgia syndrome.

From the results of the rat CRD-induced abdominal pain assay as described above, it was demonstrated that the compounds of the present invention have an abdominal pain-inhibitory action. Therefore, it is clear that the compounds of the present invention are useful as an active ingredient of a pharmaceutical composition for preventing and/or treating abdominal symptoms, particularly abdominal symptoms of IBS.

From the results of the mouse loperamide-induced colorectal bead transit delay test, it was demonstrated that the compounds of the present invention have an opioid-induced constipation-improving action. Based on this fact, it is clear that the compounds of the present invention are useful as an active ingredient of a pharmaceutical composition for preventing and/or treating spastic constipation, particularly constipation in OBD. In addition, from the fact that constipation in IBS-C is spastic constipation, similar to constipation caused by opioids, it is clear that the compounds of the present invention are also useful as an active ingredient of a pharmaceutical composition for preventing and/or treating constipation in IBS-C.

From the fact demonstrating that the compounds of the present invention are effective in both of the rat CRD-induced abdominal pain assay and the mouse loperamide-induced colorectal bead transit delay test, it is clear that the compounds of the present invention are also useful as an active ingredient of an excellent pharmaceutical composition for preventing and/or treating IBS-C, having a combination of an abdominal symptom-improving action and a constipation-improving action.

It is known that use of a selective N-type Ca.sup.2+ channel-blocking peptide, .omega.-conotoxin (.omega.-CTx) in combination with morphine enhances analgesic effects over those obtained by use of morphine alone (add-on effects) (Pain 84: 271-281 (2000), Life Science 73: 2873-2881 (2003)). Therefore, it can be expected that combined use of the compounds of the present invention and opioids results in an excellent pharmaceutical composition for preventing and/or treating pain, which exerts more potent analgesic effects than single use of opioids.

Opioids are used as a therapeutic agent for severe pain such as cancer pain, but suffer from clinical problems associated with dose-dependent side effects on the digestive system, such as vomiting or constipation (Eur. J. Pharmaceutical Sci. 20: 357-363 (2003)). The compounds of the present invention exhibit excellent improving effects on opioid-induced constipation (OIC). Based on this fact, it can be expected that the compounds of the present invention in combined use with opioids would result in a pharmaceutical composition for preventing and/or treating pain, which inhibits opioid-induced constipation with less side effects. In addition, it can be expected that combined use of the compounds of the present invention and a low dose of opioids would result in an excellent pharmaceutical composition for preventing and/or treating pain, which is capable of exerting sufficient analgesic effects while reducing a dose of opioids and which is also capable of decreasing the onset of constipation through a reduction of the opioid dose.

A preparation containing one or two or more kinds of the compound of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared in accordance with a generally used method, using a pharmaceutically acceptable carrier, excipient, or the like, that is usually used in the art.

The administration can be carried out by oral administration via tablets, pills, capsules, granules, powders, liquid preparations, or the like, or parenteral administration via injections such as intraarticular injection, intravenous injection, intramuscular injection, or the like, as well as suppositories, eye drops, eye ointments, percutaneous liquid preparations, ointments, percutaneous patches, transmucosal liquid preparations, transmucosal patches, inhalations, and the like.

As solid compositions for oral administration according to the present invention, tablets, powders, granules, or the like are used. In such a solid composition, one or two or more kinds of active ingredients are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and/or magnesium aluminometasilicate. According to a conventional method, the composition may contain inert additives such as a lubricant such as magnesium stearate, a disintegrator such as carboxymethyl starch sodium, a stabilizing agent, and a solubilizing aid. As occasion demands, the tablets or the pills may be coated with a film of a sugar coating, or a gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and contain a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, the liquid composition may contain an adjuvant such as a solubilizing agent, a moistening agent, and a suspending agent, a sweetener, a flavor, an aromatic, and a preservative.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The aqueous solvent includes, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (Japanese Pharmacopeia), and the like. Such a composition may further contain a tonicity agent, a preservative, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing aid. These are sterilized, for example, by filtration through a bacteria-retaining filter, incorporation of a sterilizing agent, or irradiation. In addition, these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.

External preparations include ointments, plasters, creams, jellies, adhesive skin patches, sprays, lotions, eye drops, eye ointments, and the like. The external preparation contains generally used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, and the like. Examples of the ointment or lotion bases include polyethylene glycol, propylene glycol, white Vaseline, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like.

Transmucosal preparations such as inhalations and transnasal preparations are used in a solid, liquid or semi-solid form and may be prepared in accordance with a conventionally known method. For example, a known excipient, and also a pH-adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or blowing may be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, it may be in a form such as a pressurized aerosol spray or the like which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.

In oral administration, the daily dose is generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg, per body weight, administered in one portion or in 2 to 4 divided portions. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.

The compounds of the present invention can be used in combination with various agents for treating or preventing the diseases for which the compounds of the present invention are considered to be effective. Examples of the drugs that can be used in combination with the compounds of the present invention include opioids such as morphine, antidepressants such as duloxetine and amitriptylin, antiepileptic drugs such as pregabalin and mexiletine, non-steroidal anti-inflammatory drugs such as diclofenac, and the like. For this combined use, the compounds of the present invention are formulated into appropriate dosage forms such as liquid preparations, capsules, granules, pills, powders, tablets, external preparations, jellies, sprays, patches, suppositories, and self-contained implantable pumps, and the combined preparation may be administered simultaneously, or separately and continuously, or at a desired time interval, via an oral, transvenous, percutaneous, transnasal, enteral, spinal epidural, or spinal subarachnoid route. The preparations to be co-administered may be a blend, or may be prepared individually.

EXAMPLES

Hereinafter, production processes of the compound of the present invention will be described in more detail with reference to Examples. The present invention is not limited to the following Examples. In addition, production processes of starting compounds are shown in Production Examples. The production processes of the compound of the present invention are not limited to the production processes of the specific Examples as described below. The compound of the present invention may be produced in accordance with a combination of these production processes or in accordance with a method obvious to a person skilled in the art.

As for Examples, Production Examples and Tables described below, the following abbreviations will be used.

Rex: Production Example number, Ex: Example number, No: compound number, STRUCTURE: structural formula, Data: physicochemical data (FAB: FAB-MS[M+H].sup.+, FAN: FAB-MS[M-H].sup.-, FA1: FAB-MS[M].sup.+, FA2: FAB-MS[M+2H].sup.+, ES: ESI-MS[M+H].sup.+, ES1: ESI-MS[M].sup.+, ES2: ESI-MS[M+2H].sup.+, ESNa: ESI-MS[M+Na].sup.+, AP: APCI-MS[M+H].sup.+, API: APCI-MS[M].sup.+, CI: CI[M+H].sup.+, CIN: CI[M-H].sup.-, CI1: CI[M].sup.+, EI: EI[M+H].sup.+, EIN: EI[M-H].sup.-, EI1: EI[M].sup.+, EIBr: EI[M-Br].sup.-, NMR: .delta. (ppm) of peak of .sup.1H-NMR in DMSO-d.sub.6), N/D: not determined, salt: salt (with blank column or no column: it represents that the compound is a free form), CL: hydrochloride, BR: hydrobromate, OX: oxalate, FM: fumarate, MD: D-mandelate, ML: L-mandelic acid, LL: N-acetyl-L-leucine salt, T1: L-tartrate, T2: D-tartrate, TX: dibenzoyl-D-tartrate, TY: dibenzoyl-L-tartrate, TP: diparatoluoyl-D-tartrate, TQ: diparatoluoyl-L-tartrate, MA: L-malic acid, MB: D-malic acid), Me: methyl, Et: ethyl, nPr: normal propyl, iPr: isopropyl, tBu: tert-butyl, cPr: cyclopropyl, cBu: cyclobutyl, cPen: cyclopentyl, cHex: cyclohexyl, Admt: adamantyl, Ph: phenyl, Bn: benzyl, Thp: tetrahydropyranyl, pipe: piperidinyl, pipa: piperadinyl, CN: cyano, boc: tert-butyloxycarbonyl, Ac: acetyl, MOM: methoxymethyl, TMS: trimethylsilyl, di: di, THF: tetrahydrofuran, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide. The numeral before the substituent represents a substitution position, and for example, 6-Cl-2-Py represents 6-chloropyridin-2-yl and 3,3-diF-cHex represents 3,3-difluorocyclohexyl. Rsyn and Syn: Production method (the numerals indicate that the compounds were produced using the corresponding starting materials, with the method similar to the case of compounds respectively having the numerals as the production example numbers or Example numbers). In addition, among the compounds of Production Examples or Examples in Tables, for the compound in which a configuration of a substituent at the 1-position of tetrahydroisoquinoline is not determined but a single configuration is shown in any sides, the configuration in any sides is labeled and then the Production Example number or the Example number is given *. On the other hand, for the compound in which a configuration of a substituent at the 1-position of tetrahydroisoquinoline is determined or the compound in which the configuration is reasonably analogized on the basis of behavior in chiral column chromatography or activity behavior in N-type Ca.sup.2+-blocking test, the configuration is only labeled.

In addition, the compound in which the same number is given subsequent to * represents that the compound is produced using a compound, to which the same number is given and in which a configuration of a substituent at the 1-position of tetrahydroisoquinoline is not determined but a single configuration is labeled in any sides, as a starting material.

Production Example 1

N-(2-cyclohexa-1-en-1-ylethyl)-2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1- H)-yl)-2-oxoethanamine (431 mg) was dissolved in chloroform (12 mL), and trifluoroacetic anhydride (0.3 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 10 hours and then stirring at 60.degree. C. for 2 hours. The solvent was evaporated, and saturated aqueous sodium bicarbonate was added to the reaction liquid which was then extracted with chloroform. The reaction liquid was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain N-(2-cyclohexa-1-en-1-ylethyl)-N-[2-(1-cyclohexyl-3,4-dihydroisoquinolin-- 2(1H)-yl)-2-oxoethyl]-2,2,2-trifluoroacetamide (419 mg).

Production Example 2

N-(2-cyclohexa-1-en-1-ylethyl)-N-[2-(1-cyclohexyl-3,4-dihydroisoquinolin-- 2(1H)-yl)-2-oxoethyl]-2,2,2-trifluoroacetamide (408 mg) was dissolved in a 3:1 mixture (8 mL) of acetone-water. To the reaction liquid were added 4-methylmorpholine 4-oxide (200 mg) and a solution of 2.5% osmium tetroxide in tert-butyl alcohol (2.68 mL), followed by stirring at room temperature for 18 hours. Then, the reaction solvent was evaporated under reduced pressure, and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain N-[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-N-{2-[cis- -1,2-dihydroxycyclohexyl]ethyl}-2,2,2-trifluoroacetamide (276 mg).

Production Example 3

2-(chloroacetyl)-1-cyclohexyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (700 mg) was dissolved in acetonitrile (15 mL), to which potassium carbonate (2.1 g), 2-cyclopenta-1-en-1-lyethanamine hydrochloride (1.6 g), and tetra-n-butylammonium iodide (80 mg) were then added, followed by stirring at 70.degree. C. for 5 hours. Thereafter, the solvent was evaporated, and water was added to the reaction liquid, followed by extraction with EtOAc. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH).

The resulting compound was dissolved in chloroform (10 mL) and trifluoroacetic anhydride (0.34 mL) was added thereto, followed by stirring at room temperature for 14 hours. Then, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain N-[2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]- -N-(2-cyclopenta-1-en-1-ylethyl)-2,2,2-trifluoroacetamide (450 mg).

Production Example 4

(1R)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (L)-tartrate (520 mg) was dissolved in EtOAc (10 mL) and saturated aqueous sodium bicarbonate (10 mL) was added thereto. Under ice-cooling, a solution of chloroacetyl chloride (0.14 mL) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring at room temperature for 1 hour. The reaction liquid was extracted with EtOAc and dried over magnesium sulfate to obtain (1R)-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (415 mg).

Production Example 5

7-chloro-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (899 mg) was added to saturated aqueous sodium bicarbonate (15 mL), to which EtOAc (10 mL) was then further added. A solution of chloroacetyl chloride (390 mg) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes. The reaction liquid was stirred for 1 hour, extracted with EtOAc, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 7-chloro-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (888 mg).

Production Example 6

A mixture of chloroacetyl chloride (1.03 g) and EtOAc (5 mL) was added dropwise with stirring to a mixture of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.58 g), sodium hydrogen carbonate (960 mg), water (25 mL) and EtOAc (25 mL), followed by stirring at room temperature for 2 hours. The reaction liquid was extracted with EtOAc, and the extract was washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-AcOEt, 4:1) to obtain (1S)-2-(chloroacetyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2.14 g).

Production Example 7

1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (800 mg) was dissolved in methylene chloride (12 mL), to which triethylamine (1.1 mL) and acryloyl chloride (0.28 mL) were then added under ice-cooling, followed by stirring under ice-cooling for 30 minutes and then stirring at room temperature for 14 hours. Water was added to the reaction liquid which was then extracted with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to obtain 2 acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (856 mg).

Production Example 8

1-benzyl-4-hydroxypiperidine-4-carboxylic acid (951 mg) was dissolved in DMF (25 mL), and N,N'-carbonyldiimidazole (720 mg) was added thereto, followed by stirring at room temperature for 18 hours. Thereafter, N,N-diisopropylethylamine (784 mg) and 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.22 g) were added to the reaction liquid, followed by stirring at 60.degree. C. for 18 hours. The solvent was evaporated, and water and EtOAc were added to the reaction liquid. The resulting insoluble materials were separated through celite, extracted with EtOAc and dried over magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-MeOH) and dissolved in 1,4-dioxane (12 mL), and di-tert-butyl dicarbonate (1.3 g) was added thereto, followed by stirring at room temperature for 1 hour. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc and then chloroform-MeOH) to obtain 1-benzyl-4-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperi- din-4-ol (115 mg).

Production Example 9

1-benzyl-4-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperi- din-4-ol (220 mg) was dissolved in MeOH (12 mL), and 20% palladium hydroxide-supported activated carbon (360 mg) was added thereto, followed by stirring under a hydrogen atmosphere, at room temperature and normal pressure, for 15 hours. Thereafter, the catalyst was separated through celite. The solvent was evaporated to obtain 4-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-4-ol (154 mg).

Production Example 10

N-methylmorpholine (0.873 mL) was added to a solution of 1-(tert-butoxycarbonyl)-L-proline (1.28 g) in 1,2-dichloroethane (10 mL) under ice-cooling, followed by further addition of pivaloyl chloride (0.734 mL). The reaction liquid was stirred for 1 hour, and N-methylmorpholine (1.09 mL) and 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g) were then added thereto. The mixture was stirred at room temperature for 15 hours. To the reaction solution were added EtOAc and an aqueous 1 M HCl solution. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl (2S)-2-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]pyrrolidin- e-1-carboxylate (1.79 g).

Production Example 11

1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g) was dissolved in methylene chloride (20 mL), and pivaloyl chloride (0.98 mL) and 4-methylmorpholine (2.2 mL) were added thereto under ice-cooling. The reaction liquid was stirred at room temperature for 30 minutes and then ice-cooled, and [(tert-butoxycarbonyl)amino]acetic acid (1.54 g) was added thereto. The reaction liquid was stirred at room temperature for 14 hours and then water was added thereto, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain tert-butyl[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]ca- rbamate (1.49 g).

Production Example 12

4 M HCl/EtOAc (4 mL) was added to a solution of tert-butyl (2S)-2-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]pyrrolidin- e-1-carboxylate (1.79 g) in EtOAc (4 mL). The mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated to obtain 1-cyclohexyl-2-L-prolyl-1,2,3,4-tetrahydroisoquinoline (1.26 g).

Production Example 13

Tert-butyl[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]ca- rbamate (1.5 g) was dissolved in EtOAc (20 mL), and 4 M HCl/EtOAc (3 mL) was added thereto under ice-cooling, followed by stirring at 50.degree. C. for 5 hours. Then, the reaction solvent was evaporated. Saturated aqueous sodium bicarbonate was added to the reaction liquid which was then extracted with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanamine (1.09 g).

Production Example 14

2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanamine (695 mg) was dissolved in methylene chloride (12 mL), and titanium tetraisopropoxide (1.1 mL) and 1-cyclohexene-1-carboaldehyde (309 mg) were added thereto, followed by stirring at room temperature for 3 hours. Thereafter, the solvent was evaporated, and MeOH (15 mL) and then sodium cyanotrihydroborate (190 mg) were added to the mixture, followed by stirring for 14 hours. The solvent was evaporated, and water and EtOAc were added to the mixture. The mixture was filtered through celite and extracted with EtOAc. The extract was washed with saturated brine and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain N-(cyclohexa-1-en-1-ylmethyl)-2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H- )-yl)-2-oxoethanamine (585 mg).

The resulting compound (525 mg) was dissolved in 1,4-dioxane (10 mL), and di-tert-butyl dicarbonate (312 mg) was added thereto, followed by stirring at room temperature for 4 hours. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain tert-butyl N-(cyclohexa-1-en-1-ylmethyl)-N-[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2- (1H)-yl)-2-oxoethyl]carbamate (564 mg).

Production Example 15

Chloroacetyl chloride (0.151 mL) was added to a solution of 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg) and p-toluenesulfonate monohydrate (11.3 mg) in toluene (5 mL). The mixture was heated under reflux for 3 hours. The solvent was evaporated under reduced pressure, and EtOAc and an aqueous 1 M HCl solution were added to the residue. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(chloroacetyl)-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (452 mg).

Production Example 16

10% Pd-supported carbon (900 mg) was added to a solution of 2-benzyl-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (1.81 g) in a 2:1 THF-MeOH mixture (30 mL). The mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. Further, 10% Pd-supported carbon (900 mg) was added to the mixture, followed by stirring for 8 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg).

Production Example 17

In an ice bath under argon flow, a solution of 1.07 M phenylmagnesium bromide in THF (33.2 mL) was added dropwise to a solution of 2-benzyl-1-phenyl-3,4-dihydroisoquinoline hydrobromate (8.95 g) in THF (80 mL) over 1 hour. The mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the mixture which was then extracted with EtOAc. The extract was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-benzyl-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (1.81 g).

Production Example 18

Sodium borohydride (450 mg) was added with stirring to a solution of 6,8-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (1.96 g) in EtOH (50 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours and then further stirred at 60.degree. C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. An aqueous 3 M HCl solution (60 mL) was added to the resulting residue, followed by heating under reflux for 3 minutes. After cooling, an aqueous 20% NaOH solution was added to the mixture to have strong alkalinity, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 6,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.88 g).

Production Example 19

1-cyclohexyl-6-methyl-3,4-dihydroisoquinoline (4.84 g) was dissolved in MeOH (100 mL), and then sodium borohydride (966 mg) was added thereto, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure. Water was added to the reaction mixture which was then extracted with chloroform. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.

The resulting residue was dissolved in EtOAc (100 mL), and a 4 M HCl/EtOAc solution (8 mL) was added thereto under ice-cooling, followed by stirring at room temperature. The resulting insoluble materials were collected and washed with EtOAc to obtain 1-cyclohexyl-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.6 g).

Production Example 20

Potassium carbonate (92 g) and water (500 mL) were added to 1-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (86 g). The reaction mixture was extracted with EtOAc and dried over magnesium sulfate, and then the solvent was evaporated. To the resulting residue were added iPrOH (1100 mL) and (+)-mandelic acid (50 g), followed by stirring under heating at 95.degree. C. for dissolution. The mixture was left to cool and stirred at room temperature overnight. The resulting solid was collected and repeatedly recrystallized three times using iPrOH to obtain 1-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (+)-mandelate (43 g) as a single enantiomer.

Production Example 21

1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (31.1 g) was dissolved in EtOH (1.26 L) at 80.degree. C., and (D)-tartaric acid (10.83 g) was then added thereto. The reaction mixture was left to cool and stirred at room temperature overnight. The resulting insoluble materials (16.64 g) were collected and dried.

The solid was mixed with a solid obtained in the same manner as mentioned above, and the mixture (33.26 g) was dissolved in EtOH (1 L), followed by stirring under heating at reflux for 2 hours and then stirring at 80.degree. C. for 5 hours. The mixture was stirred at room temperature overnight and then the insoluble materials were collected to obtain (1S)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (D)-tartrate (30.8 g).

Production Example 22

Under an argon atmosphere, a 1.0 M borane-THF complex solution (110 mL) was added to a mixture of (1R,2S)-1-amino-2-indanol (8.17 g) and diethyl ether (200 mL) under stirring at an internal temperature of 5.degree. C. or lower. The mixture was further stirred at room temperature for 1.5 hours. The mixture was cooled to an internal temperature of 4.degree. C. 1-(2-methoxyphenyl)-3,4-dihydroisoquinoline (10 g) was gradually added to the mixture at an internal temperature of 5.degree. C. or lower, followed by stirring at the same temperature for 30 minutes. The mixture was stirred at room temperature for 3 days. Trifluoroacetic acid (61 mL) was added to the reaction mixture to decompose an excess of reagent, further followed by heating under reflux for 3 hours. After cooling, diethyl ether was evaporated under reduced pressure and the mixture was heated under reflux for 10 minutes. The residue was diluted with chloroform and extracted with concentrated aqueous ammonia to be alkaline. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-EtOH-aqueous ammonia) to obtain 1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (8.23 g).

1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (8.227 g) and (2S,3S)-2,3-bis[(4-methybenzoyl)oxy]succinic acid (13.282 g) were dissolved with stirring in acetonitrile (246 mL) at 70.degree. C. The mixture was slowly cooled with stirring. The resulting crystal was collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain (1S)-1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate (16.193 g).

Production Example 23

Under cooling in a dry ice-acetone bath, lithium aluminum hydride (1.03 g) was added to THF (30 mL) to make a suspension. A solution of 1-[2-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline (6.22 g) in THF (30 mL) was added dropwise to the suspension under an argon atmosphere. The reaction solution was stirred at room temperature for 15 hours. The reaction liquid was cooled in ice and then a saturated aqueous Rochelle salt solution (1.5 mL) was added to stop the reaction. The liquid was stirred at room temperature for 1 hour and magnesium sulfate and celite were then added thereto. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1-[2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline (5.42 g).

Production Example 24

N-[2-(4-chlorophenyl)ethyl]cyclohexanecarboxamide (2.03 g) was dissolved in 1,2-dichloroethane (15 mL), and oxalyl chloride (0.8 mL) was added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and then cooled to -20.degree. C. Ferric chloride (1.49 g) was added to the mixture, followed by stirring at room temperature for 16 hours. An aqueous 1 M HCl solution was added to the mixture which was then stirred at room temperature for 30 minutes, followed by extraction with chloroform. The extract was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dried to obtain 9-chloro-10b-cyclohexyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-- 2,3-dione (2.38 g).

Production Example 25

9-chloro-10b-cyclohexyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-- 2,3-dione (2.37 g) was dissolved in MeOH (16 mL), and a solution of sulfuric acid (8 mL) in MeOH (24 mL) was added thereto, followed by stirring under heating at reflux for 18 hours. The reaction mixture was left to cool and then the solvent was evaporated. The reaction mixture was neutralized by an aqueous 1 M sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and then the resulting residue was dried to obtain 7-chloro-1-cyclohexyl-3,4-dihydroisoquinoline (1.78 g).

Production Example 26

N-[2-(2-chlorophenyl)ethyl]cyclohexanecarboxamide (2.55 g) was dissolved in 1,2-dichloroethane (25 mL), and oxalyl chloride (1.0 mL) was added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and then cooled to -20.degree. C. Iron chloride (1.87 g) was added to the mixture, followed by stirring at room temperature for 16 hours. An aqueous 1 M HCl solution was added to the mixture, followed by stirring at room temperature for 30 minutes and extraction with chloroform. The extract was washed with water and saturated brine, and dried over magnesium sulfate. Then, the solvent was evaporated.

The resulting residue (2.55 g) was dissolved in 1,2-dichloroethane (25 mL), and oxalyl chloride (1.0 mL) was added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and then cooled to -20.degree. C. To the mixture was added iron chloride (1.87 g), followed by stirring at room temperature for 16 hours. An aqueous 1 M HCl solution was added to the mixture which was then stirred at room temperature for 30 minutes, followed by extraction with chloroform. The extract was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dissolved in MeOH (16 mL), and a solution of sulfuric acid (8 mL) in MeOH (24 mL) was added thereto, followed by stirring under heating at reflux for 18 hours. The reaction mixture was left to cool and then the solvent was evaporated. The reaction mixture was neutralized by an aqueous 1 M sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dried to obtain 5-chloro-1-cyclohexyl-3,4-dihydroisoquinoline (2.22 g).

Production Example 27

N-[2-(4-methoxyphenyl)ethyl]cyclohexanecarboxamide (5.56 g) was dissolved in toluene (120 mL), and diphosphorus pentoxide (3.0 g) and phosphorus oxychloride (6.0 mL) were sequentially added thereto, followed by stirring under heating at reflux for 5.5 hours. The reaction mixture was left to cool and then the solvent was evaporated. An aqueous 8 M potassium hydroxide solution, water and chloroform were added to the resulting residue to completely dissolve the insoluble materials to achieve a pH of around pH 8, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-cyclohexyl-7-methoxy-3,4-dihydroisoquinoline (1.87 g).

Production Example 28

Phosphoric acid (11.9 mL) was added to diphosphorus pentoxide (20.0 g) over 5 minutes. The mixture was stirred at 150.degree. C. for 0.5 hours. 3-fluoro-N-(2-phenylethyl)benzamide (5.00 g) was added to the mixture, followed by stirring at 160.degree. C. for 2.5 hours. After cooling, water was added to the reaction solution to which 28% aqueous ammonia was then added to be alkaline. The reaction solution was extracted with EtOAc, washed with saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1-(3-fluorophenyl)-3,4-dihydroisoquinoline (4.87 g).

Production Example 29

Ethyl polyphosphoric acid (50 mL) was added to 3,3-difluoro-N-(2-phenylethyl)cyclohexanecarboxamide (6.4 g), followed by stirring under heating at 120.degree. C. for 2 hours. The reaction liquid was added to ice water (150 mL), extracted with chloroform and dried over magnesium sulfate. The solvent was evaporated to obtain 1-(3,3-difluorocyclohexyl)-3,4-dihydroisoquinoline (4.1 g).

Production Example 30

Ethyl polyphosphoric acid (10 mL) was added to trans-4-methyl-N-(2-phenylethyl)cyclohexanecarboxamide (2 g), followed by stirring under heating at 120.degree. C. for 2 hours. Water was added to the reaction liquid which was then extracted with EtOAc. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated. To the resulting residue were added EtOH (10 mL) and then sodium borohydride (0.31 g) under ice-cooling, directly followed by stirring for 2 hours. Water was added to the reaction liquid, followed by extraction with EtOAc. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated to obtain 1-(trans-4-methylcyclohexyl)-1,2,3,4-tetrahydroisoquinoline (2 g).

Production Example 31

N-[2-(2-methylphenyl)ethyl]butanamide (4.58 g) was dissolved in xylene (30 mL), and then diphosphorus pentoxide (10 g) was added thereto, followed by stirring at 140.degree. C. for 4 hours. The reaction mixture was left to cool and then the solvent was evaporated. An aqueous 8 M potassium hydroxide solution, water, and chloroform were used to dissolve completely the insoluble materials. The reaction mixture was adjusted to a pH of around 8, and extracted with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 5-methyl-1-propyl-3,4-dihydroisoquinoline (2.14 g).

Production Example 32

N-[2-(2-bromo-5-methoxyphenyl)ethyl]-2-methoxyacetamide (7.8 g) was dissolved in xylene (80 mL), and diphosphorus pentoxide (11 g) was added thereto, followed by stirring at 140.degree. C. for 4 hours. Then, the solvent was evaporated, and an aqueous 6 M sodium hydroxide solution was added to the reaction mixture to be around a pH of 8. The reaction mixture was extracted with chloroform, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc).

The resulting compound was dissolved in EtOH (30 mL), and N,N-diisopropylethylamine, and 20% palladium hydroxide-supported activated carbon (400 mg) was added thereto, followed by stirring under a hydrogen atmosphere, at normal pressure and room temperature, for 3 hours. Thereafter, the reaction mixture was filtered through celite to separate the catalyst, and the solvent was evaporated.

To the resulting residue were added saturated aqueous sodium bicarbonate (30 mL) and then EtOAc (20 mL). A solution of chloroacetyl chloride (1.17 mL) in EtOAc (10 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring for 5 hours. Then, the reaction liquid was extracted with EtOAc and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-(chloroacetyl)-8-methoxy-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoli- ne (367 mg).

Production Example 33

[2-(4-chlorophenyl)ethyl]amine (3.5 g) was dissolved in a 1:2 mixed solution (45 mL) of EtOAc-saturated aqueous sodium bicarbonate. A solution of cyclohexanecarbonyl chloride (3.35 mL) in EtOAc (18 mL) was added dropwise to the reaction liquid over 5 minutes. After stirring for 1.5 hours, the reaction liquid was extracted with EtOAc, washed with an aqueous 1 M sodium hydroxide solution and water, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dried to obtain N-[2-(4-chlorophenyl)ethyl]cyclohexanecarboxamide (5.69 g).

Production Example 34

4,4-difluorocyclohexanecarboxylic acid (1.48 g) was dissolved in methylene chloride (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.68 g), 1-hydroxybenzotriazole (1.21 g), and (2-phenylethyl)amine (1.2 mL) were sequentially added thereto, followed by stirring at room temperature for 18 hours. Then, saturated aqueous sodium bicarbonate was added to the reaction liquid which was then extracted with chloroform. The extract was washed with water and further saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 4,4-difluoro-N-(2-phenylethyl)cyclohexanecarboxamide (1.96 g).

Production Example 35

A solution of 1.64 M tert-butyllithium in n-pentane (12 mL) was added to a mixture of 2-(2,2-dimethylpropanoyl)-1,2,3,4-tetrahydroisoquinoline (3.0 g), tetramethylethylenediamine (2.2 ml), and THF (40 mL) at -78.degree. C. The reaction liquid was stirred at -78.degree. C. for 10 minutes. Then, acetone (1.8 mL) was further added to the liquid at -78.degree. C., followed by stirring at -78.degree. C. for 1 hour. Acetic acid (2 mL) was added to the reaction liquid, and the temperature was raised to room temperature. The reaction liquid was evaporated under reduced pressure. EtOAc and water were added thereto, followed by liquid separation. The organic layer was washed sequentially with an aqueous 5% citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-[2-(2,2-dimethylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]propan-2-- ol (2.62 g).

Production Example 36

Trifluoroacetic acid (27 mL) was added to 2-[2-(2,2-dimethylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]propan-2-- ol (2.79 g), followed by stirring at room temperature for 4 hours. Thereafter, the solvent was evaporated and saturated aqueous sodium bicarbonate was added to the resulting residue, followed by extraction with EtOAc. The extract was washed with water, and then dried over magnesium sulfate. The solvent was evaporated to obtain 1-methyl-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl pivalate.

1-methyl-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl pivalate (2.79 g) was dissolved in a 1:4 mixed solvent (30 mL) of EtOAc-saturated aqueous sodium bicarbonate. A solution of chloroacetyl chloride (0.9 mL) in EtOAc (6 mL) was added dropwise to the reaction liquid under ice-cooling, followed by stirring at room temperature for 2 hours and extraction with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1-[2 (chloroacetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-methylethyl pivalate (3.01 g).

Production Example 37

Water (5 mL) and potassium carbonate (1.04 g) were added to a solution of 6-bromo-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g) in 1,2-dichloroethane (5 mL). To the reaction mixture were added di-tert-butyl dicarbonate (726 mg) and further dimethylaminopyridine (36.9 mg). The mixture was stirred at room temperature for 4 hours and extracted with chloroform. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain tert-butyl 6-bromo-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.11 g).

Production Example 38

DMF (20 mL) was added to a mixture of tert-butyl 6-bromo-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.41 g), zinc cyanide (848 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (535 mg), which was then purged with argon gas. Subsequently, tris(dibenzylideneacetone)dipalladium (458 mg) was added to the mixture which was then stirred at 120.degree. C. under an argon atmosphere for 10 hours. Further, tris(dibenzylideneacetone)dipalladium (200 mg) was added thereto, followed by stirring for 10 hours. The reaction material was filtered through celite, and EtOAc and water were added to the filtrate. The organic layer was collected, washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain tert-butyl 6-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (361 mg).

Production Example 39

4 M HCl/EtOAc (2 mL) was added to a solution of tert-butyl 6-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (361 mg) in EtOAc (1 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture together with the precipitated crystal was diluted with diethyl ether (5 mL). The crystal was collected by filtration, washed with diethyl ether, and dried in air to obtain 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile hydrochloride (259 mg).

Production Example 40

Tert-butyl 7-(acetamidemethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylat- e (861 mg) was dissolved in a 1:1 mixed solution (8 mL) of EtOAc-MeOH, to which 4 M HCl/EtOAc (2.8 mL) was then added. The reaction mixture was stirred at 50.degree. C. for 6 hours and then the solvent was evaporated.

To the resulting residue were added saturated aqueous sodium bicarbonate (15 mL) and then EtOAc (10 mL). A solution of chloroacetyl chloride (0.2 mL) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring for 1 hour. The reaction liquid was extracted with EtOAc and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dried to obtain N-{[2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinolin-7-yl]meth- yl}acetamide (655 mg).

Production Example 41

7-bromo-1-cyclohexyl-3,4-dihydroisoquinoline (9.47 g) was dissolved in N-methyl-2-pyrrolidone (150 mL) to which tris(dibenzylideneacetone)dipalladium (2.97 g), 1,1'-bis(diphenylphosphino)ferrocene (7.19 g), and zinc cyanide (11.5 g) were then added, followed by stirring at 120.degree. C. for 18 hours. Then, water was added to the reaction liquid which was then filtered through celite to separate the insoluble materials. The insoluble materials were extracted with EtOAc, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1-cyclohexyl-3,4-dihydroisoquinoline-7-carbonitrile (7.19 g).

Production Example 42

7-bromo-1-cyclohexyl-3,4-dihydroisoquinoline (4.01 g) was dissolved in 1,4-dioxane (100 mL), to which tributyl(1-ethoxyvinyl)tin (7.43 g), potassium fluoride (2.39 g), and tetrakis(triphenylphosphine)palladium (1.58 g) were then added, followed by stirring at 80.degree. C. for 5 hours. Thereafter, to the reaction liquid were further added tributyl(1-ethoxyvinyl)tin (2.47 g) and tetrakis(triphenylphosphine)palladium (1.58 g), followed by stirring for 14 hours. Then, the reaction liquid was filtered through celite and the insoluble materials were separated. 4 M HCl/dioxane (20 mL) was added to the insoluble materials, followed by stirring at 60.degree. C. for 30 minutes. The solvent was evaporated and water was added to the mixture which was then extracted with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-(1-cyclohexyl-3,4-dihydroisoquinolin-7-yl)ethanone (2.24 g).

Production Example 43

1-(1-cyclohexyl-3,4-dihydroisoquinolin-7-yl)ethanone (600 mg) was dissolved in THF (6 mL). A solution of 0.5 M Tebbe reagent in toluene (4.7 mL) was added to the reaction liquid under ice-cooling, followed by stirring at room temperature for 45 minutes. Then, diethyl ether and 10 drops of an aqueous 1 M NaOH solution were sequentially added to the reaction liquid. The reaction liquid was dried over sodium sulfate and filtered through celite.

To the resulting solution were added EtOH (8 mL) and 20% palladium hydroxide-supported activated carbon (900 mg). The solution was stirred under a hydrogen atmosphere, at room temperature and normal pressure, for 13 hours. Then, the catalyst was separated by filtration through celite and then the solvent was evaporated.

To the resulting residue were added saturated aqueous sodium bicarbonate (15 mL) and then EtOAc (10 mL). A solution of chloroacetyl chloride (265 mg) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring for 1 hour. The reaction liquid was extracted with EtOAc and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-(chloroacetyl)-1-cyclohexyl-7-isopropyl-1,2,3,4-tetrahydroisoquinoline (186 mg).

Production Example 44

6-bromo-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.0 g) was dissolved in THF (20 mL). A solution of 1.6 M n-butyllithium in n-hexane (6 mL) was added to the reaction liquid at -78.degree. C., followed by stirring at -78.degree. C. for 0.5 hours. Thereafter, acetone (20 mL) was added to the reaction liquid, followed by further stirring for 2 hours. The solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated.

To the resulting residue were added saturated aqueous sodium bicarbonate (15 mL) and then EtOAc (10 mL). A solution of chloroacetyl chloride (0.24 mL) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring for 18 hours. The reaction liquid was extracted with EtOAc and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-[2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinolin-6-yl]propa- n-2-ol (646 mg).

Production Example 45

To 5-bromo-1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.0 g) were added EtOH (30 mL), triethylamine (1.3 mL), and 10% palladium-supported carbon (0.30 g), followed by stirring under a hydrogen atmosphere for 2 hours. The reaction liquid was filtered through celite and the solvent was evaporated. An aqueous 1 M NaOH solution was added to the reaction liquid, followed by extraction with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dissolved in EtOAc (30 mL). 4 M HCl/EtOAc (5 mL) was added to the mixture, and the precipitated solid was collected to obtain 1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.2 g).

Production Example 46

(2-bromo-5-methylphenyl)acetonitrile (8.2 g) was dissolved in THF (60 mL) to which a borane-dimethyl sulfide complex (5 mL) was then added, followed by stirring at 80.degree. C. for 4 hours. The reaction liquid was cooled in ice, and MeOH (15 mL) was added thereto, followed by stirring for a while. Then, the solvent was evaporated. 4 M HCl/dioxane (30 mL) was added to the residue which was then stirred under heating at 50.degree. C. for 1 hour. After being left to cool, toluene (100 mL) was added to the mixture and the precipitated solid was collected to obtain 2-(2-bromo-5-methylphenyl)ethaneamine hydrochloride (5.5 g).

Production Example 47

Methanesulfonyl chloride (3.9 mL) was added to a mixture of (2-bromo-5-methylphenyl)methanol (9.2 g), dichloromethane (100 mL), and triethylamine (8 mL) under ice-cooling, followed by stirring at room temperature for 5 hours. An aqueous 1 M HCl solution was added to the reaction liquid which was then extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. Thereafter, the solvent was evaporated.

To the resulting residue (11 g) were added EtOH (60 mL), water (40 mL), and sodium cyanide (2.1 g), followed by stirring at 80.degree. C. for 5 hours. Water was added to the reaction liquid, followed by extraction with EtOAc. The organic layer was dried over magnesium sulfate. The solvent was evaporated to obtain (2-bromo-5-methylphenyl)acetonitrile (8.3 g).

Production Example 48

Aluminum chloride (30 g) was added to benzene (60 mL). 2,6-dimethylbenzoic acid (10 g) was gradually added to the mixture with stirring under ice-cooling, followed by stirring for 30 minutes. The temperature was returned to room temperature, and the mixture was further stirred for 1 hour, followed by stirring under heating at reflux for 4 hours. The reaction liquid was poured into ice water (300 mL), filtered through celite, and extracted with chloroform. The extract was washed with an aqueous 1 M NaOH solution, and then dried over magnesium sulfate. The solvent was evaporated.

The resulting residue (13 g) was dissolved in carbon tetrachloride (150 mL). With stirring under heating at reflux, N-bromosuccinimide (10 g) and 2,2'-azobis(isobutylonitrile) (0.20 g) were added thereto, followed by stirring under heating at reflux for 7 hours. The reaction liquid was left to cool and filtered. The resulting liquid was washed with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution, and dried over magnesium sulfate. The solvent was evaporated.

To the resulting residue (15 g) were added EtOH (60 mL), water (40 mL), and sodium cyanide (1.5 g), followed by stirring under heating at 80.degree. C. for 5 hours. Water (200 mL) was added to the reaction liquid which was then extracted with EtOAc and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane:chloroform) to obtain (2-benzoyl-3-methylphenyl)acetonitrile (4.7 g).

Production Example 49

To (2-benzoyl-3-methylphenyl)acetonitrile (3.3 g) were added EtOH (40 mL), 4 M HCl/EtOAc (5 mL), and platinum oxide (IV) (0.53 g), followed by stirring under a hydrogen atmosphere for 5 hours. The reaction liquid was filtered through celite and then concentrated. Toluene was added to the concentrate, followed by extraction with an aqueous 1 M HCl solution. A 28% aqueous ammonia solution was added to the aqueous layer, which was then extracted with toluene and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in toluene to which 4 M HCl/EtOAc (5 mL) was then added, followed by concentration. iPrOH and diisopropyl ether were added to the resulting residue, and the precipitated solid was collected to obtain 8-methyl-1-phenyl-3,4-dihydroisoquinoline hydrochloride (1.5 g).

Production Example 50

To (2-benzoyl-3-methylphenyl)acetonitrile (4.6 g) were added EtOH (70 mL), 4 M HCl/EtOAc (15 mL), and platinum oxide (IV) (0.40 g), followed by stirring under a hydrogen atmosphere for 3 days. The reaction liquid was filtered through celite and then concentrated. Toluene was added to the concentrate, followed by extraction with an aqueous 1 M HCl solution. A 28% aqueous ammonia solution was added to the aqueous layer, which was then extracted with toluene and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in toluene. 4 M HCl/EtOAc (7 mL) was added to the mixture, followed by concentration under reduced pressure. iPrOH and diisopropyl ether were added to the resulting residue, and the precipitated solid was collected to obtain 1-cyclohexyl-8-methyl-3,4-dihydroisoquinoline hydrochloride (2.2 g).

Production Example 51

A mixture of tetralone (1.50 g), 3-methoxyphenethylamine (1.86 g), and titanium tetraisopropoxide (4.55 mL) was stirred under an argon atmosphere at 80.degree. C. for 1 hour. The reaction mixture was cooled in an ice-MeOH bath. A mixture of formic acid (39 mL) and acetic anhydride (97 mL) was added to the reaction mixture under stirring at an internal temperature of 0.degree. C. or lower. After the addition was complete, the reaction mixture was stirred at 80.degree. C. for 2 hours, and trifluoroacetic acid (158 mL) was added thereto, followed by stirring at an internal temperature of 70.degree. C. for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was made weak alkaline by using a saturated aqueous sodium hydrogen carbonate solution and was extracted with EtOAc. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 6 methoxy-3,3',4,4'-tetrahydro-2H,2'H-spiro[isoquinoline-1,1'-naphthalene]-- 2-carbaldehyde (1.86 g).

A mixture of the resulting compound (1.86 g), dioxane (15 mL), and concentrated hydrochloric acid (3 mL) was refluxed for 2 hours. After being cooled, the reaction liquid was concentrated under reduced pressure, and the resulting residue was made alkaline by addition of saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (40 mL), and saturated aqueous sodium bicarbonate (40 mL) was added thereto. A solution of chloroacetyl chloride (700 mg) in EtOAc (10 mL) was added dropwise with stirring to the mixture, followed by stirring for 1 hour at room temperature. The reaction mixture was diluted with EtOAc, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-(chloroacetyl)-6-methoxy-3,3',4,4'-tetrahydro-2H,2'H-spiro[is- oquinoline-1,1'-naphthalene] (1.28 g).

Production Example 52

To polyphosphoric acid produced from 80% phosphoric acid (25 g) and diphosphorus pentoxide (25 g) was added a mixture of 3-methoxyphenethylamine (5.2 g) and tetrahydro-4H-4-pyrone (4.13 g) at an internal temperature of 90.degree. C. over 5 minutes. Further, the reaction mixture was stirred for 40 minutes, cooled to room temperature, and poured into ice water (500 mL). Concentrated aqueous ammonia was added to the reaction mixture to be strongly alkaline, followed by extraction with EtOAc. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-EtOH-aqueous ammonia) to obtain 6-methoxy-2',3,3',4,5',6'-hexahydro-2H-spiro[isoquinolone-1,4'-pyrane] (2.36 g).

Production Example 53

Under cooling in an ice-MeOH bath, THF (80 mL) was added to lithium aluminum hydride (3.03 g) to make a suspension. Dicyclopropyl[(trimethylsilyl)oxy]acetonitrile (8.36 g) was added to the suspension. The mixture was stirred at room temperature for 20 hours and cooled in an ice bath. To the mixture were added sodium fluoride (3.35 g) and further water (4.23 mL), followed by stirring at room temperature for 1 hour. Thereafter, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain an oily material (4.38 g). EtOAc (80 mL) was added to the oily material which was then cooled in ice. 4 M HCl/EtOAc (8 mL) was added to the mixture, which was then stirred together with the precipitated solid at room temperature for 1 hour. Thereafter, the solid was collected by filtration, washed with EtOAc, and dried under reduced pressure at 90.degree. C. to obtain 2-amino-1,1-dicyclopropylethanol hydrochloride (3.68 g).

Production Example 54

In an ice bath under an argon atmosphere, zinc iodide (290 mg) was added to a solution of dicyclopropylmethanone (5.00 g) in 1,2-dichloroethane (50 mL). Subsequently, trimethylsilyl cyanide (6.84 mL) was added dropwise to the mixture over 10 minutes. The mixture was stirred at room temperature for 4 hours and trimethylsilyl cyanide (1.71 mL) was further added thereto, followed by stirring at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with EtOAc. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. Activated carbon was added to the mixture which was then filtered through celite. The filtrate was concentrated under reduced pressure to obtain dicyclopropyl[(trimethylsilyl)oxy]acetonitrile (8.36 g).

Production Example 55

10% palladium-supported carbon (300 mg) was added to a solution of 2-benzyl-1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (1.17 g) in MeOH (12 mL). The reaction material was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction liquid was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (770 mg).

Production Example 56

With cooling in an ice-MeOH bath under an argon atmosphere, a solution of 2-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-ol (1.27 g) in THF (7 mL) was added dropwise to a solution of sodium hydride (60%, 199 mg) in THF (5 mL), followed by stirring at room temperature for 0.5 hours. Then, the reaction liquid was cooled in ice and methyl iodide (0.42 mL) was added thereto. The mixture was stirred at room temperature for 8 hours. To the mixture were added sodium hydride (60%, 199 mg) and methyl iodide (0.42 mL), followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-benzyl-1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (1.17 g).

Production Example 57

In a dry ice-acetone bath under an argon atmosphere, a solution of 1.0 M methyllithium in diethyl ether (16.2 mL) was added dropwise to a solution of ethyl 2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (1.99 g) in THF (20 mL) over 15 minutes. The reaction liquid was stirred in a dry ice-acetone bath for 0.5 hours and then further stirred in an ice bath for 1 hour. The reaction liquid was cooled again in the dry ice-acetone bath, and a solution of 1.04 M methyllithium in diethyl ether (3.24 mL) was added thereto. The reaction liquid was stirred in the dry ice-acetone bath for 0.5 hours and then stirred in the ice bath for 1 hour. Water was added to the reaction liquid, followed by extraction with EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-ol (1.27 g).

Production Example 58

In an ice bath, sodium triacetoxyborohydride (6.11 g) was added to a solution of ethyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrochloride (4.98 g) and benzaldehyde (2.72 g) in acetic acid (50 mL). The mixture was stirred at room temperature for 15 hours. A 1 M aqueous NaOH solution was added to the reaction liquid which was then extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain ethyl 2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (1.99 g).

Production Example 59

A solution of 5-bromo-7,8-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (450 mg), EtOH (30 mL), 10% palladium-supported carbon (80 mg) and 28% sodium methoxide in MeOH (0.1 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The insoluble materials were subjected to filtration and the filtrate was concentrated to obtain 7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (350 mg).

A solution of chloroacetyl chloride (177 mg) in EtOAc (12 mL) was added dropwise to a mixture of 7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (350 mg), a saturated aqueous sodium hydrogen carbonate solution (50 mL), and EtOAc (50 mL) under stirring. After the dropwise addition was complete, the mixture was stirred for 2 hours and extracted with EtOAc. The extract was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-EtOH) to obtain 2-(chloroacetyl)-7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (349 mg).

Production Example 60

1-cyclohexyl-N-isobutyl-3,4-dihydroisoquinoline-7-carboxamide (689 mg) was dissolved in MeOH (12 mL). Sodium borohydride (100 mg) was added to the reaction mixture, followed by stirring at room temperature for 5 hours. The solvent was evaporated. To the resulting residue were added water and chloroform. The residue was extracted with chloroform and dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain 1-cyclohexyl-N-isobutyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide.

To the resulting residue were added saturated aqueous sodium bicarbonate (10 mL) and then EtOAc (5 mL). A solution of chloroacetyl chloride (0.19 mL) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stifling for 1 hour. Then, the reaction liquid was extracted with EtOAc and dried over magnesium sulfate. The solvent was evaporated to obtain 2-(chloroacetyl l)-1-cyclohexyl-N-isobutyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (410 mg).

Production Example 61

5-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinoline (1.7 g) was dissolved in MeOH (15 mL) to which sodium borohydride (376 mg) was then added, followed by stifling at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and water and chloroform were added to the mixture. The mixture was extracted with chloroform and dried over magnesium sulfate. The solvent was evaporated.

To the resulting residue were added saturated aqueous sodium bicarbonate (20 mL) and then EtOAc (15 mL). A solution of chloroacetyl chloride (0.66 mL) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring for 1 hour. The reaction liquid was extracted with EtOAc and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-(chloroacetyl)-5-methoxy-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoli- ne (550 mg).

Production Example 62

5-bromo-8-methoxy-1-propyl-1,2,3,4-dihydroisoquinoline (5.5 g) was dissolved in EtOH (30 mL). To the reaction mixture were added DMF (3.4 mL) and 10% palladium-supported carbon (500 mg), followed by stirring under a hydrogen atmosphere, at normal pressure and room temperature, for 3 hours. Thereafter, the catalyst was separated by filtration through celite and sodium borohydride (740 mg) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and water and chloroform were added to the resulting residue. The mixture was extracted with chloroform and dried over magnesium sulfate. The solvent was evaporated under reduced pressure.

The resulting residue was dissolved in EtOAc (10 mL), to which 4 M HCl/EtOAc (15 mL) was then added under ice-cooling, followed by stirring at room temperature. The resulting insoluble materials were collected and washed with EtOAc to obtain 8-methoxy-1-propyl-1,2,3,4-tetrahydroisoquinoline (3.67 g).

Production Example 63

7-bromo-1-cyclohexyl-3,4-dihydroisoquinoline (24.45 g) was dissolved in MeOH (400 mL). The solution was cooled to 0.degree. C. and sodium borohydride (4.8 g) was added thereto, followed by stirring at room temperature for 2 hours. Then, the solvent was evaporated under reduced pressure. Water was added to the residue, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in EtOAc (200 mL), to which 4 M HCl/EtOAc (21 mL) was then added. The resulting solid was collected.

The resulting residue (1 g) was dissolved in THF (30 mL), followed by cooling at -78.degree. C. To the reaction mixture was added a solution of 2.6 M n-butyllithium in n-hexane (3.7 mL), followed by stirring for 30 minutes. Acetone (30 mL) was added to the mixture at -78.degree. C., and the temperature was raised to room temperature, followed by stirring for 1 hour. Then, the solvent was evaporated under reduced pressure. To the resulting residue was added water, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and then the solvent was evaporated under reduced pressure.

The resulting residue was dissolved in a mixed solution of EtOAc (10 mL) and saturated aqueous sodium bicarbonate (15 mL). A solution of chloroacetyl chloride (683 mg) in EtOAc (5 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for two days. Then, water was added to the mixture, followed by extraction with EtOAc. The organic layer was washed with saturated brine and dried over magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-[2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinolin-7-yl]propa- n-2-ol (606 mg).

Production Example 64

1-cyclohexyl-3,4-dihydroisoquinoline-7-carbonitrile (1.01 g) was dissolved in EtOH (15 mL), to which a 6 M aqueous NaOH solution (7.0 mL) was then added, followed by stirring under heating at reflux for 6 hours. Water was added to the mixture which was then washed with EtOAc. A 1 M aqueous HCl solution was added to the mixture to have a pH of about 3 and then a saturated aqueous sodium sulfate solution was added thereto. The mixture was extracted with a 4:1 mixed solution of chloroform-iPrOH, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated to obtain 1-cyclohexyl-3,4-dihydroisoquinoline-7-carboxylic acid (1.09 g).

Production Example 65

1-cyclohexyl-3,4-dihydroisoquinoline-7-carboxylic acid (1.15 g) was dissolved in methylene chloride (15 mL). O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.03 g), N,N-diisopropylethylamine (1.55 mL), and 2-methyl-1-propanamine (0.87 mL) were added thereto, followed by stirring at room temperature for 18 hours. Then, water was added to the mixture, followed by extraction with chloroform. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-cyclohexyl-N-isobutyl-3,4-dihydroisoquinoline-7-carboxamide (700 mg).

Production Example 66

Sodium methoxide (9.46 g) was added to a suspension of 10b-(chloromethyl)-9-ethyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoli- ne-2,3-dione (14.0 mL) in MeOH (140 mL) under ice-cooling. The mixture was stirred at room temperature for 0.5 hours and then heated under reflux for 3 hours. EtOAc and water were added to the mixture, followed by filtration. The organic layer of the filtrate was collected, washed with saturated brine, and dried over magnesium sulfate. Activated carbon and silica gel were added thereto, followed by filtration. The filtrate was concentrated under reduced pressure to obtain 7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline (4.75 g).

Production Example 67

Sodium borohydride (900 mg) was added to a mixed solution of a solution of 5,8-dimethoxy-1-phenyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin- e (4.21 g) in THF (30 mL), and EtOH (100 mL) at room temperature under stirring. The reaction mixture was stirred at room temperature for 3 hours and then stirred at 40.degree. C. for 30 minutes, and concentrated under reduced pressure. To the resulting residue was added a 3 M aqueous HCl solution (30 mL), followed by refluxing for 5 minutes. After cooling, the mixture was made strong alkaline by using a 20% aqueous NaOH solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 5,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (3.05 g).

Production Example 68

Under an argon atmosphere, a solution of 2,5-dimethoxyphenethylamine (3.175 g) in benzene (4 mL) was added with stirring to a suspension of benzaldehyde (1.86 g) and magnesium sulfate (3.89 g) in benzene (10 mL). An exothermic reaction took place, followed by further stirring overnight. After the reaction was complete, the reaction liquid was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(2,5-dimethoxyphenyl)-N-[(1E)-phenylmethylene]ethanamine (4.72 g).

Production Example 69

2-(2,5-dimethoxyphenyl)-N-[(1E)-phenylmethylene]ethanamine (4.719 g) was dissolved in trifluoroacetic acid (140 mL), followed by refluxing for 2 days. The reaction mixture was cooled to room temperature and trifluoroacetic anhydride (55 mL) was gradually added thereto. The mixture was refluxed for 3 days, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was extracted with a saturated aqueous sodium hydrogen carbonate solution and chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 5,8-dimethoxy-1-phenyl-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (4.168 g).

Production Example 70

Tert-butyl 7-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.38 g) was dissolved in methylene chloride (40 mL). A solution of 0.99 M isobutylaluminum hydride in n-hexane (7.8 mL) was added thereto, followed by stirring at -78.degree. C. for 4 hours. Then, a solution of 0.99 M isobutylaluminium hydride in n-hexane (28 mL) was further added to the reaction mixture. A saturated aqueous Rochelle salt solution was added to stop the reaction, followed by stirring overnight. The mixture was extracted with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (benzene-EtOAc).

The resulting residue was dissolved in an 8:1 mixed solvent (90 mL) of EtOH-water. Hydroxylamine hydrochloride (812 mg) and sodium acetate (930 mg) were added thereto, followed by stirring at room temperature for 28 hours. Then, the solvent was evaporated. Water was added to the mixture, which was then extracted with chloroform, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated to obtain tert-butyl 1-cyclohexyl-7-[(hydroxyimino)methyl]-3,4-dihydroisoquinoline-2(1H)-carbo- xylate (2.03 g).

Production Example 71

Tert-butyl 1-cyclohexyl-7-[(hydroxyimino)methyl]-3,4-dihydroisoquinoline-2(1H)-carbo- xylate (1.04 g) was dissolved in an 8:1:1 mixed solvent (20 mL) of EtOH-acetic acid-water. 10% palladium-supported activated carbon (500 mg) was added thereto, followed by stirring under a hydrogen atmosphere, at room temperature and normal pressure, for 4 hours. Then, the reaction mixture was filtered through celite and the solvent was evaporated.

The resulting residue was dissolved in methylene chloride (12 mL), to which triethylamine (880 mg), acetic anhydride (385 mg), and 4-dimethylaminopyridine (70 mg) were then added, followed by stirring at room temperature for 16 hours. Then, water was added to the mixture which was then extracted with chloroform. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain tert-butyl 7-(acetamidemethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylat- e (875 mg).

Production Example 72

Tert-butyl 1-cyclohexyl-7-[(hydroxyimino)methyl]-3,4-dihydroisoquinoline-2(1H)-carbo- xylate (995 mg) was dissolved in EtOH-acetic acid-water (8:1:1, 20 mL). To the reaction mixture was added 10% palladium-supported carbon (480 mg), followed by stirring under a hydrogen atmosphere, at room temperature and normal pressure, for 4 hours. Then, the reaction mixture was filtered through celite and the solvent was evaporated to obtain tert-butyl 7-(aminomethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (956 mg).

Production Example 73

Tert-butyl 7-(aminomethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (999 mg) was dissolved in methylene chloride. Isobutyric acid (0.33 mL), triethylamine (1.2 mL), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.32 g) were added thereto, followed by stirring at room temperature for 18 hours. Water was added to the mixture which was then extracted with chloroform. The extract was washed with a 1 M aqueous NaOH solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to obtain tert-butyl-1-cyclohexyl-7-[(isobutylamino)methyl]-3,4-dihydroisoquinoline- -2(1H)-carboxylate (468 mg).

Production Example 74

1-cyclohexyl-3,4-dihydroisoquinolin-7-ol (2 g) was dissolved in MeOH (40 mL), to which sodium borohydride (396 mg) was then added, followed by stirring at room temperature for 4 hours. Then, the solvent was evaporated. Water was added to the mixture which was then extracted with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated.

The resulting residue was dissolved in dioxane (40 mL). Di-tert-butyl dicarbonate (2.28 g) was added thereto, followed by stirring at room temperature for 2 days. Then, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain tert-butyl 1-cyclohexyl-7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.66 g).

Production Example 75

Tert-butyl 1-cyclohexyl-7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (700 mg) was dissolved in acetonitrile (12 mL). 1-chloroacetone (0.2 mL), potassium carbonate (438 mg), and tetra-n-butylammonium iodide (78 mg) were added thereto, followed by stirring at 60.degree. C. for 16 hours. Then, water was added to the mixture which was then extracted with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain tert-butyl 1-cyclohexyl-7-(2-oxopropoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (818 mg).

Production Example 76

Tert-butyl 1-cyclohexyl-7-(2-oxopropoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (808 mg) was dissolved in methylene chloride (15 mL). At -78.degree. C., a solution of bis(2-methoxyethyl)aminosulfur trifluoride (0.65 mL) in methylene chloride (5 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 14 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture which was then extracted with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain tert-butyl 1-cyclohexyl-7-(2,2-difluoropropoxy)-3,4-dihydroisoquinoline-2(1H)-carbox- ylate (747 mg).

Production Example 77

A 1 M aqueous NaOH solution was added to (1S)-1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (808 mg). The reaction mixture was extracted with chloroform and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. A mixed solution of a solution of 1 M boron tribromide in dichloromethane (13.4 mL), and dichloromethane (10 mL) was cooled to -78.degree. C. and a solution of the extraction residue in dichloromethane (10 mL) was added dropwise thereto. The temperature was gradually raised and the reaction mixture was stirred at room temperature for 24 hours. Then, saturated aqueous sodium bicarbonate and chloroform were added to the reaction mixture. After liquid separation was complete, the aqueous layer was used in subsequent reaction.

Di-tert-butyl dicarbonate was added to the resulting aqueous layer, followed by stirring at room temperature for 5 hours. The mixture was neutralized by a 1 M aqueous HCl solution and extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure to obtain tert-butyl-(1S)-8-hydroxy-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-carbo- xylate (973 mg).

Production Example 78

Tert-butyl (1S)-8-hydroxy-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (973 mg) was dissolved in a mixed solution of iPrOH (6 mL) and a 30% aqueous potassium hydroxide solution (3 mL). To the reaction mixture was added chlorodifluoromethane by ventilation, followed by stirring at 70.degree. C. for 20 hours. Water was added to the mixture which was then extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane-EtOAc).

The resulting residue (790 mg) was dissolved in EtOAc. 4 M HCl/EtOAc (5.8 mL) was added thereto, followed by stirring at 60.degree. C. for 18 hours. Then, the solvent was evaporated under reduced pressure to obtain (1S)-8-(difluoromethoxy)-1-isopropyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (642 mg).

Production Example 79

A 1 M aqueous NaOH solution was added to (1S)-8-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.81 g). The reaction mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. A mixed solution of a solution of 1 M boron tribromide in dichloromethane (26.3 mL) and dichloromethane (30 mL) was cooled to -78.degree. C. and a solution of the extraction residue in dichloromethane (10 mL) was added dropwise thereto. The temperature was gradually raised and the reaction mixture was stirred at room temperature for 24 hours. Then, saturated aqueous sodium bicarbonate and chloroform were added to the reaction mixture. After liquid separation was complete, the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure.

The resulting residue (1.48 g) was dissolved in THF (50 mL). A 1 M aqueous NaOH solution (8 mL) and di-tert-butyl dicarbonate (2.87 g) were added thereto, followed by stirring at room temperature for 5 hours. Then, the solvent was evaporated under reduced pressure. To the resulting residue were added water and a 1 M aqueous HCl solution, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc).

The resulting residue (1.24 g) was dissolved in a mixed solution of iPrOH (20 mL) and a 50% aqueous potassium hydroxide solution (10 mL). To the reaction mixture was added chlorodifluoromethane by ventilation, followed by stirring at 70.degree. C. for 14 hours. Water was added to the mixture which was then extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the resulting residue was purified by silica gel column chromatography (hexane-EtOAc).

The resulting residue (927 mg) was dissolved in EtOAc (25 mL), to which 4 M HCl/EtOAc (6.2 mL) was then added, followed by stirring at 60.degree. C. for 18 hours. Then, the solvent was evaporated under reduced pressure to obtain (1S)-8-(difluoromethoxy)-1-phenyl-1,2,3,4-tetrahydroisoquinolin- e hydrochloride (770 mg).

Production Example 80

28% aqueous ammonia was added to 1-oxiran-2-ylcyclohexanol, followed by stirring for 11 hours. The solvent was evaporated under reduced pressure and then water was removed azeotropically with toluene.

The resulting residue was dissolved in a mixed solution of EtOH-diethyl ether. Oxalic acid was added thereto, followed by stirring for a while. The resulting insoluble materials were collected to obtain 1-(2-amino-1-hydroxyethyl)cyclohexanol oxalate (853 mg).

Production Example 81

(1R,2S)-1-amino-2-indanol (511 mg) was dissolved in toluene (60 mL). Under ice-cooling, a solution of a 1 M borane-THF complex in THF (8.16 mL) was added thereto, followed by stirring at room temperature for 1 hour. Then, 7-bromo-1-cyclohexyl-3,4-dihydroisoquinoline (1 g) was added to the mixture, followed by stirring at room temperature for 3 days. The reaction was stopped by addition of trifluoroacetic acid, followed by further stirring at 60.degree. C. for 1 hour. The solvent was evaporated. A 1 M aqueous sodium hydroxide solution was added to the mixture which was then extracted with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain crude (1S)-7-bromo-1-cyclohexyl-3,4-tetrahydroisoquinoline (1.06 g). The resulting crude product (203 mg) was dissolved in EtOH (9 mL). To the mixture was added D-(-)-tartaric acid (104 mg) at 80.degree. C. The mixture was gradually cooled to room temperature, followed by stirring for 12 hours. The resulting insoluble materials were collected to obtain (1S)-7-bromo-1-cyclohexyl-3,4-tetrahydroisoquinoline (72 mg).

Production Example 82

Under an argon atmosphere, a 1.09 M borane-THF solution (18.7 mL) was added to a suspension of (1R,2S)-1-aminoindan-2-ol (3.04 g) in toluene (60 mL) under ice-cooling, followed by stirring at room temperature for 1 hour. Then, a solution of 1-[2[(trifluoromethyl)benzyl]-3,4-dihydroisoquinoline (4.00 g) in toluene (20 mL) was added to the reaction mixture under ice-cooling. The mixture was stirred at 4.degree. C. for 45 hours. Trifluoroacetic acid (20 mL) was added to stop the reaction. The mixture was heated under reflux for 1 hour and then cooled. 28% aqueous ammonia (30 mL) was added to the mixture to be alkaline. The mixture was extracted with EtOAc. The extract was washed 3 times and further washed with saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated to obtain a yellow oily material (4.11 g). The oily material was dissolved in acetonitrile (80 mL). To the mixture was added N-acetyl-L-leucine (2.39 g) at 80.degree. C. The mixture was gradually cooled, followed by stirring at 60.degree. C. for 2 hours and at room temperature for 12 hours. When the crystal was precipitated, the crystal was collected by filtration, cooled in ice, washed with acetonitrile, and dried in air to obtain a crystal (2.48 g). The crystal was recrystallized from acetonitrile (50 mL) to obtain 1-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydroisoquinoline N-acetyl-L-leucine salt (1.72 g).

Production Example 83

Under an argon atmosphere, a 1.09 M borane-THF solution (48.8 mL) was added to a suspension of (1R,2S)-1-aminoindan-2-ol (3.79 g) in toluene (60 mL) under ice-cooling, followed by stirring at room temperature for 1 hour. Then, a solution of 7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline (4.70 g) in THF (40 mL) was added to the reaction mixture under ice-cooling. The mixture was stirred at 4.degree. C. for 8 hours. Trifluoroacetic acid (15 mL) was added to stop the reaction. The mixture was heated under reflux for 1 hour. To the mixture were added chloroform and 28% aqueous ammonia. The organic layer was washed 3 times with water and extracted with a 5% aqueous acetic acid solution. The extract was adjusted to have alkalinity by addition of 28% aqueous ammonia and extracted with EtOAc. The extract was washed two times with water and further washed with saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain a yellow oily material (3.15 g). The oily material was dissolved in iPrOH (63 mL), to which (2S,3S)-2,3-bis(benzoyloxy)succinic acid (4.14 g) was gradually added at 90.degree. C. The mixture was heated under reflux for 1 hour and was gradually cooled to room temperature, followed by stirring at room temperature for 3 hours. When the crystal was precipitated, the crystal was collected by filtration, washed with iPrOH and ether, and dried under reduced pressure to obtain (7-ethyl-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline (2S,3S)-2,3-bis(benzoyloxy)succinate (5.54 g).

Production Example 84

Phosphorus pentoxide (15.85 g) was added to a solution of 2-chloro-N-[2-(4-ethylphenyl)ethyl]acetamide (7.87 g) in xylene (140 mL) under stirring at 90.degree. C. over 5 minutes. The reaction mixture was heated at 120.degree. C. and stirred for 2 hours. The reaction mixture was cooled to room temperature. The supernatant was removed and the residue was washed sequentially with toluene and ether. Crushed ice (150 g) was added to the residue, followed by stirring. A 20% aqueous sodium hydroxide solution was further added to the mixture to be a pH of 10 or higher, and the mixture was extracted with chloroform. The organic layer was collected, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. To the organic layer was added a 4 M HCl/EtOAc solution (15 mL), and the mixture was concentrated under reduced pressure to obtain 1-(chloromethyl)-7-ethyl-3,4-dihydroisoquinoline hydrochloride (8.5 g).

Production Example 85

Tert-butyl (1S)-8-hydroxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.53 g) was dissolved in dichloromethane (20 mL). 2,6-lutidine (1.1 mL) and trifluoromethanesulfonic anhydride (0.9 mL) were added thereto at -78.degree. C., followed by stirring at room temperature for 16 hours. Then, saturated aqueous sodium bicarbonate was added to the mixture which was then extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain tert-butyl (1S)-1-phenyl-8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinoline-- 2(1H)-carboxylate (2.08 g).

Production Example 86

To N-[2-(2-bromo-5-methylphenyl)ethyl]-2-methoxyacetamide (3.9 g) was added xylene (50 mL), followed by stirring under heating at 60.degree. C. Diphosphorus pentoxide (7.0 g) was added with stirring to the reaction mixture, followed by stirring at 140.degree. C. for 3 hours. After the reaction mixture being left to cool, the supernatant of the reaction mixture was discarded. The mixture was dissolved in water, toluene, and an aqueous sodium hydroxide solution, and extracted with toluene. The extract was further extracted with a 1 M aqueous HCl solution. The recovered aqueous layer was neutralized, extracted with toluene, and dried over magnesium sulfate. After filtration was complete, a 4 M HCl/EtOAc solution (5 mL) was added to the layer, and the solvent was evaporated under reduced pressure. To the resulting residue were added EtOH (50 mL), toluene (10 mL), and sodium borohydride (1.0 g), followed by stirring for 4 days. To the reaction mixture was added a 1 M aqueous HCl solution, followed by stirring for 5 hours. Thereafter, an aqueous sodium hydroxide solution was added to the mixture which was then extracted with chloroform. The solvent was evaporated. Sodium carbonate (1.0 g), water (30 mL), toluene (30 mL), and chloroacetyl chloride (0.3 mL) were added to the resulting residue under ice-cooling, followed by stirring at room temperature for 17 hours. Water was added to the reaction liquid, which was then extracted with chloroform. The extract was washed with a 1 M aqueous HCl solution, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel chromatography to obtain 5-bromo-2-(chloroacetyl)-1-(methoxymethyl)-8-methyl-1,2,3,4-tetrahydroiso- quinoline (0.323 g).

Production Example 87

8-ethyl-5-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.06 g) was dissolved in methylene chloride (40 mL). To the reaction mixture was added a solution of boron tribromide in dichloromethane (13.6 mL) at -78.degree. C., followed by stirring at room temperature for 16 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it alkaline. Then, di-tert-butyl dicarbonate (2.96 g) was added to the reaction solution, followed by stirring at room temperature for 3 hours. The reaction liquid was extracted with chloroform, washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dissolved in dichloromethane (20 mL). To the mixture were added 2,6-lutidine (1.8 mL) and trifluoromethanesulfonic anhydride (1.55 mL), followed by stirring at room temperature for 18 hours. Thereafter, water was added to the mixture which was then extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (EtOAc:hexane). The resulting residue was dissolved in DMF (30 mL). To the mixture were added palladium (II) acetate (305 mg), triethylsilane (5.4 mL), and 1,1'-bis(diphenylphosphino)ferrocene (750 mg), followed by stirring at 70.degree. C. for 20 hours. Then, water was added to the mixture which was then filtered through celite and extracted with diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (EtOAc:hexane) to obtain tert-butyl 8-ethyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.29 g).

Production Example 88

Under cooling in an ice bath, a mixture of sodium hydride (suspension of 8 g of sodium hydride in mineral oil (60%) washed with hexane) in THF (10 mL) was added to methoxyethanol (100 mL) under stirring over 20 minutes to produce sodium 2-methoxyethoxide, followed by further stirring for 2 hours. A solution of sodium 2-methoxyethoxide in 2-methoxyethanol (55 mL) was added with stirring to a solution of 1-(chloromethyl)-7-ethyl-3,4-dihydroisoquinoline hydrochloride (8.5 g) in methoxyethanol (50 mL) under cooling in an ice bath, for 5 minutes. The reaction mixture was heated at 60.degree. C., followed by stirring for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and diluted with THF (150 mL), followed by filtration. The filtrate was concentrated under reduced pressure. To the resulting residue was added a saturated aqueous ammonium chloride solution and the residue was extracted with EtOAc. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain 7-ethyl-1-[(2-methoxyethyl)methyl]-3,4-dihydroisoquinoline (2.13 g).

Production Example 89

Tert-butyl (1S)-1-phenyl-8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinoline-- 2(1H)-carboxylate (3.75 g) was dissolved in N,N-dimethylacetamide (40 mL). To the reaction mixture were added zinc (537 mg), zinc cyanide (1.15 g), trifluoroacetic palladium (II) (682 mg), and biphenyl-2-yl(di-tert-butyl)phosphine (1.22 g). The temperature was increased from room temperature to 95.degree. C. over 45 minutes and then the mixture was stirred at 95.degree. C. for 18 hours. Water was added to the mixture which was then filtered through celite. Thereafter, the mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (EtOAc:hexane) to obtain tert-butyl (1S)-8-cyano-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (796 mg).

Production Example 90

A solution of 1.55 M n-butyllithium in hexane (10.94 mL) was added with stirring to a solution of 1-(methoxymethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline (3.07 g) in THF (60 mL) under an argon atmosphere, over about 8 minutes, at -70.degree. C. or below, followed by further stirring for 30 minutes. To the reaction mixture was added with stirring a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-methylbenzenesulfinate (3.375 g) in THF (25 ml) over 5 minutes at -70.degree. C. or below, followed by further stirring for 1 hour. Thereafter, saturated disodium phosphate was added to the mixture at the same temperature and the temperature was increased to room temperature. The mixture was extracted with ether. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain (1R)-1-(methoxymethy)-5-methyl-2-[(R)-(4-methylphenyl)sulfinyl]-1,2,3,4-t- etrahydroisoquinoline (2.144 g) (Rf value=0.14).

Production Example 91

To a mixed solution of (1R)-1-(methoxymethyl)-5-methyl-2-[(R)-(4-methylphenyl)sulfinyl]-1,2,3,4-- tetrahydroisoquinoline (2.47 g) in EtOH (45 mL) and THF (10 mL) was added concentrated hydrochloric acid (3.1 mL) under stirring at 0.degree. C., followed by further stirring for 10 minutes. To the mixture was added saturated sodium carbonate water (50 mL), followed by extraction with EtOAc. The organic layer was washed with a 1 M aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:EtOH:aqueous ammonia) to obtain (1R)-1-(methoxymethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline (1.276 g).

Chemical structures of the compounds produced by the above-mentioned Production Examples are shown in Tables 6 to 12. In addition, in the same manner as in the methods in the above-mentioned Production Examples, the compounds of Production Examples shown in Tables 13 to 35 are produced using respective corresponding starting materials. The data from instrumental analysis of these compounds of Production Examples is shown in Tables 36 to 42.

Example 1

(1S)-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (4.496 g) was dissolved in acetonitrile (100 mL). To the mixture were added potassium carbonate (6.25 g), tetra-n-butylammoniumiodide (679 mg), and 1-(aminomethyl)cyclohexanol hydrochloride (4.50 g), followed by stirring at 60.degree. C. for 6 hours. Thereafter, the solvent was evaporated and water was added to the reaction mixture, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to obtain 1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}ami- no)methyl]cyclohexanol (3.02 g).

The resulting compound (3.02 g) was dissolved in EtOH, to which oxalic acid (777 mg) was added. After complete dissolution was achieved, the mixture was stirred for a while and the resulting insoluble materials were collected to obtain 1-[({2-(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amin- o)methyl]cyclohexanol oxalate (2.985 g).

Example 2

2-acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (516 mg) was dissolved in iPrOH (15 mL). To the reaction mixture were added 1-(aminomethyl)cyclohexanol hydrochloride (635 mg) and triethylamine (0.59 mL), followed by stirring under heating at reflux for 16 hours. Thereafter, the solvent was evaporated and water was added to the mixture, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) and then further purified by alkaline silica gel column chromatography (chloroform) to obtain 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]amino}m- ethyl)cyclohexanol (214 mg).

The resulting compound (214 mg) was dissolved in EtOH (8 mL). Oxalic acid (51 mg) was added to the reaction mixture to obtain 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]amino}m- ethyl)cyclohexanol oxalate (229 mg).

Example 3

1-cyclohexyl-7-isopropoxide-3,4-dihydroisoquinoline (245 mg) was dissolved in MeOH (6 mL). Thereafter, sodium borohydride (40 mg) was added to the reaction liquid, followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and water and chloroform were added to the mixture. The reaction liquid was extracted with chloroform and dried over magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure.

Saturated aqueous sodium bicarbonate (6 mL) was added to the resulting residue, to which EtOAc (3 mL) was added. A solution of chloroacetyl chloride (102 mg) in EtOAc (3 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring for 1 hour. Thereafter, the reaction liquid was extracted with EtOAc and dried over magnesium sulfate, and then the solvent was evaporated.

The resulting residue was dissolved in 1,4-dioxane (8 mL). (2R)-1-amino-2-propanol (180 mg) and 1,8-diazabicyclo[5.4.0]undeca-7-en (146 mg) were added thereto, followed by stirring at 50.degree. C. for 3 hours. Thereafter, the solvent was evaporated and water was added to the reaction liquid, followed by extraction with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH).

The resulting residue (211 mg) was dissolved in a 1:4 mixed solution of iPrOH-diethyl ether. Oxalic acid (49 mg) was added to the reaction liquid to obtain (2R)-1-{[2-(1-cyclohexyl-7-isopropoxide-3,4-dihydroisoquinolin-- 2(1H)-yl)-2-oxoethyl]amino}propan-2-ol oxalate (223 mg).

Example 4

N-(2-cyclohexa-1-en-1-ylethyl)-N-[2-(1-cyclohexyl-3,4-dihydroisoquinolin-- 2(1H)-yl)-2-oxoethyl]-2,2,2-trifluoroacetamide (210 mg) was dissolved in methylene chloride (5 mL). 75% 3-chloroperbenzoic acid (152 mg) was added thereto, followed by stirring at room temperature for 18 hours. Thereafter, a saturated aqueous sodium sulfite solution was added to the reaction liquid, followed by stirring for a while. The reaction liquid was extracted with chloroform, and the extract was washed with a 1 M aqueous NaOH solution and saturated brine, and then dried over magnesium sulfate.

The solvent was evaporated and the resulting residue was dissolved in a 4:1 mixed solvent (7.5 mL) of THF-1.5% sulfuric acid aqueous solution, followed by stirring under heating at reflux for 5 hours. Water was added to the reaction liquid which was then extracted with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate.

The solvent was evaporated and the resulting residue was dissolved in MeOH (6 mL). To the reaction liquid was added potassium carbonate (304 mg), followed by stirring at 60.degree. C. for 5 hours. Thereafter, the solvent was evaporated and water was added to the reaction liquid which was then extracted with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain trans-1-(2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]- amino}ethyl)cyclohexane-1,2-diol (93 mg).

The resulting compound (93 mg) was dissolved in a mixed solvent of chloroform-EtOH. Oxalic acid (22 mg) was added to the reaction liquid to obtain trans-1-(2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-ox- oethyl]amino}ethyl)cyclohexane-1,2-diol oxalate (66 mg).

Example 5

2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(cyclohexylmethyl)-2-o- xoethanamine (296 mg) was dissolved in acetonitrile (10 mL). To the reaction liquid were added 2-bromoethanol (400 mg), potassium carbonate (555 mg), and potassium iodide (133 mg), followed by stirring under heating at reflux for 16 hours. Thereafter, the solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](cyclohex- ylmethyl)amino}ethanol (155 mg).

The resulting compound (155 mg) was dissolved in EtOH. Oxalic acid (36 mg) was added to the reaction liquid to obtain 2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](cyclohex- ylmethyl)amino}ethanol oxalate (159 mg).

Example 6

A mixture of 1-({[2-(5-bromo-1-isopropyl-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-o- xoethyl]amino}methyl)cyclohexanol (0.14 g), EtOH (10 mL), triethylamine (0.05 mL), and 10% palladium-supported carbon (10 mg) was stirred under a hydrogen atmosphere for 6 hours. The reaction liquid was filtered and the solvent was evaporated. A 1 M NaOH aqueous solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-MeOH). The resulting residue was dissolved in 2-propanol (0.8 mL). To the reaction liquid were added oxalic acid (23 mg) and diethyl ether (5 mL) and the precipitated solid was collected by filtration and dried to obtain 1-({[2-(1-isopropyl-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]- amino}methyl)cyclohexanol oxalate (0.066 g).

Example 7

2 (1 cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanamine (400 mg) was dissolved in EtOH (10 mL). To the reaction liquid were added 2-methyl-1-oxaspiro[2.5]octane (555 mg) and water (5 mL), followed by stirring under heating at reflux for 2 days. The solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-(1-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}- ethyl)cyclohexanol (585 mg).

The resulting compound (325 mg) was dissolved in a mixed solution of EtOH-acetonitrile. Oxalic acid (80 mg) was added to the reaction liquid to obtain 1-(1-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoet- hyl]amino}ethyl)cyclohexanol oxalate (292 mg).

Example 8

2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}eth- anol (342 mg) was dissolved in EtOH (5 mL). 1-oxaspiro[2.5]octane (363 mg) and water (5 mL) were added thereto, followed by stirring under heating at reflux for 2 days. The solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](2-hydro- xyethyl)amino}methyl)cyclohexanol (346 mg).

The resulting compound (346 mg) was dissolved in EtOH (10 mL). Oxalic acid (76 mg) was added to the reaction liquid to obtain 1-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](2-hydro- xyethyl)amino}methyl)cyclohexanol oxalate (210 mg).

Example 9

N-[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-N-{2-[cis- -1,2-dihydroxycyclohexyl]ethyl}-2,2,2-trifluoroacetamide (255 mg) was dissolved in MeOH (10 mL). Potassium carbonate (345 mg) was added thereto, followed by stirring at 60.degree. C. for 4 hours. The solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain cis-1-(2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]am- ino}ethyl)cyclohexane-1,2-diol (212 mg).

The resulting compound (212 mg) was dissolved in EtOH. Oxalic acid (46 mg) was added to the reaction liquid to obtain cis-1-(2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]am- ino}ethyl)cyclohexane-1,2-diol oxalate (170 mg).

Example 10

Tert-butyl[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]{[- cis-1,2-dihydroxycyclohexyl]methyl}carbamate (92 mg) was dissolved in EtOAc (4 mL). 4 M HCl/EtOAc (0.45 mL) was added thereto, followed by stirring at room temperature for 14 hours. The solvent was evaporated and a 1 M NaOH aqueous solution was added to the resulting residue, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain cis-1-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amin- o}methyl)cyclohexane-1,2-diol (174 mg).

The resulting compound (174 mg) was dissolved in iPrOH. Oxalic acid (43 mg) was added to the reaction liquid to obtain cis-1-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amin- o}methyl)cyclohexane-1,2-diol oxalate (88 mg).

Example 11

Tert-butyl[2-(6-carbamoyl-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2- -oxoethyl][(1-hydroxycyclohexyl)methyl]carbamate (357 mg) was dissolved in EtOAc (8 mL). 4 M HCl/EtOAc (0.85 mL) was added to the reaction liquid under ice-cooling, followed by stirring at 60.degree. C. for 5 hours. The solvent was evaporated and water was added to the resulting residue, followed by washing with chloroform. Saturated aqueous sodium bicarbonate was added to the aqueous layer which was then adjusted to a pH of around 8, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate to obtain 1-cyclohexyl-2-{N-[(1-hydroxycyclohexyl)methyl]glycyl}-1,2,3,4-tetrahydro- isoquinoline-6-carboxamide (116 mg).

The resulting compound (116 mg) was dissolved in a mixed solution of iPrOH-diethyl ether. Oxalic acid (24 mg) was added to the reaction liquid to obtain 1-cyclohexyl-2-{N-[(1-hydroxycyclohexyl)methyl]glycyl}-1,2,3,4-- tetrahydroisoquinoline-6-carboxamide oxalate (70 mg).

Example 12

1-[2-(chloroacetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-methylethyl pivalate (1.2 g) was dissolved in acetonitrile (20 mL). Potassium carbonate (2.36 g), 1-(aminomethyl)cyclohexanol hydrochloride (2.26 g), and tetra-n-butylammoniumiodide (126 mg) were added thereto, followed by stirring at 60.degree. C. for 5 hours. Water was added to the reaction liquid, followed by extraction with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH).

The resulting residue (1.43 g) was dissolved in methylene chloride (20 mL). To the reaction liquid was added a solution of 1.01 M diisobutylaluminium hydride/n-hexane (9.55 mL) at -78.degree. C., followed by stirring at -78.degree. C. for 5 hours. Thereafter, the temperature was increased to 0.degree. C. over 2 hours. To the reaction liquid was added a saturated aqueous Rochelle salt solution, followed by stirring for 20 minutes. Then, celite was added to the reaction liquid which was then subjected to separation by filtration, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-[({2-[1-(1-hydroxy-1-methylethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-ox- oethyl}amino)methyl]cyclohexanol (118 mg).

The resulting compound (150 mg) was dissolved in acetonitrile. Oxalic acid (41 mg) was added to the reaction liquid to obtain 1-[({2-[1-(1-hydroxy-1-methylethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-ox- oethyl}amino)methyl]cyclohexanol oxalate (151 mg).

Example 13

2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-{[cis-2-(- methoxymethoxy)cyclopentyl]oxy}ethyl)-2-oxoethanamine (500 mg) was dissolved in MeOH (8 mL). To the reaction liquid was added 4 M HCl/EtOAc (0.8 mL) under ice-cooling, followed by stirring at 60.degree. C. for 5 hours. The solvent was evaporated and saturated aqueous sodium bicarbonate was added to the resulting residue, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain cis-2-(2-{[2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-o- xoethyl]amino}ethoxy)cyclopentanol (380 mg).

The resulting compound (380 mg) was dissolved in iPrOH. Oxalic acid (80 mg) was added to the reaction liquid to obtain cis-2-(2-{[2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-o- xoethyl]amino}ethoxy)cyclopentanol oxalate (384 mg).

Example 14

1-(4-chloropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (200 mg) and potassium carbonate (344 mg) were dissolved in EtOAc-water (1:1, 4 mL) under ice-cooling. Chloroacetyl chloride (0.85 mL) and benzyltriethylamine hydroboromate (9.2 mg) were added thereto, followed by stirring at room temperature for 1 hour. To the mixture were added 2-amino-1,1-dicyclopropylethanol hydrochloride (190 mg) and potassium carbonate (246 mg). The mixture was stirred at 50.degree. C. for 8 hours. The organic layer was collected, washed with saturate brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 2-({2-[1-(4-chloropyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl-2-oxoethy- l]amino}-1,1-dicyclopropylethanol (143 mg) as a yellow oily material. The oily material was dissolved in a 3:1 mixed liquid (4 mL) of diethyl ether-iPrOH. Oxalic acid (30.2 mg) was added to the reaction mixture to obtain 2-({2-[1-(4-chloropyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl-2-- oxoethyl]amino}-1,1-dicyclopropylethanol oxalate (128 mg).

Example 15

To a solution of 8-({[2-(1-cyclohexyl-3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethyl]amino}me- thyl)-1,4-dioxaspiro[4.5]decan-8-ol (324 mg) in THF (2 mL) were added water (1 mL) and concentrated hydrochloric acid (1 mL). The reaction mixture was refluxed for 5 hours. The temperature was cooled to room temperature and sodium hydrogen carbonate was added to the mixture to make it alkaline, followed by extraction with chloroform. The extract was purified by silica gel column chromatography (chloroform-MeOH) to obtain a targeted amine (176 mg).

The amine was dissolved in iPrOH (3 mL), to which oxalic acid (41.7 mg) was added, followed by stirring at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with ether, and dried at 90.degree. C. under reduced pressure to obtain 4-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}me- thyl)-4-hydroxycyclohexanone oxalate (139 mg).

Example 16

To a solution of 2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (12 mg) in acetonitrile (0.5 mL) were added potassium carbonate (3 mg) and (S)-(+)-2-amino-3-cyclohexyl-1-propanol hydrochloride (15 mg), followed by stirring at 80.degree. C. for 4 hours. Thereafter, a saturated aqueous ammonium chloride solution was added to the reaction liquid, followed by extraction with chloroform. The solvent was evaporated and the resulting residue was purified by preparative HPLC to obtain (2S)-3-cyclohexyl-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-- oxoethyl]amino}propan-1-ol (4.1 mg).

Example 17

2-(isopentylamino)-ethanol (26 mg) was added to a solution of 2-acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (7 mg) in iPrOH (0.1 mL), followed by stirring at 90.degree. C. for 10 hours. Thereafter, the reaction liquid was purified by preparative HPLC to obtain 2-[[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl](3-methy- lbutyl)amino]ethanol (3 mg).

Chemical structures of the compounds produced by the above-mentioned Examples are shown in Tables 43 and 44. In addition, in the same manner as in the methods in the above-mentioned Examples, compounds of Examples shown in Tables 45 to 110 were produced using respective corresponding starting materials. The data from instrumental analysis of these compounds of Examples is shown in Tables 111 to 125.

TABLE-US-00006 TABLE 6 Rex/ salt STRUCTURE 1 ##STR00021## 2 ##STR00022## 3 ##STR00023## 4* ##STR00024## 5 ##STR00025## 6 ##STR00026## 7 ##STR00027## 8 ##STR00028## 9 ##STR00029## 10 ##STR00030## 11 ##STR00031## 12 ##STR00032## 13 ##STR00033## 14 ##STR00034##

TABLE-US-00007 TABLE 7 Rex/ salt STRUCTURE 15 ##STR00035## 16 ##STR00036## 17 ##STR00037## 18 ##STR00038## 19/ CL ##STR00039## 20*/ MD ##STR00040## 21*/ T2 ##STR00041## 22/ TP ##STR00042## 23 ##STR00043## 24 ##STR00044## 25 ##STR00045## 26 ##STR00046## 27 ##STR00047## 28 ##STR00048##

TABLE-US-00008 TABLE 8 Rex/ salt STRUCTURE 29 ##STR00049## 30 ##STR00050## 31 ##STR00051## 32 ##STR00052## 33 ##STR00053## 34 ##STR00054## 35 ##STR00055## 36 ##STR00056## 37 ##STR00057## 38 ##STR00058## 39/ CL ##STR00059## 40 ##STR00060## 41 ##STR00061## 42 ##STR00062##

TABLE-US-00009 TABLE 9 Rex/ salt STRUCTURE 43 ##STR00063## 44 ##STR00064## 45/ CL ##STR00065## 46/ CL ##STR00066## 47 ##STR00067## 48 ##STR00068## 49/ CL ##STR00069## 50/ CL ##STR00070## 51 ##STR00071## 52 ##STR00072## 53/ CL ##STR00073## 54 ##STR00074## 55 ##STR00075## 56 ##STR00076##

TABLE-US-00010 TABLE 10 Rex/ salt STRUCTURE 57 ##STR00077## 58 ##STR00078## 59 ##STR00079## 60 ##STR00080## 61 ##STR00081## 62/ CL ##STR00082## 63 ##STR00083## 64 ##STR00084## 65 ##STR00085## 66 ##STR00086## 67 ##STR00087## 68 ##STR00088## 69 ##STR00089## 70 ##STR00090##

TABLE-US-00011 TABLE 11 Rex/ salt STRUCTURE 71 ##STR00091## 72 ##STR00092## 73 ##STR00093## 74 ##STR00094## 75 ##STR00095## 76 ##STR00096## 77* ##STR00097## 78*/ CL ##STR00098## 79*/ CL ##STR00099## 80/ OX ##STR00100## 81*/ T2 ##STR00101## 82*/ LL ##STR00102## 83/ TX ##STR00103## 84/ CL ##STR00104##

TABLE-US-00012 TABLE 12 Rex/ salt STRUCTURE 85* ##STR00105## 86 ##STR00106## 87 ##STR00107## 88 ##STR00108## 89* ##STR00109## 90*.sup.1 ##STR00110## 91*.sup.1 ##STR00111##

TABLE-US-00013 TABLE 13 ##STR00112## Rex R.sup.A R.sup.B 101 --H 2-OMe--Bn 102 --H 4-Thp 103 3-Br cHex 104 2-OMe cHex 105 3-Cl cHex 106 3-F cHex 107 --H 2-CF.sub.3--Ph 108 --H 3-F--Ph 109 --H 3-CF.sub.3--Ph 110 --H cyclohexen-4-yl 111 --H 2-F--Ph 112 4-OMe cHex 113 2-Cl cHex 114 2-Me cHex 115 4-F cHex 116 2-F cHex 117 --H 2-CF.sub.3-5-F--Ph 118 --H 2-OCF.sub.3--Ph 119 --H 2-Et--Ph 120 --H 2-Cl-3-Py 121 --H 3-CF.sub.3--Bn 122 4-Me cHex 123 4-CF.sub.3 cHex 124 4-F iPr 125 --H --(CH.sub.2).sub.2--OMe 126 3-F --CH.sub.2--OMe 127 4-F --CH.sub.2--OMe 128 4-Et --CH.sub.2--OMe 129 --H 2-Me--Bn 130 4-Et --CH.sub.2--Cl 131 2-Me nPr 132 3-F nPr 133 2-F --CH.sub.2--OMe 134 2-Me --CH.sub.2--OMe 135 4-Me --CH.sub.2--OMe 136 2-F nPr 137 4-Me nPr 138 2-Me iPr 139 2-F Ph 140 4-Me Ph 141 4-Me iPr 142 3-Me cHex 143 3-Me iPr 144 3-Me nPr 145 3-Me --CH.sub.2--OMe 146 --H 3,3-diF-cHex 147 --H 6-Me-2-Py 148 --H 6-Br-2-Py 149 --H 6-Cl-2-Py 150 --H 4-Cl-2-Py 151 --H ##STR00113## 152 4-Me --CH.sub.2--OEt 153 4-Me --CH.sub.2--O--(CH.sub.2).sub.2--OMe 153A 3-F iPr 609 4-Et --CH.sub.2--Cl 624 4-Et nPr 641 4-Et Me 661 --H 2-OMe-5-F--Ph 662 --H 4-CF.sub.3--Bn

TABLE-US-00014 TABLE 14 ##STR00114## Rex R.sup.A R.sup.B R.sup.C R.sup.D 154 iPr --Br --H --OMe 155 cHex --Br --H --OMe 156 tBu --Br --H --OMe 157 Ph --Br --H --OMe 158 Ph --H --OMe --OMe 159 cHex --Br --H --F 160 nPr --Br --H --OMe 161 iPr --Br --H Me 162 --CH.sub.2-iPr --Br --H --OMe 610 iPr --Br --H --F 615 nPr --Br --H Me 616 nPr --Br --H --F 619 --CH.sub.2--OMe --Br --H Me 639 --CH.sub.2Cl --Br --H --F

TABLE-US-00015 TABLE 15 ##STR00115## Rex R.sup.A R.sup.B 163 Me --F 164 --F --CH.sub.2--Br 165 --F --CH.sub.2--CN

TABLE-US-00016 TABLE 16 ##STR00116## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 166 cPen --H --H --H --H 167 cHex --H --Br --H --H 168 cHex --H --H --H --Br 169 cHex --H --H --H --H 170 --CHEt.sub.2 --H --H --H --H 171 cHex --H --H --Br --H 172 cHex --H --H CN --H 173 cHex --H --H --H --OMe 174 cHex --H --H --F --H 175 cHex --H --H --Cl --H 176 iPr --H --F --H --H 177 4-F--Ph --H --H --H --H 178 4-CN--Ph --H --H --H --H 179 cyclohexen-4-yl --H --H --H --H 180 3-CF.sub.3--Ph --H --H --H --H 181 2-CF.sub.3--Ph --H --H --H --H 182 2-F--Ph --H --H --H --H 183 cHex --H --H --H --Cl 184 cHex --H --OMe --OMe --H 185 cHex --H --OMe --H --H 186 cHex --H --H --OMe --H 187 2-Cl--Ph --H --H --H --H 188 3-F--Ph --H --H --H --H 189 3-Cl--Ph --H --H --H --H 190 cHex --H --H --H --F 191 cHex --H --F --H --H 192 1-OH-cHex --H --H --H --H 193 2-OMe-Ph --H --H --H --H 194 2-OCF.sub.3-Ph --H --H --H --H 195 cHex --H --H --CONH.sub.2 --H 196 2-CF.sub.3-5-F--Ph --H --H --H --H 197 2-OEt--Ph --H --H --H --H 198 tBu --H --H --H --H

TABLE-US-00017 TABLE 17 ##STR00117## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 199 iPr --H --H --H --H 200 2-Et--Ph --H --H --H --H 201 2-SMe--Ph --H --H --H --H 202 2-OMe-5-F--Ph --H --H --H --H 203 cHex --H --O--CH.sub.2--O-- --H 204 4-CF.sub.3--Bn --H --H --H --H 205 2-Cl--Ph --H --Cl --H --H 206 2-Cl--Ph --H --F --H --H 207 cHex --H Me --H --H 208 3-CF.sub.3--Bn --H --H --H --H 209 cHex --H --CF.sub.3 --H --H 210 4-Me--Ph --H --H --H --H 211 cHex --H Et --H --H 212 cHex --H --CH.sub.2NHCO-Pr --H --H 213 iPr --H --H --OMe --H 214 cBu --H --H --H --H 215 --CH.sub.2--OMe --H --H --H --H 216 --CH(Et)Me --H --H --H --H 217 cHex --H --OCH.sub.2CHF.sub.2 --H --H 218 cHex --H --OCH.sub.2CF.sub.2--Me --H --H 219 --(CH.sub.2).sub.2--OMe --H --H --H --H 220 iPr --H --OMe --OMe --H 221 iPr --H --OMe --H --H 222 tBu --H --OMe --H --H 223 iPr --H --F --H --H 224 --CH.sub.2--OMe --H --F --H --H 225 --CMe.sub.2--OMe --H --H --H --H 226 --CH.sub.2--OMe --H Et --H --H 227 2-F-Bn --H --H --H --H 228 cHex --OMe --H --H --H 229 cHex --OMe --H --H --Br

TABLE-US-00018 TABLE 18 ##STR00118## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 232 2-OMe--Bn --H --H --H --H 233 2-Me--Bn --H --H --H --H 234 iPr --OMe --H --H --H 235 tBu --OMe --H --H --H 236A 2-CF.sub.3--Bn --H --H --H --H 237 Ph --OMe --H --H --OMe 238 Ph --H --OMe --H --H 241 Ph --H --H Me --H 242 iPr --H --H Me --H 243 cHex --H --H Me --H 244 iPr --H Me --H --H 245 --CH.sub.2--OMe --H --H --OMe --H 246 Ph --H --H --H Me 247 iPr --H --H --H Me 248 cHex --H --H --H Me 249 nPr --H --H --F --H 250 Ph --H --H --F --H 251 nPr --H --H --H Me 252 nPr --H --H --H --OMe 253 nPr --H --F --H --H 254 nPr --H --H --H --F 255 --CH.sub.2--OMe --H Me --H --H 256 --CH.sub.2--OMe --H --OMe --H --H 257 nPr --H Me --H --H 258 Ph --OMe --H --OMe --H 259 --CH.sub.2--OMe --H --H --H Me 260 --CH.sub.2--OMe --H --H --H --F 261 nPr --OMe --H --H --H 262 --CH.sub.2--OMe --H --H Me --H 263 nPr --H --H Me --H 264 cHex Me --H --H --H 265 cHex --F --H --H --H

TABLE-US-00019 TABLE 19 ##STR00119## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 266 Ph Me --H --H --H 267 Ph --F --H --H --H 268 nPr --H --H --OMe --H 269 Ph --H --H --OMe --H 270 4,4-diF-cHex --H --H --H --H 271 3,3-diF-cHex --H --H --H --H 272 4-Thp --H --H --H --H 273 2-C1-3-Py --H --H --H --H 274 6-C1-2-Py --H --H --H --H 275 6-Br-2-Py --H --H --H --H 276 6-Me-2-Py --H --H --H --H 277 4-C1-2-Py --H --H --H --H 278 2-Py --H --H --H --H 279 2-Me--Ph --H --H --H --H 280 iPr Me --H --H --Br 281 --CH.sub.2--OEt --H Me --H --H 282 --CH.sub.2-iPr --H --OMe --H --H 283 --CH.sub.2-iPr --OMe --H --H --H 284 --CH.sub.2--O--(CH.sub.2).sub.2--OMe --H Me --H --H 285 ##STR00120## --H --H --H --H 286 1-Admt --H --H --H --H 614 iPr --F --H --H --Br 628 Ph Et --H --H --H 629 Me --H Et --H --H 633 Me --H Me --H --H 635 nPr Me --H --H --Br 638 nPr --F --H --H --Br 655 --CH.sub.2--O--(CH.sub.2).sub.3--OMe --H Et --H --H 648 --CH.sub.2--O--(CH.sub.2).sub.2--OMe --H Et --H --H 656 --CH.sub.2--OMe --F --H --H --Br

TABLE-US-00020 TABLE 20 ##STR00121## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 230* iPr --H --H --OMe --H 240 --CH.sub.2--OMe --H Et --H --H 287 2-OMe--Ph --H --H --H --H 288 Ph --H --H --H --H 289* cHex --H --CMe.sub.2--OH --H --H 290* Ph --OMe --H --H --H 653* Ph --H --H --F --H 660*.sup.2 --CH.sub.2--OMe --H --H --H Me

TABLE-US-00021 TABLE 21 ##STR00122## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 231* iPr --H --H --OMe --H 236* 2-CF.sub.3--Bn --H --H --H --H 239 --CH.sub.2--OMe --H Et --H --H 291 2-OMe--Ph --H --H --H --H 292* cHex --H --CMe.sub.2--OH --H --H 293* cHex --H --OMe --H --H 294* Ph --H --OMe --H --H 295* Ph --OMe --H --H --H 296* iPr --O--CHF.sub.2 --H --H --H 297* Ph --O--CHF.sub.2 --H --H --H 644* Ph --CN --H --H --H 651* Ph --H --H --F --H 659*.sup.1 --CH.sub.2--OMe --H --H --H Me

TABLE-US-00022 TABLE 22 ##STR00123## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 298 cHex --H --H --H Me 299 cHex --H Me Me --H 300 cHex Me --H --H --H 301 --(CH.sub.2).sub.2--O--(CH.sub.2).sub.2-- --H --H --H 302 Me Me --H --H --H

TABLE-US-00023 TABLE 23 ##STR00124## Rex salt R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 303 Ph --H Me --H --H 304 --CHEt.sub.2 --H --H --H --H 305 cHex --H --H --Br --H 306 iPr --OMe --H --H --Br 307 iPr --H --OMe --H --H 308 cHex --H --OH --H --H 309 cHex --H --H --H --OMe 310 cHex --H --H --F --H 311 cHex --H --H --Cl --H 312 2-CF.sub.3--Ph --H --H --H --H 313 cyclohexen-4-yl --H --H --H --H 314 3-CF.sub.3--Ph --H --H --H --H 315 2-F--Ph --H --H --H --H 316 4,4-diF-cHex --H --H --H --H 317 cHex --H --H --H --F 318 cHex --H --F --H --H 319 2-CF.sub.3-5-F--Ph --H --H --H --H 320 2-COCF.sub.3--Ph --H --H --H --H 321 2-OEt--Ph --H --H --H --H 322 2-Et--Ph --H --H --H --H 323 2-SMe--Ph --H --H --H --H 324 2-Cl--Ph --H --Cl --H --H 325 CL 2-Cl--Ph --H --F --H --H 326 2-OMe-5-F--Ph --H --H --H --H 327 4-CF.sub.3--Bn --H --H --H --H 328 3-CF.sub.3--Bn --H --H --H --H 329 cHex --H --CF.sub.3 --H --H 330 cHex --H Et --H --H 331 --CH(Et)--Me --H --H --H --H 332 cHex --H --OiPr --H --H 333 iPr --H --F --H --H 334 --(CH.sub.2).sub.2--OMe --H --H --H --H 335 --CH.sub.2--OMe --H --F --H --H

TABLE-US-00024 TABLE 24 ##STR00125## Rex salt R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 336 cHex --OMe --H --H --Br 337 2-F--Bn --H --H --H --H 338 2-OMe--Bn --H --H --H --H 339 2-Me--Bn --H --H --H --H 340 Ph --OMe --H --H Br 341 iPr --H --H --OMe --H 342 --CH.sub.2--OMe --H Me --H --H 343 Ph --OMe --H --OMe --H 344 Ph --H --H --H --F 345 --CH.sub.2--OMe --H --H --OMe --H 346 iPr --H --H --H Me 347 cHex --H --H --H Me 348 iPr --H Me --H --H 349 cHex --H --H Me --H 350 iPr --H --H Me --H 351 Ph --H --F --H --H 352 nPr --H --H --H --OMe 353 nPr --H Me --H --H 354 nPr --H --H --H --F 355 nPr --H --OMe --H --H 356 --CH.sub.2--OMe --H --OMe --H --H 357 --CH.sub.2--OMe --H --H --H Me 358 nPr --H --H Me --H 359 nPr --OMe --H --H --Br 360 cHex --F --H --H --Br 361 --CH.sub.2--OMe --H --H --H --OMe 362 CL Ph --F --H --H --H 363 --CH.sub.2--OMe --H --H --H --F 364 4-Thp --H --H --H --H 365 2-Cl-3Py --H --H --H --H 366 6-Me-2-Py --H --H --H --H 367 6-Br-2-Py --H --H --H --H 368 6-Cl-2-P --H --H --H --H 369 4-Cl-2-P --H --H --H --H

TABLE-US-00025 TABLE 25 ##STR00126## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 370 tBu --OMe --H --H --Br 371 iPr Me --H --H --Br 372 --CH.sub.2--OEt --H Me --H --H 373 --CH.sub.2-iPr --H --OMe --H --H 374 --CH.sub.2-iPr --OMe --H --H --Br 375 --CH.sub.2--O--(CH.sub.2).sub.2--OMe --H Me --H --H 375A iPr --H --H --F --H 612 iPr --F --H --H --Br 620 nPr Me --H --H --Br 621 nPr --F --H --H --Br 625 Ph Et --H --H --OMe 626 nPr --H Et --H --H 637 --CH.sub.2--OMe --F --H --H --Br 643 Me --H Et --H --H

TABLE-US-00026 TABLE 26 ##STR00127## Rex salt R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 376 CL iPr --H --H --OMe --H 377 cHex --H --H --H --H 378 CL cHex --H --H --H --Br 379 --CHEt.sub.2 --H --H --H --H 380 CL cHex --H --H --Br --H 381 CL iPr --OMe --H --H --Br 382 CL cHex --H --H --F --H 383 CL cHex --H --H --Cl --H 384 cyclohexen-4-yl --H --H --H --H 385 3-CF.sub.3--Ph --H --H --H --H 386 2-F----Ph --H --H --H --H 387 CL cHex --H --H --H --OMe 388 CL 4,4-diF-cHex --H --H --H --H 389 CL cHex --H --H --H --Cl 390 CL cHex --H --OMe --H --H 391 CL cHex --H --H --OMe --H 392 3-F--Ph --H --H --H --H 393 CL cHex --H --H --H --F 394 CL 2-OCF.sub.3--Ph --H --H --H --H 395 2-CF.sub.3-5-F--Ph --H --H --H --H 396 CL 2-OEt--Ph --H --H --H --H 397 CL 2-Et--Ph --H --H --H --H 398 2-SMe--Ph --H --H --H --H 399 CL 2-OMe-5-F-Ph --H --H --H --H 400 4-Thp --H --H --H --H 401 CL 2-Cl-Ph --H --Cl --H --H 402 CL 2-Cl-Ph --H --F --H --H 403 4-CF.sub.3--Bn --H --H --H --H 404 CL cHex --H CN --H --H 405 3-CF.sub.3--Bn --H --H --H --H 406 CL cHex --H --CF.sub.3 --H --H 407 CL cHex --H --CH.sub.2NHCO-iPr --H --H 408 CL --CH(Et)--Me --H --H --H --H

TABLE-US-00027 TABLE 27 ##STR00128## Rex salt R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 409 CL iPr --H --OMe --H --H 500 CL iPr --H --F --H --H 501 --(CH.sub.2).sub.2--OMe --H --H --H --H 502 --CH.sub.2--OMe --H --F --H --H 503 CL cHex --OMe --H --H --Br 504 CL cHex --OMe --H --H --H 505 --CH.sub.2--OMe --H Et --H --H 506 CL 2-F--Bn --H --H --H --H 507 2-OMe--Bn --H --H --H --H 508 2-Me--Bn --H --H --H --H 509 CL tBu --OMe --H --H --Br 510 CL tBu --OMe --H --H --H 514 CL Ph --H --H --H --F 515 CL Ph --H --H --H Me 516 CL iPr --H --H --H Me 517 CL cHex --H --H --H Me 518 --CH.sub.2--OMe --H --H --OMe --H 519 nPr --H --H --F --H 520 CL iPr --H Me --H --H 521 CL Ph --H Me --H --H 522 CL iPr --H --H Me --H 523 CL Ph --H --F --H --H 524 CL nPr --H --H --H Me 525 CL nPr --H Me --H --H 526 CL nPr --H --H --H --F 527 CL nPr --H --OMe --H --H 528 CL --CH.sub.2--OMe --H Me --H --H 529 nPr --H --H Me --H 530 CL cHex --F --H --H --Br

TABLE-US-00028 TABLE 28 ##STR00129## Rex salt R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 531 BR cHex --F --H --H --H 532 CL cHex Me --H --H --H 533 CL --CH.sub.2--OMe --H --H --H Me 534 CL Ph Me --H --H --H 535 CL Ph --F --H --H --H 536 CL 3,3-diF-cHex --H --H --H --H 537 CL 2-Cl-3-Py --H --H --H --H 538 6-Me-2-Py --H --H --H --H 539 6-Br-2-Py --H --H --H --H 540 6-Cl-2-Py --H --H --H --H 541 CL 4-Cl-2-Py --H --H --H --H 542 iPr Me --H --H --Br 543 --CH.sub.2--OEt --H Me --H --H 544 --CH.sub.2-iPr --H --OMe --H --H 545 --CH.sub.2-iPr --OMe --H --H --Br 545A OX cPen --H --H --H --H 546 --CH.sub.2-iPr --OMe --H --H --H 546A CL iPr --H --H --F --H 547 --CH.sub.2--O--(CH.sub.2).sub.2--OMe --H Me --H --H 613 CL iPr --F --H --H --Br 622 CL nPr Me --H --H --Br 627 nPr --H Et --H --H 631 CL Me --H Et --H --H 634 Ph Et --H --H --H 640 CL --CH.sub.2--O--(CH.sub.2).sub.3--OMe --H Et --H --H 647 --CH.sub.2--O--(CH.sub.2).sub.2--OMe --H Et --H --H 649 CL Ph Et --H --H --OMe 654 --CH.sub.2--OMe --F --H --H --Br

TABLE-US-00029 TABLE 29 ##STR00130## Rex R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 548 cHex --H --H --Br --H 549 cHex --H --H --F --H 550 cHex --H --H --Cl --H 551 cHex --H --H --H --F 552 cHex --H --F --H --H 553 cHex --H --CF.sub.3 --H --H 554 cHex --H Et --H --H 555 --(CH.sub.2).sub.2--OMe --H --H --H --H 556 --CH.sub.2--OMe --H --F --H --H 557 2-F--Bn --H --H --H --H 558 2-OMe--Bn --H --H --H --H 559 2-Me-Bn --H --H --H --H 560 --CH.sub.2--Cl --H Et --H --H 561 iPr --H --H --H Me 562 cHex --H --H --H Me 563 Ph --H --H --H --F 564 cHex --F --H --H --Br 565 --CH.sub.2-iPr --H --OMe --H H 611 iPr --F --H --H --Br 617 nPr Me --H --H --Br 618 nPr --F --H --H --Br 623 Ph Et --H --H --OMe 636 --CH.sub.2--Cl --F --H --H --Br 642 Me --H Et --H --H

TABLE-US-00030 TABLE 30 ##STR00131## Rex salt R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 566 TQ -2-OMe--Ph --H --H --H --H 567* T2 Ph --OMe --H --H --Br 568* CL Ph --OMe --H --H --H 570* T2 iPr --OMe --H --H --Br 571* CL iPr --OMe --H --H --H 645* CL Ph --CN --H --H --H 650* T2 Ph --H --H --F --H

TABLE-US-00031 TABLE 31 ##STR00132## Rex salt R.sup.A R.sup.B R.sup.C R.sup.D R.sup.E 513 TY --CH.sub.2--OMe --H Et --H --H 547A* ML iPr --H --H --OMe --H 572* T1 cHex --H --H --H --H 575* T1 cHex --H --Br --H --H 576* T1 Ph --OMe --H --H --Br 577* CL Ph --OMe --H --H --H 652* T1 Ph --H --H --F --H 658*.sup.2 --CH.sub.2--OMe --H --H --H Me

TABLE-US-00032 TABLE 32 ##STR00133## Rex R.sup.A R.sup.B 578 ##STR00134## --H 579 ##STR00135## --H 580 1-boc-4-pipe --H 581 --CH.sub.2-(1-boc-4-pipa) --H 582 4-pipe --H 583 --CH.sub.2-1-pipa --H 584 boc CN 585 boc --O--CH.sub.2--CHF.sub.2

TABLE-US-00033 TABLE 33 ##STR00136## Rex R.sup.A R.sup.B 586 ##STR00137## --H 587 ##STR00138## --H 588 ##STR00139## --H 630 Me Et 632 Me Me 646 ##STR00140## Et

TABLE-US-00034 TABLE 34 ##STR00141## Rex R.sup.A R.sup.b R.sup.C R.sup.D 589 --(CH.sub.2).sub.2--OMe --H --H --H 590 ##STR00142## --H --H --H 591 cPr --H --H --H 592 --CH.sub.2-cHex --H --H --H 593 --(CH.sub.2).sub.2--OH --H --H --H 594 ##STR00143## --H --H --H 595 ##STR00144## boc --H --H 596 --CH.sub.2-(1-OH-cHex) boc --H --CONH.sub.2 597 ##STR00145## --COCF.sub.3 --OMe --H 598 ##STR00146## --COCF.sub.3 --OMe --H 599 ##STR00147## --H --OMe --H 600 ##STR00148## --COCF.sub.3 --OMe --H 601 ##STR00149## --H --OMe --H 602 --CH.sub.2-(1-OH-cHex) --H --H --CONH.sub.2

TABLE-US-00035 TABLE 35 Rex STRUCTURE 603 ##STR00150## 604 ##STR00151## 605 ##STR00152## 606 ##STR00153## 607 ##STR00154## 608 ##STR00155## 657*.sup.2 ##STR00156##

TABLE-US-00036 TABLE 36 Rex Data 1 FAB: 477 2 FAB: 511 3 ES: 493 4 CI: 292 5 FAB: 326 6 AP1: 285.87 7 FAB: 270 8 FAB: 433 9 FAB: 343 10 APN: 411 11 FAB: 373 12 ES: 313 13 ES: 273 14 FAB: 467 15 ES: 362 16 ES: 286 17 ES: 376 18 AP1: 269.96 19 CI: 230 20 FAB: 206 21 ES: 216 22 ES: 240 23 AP: 278 24 FAB: 320 25 FAB: 248 26 FAB: 248 27 FAB: 244 28 ES: 226 29 FAB: 250 30 AP: 230 31 FAB: 188 32 CI: 284 33 FAB: 266 34 FAB: 268 35 FAB: 276 36 ESNa: 374 37 ES: 418 38 ES: 285 39 ES: 241 40 FAB: 363 41 EI: 238 42 FAB: 256 43 ES: 334 44 FAB: 350 45 FAB: 206 46 FAB: 214 47 EI1: 209 48 CI: 236 49 FAB: 222 50 FAB: 228 51 FA1: 355.98 52 FAB: 234.13 53 ES: 142 54 ES: 183 55 ES: 206 56 ES: 297 57 ES: 283 58 NMR (CDCl.sub.3): 1.28 (3 H, t, J = 7 Hz), 2.73-2.95 (3H, m), 3.45 (1H, m), 3.80 (1H, d, J = 13.4 Hz), 3.87 (1H, d, J = 13.4 Hz), 4.16-4.24 (2H, m), 4.52 (1H, s), 7.11-7.39 (9H, s). 59 ES: 346.05 60 FAB: 391 61 ES: 284 62 CI: 206 63 ESNa: 372 64 ES: 258 65 FAB: 313 66 ES: 205 67 FAB: 270.98 68 N/D 69 ES: 366.4 70 FAB: 359 71 FAN: 385 72 N/D 73 FAB: 413 74 FA1: 331 75 FAB: 388 76 FAB: 410 77 ESNa: 314 78 ES: 242 79 ES2: 277 80 ES: 160 81 ES1: 294 82 ES: 292 83 ES: 207 84 N/D 85 FAB: 458 86 CI: 348 87 FAB: 338 88 AP: 248.00 89 ES: 357 90 ES: 330.13 91 ES: 192.18

TABLE-US-00037 TABLE 37 Rex Rsyn Data 101 34 ES: 270 102 34 AP: 234 103 34 ES: 310, 312 104 33 FAB: 262 105 34 ES: 266, 268 106 34 ES: 250 107 33 ES: 294 108 33 ES: 244 109 33 ES: 294 110 33 FAB: 230.16 111 33 ES: 244 112 33 FAB: 262 113 33 FAB: 266 114 33 FAB: 246 115 33 FAB: 250 116 33 FAB: 250 117 33 ES: 312 118 34 ES: 310 119 34 ES: 254 120 34 ES: 261 121 34 ES: 308 122 33 FAB: 246 123 33 FAB: 300 124 33 FAB: 210 125 34 ES: 208 126 33 ES: 212.0 127 33 ES: 212 128 33 ES: 222.18 129 34 ES: 254 130 33 ES: 226 131 33 ES: 206.19 132 33 ES: 210.08 133 33 ES: 212.11 134 33 AP: 208.00 135 33 ES: 208.1 136 33 AP: 210.06 137 33 ES: 206.18 138 33 EI1: 204 139 33 ES: 244 140 33 FAB: 240 141 33 FAB: 206 142 33 FAB: 246 143 33 FAB: 206 144 33 ES: 206.97 145 33 ES: 208.17 146 34 FAB: 268 147 34 ES: 241 148 34 ES: 305 149 34 ES: 261 150 34 ES: 261 151 34 AP: 246 152 34 ES: 222 153 34 CI: 252 153A 33 FAB: 210 154 33 FAB: 302 155 33 FAB: 340 156 33 FAB: 314 157 33 FAB: 334 158 33 ES: 286.79 159 33 FAB: 328 160 33 CI1: 300 161 33 CI: 284 162 34 CI1: 314 163 48 EIN: 213 164 48 EIBr: 213 165 48 EI1: 239 166 4 FAB: 278 167 4 ES: 372 168 4 ES: 371 169 4 FAB: 292.1 170 4 ES: 280 171 4 ES: 370, 372 172 4 ES: 317 173 4 FAB: 322 174 4 ES: 310 175 4 AP: 326, 328 176 4 FAB: 270 177 4 ES: 304 178 4 ES: 311 179 4 FA2: 291.93 180 4 ES: 354

TABLE-US-00038 TABLE 38 Rex Rsyn Data 181 4 ES: 354 182 4 ES: 304 183 4 ES1: 326 184 4 FAB: 352.07 185 4 FAB: 322 186 4 FA1: 322 187 4 ES: 322 188 4 ES: 304 189 4 ES: 320 190 4 FAB: 310 191 4 ES: 310 192 4 FAB: 308 193 4 ES: 316 194 4 ES: 370 195 Syn: 14 N/D 196 4 ES: 372 197 4 ES: 330 198 4 FAB: 266 199 4 FAB: 252 200 4 ES: 314 201 4 ES: 332 202 4 ES: 334 203 4 FAB: 336.07 204 4 ES: 368 205 4 FAB: 354 206 4 FAB: 338 207 4 FAB: 306 208 4 ES: 368 209 4 FAB: 360 210 4 FAB: 300.02 211 60 FAB: 320 212 4 FAB: 391 213 4 FAB: 282 214 4 FAB: 264 215 4 ES: 276 216 4 FAB: 266 217 40 FAB: 372 218 40 FAB: 386 219 4 ES: 268 220 4 EI1: 311 221 4 CI: 282 222 4 FAB: 296 223 4 FAB: 270 224 4 ES: 272 225 4 ES: 282 226 4 ES: 282 227 4 ES: 318 228 4 FAB: 322 229 4 FAB: 402 230 4 FAB: 282 231 4 CI: 282 232 4 ES: 330 233 4 ES: 314 234 4 FAB: 282 235 4 FAB: 296 236 4 ES: 368 236A 4 ES: 368.08 237 4 FAB: 346.11 238 4 FAB: 316.02 239 4 ES: 282 240 4 ES: 282 241 4 FAB: 300 242 4 FAB: 266 243 4 ES: 306 244 4 FAB: 266 245 4 ES: 284.08 246 4 FAB: 300 247 4 FAB: 266 248 4 FAB: 306 249 4 ES: 270.03 250 4 ES: 304 251 4 FAB: 266 252 4 FAB: 282 253 60 ES2: 271.70 254 4 CI: 270 255 4 FAB: 268 256 60 FAB: 284 257 4 FAB: 266 258 4 ES2: 347.82 259 4 CI: 268

TABLE-US-00039 TABLE 39 Rex Rsyn Data 260 60 ESNa: 294 261 4 CI: 282 262 4 ES2: 269.73 263 4 ES1: 265.98 264 4 CI: 306 265 4 CI: 310 266 4 CI: 300 267 4 CI: 304 268 4 ES: 282.07 269 4 ES: 316 270 4 FAB: 328 271 4 FAB: 328 272 4 FAB: 294 273 4 ES: 321 274 4 ES: 321 275 4 ES: 365 276 4 ES: 301 277 4 ES: 321 278 4 ES: 287 279 4 FAB: 00 280 4 FAB: 346 281 4 CI: 282 282 4 ES: 296 283 4 CI: 296 284 60 CI: 312 285 4 AP: 306 286 4 FAB: 344 287 4 ES: 316 288 4 FAB: 286.35 289 44 ESNa: 372 290 4 EI1: 315 291 4 ES: 316 292 44 CI: 350 293 4 EI: 321 294 4 FAB: 316 295 4 FAB: 316 296 4 ES: 318 297 4 ES: 352 298 4 FAB: 306 299 4 FAB: 320.0 300 4 FAB: 306.06 301 4 FAB: 310.12 302 4 FAB: 238 303 27 CI: 222 304 28 ES: 202 305 25 ES: 292, 294 306 27 FAB: 282 307 26 EIN: 202 308 26 FAB: 230 309 27 FAB: 244 310 25 ES: 232 311 25 ES: 248 312 27 ES: 276 313 27 FA2: 213.28 314 27 ES: 276 315 27 ES: 226 316 27 FAB: 250 317 25 ES: 232 318 25 FAB: 232 319 28 ES: 294 320 27 ES: 292 321 27 ES: 252 322 27 ES: 236 323 27 ES: 254 324 26 FAB: 276 325 26 ES: 260 326 27 ES: 256 327 29 ES: 290 328 29 ES: 291 329 25 FAB: 282 330 25 FAB: 242 331 28 EIN: 186 332 27 FAB: 272 333 27 FAB: 192 334 25 ES: 190 335 25 ES: 194.22 (M + H) 336 27 FAB: 322 337 25 ES: 241 338 25 ES: 252 339 25 ES: 236

TABLE-US-00040 TABLE 40 Rex Rsyn Data 340 27 FAB: 318 341 27 EIN: 202 342 31 CI: 190 343 31 ES2: 269.20 344 25 ES: 226 345 31 ES: 206.23 346 25 FAB: 188 347 25 FAB: 228 348 27 CI: 188 349 26 CI: 228 350 27 CI: 188 351 26 ES: 226 352 31 FAB: 204 353 31 FAB: 188 354 31 FAB: 192 355 29 FAB: 204 356 29 CI: 206 357 31 CI: 190 358 31 AP: 188.15 359 31 CI1: 282 360 25 EI1: 311 361 29 ES: 206 362 49 EIN: 224 363 31 CIN: 192 364 29 AP: 216 365 28 ES: 245 366 28 ES: 223 367 28 ES: 287 368 28 ES: 243 369 28 ES: 243 370 27 FAB: 296 371 27 EI1: 265 372 31 ES: 204 373 26 ES: 218 374 31 CI1: 296 375 31 CI: 234 375A 27 FAB: 192 376 18 FAB: 206 377 18 FA2: 217.3 378 18 ES: 294, 296 379 18 ES: 204 380 18 ES: 296 381 18 FAB: 284 382 18 ES: 234 383 18 ES: 250 384 18 AP: 214.08 385 18 ES: 278 386 18 ES: 228 387 18 FAB: 246 388 18 FAB: 252 389 18 ES: 250 390 18 FAB: 246 391 18 FAB: 246 392 18 ES: 228 393 18 FAB: 243 394 18 AP: 294 395 23 ES: 296 396 18 ES: 254 397 18 ES: 238 398 18 ES: 256 399 18 ES: 258 400 18 AP: 218 401 18 FAB: 278 402 18 FAB: 262 403 18 ES: 292 404 18 FAB: 241 405 18 ES: 292 406 18 FAB: 284 407 39 FAB: 315 408 18 ES: 190 409 18 FAB: 206 500 18 FAB: 194 501 18 ES: 192 502 18 ES: 197 503 18 FAB: 324 504 45 FAB: 246 505 18 ES: 206 506 18 ES: 242 507 18 ES: 254 508 18 ES: 238 509 18 FAB: 298

TABLE-US-00041 TABLE 41 Rex Rsyn Data 510 45 FAB: 220 513 83 ES: 206 514 18 ES: 228 515 18 FAB: 224 516 18 FAB: 190 517 18 FAB: 230 518 18 ES: 208.15 519 18 ES2: 195.05 520 18 CI: 190 521 18 CI: 224 522 18 CI: 190 523 18 ES: 228 524 18 FAB: 190 525 18 FAB: 190 526 18 FAB: 194 527 18 FAB: 206 528 18 CI: 192 529 18 AP: 190.19 530 18 FAB: 312 531 45 FAB: 234 532 18 FAB: 230 533 18 ES: 192 534 18 ES: 224 535 18 CI: 228 536 18 FAB: 252 537 18 ES: 245 538 18 ES: 225 539 18 ES: 289 540 18 ES: 245 541 18 ES: 245 542 18 CI: 268 543 18 ES: 206 544 18 ES: 220 545 18 CI1: 298 546 45 ES: 220 547 60 CI: 312 548 24 ES: 364, 366 549 24 ES: 304 550 24 ES: 320 551 24 FAB: 304 552 24 FAB: 304 553 24 FAB: 354 554 24 FAB: 314 555 25 ESNa: 284 556 24 ES: 266 557 24 ES: 312 558 24 ES: 324 559 24 ES: 308 560 24 ES: 280 561 24 FAB: 260 562 24 FAB: 300 563 24 ES: 298 564 24 FAB: 382 565 26 N/D 566 22 ES: 240 567 81 EI1: 317 568 45 CI: 240 570 81 ES: 286 571 45 ES: 206 572 21 ES: 216 575 81 FAB: 294 576 81 EI1: 317 577 45 CI: 240 578 10 ES: 413 579 12 ES: 313 580 10 ES: 427 581 Syn: 1 ES: 442 582 12 ES: 327 583 Syn: 10 ES: 342 584 37 FAB: 341 585 75 FAB: 396 586 7 FAB: 294.01 587 7 FAB: 264.01 588 7 FAB: 264.03 589 Syn: 1 ES: 331 590 Syn: 1 N/D 591 Syn: 1 ES: 313 592 Syn: 1 FAB: 369 593 Syn: 1 FAB: 317 594 Syn: 1 ES: 381

TABLE-US-00042 TABLE 42 Rex Rsyn Data 595 2 ES: 501 596 14 FAB: 528 597 2 FAN: 541 598 1 FAB: 507 599 Syn: 1 FAB: 411 600 2 ES: 526 601 Syn: 1 FAB: 475 602 Syn: 10 N/D 603 Syn: 1 FAB: 360 604 Syn: 1 FAB: 437 605 33 FA2: 261.2 606 27 FA2: 243.5 607 18 FA2: 245.4 608 80 AP: 106.0 609 33 ES: 255.99 610 33 CI: 288 611 24 CI: 344 612 25 ES: 270 613 18 ES: 272 614 4 CI: 350 615 33 CI: 284 616 33 CI: 288 617 24 FAB: 338 618 24 FAB: 342 619 33 CI: 286 620 25 EIN: 264 621 25 EIN: 268 622 18 ES: 268 623 24 ES: 338 624 33 AP: 220.03 625 25 CI: 266 626 84 AP: 202.06 627 18 AP: 204.00 628 40 EI1: 313 629 4 CI: 252 630 7 CI: 230 631 18 ES: 176 632 7 EI1: 215 633 4 CI: 238 634 40 EI1: 237 635 4 CI: 344 636 24 FAB: 350 637 66 N/D 638 4 CI: 350 639 33 ES: 296 640 88 CI: 264 641 33 EI: 192 642 24 ES: 246 643 25 EI1: 173 644 40 FAB: 311 645 40 ES: 235 646 7 CI: 260 647 18 ES: 250.25 648 4 ES: 326 649 18 ES: 268 650 21 FAB: 228 651 4 CI: 304 652 21 FAB: 228 653 4 FAB: 304 654 18 CI: 274 655 4 CI: 340 656 4 CI: 352 657 90 ES: 330.14 658 91 ES: 192.13 659 4 ES: 268.09 660 4 ES: 268.09 661 34 ES: 274 662 34 ES: 308

TABLE-US-00043 TABLE 43 Ex/ salt STRUCTURE 1/ OX ##STR00157## 2/ OX ##STR00158## 3/ OX ##STR00159## 4/ OX ##STR00160## 5/ OX ##STR00161## 6/ OX ##STR00162## 7/ OX ##STR00163## 8/ OX ##STR00164## 9/ OX ##STR00165## 10/ OX ##STR00166## 11/ OX ##STR00167## 12/ OX ##STR00168##

TABLE-US-00044 TABLE 44 Ex/ salt STRUCTURE 13/ OX ##STR00169## 14/ OX ##STR00170## 15/ OX ##STR00171## 16 ##STR00172## 17 ##STR00173##

TABLE-US-00045 TABLE 45 Ex salt STRUCTURE 101 OX ##STR00174## 102 OX ##STR00175## 103 OX ##STR00176## 104 OX ##STR00177## 105 OX ##STR00178## 106 OX ##STR00179## 107 OX ##STR00180##

TABLE-US-00046 TABLE 46 Ex salt STRUCTURE 108 OX ##STR00181## 109 OX ##STR00182## 110 OX ##STR00183## 111 OX ##STR00184## 112 OX ##STR00185## 113 OX ##STR00186## 114 ##STR00187##

TABLE-US-00047 TABLE 47 Ex salt STRUCTURE 115 ##STR00188## 116 OX ##STR00189## 117 OX ##STR00190## 118 OX ##STR00191## 119 OX ##STR00192## 120 OX ##STR00193## 121 OX ##STR00194##

TABLE-US-00048 TABLE 48 Ex salt STRUCTURE 122 OX ##STR00195## 123 OX ##STR00196## 124 OX ##STR00197## 125 OX ##STR00198## 126 OX ##STR00199## 127 OX ##STR00200## 128 OX ##STR00201##

TABLE-US-00049 TABLE 49 Ex salt STRUCTURE 129 OX ##STR00202## 130 OX ##STR00203## 131 OX ##STR00204## 132 OX ##STR00205## 133 OX ##STR00206## 134 OX ##STR00207## 135 OX ##STR00208##

TABLE-US-00050 TABLE 50 Ex salt STRUCTURE 136 OX ##STR00209## 137 OX ##STR00210## 138 OX ##STR00211## 139 OX ##STR00212## 140 OX ##STR00213## 141 OX ##STR00214##

TABLE-US-00051 TABLE 51 Ex salt STRUCTURE 143 FM ##STR00215## 144 OX ##STR00216## 145 FM ##STR00217## 146 OX ##STR00218## 147 OX ##STR00219## 148 OX ##STR00220## 149 OX ##STR00221##

TABLE-US-00052 TABLE 52 Ex salt STRUCTURE 150 OX ##STR00222## 151 OX ##STR00223## 152 OX ##STR00224## 153 FM ##STR00225## 154 OX ##STR00226## 155 OX ##STR00227##

TABLE-US-00053 TABLE 53 Ex salt STRUCTURE 156 OX ##STR00228## 157 CL ##STR00229## 158 OX ##STR00230## 159 OX ##STR00231## 160 OX ##STR00232## 161 OX ##STR00233##

TABLE-US-00054 TABLE 54 Ex salt STRUCTURE 162 OX ##STR00234## 163 OX ##STR00235## 164 OX ##STR00236## 165 OX ##STR00237## 166 OX ##STR00238## 167 OX ##STR00239##

TABLE-US-00055 TABLE 55 Ex salt STRUCTURE 168 FM ##STR00240## 169 FM ##STR00241## 170 OX ##STR00242## 171 OX ##STR00243## 172 OX ##STR00244## 173 OX ##STR00245## 174 OX ##STR00246##

TABLE-US-00056 TABLE 56 Ex salt STRUCTURE 175 OX ##STR00247## 176 OX ##STR00248## 177 OX ##STR00249## 178 OX ##STR00250## 179 OX ##STR00251## 180 OX ##STR00252## 181 OX ##STR00253##

TABLE-US-00057 TABLE 57 Ex salt STRUCTURE 182 OX ##STR00254## 183 OX ##STR00255## 184 OX ##STR00256## 185 OX ##STR00257## 186 OX ##STR00258## 187 OX ##STR00259## 188 OX ##STR00260##

TABLE-US-00058 TABLE 58 Ex salt STRUCTURE 189 OX ##STR00261## 190 OX ##STR00262## 191 OX ##STR00263## 192 OX ##STR00264## 193 OX ##STR00265## 194 OX ##STR00266##

TABLE-US-00059 TABLE 59 Ex salt STRUCTURE 195 OX ##STR00267## 196 OX ##STR00268## 197 OX ##STR00269## 198 OX ##STR00270## 199 FM ##STR00271## 200 FM ##STR00272## 201 FM ##STR00273##

TABLE-US-00060 TABLE 60 Ex salt STRUCTURE 202 FM ##STR00274## 203 OX ##STR00275## 204 FM ##STR00276## 205 OX ##STR00277## 206 OX ##STR00278## 207 OX ##STR00279## 208 OX ##STR00280##

TABLE-US-00061 TABLE 61 Ex salt STRUCTURE 209 FM ##STR00281## 210 FM ##STR00282## 211 OX ##STR00283## 212 OX ##STR00284## 213 OX ##STR00285## 214 OX ##STR00286## 215 OX ##STR00287##

TABLE-US-00062 TABLE 62 Ex salt STRUCTURE 216 OX ##STR00288## 217 OX ##STR00289## 218 OX ##STR00290## 219 OX ##STR00291## 220 OX ##STR00292## 221 OX ##STR00293## 222 OX ##STR00294##

TABLE-US-00063 TABLE 63 Ex salt STRUCTURE 223 OX ##STR00295## 224 OX ##STR00296## 225 OX ##STR00297## 226 OX ##STR00298## 227 OX ##STR00299## 228 OX ##STR00300## 229 OX ##STR00301##

TABLE-US-00064 TABLE 64 Ex salt STRUCTURE 230 OX ##STR00302## 231 OX ##STR00303## 232 OX ##STR00304## 233 OX ##STR00305## 234 OX ##STR00306## 235 OX ##STR00307## 236 OX ##STR00308##

TABLE-US-00065 TABLE 65 Ex salt STRUCTURE 237 OX ##STR00309## 238 OX ##STR00310## 239 OX ##STR00311## 240 OX ##STR00312## 241 OX ##STR00313## 242 OX ##STR00314## 243 OX ##STR00315##

TABLE-US-00066 TABLE 66 Ex salt STRUCTURE 244 OX ##STR00316## 245 OX ##STR00317## 246 OX ##STR00318## 247 OX ##STR00319## 249 OX ##STR00320## 250 OX ##STR00321##

TABLE-US-00067 TABLE 67 Ex salt STRUCTURE 252 OX ##STR00322## 253 OX ##STR00323## 254 OX ##STR00324## 255 OX ##STR00325## 256 OX ##STR00326## 257 OX ##STR00327## 258 OX ##STR00328## 259 OX ##STR00329##

TABLE-US-00068 TABLE 68 Ex salt STRUCTURE 260 OX ##STR00330## 261 OX ##STR00331## 262 FM ##STR00332## 263 FM ##STR00333## 264 OX ##STR00334## 265 OX ##STR00335## 266 OX ##STR00336##

TABLE-US-00069 TABLE 69 Ex salt STRUCTURE 267 OX ##STR00337## 268 ##STR00338## 269 OX ##STR00339## 270 OX ##STR00340## 271 OX ##STR00341## 272 OX ##STR00342##

TABLE-US-00070 TABLE 70 Ex salt STRUCTURE 273 OX ##STR00343## 274 OX ##STR00344## 275 OX ##STR00345## 276 OX ##STR00346## 277 OX ##STR00347## 278 FM ##STR00348## 279 OX ##STR00349##

TABLE-US-00071 TABLE 71 Ex salt STRUCTURE 280 FM ##STR00350## 281 OX ##STR00351## 282 OX ##STR00352## 283 OX ##STR00353## 284 OX ##STR00354## 285 OX ##STR00355## 286 OX ##STR00356## 287 OX ##STR00357##

TABLE-US-00072 TABLE 72 Ex salt STRUCTURE 288 OX ##STR00358## 289 OX ##STR00359## 290 FM ##STR00360## 291 FM ##STR00361## 292 OX ##STR00362## 293 OX ##STR00363## 294 OX ##STR00364## 295 OX ##STR00365##

TABLE-US-00073 TABLE 73 Ex salt STRUCTURE 296 OX ##STR00366## 297 OX ##STR00367## 298 OX ##STR00368## 299 OX ##STR00369## 300 OX ##STR00370## 301 OX ##STR00371## 302 OX ##STR00372## 303 OX ##STR00373##

TABLE-US-00074 TABLE 74 Ex salt STRUCTURE 304 OX ##STR00374## 305 OX ##STR00375## 306 T2 ##STR00376## 307 T1 ##STR00377## 308 OX ##STR00378## 309 OX ##STR00379## 310 FM ##STR00380##

TABLE-US-00075 TABLE 75 Ex salt STRUCTURE 311 OX ##STR00381## 312 OX ##STR00382## 313 OX ##STR00383## 314 OX ##STR00384## 315 OX ##STR00385## 316 OX ##STR00386## 317 OX ##STR00387## 318 OX ##STR00388##

TABLE-US-00076 TABLE 76 Ex salt STRUCTURE 319 OX ##STR00389## 320 OX ##STR00390## 321 OX ##STR00391## 322 OX ##STR00392## 323 OX ##STR00393## 324 OX ##STR00394## 325 OX ##STR00395## 326 OX ##STR00396##

TABLE-US-00077 TABLE 77 Ex salt STRUCTURE 327 OX ##STR00397## 328 OX ##STR00398## 329 OX ##STR00399## 330 OX ##STR00400## 331 OX ##STR00401## 332 BR ##STR00402## 333 FM ##STR00403##

TABLE-US-00078 TABLE 78 Ex salt STRUCTURE 334 OX ##STR00404## 335 OX ##STR00405## 336 OX ##STR00406## 337 OX ##STR00407## 338 OX ##STR00408## 339 OX ##STR00409## 340 OX ##STR00410## 341 OX ##STR00411##

TABLE-US-00079 TABLE 79 Ex salt STRUCTURE 342 OX ##STR00412## 343 OX ##STR00413## 344 OX ##STR00414## 345 OX ##STR00415## 346 OX ##STR00416## 347 OX ##STR00417## 348 OX ##STR00418## 349 OX ##STR00419##

TABLE-US-00080 TABLE 80 Ex salt STRUCTURE 350 OX ##STR00420## 351 OX ##STR00421## 352 OX ##STR00422## 353 OX ##STR00423## 354 OX ##STR00424## 355 OX ##STR00425## 356 OX ##STR00426##

TABLE-US-00081 TABLE 81 Ex salt STRUCTURE 357 OX ##STR00427## 358 OX ##STR00428## 359 OX ##STR00429## 360 OX ##STR00430## 361 OX ##STR00431## 362 OX ##STR00432## 363 OX ##STR00433## 364 OX ##STR00434##

TABLE-US-00082 TABLE 82 Ex salt STRUCTURE 365 OX ##STR00435## 366 OX ##STR00436## 367 OX ##STR00437## 368 OX ##STR00438## 369 OX ##STR00439## 370 OX ##STR00440## 371 OX ##STR00441## 372 OX ##STR00442##

TABLE-US-00083 TABLE 83 Ex salt STRUCTURE 373 OX ##STR00443## 374 OX ##STR00444## 375 OX ##STR00445## 376 OX ##STR00446## 377 OX ##STR00447## 378 OX ##STR00448## 379 OX ##STR00449## 380 OX ##STR00450##

TABLE-US-00084 TABLE 84 Ex salt STRUCTURE 381 OX ##STR00451## 382 OX ##STR00452## 383 OX ##STR00453## 384 OX ##STR00454## 385 OX ##STR00455## 386 OX ##STR00456## 387 OX ##STR00457## 388 OX ##STR00458##

TABLE-US-00085 TABLE 85 Ex salt STRUCTURE 389 OX ##STR00459## 390 OX ##STR00460## 391 OX ##STR00461## 392 OX ##STR00462## 393 OX ##STR00463## 394 OX ##STR00464## 395 OX ##STR00465##

TABLE-US-00086 TABLE 86 Ex salt STRUCTURE 396 OX ##STR00466## 397 OX ##STR00467## 398 OX ##STR00468## 399 OX ##STR00469## 400 OX ##STR00470## 401 OX ##STR00471## 402 OX ##STR00472##

TABLE-US-00087 TABLE 87 Ex salt STRUCTURE 403 OX ##STR00473## 404 OX ##STR00474## 405 OX ##STR00475## 406 OX ##STR00476## 407 OX ##STR00477## 408 OX ##STR00478## 409 OX ##STR00479##

TABLE-US-00088 TABLE 88 Ex salt STRUCTURE 410 OX ##STR00480## 411 OX ##STR00481## 412 OX ##STR00482## 413 OX ##STR00483## 414 OX ##STR00484## 415 FM ##STR00485## 416 OX ##STR00486## 417 OX ##STR00487##

TABLE-US-00089 TABLE 89 Ex salt STRUCTURE 418 OX ##STR00488## 419 OX ##STR00489## 420 OX ##STR00490## 421 OX ##STR00491## 422 OX ##STR00492## 423 OX ##STR00493## 424 OX ##STR00494##

TABLE-US-00090 TABLE 90 Ex salt STRUCTURE 425 OX ##STR00495## 426 OX ##STR00496## 427 OX ##STR00497## 428 OX ##STR00498## 429 OX ##STR00499## 430 OX ##STR00500## 431 OX ##STR00501## 432 OX ##STR00502##

TABLE-US-00091 TABLE 91 Ex salt STRUCTURE 433 OX ##STR00503## 434 OX ##STR00504## 435 FM ##STR00505## 436 T2 ##STR00506## 437 OX ##STR00507## 438 OX ##STR00508## 439 T1 ##STR00509##

TABLE-US-00092 TABLE 92 Ex salt STRUCTURE 440 OX ##STR00510## 441 OX ##STR00511## 442 OX ##STR00512## 443 OX ##STR00513## 444 OX ##STR00514## 445 FM ##STR00515## 446 FM ##STR00516## 447 OX ##STR00517##

TABLE-US-00093 TABLE 93 Ex salt STRUCTURE 448 FM ##STR00518## 449 OX ##STR00519## 450 OX ##STR00520## 451 OX ##STR00521## 452 OX ##STR00522## 453 OX ##STR00523## 454 OX ##STR00524## 455 OX ##STR00525##

TABLE-US-00094 TABLE 94 Ex salt STRUCTURE 456 OX ##STR00526## 457 OX ##STR00527## 458 ##STR00528## 459 OX ##STR00529## 460 ##STR00530## 461 OX ##STR00531## 462 OX ##STR00532## 463 OX ##STR00533##

TABLE-US-00095 TABLE 95 Ex salt STRUCTURE 464 OX ##STR00534## 465 FM ##STR00535## 466 OX ##STR00536## 467 OX ##STR00537## 468 ##STR00538## 469 OX ##STR00539## 470 OX ##STR00540## 471 OX ##STR00541##

TABLE-US-00096 TABLE 96 Ex salt STRUCTURE 472 OX ##STR00542## 473 OX ##STR00543## 474 OX ##STR00544## 475 OX ##STR00545## 476 OX ##STR00546## 477 OX ##STR00547## 478 OX ##STR00548## 479 OX ##STR00549##

TABLE-US-00097 TABLE 97 Ex salt STRUCTURE 480 OX ##STR00550## 481 OX ##STR00551## 482 OX ##STR00552## 483 OX ##STR00553## 484 OX ##STR00554## 485 OX ##STR00555## 486 OX ##STR00556## 487 OX ##STR00557##

TABLE-US-00098 TABLE 98 Ex salt STRUCTURE 488 OX ##STR00558## 489 ##STR00559## 490 OX ##STR00560## 491 ##STR00561## 492 OX ##STR00562## 493 OX ##STR00563## 494 ##STR00564## 495 OX ##STR00565## 496 OX ##STR00566##

TABLE-US-00099 TABLE 99 Ex salt STRUCTURE 497 OX ##STR00567## 498 OX ##STR00568## 499 OX ##STR00569## 500 OX ##STR00570## 501 OX ##STR00571## 502 OX ##STR00572## 503 OX ##STR00573##

TABLE-US-00100 TABLE 100 Ex salt STRUCTURE 504 OX ##STR00574## 505 OX ##STR00575## 506 OX ##STR00576## 507 OX ##STR00577## 508 OX ##STR00578## 509 OX ##STR00579## 510 OX ##STR00580##

TABLE-US-00101 TABLE 101 Ex salt STRUCTURE 511 ##STR00581## 512 ##STR00582## 513 ##STR00583## 514 ##STR00584## 515 ##STR00585## 516 ##STR00586## 517 ##STR00587##

TABLE-US-00102 TABLE 102 Ex salt STRUCTURE 518 ##STR00588## 519 ##STR00589## 520 ##STR00590## 521 ##STR00591## 522 ##STR00592## 523 ##STR00593## 524 ##STR00594##

TABLE-US-00103 TABLE 103 Ex salt STRUCTURE 525 ##STR00595## 526 ##STR00596## 527 ##STR00597## 528 ##STR00598## 529 ##STR00599## 530 ##STR00600## 531 ##STR00601##

TABLE-US-00104 TABLE 104 Ex salt STRUCTURE 532 ##STR00602## 533 ##STR00603## 534 ##STR00604## 535 ##STR00605## 536 ##STR00606##

TABLE-US-00105 TABLE 105 Ex salt STRUCTURE 537 OX ##STR00607## 538 OX ##STR00608## 539 OX ##STR00609## 540 OX ##STR00610## 541 OX ##STR00611## 542 OX ##STR00612## 543 OX ##STR00613##

TABLE-US-00106 TABLE 106 Ex salt STRUCTURE 544 OX ##STR00614## 545 OX ##STR00615## 546 OX ##STR00616## 547 OX ##STR00617## 548 OX ##STR00618## 549 OX ##STR00619## 550 OX ##STR00620##

TABLE-US-00107 TABLE 107 Ex salt STRUCTURE 551 OX ##STR00621## 552 OX ##STR00622## 553 OX ##STR00623## 554 OX ##STR00624## 555 OX ##STR00625## 556 OX ##STR00626## 557 OX ##STR00627##

TABLE-US-00108 TABLE 108 Ex salt STRUCTURE 558 OX ##STR00628## 559 OX ##STR00629## 560 OX ##STR00630## .sup. 561*.sup.1 T1 ##STR00631## .sup. 562*.sup.2 T2 ##STR00632## 563 ##STR00633## 564 ##STR00634## 565 ##STR00635##

TABLE-US-00109 TABLE 109 Ex salt STRUCTURE 566 ##STR00636## 567 ##STR00637## 568 FM ##STR00638## 569 T2 ##STR00639## 570 T1 ##STR00640## 571 MB ##STR00641## 572 MA ##STR00642##

TABLE-US-00110 TABLE 110 Ex salt STRUCTURE 573 T1 ##STR00643## 574 MA ##STR00644## 575 OX ##STR00645## 576 T2 ##STR00646## 577 T1 ##STR00647## 578 MB ##STR00648## 579 MA ##STR00649##

TABLE-US-00111 TABLE 111 Ex Data 1 FAB: 385 2 FAB: 399 3 FAB: 389 4 FAB: 415 5 FAB: 413 6 ES: 359 7 FAB: 399 8 FAB: 429 9 FAB: 415 10 FAB: 401 11 FAB: 428 12 FAB: 361 13 FAB: 431 14 FAB: 426 15 FAB: 399 16 ES: 413 17 ES: 401

TABLE-US-00112 TABLE 112 Ex Syn Data 101 1 FAB: 385 102 1 FAB: 385 103 1 FAB: 385 104 1 FAB: 385 105 1 FAB: 423 106 1 FAB: 371 107 1 FAB: 393 108 1 FAB: 393 109 1 FAB: 407 110 1 FAB: 407 111 1 FAB: 465 112 1 FAB: 410 113 1 FAB: 403 114 1 FAB: 469 115 1 FAB: 469 116 1 FAB: 419 117 1 FAB: 423 118 1 FAB: 423 119 1 FAB: 449 120 1 FAB: 371 121 7 FAB: 425 122 1 FAB: 425 123 1 FAB: 441 124 1 FAB: 373 125 1 FAB: 373 126 1 FAB: 443 127 1 FAB: 373 128 7 FAB: 425 129 5 FAB: 399 130 7 FAB: 399 131 1 FAB: 385 132 1 FAB: 371 133 1 FAB: 331 134 1 FAB: 331 135 1 FAB: 334 136 1 FAB: 347 137 1 FAB: 343 138 7 FAB: 425 139 7 FAB: 443 140 1 FAB: 387 141 7 FAB: 439 143 1 FAB: 317.2 144 1 FAB: 359 145 1 FAB: 345 146 1 FAB: 361 147 1 FAB: 345 148 1 FAB: 399 149 2 FAB: 345 150 1 FAB: 415 151 1 FAB: 400.5 152 1 FAB: 345 153 1 FAB: 331 154 1 FAB: 413.3 155 1 FAB: 359.3 156 7 FAB: 447 157 1 FAB: 361 158 1 FAB: 423 159 1 FAB: 397 160 1 FAB: 343 161 1 FAB: 373 162 7 FAB: 455 163 1 FAB: 404 164 1 FAB: 350 165 1 FAB: 447 166 1 FAB: 393 167 1 FAB: 447 168 1 FAB: 383.0 169 1 FAB: 329.1 170 7 ES: 401 171 1 FAB: 423 172 1 FAB: 343 173 1 FAB: 397 174 1 FAB: 393 175 1 FAB: 373 176 1 FAB: 409 177 1 FAB: 439 178 1 FAB: 365 179 1 FAB: 395 180 1 FAB: 439

TABLE-US-00113 TABLE 113 Ex Syn Data 181 1 FAB: 409 182 1 FAB: 411 183 1 FAB: 439 184 1 FAB: 415 185 1 FAB: 391 186 1 FAB: 419 187 1 FAB: 365 188 1 FAB: 395 189 1 FAB: 419 190 1 FAB: 361 191 1 FAB: 391 192 1 FAB: 415 193 1 FAB: 365 194 1 FAB: 395 195 1 FAB: 391 196 1 FAB: 421 197 1 FAB: 367 198 1 FAB: 397 199 1 FAB: 345.2 200 1 FAB: 445.2 201 1 FAB: 391.2 202 1 FAB: 371.2 203 1 FAB: 361 204 1 FAB: 387 205 1 FAB: 413 206 1 FAB: 359 207 1 FAB: 389 209 1 FAB: 399.2 210 1 FAB: 317.1 212 1 FAB: 397 213 1 FAB: 361 214 1 FAB: 415 215 1 FAB: 349 216 1 FAB: 379 217 1 FAB: 403 218 1 FAB: 349 219 1 FA1: 378 220 1 FAB: 413 221 1 FAB: 359 222 1 FAB: 373 223 1 ES: 389 224 1 ES: 373 225 1 FAB: 347 226 1 FAB: 319 227 1 ES: 349 228 1 FAB: 349 229 1 FAB: 379 230 1 FAB: 403 231 1 FAB: 380 232 1 FAB: 404 233 1 FAB: 458 234 1 FAB: 360 235 1 FAB: 414 236 1 FAB: 409 237 1 FAB: 439 238 1 FAB: 355 239 1 FAB: 385 240 1 FAB: 411 241 1 FAB: 441 242 1 ES: 369 243 1 FAB: 399 244 1 FAB: 414 245 1 FAB: 360 246 1 FAB: 353 247 1 FAB: 383 249 1 FAB: 386 250 1 FAB: 356 252 1 FAB: 371 253 1 ES: 401 254 1 FAB: 373 255 1 FAB: 403 256 1 FAB: 359 257 1 FAB: 305 258 1 FAB: 335 259 1 FAB: 345 260 1 FAB: 291

TABLE-US-00114 TABLE 114 Ex Syn Data 261 1 FAB: 321 262 1 FAB: 403.3 263 1 FAB: 375.2 264 1 FAB: 387 265 1 FAB: 333 266 1 FAB: 363 267 10 FAB: 374 268 10 N/D 269 10 FAB: 404 270 1 FAB: 416 271 1 FAB: 356 272 1 FAB: 386 273 1 FAB: 345 274 1 FAB: 375 275 1 FAB: 407 276 1 FAB: 437 277 1 FAB: 414 278 1 FAB: 349.14 279 1 FAB: 437 280 1 FAB: 405.2 281 1 FAB: 430 282 1 FAB: 399 283 1 FAB: 429 284 1 FAB: 447 285 1 ES: 393 286 1 FAB: 423 287 1 FAB: 431 288 1 FAB: 377 289 1 FAB: 407 290 1 FAB: 355.24 291 1 FAB: 411.22 292 1 ES: 359 293 1 ES: 389 294 1 FAB: 402 295 1 ES: 379 296 1 ES: 325 297 1 ES: 355 298 1 FAB: 371 299 1 FAB: 317 300 1 FAB: 347 301 1 FAB: 383 302 1 FAB: 456 303 1 FAB: 430 304 1 FAB: 407 305 1 FAB: 437 306 1 FAB: 385 307 1 FAB: 385 308 1 FAB: 389 309 1 FAB: 373 310 1 FAB: 399.2 311 1 FAB: 355 312 1 FAB: 417 313 1 FAB: 399 314 1 FAB: 345 315 1 FAB: 375 316 1 FAB: 363 317 1 FAB: 309 318 1 FAB: 339 319 1 FAB: 375 320 1 FAB: 321 321 1 FAB: 351 322 1 FAB: 357 323 1 FAB: 303 324 1 FAB: 333 325 1 FAB: 409 326 1 FAB: 413 327 2 ES: 369 328 1 ES: 417 329 1 FAB: 255 330 1 FAB: 381 331 1 FAB: 381 332 2 FAB: 355.1 333 2 FAB: 411.2 334 2 FAB: 381.2 335 2 FAB: 381.3 336 2 FAB: 325.2 337 1 FAB: 355 338 1 FAB: 381.31 339 9 FAB: 445 340 1 FAB: 373

TABLE-US-00115 TABLE 115 Ex Syn Data 341 1 FAB: 359 342 1 FAB: 305 343 1 FAB: 335 344 1 FAB: 317 345 1 FAB: 263 346 1 FAB: 347 347 1 FAB: 411 348 1 FAB: 425 349 1 FAB: 355 350 2 FAB: 339.1 351 2 FAB: 367.2 352 1 FAB: 415 353 9 FAB: 431 354 1 ES: 385 355 1 FAB: 311.2 356 1 FAB: 325.2 357 1 FAB: 367.2 358 1 FAB: 399 359 1 FAB: 359 360 1 FAB: 413 361 1 FAB: 373 362 1 FAB: 367 363 1 FAB: 405 364 1 FAB: 351 365 1 FAB: 335 366 2 FAB: 325.2 367 1 FAB: 363 368 1 FAB: 309 369 1 FAB: 353 370 1 FAB: 421 371 14 FAB: 402 372 1 FAB: 349 373 1 FAB: 385 374 2 FAB: 339.4 375 2 FAB: 339.28 376 2 FAB: 367.2 377 2 FAB: 381.2 378 2 FAB: 381.3 379 1 FAB: 377 380 1 FAB: 363 381 1 FAB: 365 382 1 FAB: 389 383 1 FAB: 417 384 1 FAB: 377 385 1 FAB: 381 386 1 FAB: 365 387 1 FAB: 417 388 1 FAB: 349 389 1 FAB: 347 390 1 FAB: 375 391 1 FAB: 339.3 392 1 ES: 339.3 393 1 ES: 339.3 394 1 ES: 339.3 395 1 FAB: 427 396 1 FAB: 375 397 1 ES: 347 398 1 ES: 355.4 399 1 ES: 355.3 400 1 ES: 357 401 1 ES: 383 402 1 FAB: 375 403 1 FAB: 321 404 1 FAB: 495 405 1 FAB: 441 406 1 FAB: 415 407 1 FAB: 361 408 1 FAB: 415 409 1 FAB: 375 410 1 ES: 395 411 1 FAB: 369 412 1 FAB: 389 413 1 FAB: 331 414 1 FAB: 375 415 1 ES: 375 416 1 FAB: 429 417 1 FAB: 401 418 1 FAB: 443 419 1 FAB: 415 420 1 FAB: 353

TABLE-US-00116 TABLE 116 Ex Syn Data 421 1 FAB: 401 422 1 FAB: 387 423 1 FAB: 401 424 1 FAB: 455 425 1 FAB: 407.2 426 1 FAB: 407.2 427 1 FAB: 375 428 1 FAB: 321 429 1 FAB: 389 430 1 FAB: 335 431 1 FAB: 429 432 1 FAB: 401 433 1 FAB: 407 434 1 FAB: 427 435 1 FAB: 355 436 1 FAB: 375 437 1 FAB: 355 438 1 ES: 361 439 1 FAB: 375 440 1 FAB: 385.4 441 1 FAB: 411 442 1 FAB: 357 443 1 FAB: 385.3 444 1 FAB: 391 445 1 ES: 355 446 1 ES: 355 447 1 FAB: 339 448 1 FAB: 355 449 1 FAB: 359 450 1 ES: 305 451 1 FAB: 345 452 1 FAB: 359 453 14 FAB: 339 454 14 FAB: 343 455 14 FAB: 355 456 1 ES: 343 457 14 FAB: 343 458 1 ES: 377.86 459 1 FAB: 377.2 460 1 ES: 363.81 461 1 FAB: 363.2 462 1 FAB: 345 463 1 FAB: 359 464 1 FAB: 339 465 1 FAB: 409 466 1 FAB: 359 467 1 FAB: 375 468 1 ES: 364.31 469 1 FAB: 363.2 470 1 FAB: 359 471 1 FAB: 377 472 1 FAB: 375 473 1 FAB: 361 474 1 FAB: 361 475 1 ES: 377 476 1 ES: 363 477 1 FAB: 385.4 478 1 ES: 365 479 1 ES: 375 480 1 ES: 377 481 1 ES: 403 482 1 ES: 349 483 1 ES: 345 484 1 ES: 397 485 1 ES: 343 486 1 ES: 393 487 1 ES: 339 488 1 ES: 399 489 1 ES: 362.13 490 1 FAB: 361.3 491 1 ES: 360.29 492 1 FAB: 359.3 493 1 FAB: 355 494 1 AP: 375.08 495 1 FAB: 375.2 496 1 ES: 367.3 497 1 FAB: 326 498 1 FAB: 432 499 1 ES: 448 500 1 FAB: 393

TABLE-US-00117 TABLE 117 Ex Syn Data 501 1 ES: 389 502 14 ES: 409 503 1 ES: 409 504 1 ES: 375 505 1 ES: 389 506 1 ES: 321 507 1 ES: 335 508 1 ES: 415 509 1 ES: 409 510 1 ES: 405 511 16 ES: 407 512 16 ES: 399 513 16 ES: 413 514 16 ES: 423 515 17 ES: 331 516 17 ES: 387 517 17 ES387 518 17 ES: 464 519 17 ES: 435 520 17 ES: 435 521 17 ES: 401 522 17 ES: 421 523 17 ES: 481 524 17 ES: 387 525 17 ES: 407 526 17 ES: 421 527 16 ES: 419 528 17 ES: 371 529 17 ES: 371 530 17 ES: 371 531 17 ES: 385 532 17 ES: 399 533 17 ES: 399 534 17 ES: 399 535 17 ES: 371 536 17 ES: 385 537 6 ES: 363 538 6 ES: 359 539 6 ES: 363 540 1 FAB: 407 541 1 FAB: 345 542 2 FAB: 359 543 1 ES: 353 544 2 FAB: 345 545 1 FAB: 331 546 1 APCI: 319.08 547 1 ES: 374.08 548 6 ES: 361 549 1 ES: 357 550 1 ES: 433 551 6 ES: 365 552 1 ES: 350 553 1 ES: 404 554 1 ES: 389 555 1 FAB: 419.3 556 1 FAB: 365.2 557 1 ES: 343 558 1 ES: 343 559 1 ES: 405 560 1 ES: 357 561 1 ES: 361.3 562 1 ES: 361.3 563 1 ES: 437 564 1 ES: 439 565 1 ES: 443 566 1 ES: 441 567 1 ES: 441 568 1 ES: 385.3 569 1 ES: 385.2 570 1 ES: 385.3 571 1 ES: 385.3 572 1 ES: 385.3 573 1 ES: 375.3 574 1 FAB: 375.2 575 1 FAB: 355 576 1 ES: 375.2 577 1 ES: 375.2 578 1 ES: 375.2 579 1 ES: 375.2

TABLE-US-00118 TABLE 118 Ex Data 14 NMR: 0.29-0.42(8H, m), 0.85-0.88(2H, m), 2.88-4.41(8H, m), 6.24 and 6.49(1H, s), 7.20-7.74(6H, m), 8.43 and 8.56(1H, m). 15 NMR: 1.03-2.53(19H, m), 2.93-3.01(4H, m), 3.57-3.72(2H, m), 3.99(1H, d, J = 16.2 Hz), 4.13(1H, d, J = 16.2 Hz), 5.11(1H, d, J = 9.6 Hz), 7.16-7.23(4H, m). 101 NMR: 1.01-1.73(11H, m), 2.86(2H, m), 3.58(1H, m), 3.67(1H, m), 3.97(1H, m), 4.12(1H, m), 5.11(1H, d, J = 6.9 Hz), 7.14-7.22(4H, m). 102 NMR: 1.03-1.72(16H, m), 2.79-3.01(4H, m), 3.59(1H, m), 3.68(1H, m), 3.78(1H, m), 4.03(1H, m), 4.16(1H, d, J = 12.0 Hz), 5.10(1H, d, J = 6.9 Hz), 7.16-7.22(4H, m). 103 NMR: 1.03-1.83(16H, m), 2.81-3.01(4H, m), 3.24(1H, m), 3.60(1H, m), 3.66(1H, m), 3.97-4.19(2H, m), 5.10(1H, d, J = 6.9 Hz), 7.15-7.23(4H, m). 104 NMR: 0.88-1.72(19H, m), 2.10(1H, m), 2.51-2.99(4H, m), 3.42(1H, m), 3.58(1H, m), 3.66(1H, m), 3.95(1H, d, J = 11.8 Hz), 4.11(1H, s), 4.28(1H, d, J = 11.8 Hz), 5.07(1H, m), 7.15-7.23(4H, m). 105 NMR: 1.00-1.76(25H, m), 2.22(1H, s, br), 2.98(2H, m), 3.72(2H, m), 3.94(1H, d, J = 12.0 Hz), 4.10(1H, d, J = 12.0 Hz), 5.11(1H, d, J = 6.9 Hz), 7.14-7.23(4H, m). 106 NMR: 1.00-2.03(19H, m), 2.87-2.99(4H, m), 3.34(1H, m), 3.66(1H, m), 4.04(1H, d, J = 12.1 Hz), 4.19(1H, d, J = 12.1 Hz), 5.10(1H, d, J = 7.5 Hz), 7.14-7.23(4H, m). 107 NMR: 0.97-1.66(11H, m), 2.85(2H, m), 3.46(2H, m), 3.67-3.77(3H, m), 4.27(2H, m), 5.10(1H, m), 7.13-7.21(4H, M), 7.34-7.43(5H, m). 108 NMR: 0.97-1.66(11H, m), 2.85(2H, m), 3.46(2H, m), 3.67-3.77(3H, m), 4.27(2H, m), 5.10(1H, m), 7.13-7.21(4H, M), 7.34-7.43(5H, m). 109 NMR: 1.04-1.70(11H, m), 2.77-4.24(7H, m), 5.12(1H, d, J = 6.9 Hz), 7.17-7.34(9H, m). 110 NMR: 1.04-1.70(11H, m), 2.77-4.24(7H, m), 5.12(1H, d, J = 6.9 Hz), 7.17-7.34(9H, m). 111 NMR: 1.02-1.68(21H, m), 2.82(2H, m), 2.98(2H, m), 3.56-3.67(2H, m), 3.97(1H, d, J = 16.4 Hz), 4.11(1H, d, J = 16.0 Hz), 5.11(1H, d, J = 9.2 Hz), 7.13(1H, m), 7.36(1H, m), 7.42(1H, m), 7.47(1H, d, J = 1.6 Hz). 112 NMR: 1.00-1.68(21H, m), 2.85(2H, m), 3.03(2H, m), 3.64(2H, m), 3.98(1H, d, J = 16.4 Hz), 4.12(1H, d, J = 16.0 Hz), 5.22(1H, d, J = 9.2 Hz), 7.41(1H, d, J = 8.0 Hz), 7.64(1H, m), 7.69(1H, m), 7.74(1H, s). 113 NMR: 1.02-1.67(21H, m), 2.86(2H, m), 2.98(2H, m), 3.56-3.68(2H, m), 3.98(1H, d, J = 16.0 Hz), 4.10(1H, d, J = 16.0 Hz), 5.12(1H, d, J = 9.6 Hz), 7.01(1H, m), 7.09(1H, m), 7.21(1H, m). 114 NMR: 1.03-1.64(11H, m), 2.77(2H, m), 3.17(2H, m), 3.20-4.11(2H, m), 4.64-4.70(1H, m), 5.05(1H, m), 5.28-5.34(1H, m), 7.07-7.23(14H, m). 115 NMR: 1.03-1.64(11H, m), 2.77(2H, m), 3.17(2H, m), 3.20-4.11(2H, m), 4.64-4.70(1H, m), 5.05(1H, m), 5.28-5.34(1H, m), 7.07-7.23(14H, m). 116 NMR: 0.99-1.68(21H, m), 2.85(1H, m), 2.98(1H, m), 3.56-3.67(1H, m), 3.98(1H, d, J = 16.2 Hz), 4.12(1H, d, J = 16.2 Hz), 5.12(1H, d, J = 9.2 Hz), 7.19-7.33(3H, m). 117 NMR: 1.01-1.72(11H, m), 2.95(2H, m), 3.26(2H, m), 3.46-3.67(3H, m), 4.03(1H, m), 4.17(1H, m), 4.75(1H, m), 5.12(1H, m), 7.16-7.22(4H, m), 7.32-7.38(5H, m).

TABLE-US-00119 TABLE 119 Ex Data 118 NMR: 1.01-1.72(11H, m), 2.95(2H, m), 3.26(2H, m), 3.46-3.67(3H, m), 4.03(1H, m), 4.17(1H, m), 4.75(1H, m), 5.12(1H, m), 7.16-7.22(4H, m), 7.32-7.38(5H, m). 119 NMR: 0.98-1.67(17H, m), 1.88(1H, m), 2.05(1H, m), 2.75(1H, m), 2.97(2H, m), 3.49-4.20(5H, m), 5.11(1H, d, J = 9.2 Hz), 7.12(1H, d, J = 8.4 Hz), 7.36(1H, m), 7.47(1H, s). 120 NMR: 1.03-1.68(17H, m), 1.88(1H, m), 2.05(1H, m), 2.77(1H, m), 2.97(2H, m), 3.48-4.21(5H, m), 5.11(1H, d, J = 9.2 Hz), 7.16-7.22(4H, m). 121 NMR: 1.03-4.77(34H, m), 5.14 and 5.18(1H, d, J = 8.8 Hz), 7.16-7.21(4H, m). 122 NMR: 1.03-1.68(11H, m), 2.77-4.25(11H, m), 5.14(1H, d, J = 10.0 Hz), 7.01-7.35(8H, m). 123 NMR: 1.03-1.71(11H, m), 2.78-4.25(11H, m), 5.14(1H, d, J = 9.2 Hz), 7.20-7.34(8H, m). 124 NMR: 0.97-1.69(20H, m), 2.77-4.29(9H, m), 5.12(1H, d, J = 9.2 Hz), 7.16-7.22(4H, m). 125 NMR: 0.84-1.70(20H, m), 2.97-4.18(9H, m), 5.12(1H, d, J = 9.2 Hz), 7.16-7.23(4H, m). 126 NMR: 1.07-1.81(17H, m), 2.86-2.98(4H, m), 3.38-3.70(2H, m), 3.85(4H, s), 4.00(1H, d, J = 16.0 Hz), 4.14(1H, d, J = 16.0 Hz), 5.11(1H, d, J = 9.6 Hz), 7.14-7.23(4H, m). 127 NMR: 0.85-1.70(20H, m), 2.51-3.04(3H, m), 3.56-4.22(6H, m), 5.12(1H, d, J = 9.2 Hz), 7.16-7.22(4H, m). 128 NMR: 1.03-4.77(34H, m), 5.14 and 5.18(1H, d, J = 8.8 Hz), 7.16-7.21(4H, m). 129 NMR: 1.01-1.68(21H, m), 2.68-2.99(7H, m), 3.65(2H, m), 4.10(1H, d, J = 16.2 Hz), 4.22(1H, d, J = 16.2 Hz), 5.11(1H, dmJ = 9.6 Hz), 7.11-7.22(4H, m). 130 NMR: 1.05-1.73(23H, m), 2.86-2.99(4H, m), 3.55-3.67(2H, m), 4.01(1H, d, J = 16.4 Hz), 4.14(1H, d, J = 16.4 Hz), 5.11(1H, d, J = 9.2 Hz), 7.16-7.23(4H, m). 132 NMR: 1.01-1.71(19H, m), 2.95-3.10(4H, m), 3.54(1H, m), 3.66(1H, m), 4.00(1H, d, J = 16.0 Hz), 4.14(1H, d, J = 16.0 Hz), 5.11(1H, d, J = 9.2 Hz), 7.14-7.23(4H, m). 133 NMR: 1.01-1.70(14H, m), 2.74-2.97(4H, m), 3.34-4.19(5H, m), 5.10(1H, d, J = 9.6 Hz), 7.16-7.22(4H, m). 134 NMR: 1.01-1.70(14H, m), 2.74-2.97(4H, m), 3.34-4.19(5H, m), 5.10(1H, d, J = 9.6 Hz), 7.16-7.22(4H, m). 135 NMR: 1.01-2.20(15H, m), 2.56-3.81(6H, m), 4.32(1H, d, J = 16.0 Hz), 4.40(1H, m), 4.49(1H, d, J = 16.0 Hz), 5.10(1H, d, J = 9.2 Hz), 7.15-7.23(4H, m). 136 NMR: 1.02-1.70(11H, m), 2.95-3.77(9H, m), 4.05(1H, d, J = 16.2 Hz), 4.17(1H, d, J = 16.2 Hz), 5.11(1H, d, J = 9.2 Hz), 7.14-7.22(4H, m). 137 NMR: 1.03-1.60(11H, m), 1.69(1H, m), 1.85(1H, m), 2.96-4.47(11H, m), 5.10(1H, d, J = 9.6 Hz), 7.14-7.22(4H, m). 138 NMR: 0.31(2H, m), 0.96-1.70(23H, m), 2.49-4.19(9H, m), 5.11(1H, m), 7.12-7.22(4H, m). 139 NMR: 1.06-1.69(21H, m), 2.83-2.96(4H, m), 3.19(3H, s), 3.49-4.20(.12H, m), 5.11(1H, d, J = 9.2 Hz), 7.14-7.21(4H, m). 140 NMR: 1.03-1.70(15H, m), 2.86-2.99(4H, m), 3.34-3.72(6H, m), 3.98(1H, d, J = 16.4 Hz), 4.11(1H, d, J = 16.4 Hz), 5.11(1H, d, J = 9.2 Hz)m7.14-7.22(4H, m).

TABLE-US-00120 TABLE 120 Ex Data 141 NMR: 0.99-1.97(25H, m), 2.84-3.89(11H, m), 5.18(1H, d, J = 9.6 Hz), 7.10-7.18(4H, m). 145 NMR: 1.00-1.67(17H, m), 2.84-2.97(4H, m), 3.24-3.67(6H, m), 5.13(1H, d, J = 9.6 Hz), 7.11-7.18(4H, m). 146 NMR: 1.03-1.67(11H, m), 2.83-3.97(11H, m), 4.02(1H, d, J = 16.2 Hz), 4.14(1H, d, J = 16.2 Hz), 5.11(1H, d, J = 9.6 Hz), 7.16-7.22(4H, m). 147 NMR: 0.87(3H, t, J = 7.2 Hz), 1.04-1.70(10H, m), 2.78(1H, m), 2.94-3.00(4H, m), 3.56-4.02(4H, m), 4.04(1H, d, J = 16.0 Hz), 4.17(1H, d, J = 16.0 Hz), 5.11(1H, d, J = 9.6 Hz), 7.16-7.23(4H, m). 152 NMR: 0.86(3H, t, J = 7.4 Hz), 1.00-1.70(13H, m), 2.50(1H, m), 2.92-3.71(6H, m), 4.01(1H, d, J = 16.0 Hz), 4.15(1H, d, J = 16.0 Hz), 5.11(1H, d, J = 9.2 Hz), 7.14-7.22(4H, m). 153 NMR: 1.00-1.67(14H, m), 2.50-3.75(9H, m), 5.12(1H, d, J = 9.2 Hz), 6.53(2H, s), 7.14-7.19(4H, m). 156 NMR: 1.07-1.96(15H, m), 2.85-5.19(13H, m), 7.10-7.47(4H, m). 157 NMR: 1.03-1.71(11H, m), 2.86-3.05(4H, m), 3.25-3.37(5H, m), 3.57-3.68(2H, m), 4.01(1H, m), 4.08(1H, d, J = 16.0 Hz), 4.19(1H, d, J = 16.0 Hz), 5.10(1H, d, J = 9.2 Hz), 5.58(1H, m), 7.16-7.22(4H, m), 8.75(1H, br). 158 NMR: 1.01-1.70(11H, m), 2.68-3.00(4H, m), 3.20(1H, m), 3.40(1H, m), 3.54(1H, m), 3.66(1H, m), 4.05(1H, d, J = 16.2 Hz), 4.22(1H, d, J = 16.2 Hz), 5.12(1H, d, J = 9.2 Hz), 6.69(2H, d, J = 8.0 Hz), 7.03(2H, d, J = 8.4 Hz), 7.16-7.23(4H, m). 159 NMR: 1.24-1.56(10H, m), 2.78-3.04(4H, m), 3.55(1H, m), 3.64(1H, m), 4.05(1H, d, J = 16.3 Hz), 4.16(1H, d, J = 16.3 Hz), 6.65(1H, s), 7.13-7.28(8H, m). 160 NMR: 1.09(3H, m), 2.74-2.82(2H, m), 2.90-3.01(2H, m), 3.52(1H, m), 3.65(1H, m), 3.96(1H, m), 4.09(1H, d, J = 16.0 Hz), 4.18(1H, m), 6.65(1H, s), 7.13-7.28(8H, m). 161 NMR: 2.84(1H, m), 6.98(1H, m), 3.27-3.37(5H, m), 3.98(1H, m), 4.10(1H, d, J = 16.1 Hz), 4.19(1H, m), 6.65(1H, s), 7.13-7.28(4H, m). 163 NMR: 1.15-1.55(10H, m), 2.67-3.04(4H, m), 3.63(2H, m), 4.04(1H, d, J = 16 Hz), 4.20(1H, d, J = 16 Hz), 6.66(1H, s), 7.26-7.37(4H, m), 7.43(2H, m), 7.80(2H, m). 164 NMR: 1.10(6H, d, J = 6 Hz), 2.67-3.03(4H, m), 3.62(2H, m), 3.96(1H, m), 4.09(1H, d, J = 16.8 Hz), 4.23(1H, m), 6.66(1H, s), 7.27-7.37(4H, m), 7.41(2H, m), 7.80(2H, m). 165 NMR: 1.23-1.57(10H, m), 2.72-3.02(4H, m), 3.56(1H, m), 3.69(1H, m), 3.92(1H, d, J = 16.4 Hz), 4.06(1H, d, J = 16.4 Hz), 6.73(1H, s), 7.24-7.31(4H, m), 7.47(1H, m), 7.55-7.58(2H, m), 7.64(1H, m). 166 NMR: 1.10(6H, m), 2.73-3.03(4H, m), 3.58(1H, m), 3.66(1H, m), 3.97(1H, m), 4.11(1H, d, J16.4 Hz), 4.24(1H, m), 6.72(1H, s), 7.25-7.30(4H, m), 7.48(1H, m), 7.55-7.59(2H, m), 7.65(1H, m). 167 NMR: 1.22-1.56(10H, m), 2.96-3.12(4H, m), 3.54(1H, m), 3.85(1H, m), 4.06(1H, d, J = 16.6 Hz), 4.13(1H, d, J = 16.6 Hz), 6.82(1H, s), 7.14-7.31(5H, m), 7.50-7.60(2H, m), 7.80(1H, m).

TABLE-US-00121 TABLE 121 Ex Data 171 NMR: 2.80(1H, m), 2.95-2.99(2H, m), 3.07(1H, m), 3.23-3.34(5H, m), 3.55(1H, m), 3.85(1H, m), 3.95(1H, m), 4.05-4.19(2H, m), 6.80(2H, m), 7.14-7.31(4H, m), 7.52(1H, m), 7.58(1H, m), 7.79(1H, d, J = 8 Hz). 172 NMR: 1.08(6H, d, J = 6.4 Hz), 2.74-4.21(9H, m), 6.73(1H, s), 7.11-7.34(7H, m). 173 NMR: 1.09-1.57(10H, m), 2.81-3.05(4H, m), 3.67-3.72(2H, m), 4.07(1H, d, J = 16.2 Hz), 4.15(1H, d, J = 16.2 Hz), 6.73(1H, s), 7.11-7.34(7H, m). 174 NMR: 1.07(6H, d, J = 76.4 Hz), 2.72(1H, m), 2.87(1H, m), 2.96-3.12(2H, m), 3.54(1H, m), 3.84-3.94(2H, m), 4.04-4.19(2H, m), 6.80-6.83(2H, m), 7.14-7.31(4H, m), 7.50-7.60(2H, m), 7.80(1H, d, J = 7.6 Hz). 175 NMR: 2.83-3.07(4H, m), 3.24-3.38(5H, m), 3.64-3.72(2H, m), 3.96(1H, m), 4.11-4.21(2H, m), 6.74(1H, s), 7.11-7.34(7H, m). 176 NMR: 0.98-1.70(14H, m), 2.72-2.99(4H, m), 3.61(2H, m), 3.96(1H, m), 4.01(1H, d, J = 16 Hz), 4.13(1H, d, J = 16 Hz), 5.01(1H, d, J = 9.6 Hz), 7.14(1H, d, J = 8.4 Hz), 7.35-7.47(2H, m). 177 NMR: 1.01-1.70(11H, m), 2.82-3.04(4H, m), 3.24-3.36(5H, m), 3.61(2H, m), 3.98(1H, m), 4.02(1H, d, J = 16 Hz), 4.14(1H, d, J = 16 Hz), 5.11(1H, d, J = 9.2 Hz), 7.14(1H, d, J = 8.4 Hz), 7.35-7.47(2H, m). 180 NMR: 1.97-1.68(11H, m), 2.86(2H, m), 2.99(2H, m), 3.26-3.41(5H, m), 3.62(1H, m), 3.73(1H, m), 3.98(1H, m), 4.09(1H, d, J = 16.2 Hz), 4.18(1H, d, J = 16.2 Hz), 5.13(1H, d, J = 9.6 Hz), 7.12-7.23(2H, m), 7.54(1H, d, J = 8 Hz). 181 NMR: 0.99-1.68(14H, m), 2.72-3.00(4H, m), 3.62(1H, m), 3.74(1H, m), 3.95(1H, m), 4.08(1H, d, J = 16 Hz), 4.17(1H, d, J = 16 Hz), 5.13(1H, d, J = 9.6 Hz), 7.12-7.23(2H, m), 7.54(1H, m). 182 NMR: 0.99-1.67(14H, m), 2.72-2.95(4H, m), 3.61(2H, m), 3.95(1H, m), 4.01(1H, d, J = 16 Hz), 4.13(1H, d, J = 16 Hz), 5.14(1H, d, J = 9.6 Hz), 7.19(1H, m), 7.39-7.43(2H, m). 183 NMR: 1.0.95-1.68(11H, m), 2.80-3.04(4H, m), 3.24-3.36(5H, m), 3.61(2H, m), 3.98(1H, m), 4.02(1H, d, J = 16 Hz), 4.14(1H, d, J = 16 Hz), 5.14(1H, d, J = 9.6 Hz), 7.19(1H, m), 7.38-7.42(2H, m). 204 NMR: 1.03-1.66(15H, m), 2.87-2.95(4H, m), 3.54-3.80(8H, m), 5.13(1H, d, J = 9.2 Hz), 6.56(2H, s), 7.12-7.19(4H, m). 205 NMR: 1.21-1.54(10H, m), 2.80-3.07(4H, m), 3.59(1H, m), 3.78(1H, m), 4.10(2H, m), 6.76(1H, s), 7.06-7.32(7H, m), 7.49(1H, d, J = 7.2 Hz). 206 NMR: 1.08(3H, d, J = 6.4 Hz), 2.70-3.07(4H, m), 3.58(1H, m), 3.79(1H, m), 3.94(1H, m), 4.14(2H, m), 6.76(1H, m), 7.04-7.32(7H, m), 7.49(1H, d, J = 7.6 Hz). 207 NMR: 2.81-3.04(4H, m), 3.24-3.35(5H, m), 3.57(1H, m), 3.78(1H, m), 3.95(1H, m), 4.15(2H, m), 6.76(1H, m), 7.05-7.32(7H, m), 7.49(1H, d, J = 8 Hz). 208 NMR: 1.23-1.54(10H, m), 2.38 and 2.48(3H, s), 2.81-4.41(8H, m), 6.15 and 6.43(1H, s), 6.83 and 7.10(1H, d, J = 7.6 Hz), 7.18-7.32(5H, m), 7.62-7.68(1H, m). 211 NMR: 1.10(3H, d, J = 7.2 Hz), 2.74-2.99(4H, m), 3.59-3.64(4H, m), 3.97(1H, m), 4.10(1H, d, J = 16.4 Hz), 4.23(1H, m), 6.63(1H, s), 7.00-7.38(4H, m).

TABLE-US-00122 TABLE 122 Ex Data 212 NMR: 1.240-1.58(10H, m), 2.77-3.02(4H, m), 3.63(2H, m), 4.06(1H, d, J = 16 Hz), 4.22(1H, d, J = 16 Hz), 6.63(1H, s), 7.01-7.38(8H, m). 220 NMR: 1.24-1.58(10H, m), 2.77-3.05(4H, m), 3.57-3.66(2H, m), 4.06(1H, d, J = 16.2 Hz), 4.22(1H, d, J = 16.2 Hz), 6.63(1H, s), 7.13-7.41(8H, m). 221 NMR: 1.10(3H, d, J = 6.4 Hz), 2.74-3.04(4H, m), 3.56-3.66(2H, m), 3.97(1H, m), 4.10(1H, d, J = 16.4 Hz), 4.23(1H, m), 6.63(1H, s), 7.11-7.39(8H, m). 222 NMR: 2.78-3.09(4H, m), 3.27-3.37(7H, m), 3.58-3.63(2H, m), 3.99(1H, m), 4.10(1H, d, J = 16.4 Hz), 4.23(1H, m), 6.63(1H, s), 6.99-7.37(8H, m). 223 NMR: 2.78-3.09(4H, m), 3.27-3.37(7H, m), 3.56-3.66(2H, m), 3.99(1H, m), 4.11(1H, d, J = 16.4 Hz), 4.24(1H, m), 6.64(1H, s), 7.11-7.39(8H, m). 224 NMR: 0.79-1.67(21H, m), 2.82-2.99(4H, m), 3.58-3.69(2H, m), 3.99(1H, d, J = 16.4 Hz), 4.12(1H, d, J = 16.4 Hz), 5.32(1H, d, J = 9.6 Hz), 7.15-7.23(4H, m). 226 NMR: 0.81-0.89(6H, m), 1.09(3H, m), 1.24-1.41(4H, m), 1.67(1H, m), 2.72-2.99(4H, m), 3.60-3.66(2H, m), 3.95(1H, m), 4.02(1H, d, J = 16.2 Hz), 4.14(1H, d, J = 16.2 Hz), 5.32(1H, d, J = 8.8 Hz), 7.17-7.23(4H, m). 227 NMR: 0.80-0.88(6H, m), 1.24-1.41(4H, m), 1.66(1H, m), 2.79-3.02(4H, m), 3.24-3.35(7H, m), 3.95(1H, m), 3.99(1H, d, J = 16.4 Hz), 4.10(1H, d, J = 16.4 Hz), 5.32(1H, d, J = 8.8 Hz), 7.15-7.23(4H, m). 231 NMR: 1.23-1.54(10H, m), 2.81-3.01(4H, m), 3.33-4.46(4H, m), 6.22 and 6.50(1H, s), 7.13-8.58(8H, m). 232 NMR: 1.07-1.10(3H, m), 2.75-3.02(4H, m), 3.69(1H, m), 3.92-3.98(2H, m), 4.12(1H, m), 4.23(1H, m), 6.43(1H, s), 7.20-7.34(4H, m), 7.52(1H, d, J = 7.6 Hz), 7.60(1H, m), 7.74(1H, m). 233 NMR: 1.24-1.55(10H, m), 2.79-3.01(4H, m), 3.68(1H, m), 3.94(1H, m), 4.06(1H, d, J = 16.2 Hz), 4.18(1H, d, J = 16.2 Hz), 6.43(1H, s), 7.20-7.34(4H, m), 7.51(1H, d, J = 8 Hz), 7.59(1H, d, J = 7.6 Hz), 7.74(1H, m). 234 NMR: 1.08-1.11(3H, m), 2.75-3.02(4H, m), 3.69(1H, m), 3.92-3.98(2H, m), 4.12(1H, d, J = 16 Hz), 4.23(1H, m), 6.44(1H, s), 7.20-7.40(4H, m), 7.56(1H, d, J = 7.6 Hz), 7.83-7.87(2H, m). 235 NMR: 1.23-1.55(10H, m), 2.82-3.02(4H, m), 3.68(1H, m), 3.95(1H, m), 4.09(1H, d, J = 16.6 Hz), 4.22(1H, d, J = 16.6 Hz), 6.45(1H, s), 7.21-7.40(5H, m), 7.57(1H, d, J = 7.2 Hz), 7.85(1H, m). 236 NMR: 1.08(3H, d, J = 6.4 Hz), 2.73-3.07(4H, m), 3.58(1H, m), 3.73(1H, m), 3.95(1H, m), 4.13(2H, m), 6.82 and 6.83(1H, s), 7.01-7.46(8H, m). 237 NMR: 2.81-3.07(4H, m), 3.23-3.35(5H, m), 3.58(1H, m), 3.72(1H, m), 3.97(1H, m), 4.14(2H, m), 6.82 and 6.83(1H, s), 7.00-7.46(8H, m). 238 NMR: 1.08-1.11(3H, m), 2.76-3.00(4H, m), 3.68-4.35(8H, m), 6.23-7.33(9H, m). 239 NMR: 2.86-3.10(4H, m), 3.26-3.35(5H, m), 3.35-4.33(8H, m), 6.23-7.32(8H, m). 240 NMR: 1.09(3H, d, J = 6.4 Hz), 2.68-3.06(4H, m), 3.60(1H, m), 3.87-3.95(2H, m), 4.06-4.21(2H, m), 6.63 and 6.65(1H, s), 6.79(1H, m), 7.02(1H, m), 7.18(1H, m), 7.25-7.39(3H, m), 7.89(1H, m).

TABLE-US-00123 TABLE 123 Ex Data 241 NMR: 2.76-3.06(4H, m), 3.23-3.34(5H, m), 3.59(1H, m), 3.86-3.95(2H, m), 4.09 and 4.11(1H, d, J = 16.2 Hz), 4.19(1H, d, J = 16.8 Hz), 6.63 and 6.66(1H, s), 6.80(1H, m), 7.03(1H, m), 7.18(1H, m), 7.25-7.39(3H, m), 7.89(1H, m). 242 NMR: 1.08(3H, d, J = 6.4 Hz), 1.29(3H, m), 2.75-4.32(11H, m), 6.70(1H, s), 6.85-7.25(8H, m). 243 NMR: 1.29(3H, m), 2.85-4.18(16H, m), 6.71(1H, s), 6.85-7.25(8H, m). 244 NMR: 1.26-1.57(10H, m), 2.86-3.01(4 Hm), 3.65(1H, m), 3.99(1H, m), 4.12(1H, d, J = 16.2 Hz), 4.25(1H, d, J = 16.2 Hz), 6.47(1H, s), 7.20-7.43(5H, m), 7.74(1H, m), 8.43(1H, d, J = 5.2 Hz). 245 NMR: 1.09(3H, d, J = 6.4 Hz), 2.75-3.00(4H, m), 3.66(1H, m), 3.94-3.98(2H, m), 4.12(1H, d, J = 16.2 Hz), 4.22 and 4.24(1H, d, J = 16.2 Hz), 6.47(1H, s), 7.20-7.43(5H, m), 7.72(1H, m), 8.43(1H, d, J = 5.2 Hz). 246 NMR: 1.08(3H, d, J = 5.6 Hz), 1.25(3H, t, J = 7.4 Hz), 2.72-3.11(6H, m), 3.38(1H, m), 3.71(1H, m), 3.96(1H, m), 4.12(2H, m), 6.66(1H, d, J = 7.6 Hz), 6.84(1H, s), 6.94(1H, d, J = 8 Hz), 7.07(1H, m), 7.16(1H, m), 7.22-7.29(4H, m). 247 NMR: 1.25(3H, t, J = 7.6 Hz), 2.72-3.11(7H, m), 3.26(3H, s), 3.32-3.37(2H, m), 3.70(1H, m), 3.98(1H, m), 4.13(2H, m), 6.66(1H, d, J = 7.6 Hz), 6.85(1H, s), 6.94(1H, d, J = 7.6 Hz), 7.07(1H, m), 7.16(1H, m), 7.22-7.29(4H, m). 248 NMR1: 2.93(2H, t, J = 6.8 Hz), 3.72(3H, s), 3.77(2H, m), 6.86(1H, m), 7.1(1H, m), 7.23-7.36(5H, m), 7.92(1H, m). 251 NMR1: 2.75(2H, t, J = 7 Hz), 3.50(2H, m), 3.56(3H, s), 5.27(1H, br), 7.04(2H, m), 7.20-7.31(5H, m), 7.56(2H, m). 252 NMR: 1.08(2H, d, J = 6.4 Hz), 5.23(3H, s), 2.62-4.21(9H, m), 6.78(1H, s), 6.91(1H, m), 7.01(1H, m), 7.07(1H, m), 7.14-7.29(4H, m), 7.38(1H, d, J = 8 Hz). 253 NMR: 2.53(3H, s), 2.62-4.22(14H, m), 6.77 and .78(1H, s), 6.90(1H, m), 7.01(1H, m), 7.07(1H, m), 7.14-7.30(4H, m), 7.38(1H, d, J = 8 Hz). 254 NMR: 2.73-4.34(15H, m), 6.63 and 6.64(1H, s), 6.92(1H, m), 7.02-7.07(2H, m), 7.14-7.28(4H, m). 255 NMR: 2.82-4.35(17H, m), 6.63 and 6.4(1H, s), 6.91(1H, m), 7.00-7.28(6H, m). 275 NMR: 1.04(3H, d, J = 6.4 Hz), 2.49-4.02(11H, m), 5.68(1H, m), 7.18-7.73(8H, m). 276 NMR: 2.51-4.05(16H, m), 5.68(1H, m), 7.20-7.71(8H, m). 277 NMR: 1.23-1.56(10H, m), 2.79-3.80(6H, m), 4.11(2H, m), 6.67(1H, s), 7.13(1H, d, J = 8 Hz), 7.19-7.38(4H, m), 7.59(1H, m), 8.33(1H, m). 279 NMR: 2.57-4.03(16H, m), 5.71(1H, m), 7.04(1H, m), 7.18-7.27(3H, m), 7.34(1H, m), 7.43(1H, m), 7.54(1H, m), 7.68(1H, m). 304 NMR: 0.99-1.05(3H, m), 2.17-4.46(11H, m), 5.09 and 5.68(1H, m), 7.19-7.71(8H, m). 305 NMR: 2.26-4.90(16H, m), 5.10 and 5.66(1H, m), 5.18-7.70(8H, m). 306 NMR: 2.74-4.15(19H, m), 6.26 and 6.75(1H, s), 6.67-7.31(8H, m). 307 NMR: 2.74-4.15(19H, m), 6.26 and 6.75(1H, s), 6.67-7.31(8H, m).

TABLE-US-00124 TABLE 124 Ex Data 311 NMR: 1.08-1.10(3H, m), 2.73-4.35(12H, m), 6.23 and 6.74(1H, s), 6.64-7.33(8H, m). 312 NMR: 2.88-4.35(11H, m), 4.93-4.95(1H, m), 6.22 and 6.75(1H, s), 6.64-7.38(13H, m). 325 NMR: 1.40-1.54(10H, m), 2.84-2.99(3H, m), 3.62-3.76(1H, m), 3.80 and 3.93(3H, s), 4.06-4.35(4H, m), 6.23 and 6.73(1H, s), 6.66-7.33(8H, m). 327 NMR: 1.03-1.11(3H, m), 2.72-3.21(8H, m), 3.74-4.30(6H, m), 6.33 and 6.76(1H, s), 6.86-7.30(8H, m). 328 NMR: 2.87-4.35(11H, m), 4.93(1H, m), 6.26 and 6.74(1H, s), 6.64-7.38(13H, m). 329 NMR: 1.08-1.11(3H, m), 2.74-3.01(4H, m), 3.63-4.34(8H, m), 6.25 and 6.73(1H, s), 6.63-7.32(8H, m). 330 NMR: 1.47-1.93(6H, m), 2.87-3.79(4H, m), 3.79 and 3.93(3H, s), 4.01-4.36(4H, m), 6.29 and 6.74(1H, s), 6.65-7.33(8H, m). 331 NMR: 1.45-2.00(6H, m), 2.88-3.76(4H, m), 3.79 and 3.92(3H, s), 3.96-4.35(4H, m), 6.29 and 6.74(1H, s), 6.69-7.32(8H, m). 337 NMR: 2.80-3.21(4H, m), 3.24 and 3.31(3H, s), 3.54-5.58(8H, m), 7.19-7.37(9H, m). 346 NMR: 1.23-1.55(10H, m), 2.79-3.22(4H, m), 3.25 and 3.32(3H, s), 3.55-4.52(6H, m), 5.06 and 5.58(1H, m), 7.18-7.32(4H, m). 349 NMR: 1.08-1.10(3H, m), 2.72-4.35(12H, m), 6.23 and 6.74(1H, s), 6.64-7.33(8H, m). 354 NMR: 1.35-4.56(24H, m), 5.15 and 5.60(1H, m), 7.20-7.33(4H, m). 358 NMR: 1.44-1.47(2H, m), 1.64-1.79(10H, m), 2.17-2.20(2H, m), 2.81-4.52(13H, m), 5.06 and 5.58(1H, m), 7.18-7.31(4H, m). 359 NMR: 0.30-0.43(8H, m), 0.85-0.88(2H, m), 2.82-4.52(13H, m), 5.08 and 5.59(1H, m), 7.19-7.31(4H, m). 360 NMR: 1.44-2.20(14H, m), 2.79-4.43(15H, m), 4.82 and 5.54(1H, m), 7.16-7.22(4H, m). 361 NMR: 0.29-0.43(8H, m), 0.85-0.90(2H, m), 1.90-4.42(15H, m), 4.83 and 5.53(1H, m), 7.16-7.22(4H, m). 370 NMR: 0.28-0.42(8H, m), 0.85-0.88(2H, m), 2.89-3.16(4H, m), 3.63-4.35(7H, m), 6.24 and 6.74(1H, s), 6.69-7.33(8H, m). 371 NMR: 0.77-0.82(6H, m), 1.41-1.48(4H, m), 2.78-3.01(4H, m), 5.47 and 3.65(1H, m), 3.97-4.39(3H, m), 6.25 and 6.48(1H, s), 7.21-7.73(6H, m), 8.43 and 8.55(1H, m). 372 NMR: 0.78-0.83(6H, m), 1.44-1.50(4H, m), 1.89-2.06(2H, m), 2.79-4.42(13H, m), 4.83 and 5.53(1H, m), 7.16-7.22(4H, m). 373 NMR: 1.45-4.85(25H, m), 5.26 and 5.57(1H, m), 7.21-7.32(4H, m). 379 NMR: 0.30-0.43(8H, m), 0.87-0.90(2H, m), 2.77-4.52(13H, m), 5.07 and 5.58(1H, m), 7.04-7.11(2H, m), 7.34-7.40(1H, m). 380 NMR: 0.86-0.94(12H, m), 1.84-1.89(2H, m), 2.80-4.52(13H, m), 5.05 and 5.58(1H, m), 7.18-7.32(4H, m). 381 NMR: 1.24-1.55(10H, m), 2.83-4.51(13H, m), 5.07 and 5.57(1H, m), 7.05-7.08(2H, m), 7.34-7.39(1H, m). 383 NMR: 1.44-1.77(12H, m), 2.17-2.20(2H, m), 2.78-4.52(13H, m), 5.07 and 5.58(1H, m), 7.05-7.09(2H, m), 7.35-7.38(1H, m).

TABLE-US-00125 TABLE 125 Ex Data 384 NMR: 0.28-0.44(8H, m), 0.87-0.90(2H, m), 2.68-4.53(13H, m), 5.08 and 5.59(1H, m), 7.06-7.25(3H, m). 385 NMR: 0.85-0.94(12H, m), 1.84-1.89(2H, m), 2.78-4.51(13H, m), 5.06 and 5.58(1H, m), 7.05-7.08(2H, m), 7.35-7.38(1H, m). 386 NMR: 1.27-1.55(10H, m), 2.68-4.48(13H, m), 5.08 and 5.59(1H, m), 7.04-7.12(1H, m), 7.19-7.25(2H, m). 387 NMR: 1.44-1.79(12H, m), 2.17-2.20(2H, m), 2.69-4.53(13H, m), 5.07 and 5.59(1H, m), 7.06-7.10(1H, m), 7.20-7.26(2H, m). 395 NMR: 1.13-1.78(18H, m), 2.18(2H, m), 2.88-3.16(7H, m), 3.65(1H, m), 3.85(1H, m), 4.04(1H, d, J = 16.6 Hz), 4.15(1H, d, J = 16.6 Hz), 5.45(1H, s), 7.14-7.30(4H, m). 396 NMR: 1.12-1.57(16H, m), 2.81-3.07(7H, m), 3.66(1H, m), 3.84(1H, m), 4.04(1H, d, J = 16.2 Hz), 4.15(1H, d, J = 16.2 Hz), 5.44(1H, s), 7.14-7.30(4H, m). 397 NMR: 1.13-2.02(12H, m), 2.83-3.16(7H, m), 3.69-4.23(4H, m), 5.44(1H, s), 7.14-7.31(4H, m). 400 NMR: 1.01-1.07(3H, m), 2.26-4.43(10H, m), 5.00 and 5.69(1H, m), 7.05-7.40(8H, m). 401 NMR: 1.25-1.94(6H, m), 2.70-4.46(10H, m), 5.02 and 5.67(1H, m), 7.07-7.26(8H, m). 409 NMR: 1.14-1.57(13H, m), 2.53-4.50(15H, m), 5.06 and 5.55(1H, m), 7.05-7.12(4H, m). 410 NMR: 1.25-1.94(6H, m), 2.38-4.47(13H, m), 4.98 and 5.72(1H, m), 6.79-7.29(8H, m). 411 NMR: 1.02-1.06(3H, m), 2.23-4.38(14H, m), 4.96 and 5.72(1H, m), 6.79-7.29(8H, m). 415 NMR: 0.86-0.94(6H, m), 1.15-1.62(10H, m), 1.88-2.04(1H, m), 2.60-5.04(12H, m), 6.52(2H, s), 6.72-6.79(2H, m), 7.06-7.12(1H, m). 420 NMR: 1.00-1.08(3H, m), 2.10-4.51(14H, m), 4.95 and 5.59(1H, m), 6.83-7.28(8H, m). 421 NMR: 1.03(3H, d, J = 7.2 Hz), 2.58-2.95(4H, m), 3.76-3.88(2H, m), 4.13(1H, d, J = 16 Hz), 4.18(1H, d, J = 16 Hz), 6.61(1H, d, J = 7.2 Hz), 7.06-7.32(13H, m). 422 NMR: 2.67-2.97(4H, m), 3.38(2H, m), 3.80(2H, m), 4.19(2H, s), 6.61(1H, d, J = 8 Hz), 7.06-7.32(13H, m). 433 NMR: 0.99-1.11(3H, m), 2.12-4.53(13H, m), 4.94 and 5.72(1H, m), 7.03-7.80(8H, m). 434 NMR: 0.99-1.11(3H, m), 2.12-4.53(11H, m), 4.94 and 5.71(1H, m), 7.03-7.80(8H, m). 436 NMR: 1.14-1.55(13H, m), 2.49-4.50(15H, m), 5.08 and 5.56(1H, m), 7.05-7.12(3H, m). 439 NMR: 1.14-1.56(13H, m), 2.49-4.50(15H, m), 5.07 and 5.56(1H, m), 7.05-7.12(3H, m). 497 NMR: 1.09-1.10(3H, m), 2.75-3.00(4H, m), 3.37-4.48(4H, m), 6.22 and 6.50(1H, s), 7.12-8.58(8H, m).

In addition, structures of other compounds of the present invention are shown in Tables 126 and 127. It is possible to easily produce these compounds according to the above-mentioned methods described in production processes and Examples, and methods obvious to a person skilled in the art, or modifications thereof.

Further, in the Tables, No represents a number of the compound.

TABLE-US-00126 TABLE 126 No Structure 1 ##STR00650## 2 ##STR00651## 3 ##STR00652## 4 ##STR00653## 5 ##STR00654## 6 ##STR00655## 7 ##STR00656## 8 ##STR00657## 9 ##STR00658## 10 ##STR00659## 11 ##STR00660## 12 ##STR00661## 13 ##STR00662## 14 ##STR00663##

TABLE-US-00127 TABLE 127 No Structure 15 ##STR00664## 16 ##STR00665## 17 ##STR00666## 18 ##STR00667## 19 ##STR00668## 20 ##STR00669## 21 ##STR00670## 22 ##STR00671## 23 ##STR00672## 24 ##STR00673## 25 ##STR00674##

The analysis results of several compounds of Production Examples by chiral column chromatography are shown in Tables 128 and 129

In addition, in the Tables, RT represents a retention time (min) and OP represents an optical purity (% ee).

TABLE-US-00128 TABLE 128 Rex Condition RT OP 20 Column: DAICEL CHIRALPAK AD-RH 4.6 .times. 150 mm 18.22 >99.5 Detection: UV: 230 nm Flow rate: 0.5 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 60/40 Column temperature: 40.degree. C. 21 Column: DAICEL CHRALPAK AS-RH 4.6 .times. 150 mm 24.11 >99.5 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 50/50 Column temperature: 40.degree. C. 22 Column: DAICEL CHRALCEL OJ-RH 4.6 .times. 150 mm 9.24 99.20 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer (pH 9)/MeCN = 70/30 Column temperature: 40.degree. C. 81 Column: DAICEL CHRALPAK AS-RH 4.6 .times. 150 mm 15.95 >99 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 45/55 Column temperature: 40.degree. C. 82 Column: DAICEL CHRALCEL OJ-RH 4.6 .times. 150 mm 43.39 92 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 70/30 Column temperature: 40.degree. C. 83 Column: DAICEL CHRALCEL OD-RH 4.6 .times. 150 mm 52.48 98 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 20/80 Column temperature: 40.degree. C. 513 Column: DAICEL CHRALCEL OD-RH 4.6 .times. 150 mm 60.99 97.40 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 20/80 Column temperature: 40.degree. C. 547A Column: DAICEL CHIRALPAK AD-RH 4.6 .times. 150 mm 15 95 Detection: UV: 230 nm Flow rate: 0.5 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 60/40 Column temperature: 40.degree. C.

TABLE-US-00129 TABLE 129 Rex Condition RT OP 566 Column: DAICEL CHRALCEL OJ-RH 4.6 .times. 150 mm 11.28 98.30 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 70/30 Column temperature: 40.degree. C. 567 Column: DAICEL CHRALCEL OD-RH 4.6 .times. 150 mm 28.60 >99 Detection: UV230 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 45/55 Column temperature: 40.degree. C. 570 Column: DAICEL CHRALCEL OD-RH 4.6 .times. 150 mm 36.76 >99 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 60/40 Column temperature: 40.degree. C. 572 Column: DAICEL CHRALPAK AS-RH 4.6 .times. 150 mm 20.86 >99.5 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 50/50 Column temperature: 40.degree. C. 575 Column: DAICEL CHRALPAK AS-RH 4.6 .times. 150 mm 17.02 >99 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 45/55 Column temperature: 40.degree. C. 576 Column: DAICEL CHRALCEL OD-RH 4.6 .times. 150 mm 22.72 >99 Detection: UV230 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 45/55 Column temperature: 40.degree. C. 650 Column: DAICEL CHRALCEL OD-RH 4.6 .times. 150 mm 25.06 >99 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 65/35 Column temperature: 40.degree. C. 652 Column: DAICEL CHRALCEL OD-RH 4.6 .times. 150 mm 26.7 >99 Detection: UV210 nm Flow rate: 0.8 mL/min Eluent: 20 mM Phosphate buffer(pH 9)/MeCN = 65/35 Column temperature: 40.degree. C.

INDUSTRIAL APPLICABILITY

The compound of the present invention can be used as a pharmaceutical composition for preventing and/or treating various pains including neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, central nervous system diseases such as anxiety, depression, epilepsy, cerebral stroke and restless legs syndrome, abdominal symptoms such as abdominal pain and abdominal distension, stool abnormalities such as diarrhea and constipation, digestive system diseases such as irritable bowel syndrome, urinary system diseases such as overactive bladder and interstitial cystitis, etc.