Piperidine compounds and their preparation and use
Märksõnad
Patendiinfo
| Patendi number | 5019582 |
| Esitatud | 09/13/1989 |
| Patendi kuupäev | 05/27/1991 |
Abstraktne
Nõuded
We claim:
1. A piperidine compound selected from those having the formula I ##STR15## wherein R.sup.3 is 3,4-methylenedioxyphenyl, naphthyl or phenyl which may be substituted with one or more C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, C.sub.3-8 -cycloalkyl, C.sub.3-5 -alkylene, or benzyloxy groups, R.sup.1 is straight or branched C.sub.5-8 -alkyl, C.sub.4-8 -alkenyl, C.sub.4-7 -cycloalkyl, C.sub.4-8 -cycloalkylalkyl, phenyllower-alkyl, phenyloxylower-alkyl, and lower-alkoxy-lower-alkyl,
X is hydrogen or 4-fluoro and wherein
Y is O or S,
and a salt thereof with a pharmaceutically-acceptable acid.
2. A compound of claim 1 which is (-)-trans-4-(-4-fluorocyclopentyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-p entylpiperidine hydrochloride.
3. A compound of claim 1 which is (+)-trans-4-phenyl-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine hydrochloride.
4. A compound of claim 1 which is (-)-trans-4-(-4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-1-pentylpiperidin e hydrochloride.
5. A compound of claim 1 which is (-)-trans-4(-4-fluorophenyl)-3-(5,6,7,8-tetrahydro-2-naphthoxymethyl)-1-pe ntylpiperidine hydrochloride.
6. A pharmaceutical composition suitable for use in preventing calcium overload in brain cells of mammals, including humans, comprising an amount of a compound of claim 1, which is effective for inhibiting calcium uptake into brain cells, together with a pharmaceutically-acceptable carrier or diluent.
7. A pharmaceutical composition according to claim 6 in the form of an oral dosage unit containing 1-100 mg of the active compound.
8. A compound of claim 1 which is (-)-trans-4-(4-fluorophenyl)-3(3,4-methylenedioxyphenoxymethyl)-1-pentylpi peridine or a pharmaceutically-acceptable salt thereof.
9. A compound of claim 1 which is (-)-trans-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylp iperidinee hydrochloride.
Kirjeldus
The invention will now be described in further detail with reference to the following examples:
Example 1
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylp iperidine hydrochloride
10g of (-)-trans-4-(-4-fluorophenyl)-3,4-methylenedioxyphenoxymethyl)-piperidine hydrochloride in 250 ml 99.9% ethanol was mixed with 50 ml 1-bromopentane and 20 g potassium carbonate. The mixture was refluxed for 3 hours and was subsequently cooled to room temperature. 25 ml acetone and 25 ml diethylether was added to the solution. The precipitate was filtered off and the filtrate was evaporated in vacuo. 20 ml 4N NaOH was added to the residue, and the resulting mixture was extracted 3 times with diethyl ether. The combined ether phases were dried over potassium carbonate, filtered, the filtrate was acidified with conc. hydrochloric acid to pH 2, and the filtrate was evaporated in vacuo. The resulting oil was dissolved in acetone and crystals precipitated by addition of ether and after cooling at 4.degree. C. over night. The title compound was filtered off and dried giving 10.1 g of the title compound. M.p. 153.6.degree. C.
The following compounds were prepared in exactly the same manner from (-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylendioxyphenoxymethyl)-piperidin e hydrochloride and the corresponding alkyl bromide, alkoxyalkyl bromide, cycloalkyl bromide, aryloxyalkyl bromide, or alkenyl bromide.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-ethylpi peridine hydrochloride M.p. 237.degree.-238.degree. C. by refluxing the reaction mixture for 24 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-propylp iperidine hydrochloride M.p. 198.3.degree. C. by refluxing the reaction mixture for 7 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-butylpi peridine hydrochloride M.p. 190.degree.-191.degree. C. by refluxing the reaction mixture for 7 hours.
(-)-trans-4-(-4-fluoropheny1)-3-(3,4-methylenedioxyphenoxymethyl)-1-octylpi peridine hydrochloride M.p. 167.3.degree. C. by refluxing the reaction mixture for 72 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3 4-methylenedioxyphenoxymethyl)-1-isopentylpiperidine hydrochloride M.p. 152.620 C. by refluxing the reaction mixture for 6 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(4-phen oxybutyl)-piperidine hydrochloride as an oil by refluxing the reaction mixture for 240 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-hexylpi peridine hydrochloride M.p. 107.1.degree. C. by refluxing the reaction mixture for 24 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(3-phen ylpropyl)-piperidine hydrochloride as an oil by refluxing the reaction mixture for 3.5 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(2-ethy lhexyl)-piperidine hydrochloride as an oil by refluxing the reaction mixture for 240 hours.*
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(3,3-di methylbutyl)-piperidine hydrochloride M.P. 226.7.degree. C. by refluxing the reaction mixture for 336 hours *
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-cyclohe xyl-piperidine hydrochloride M.p. 140.2.degree. C. by refluxing the reaction mixture for 330 hours.*
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-heptyl- piperidine hydrochloride M.p. 146.8.degree. C. by refluxing the reaction mixture for 6 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-cyclope ntyl-piperidine hydrochloride M.p. 227.7.degree. C. by refluxing the reaction mixture for 7 hours.
(-)--trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-allyl- piperidine hydrochloride M.p. 162.2.degree. C. by refluxing the reaction mixture for 24 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(2,4-methylenedioxyphenoxymethyl)-1-cyclopr opylmethylpiperidine hydrochloride M.p. 175.5.degree. C. by refluxing the reaction mixture for 24 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-cyclohe ptyl-piperidine hydrochloride as an glas M.p. 53.7.degree. C. by refluxing the reaction mixture for 190 hours.* and **
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(2-etho xyethyl)-piperidine hydrochloride as an glass M.p. 49.5.degree. C. by refluxing the reaction mixture for 6 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(2-meth oxymethyl)-piperidine hydrochloride M.p. 164.7.degree. C. by refluxing the reaction mixture for 48 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(2-tran s-butenyl)-piperidine hydrochloride M.p. 195.5.degree. C. by refluxing the reaction mixture for 3 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(3-bute nyl)-piperidine hydrochloride M.p. 198.6.degree. C. by refluxing the reaction mixture for 288 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(5-hexe nyl)-piperidine hydrochloride M.p. 123.degree. C. by refluxing the reaction mixture for 3 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(4-pent enyl)-piperidine hydrochloride M.p. 177.7.degree. C. by refluxing the reaction mixture for 3 hours.
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(3-meth yl-butenyl)-piperidine hydrochloride M.p. 239.2.degree. C. by refluxing the reaction mixture for 4.5 hours.
(-)-cis-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpip eridine hydrochloride M.p. 195.3.degree. C. and (+)-cis-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpi peridine hydrochloride M.p. 193.7.degree. C. were prepared exactly as described above from pentyl bromide, and (-)-cis-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine hydrochloride and (+)-cis-4-(-4-fluorophenyl)-3-(3,4-methylendioxyphenoxymethyl)-piperidine hydrochloride respectively.
Example 2
(-)-trans-1-butyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride
(-)-trans-1-butyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride M.p. 163.degree.-165.degree. C. was prepared exactly as described in Example 1 from (-)-trans-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride and butyl bromide by refluxing for 120 hours.
The following compounds were prepared in exactly the same manner from (-)-trans-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride and the corresponding alkyl bromide or cycloalkyl bromide.
(-)-trans-1-propyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride M.p. 196.degree.-197.degree. C. by refluxing the reaction mixture for 7 hours.
(-)-trans-1-ethyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride M.p. 190.degree.-191.degree. C. by refluxing the reaction mixture for 170 hours.
(-)-trans-1-isopropyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperid ine hydrochloride as an oil by refluxing the reaction mixture for 210 hours.
(-)-trans-1-(2-(4-methoxyphenoxyethyl))-4-(4-fluorophenyl)-3-(4-methoxyphen oxymethyl)-piperidine hydrochloride as an oil by refluxing the reaction mixture for 48 hours.
(-)-trans-1-pentyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride as a glass M.p. 53.5.degree. C. by refluxing the reaction mixture for 8 hours.
(-)-trans-1-heptyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride M.p. 138.1.degree. C. by refluxing the reaction mixture for 8 hours.
(-)-trans-1-cyclohexyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperi dine hydrochloride M.p. 220.3.degree. C. by refluxing the reaction mixture for 330 hours.**
Example 3
trans-1-propyl-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride
trans-1-propyl-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride M.p. 221.degree. C. was prepared exactly as described in example 1 from trans-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride and propyl bromide by refluxing for 96 hours.
The following compounds were prepared in exactly the same manner from trans-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride and the corresponding alkyl bromide.
trans-1-ethyl-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)piperidine hydrochloride M.p. 220.6.degree. C.
trans-1-butyl-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)piperidine hydrochloride M.p. 183.1.degree. C.
Example 4
(-)trans- 3-(2-Cyclohexylphenoxymethyl)-4-(4-fluorophenyl)1-methyl-piperidine, HCl.
5.13g 2-cyclohexylphenol was dissolved in dry DMF.1.5g NaH (55% oil dispersion) was washed with ether and subsequently added slowly to the solution. When gas evolution had ceased, 6,4 g of (-) trans 3-chloromethyl-4-(4-fluorophenyl)1-methylpiperidine was slowly added and the mixture refluxed for 5h. Subsequently the mixture was left at room temperature overnight, evaporated to dryness in vacuo. The residue was dissolved in dilute NaOH and extracted several times with ether. The etheral layers were dried with K.sub.2 CO.sub.3, evaporated to dryness and extracted once more from NaOH with ether. The ether layer was extracted with dilute HCl, the acid solution evaporated to dryness and the residue further purified on a silicagel column using CHCl.sub.3 /CH.sub.3 OH (9/1) as eluent. The compound was isolated from the eluent by evaporation. m.p. 64.9.degree. C. (hard glass)
The following compounds were prepared in the same manner from (-) trans-3-chloromethyl-4-(4-fluorophenyl)-1-methylpiperidine and the appropriate phenol.
-trans 4-(4-Fluorophenyl)-1-methyl-3-(5,6,7,8,-tetrahydro-2-naphthoxymethyl)-pipe ridine, HCl. m.p. 198.5.degree. C.
-trans 3-(4-Benzyloxyphenoxymethyl)-4-(4-fluorophenyl)-1-methylpiperidine HCl. m.p. 112.5.degree. C.
-trans 3-(4-Benzyloxy-3-methoxyphenoxymethyl)-4-(4-fluorophenyl)-1-methylpiperidi ne, HCl. m.p. 59.6.degree. C. (hard glass)
-trans 4-(4-Fluorophenyl)-1-methyl-3-(2-naphthoxymethyl)piperidine, HCl. m.p. 214.4.degree. C.
Example 5
A): -trans 3-(2-Cyclohexylphenoxymethyl)-4-(4-fluorophenyl)piperidine, HCl was prepared by means of alpha-chloroethylchloroformate using the method described in J.Org.Chem. 1984:49:2081 (R.A. Olofson, J.T. Martz, J.P. Senet, M. Piteau and T. Malfroot), m.p. 216.7.degree. C.
The following compounds were prepared in exactly the same manner by dealkylation of the corresponding N-methyl-compound.
(+-) trans 3-(4-Benzyloxyphenoxymethyl)-4-phenylpiperidine, HCl. m.p. 132.4.degree. C.
(-) trans 4-(4-Fluorophenyl)-3-(5,6,7,8,-tetrahydro-2-naphthoxymethyl)-piperidine, HCl. m.p. 55.1.degree. C. (hard glass)
(-) trans 3-(4-Benzyloxyphenoxymethyl)-4-(4-fluorophenyl)piperidine m.p. 132.7.degree. C.
(-) trans 3-(2-Benzothiazolylthiomethyl)-4-(4-fluorophenyl)piperidine, HCl. m.p. 72.2.degree. C. (hard glass)
(-) trans 4-(4-Fluorophenyl)-3-(2-naphthoxymethyl)-piperidine, HCl. m.p. 238.6.degree. C.
B): The following compounds were prepared from the corresponding piperidine and alkyl bromide in exactly the same manner as described in Example 1.
(-) trans 3-(2-Cyclohexylphenoxymethyl)-4-(4-fluorophenyl)1-pentylpiperidine, HCl. m.p. 210.3.degree. C. Reaction time 18h.
(+) trans 3-(3,4-Methylenedioxyphenoxymethyl)-1-pentyl-4-phenylpiperidine, HCl. m.p. 175.0.degree. C. Reaction time 2.5h.
(+-) trans 3-(4-Benzyloxyphenoxymethyl)-1-pentyl-4-phenylpiperidine, HCl. m.p. 139.5.degree. C. Reaction time 17h.
(+-) trans 1-Allyl-3-(4-benzyloxyphenoxymethyl)-4-phenylpiperidine, HCl. m.p. 212.1.degree. C. Reaction time 3.5h. Equimolar amounts of piperidine-compound and allyl bromide was used.
(-) trans 3-(4-Methoxyphenoxymethyl)-1-pentyl-4-phenylpiperidine, HCl. m.p. 138.7.degree. C. Reaction time 18h.
(-), trans 1-Allyl-3-(4-methoxyphenoxymethyl)-4-phenylpiperidine, HCl. m.p. 197.5.degree. C. Reaction time 1.5h. Equimolar amounts of allyl bromide and piperidine-compound was used.
(+) trans 3-(4-Methoxyphenoxymethyl)-1-pentyl-4-phenylpiperidine, HCl. m.p. 138.7.degree. C. Reaction time 18.5h.
(+) trans 1-Allyl-3-(4-methoxyphenoxymethyl)-4-phenylpiperidine, HCl. m.p. 195.9.degree. C. Reaction time 20.5h. Equimolar amounts of allyl bromide and piperidine-compound was used.
(-) trans 4-(4-Fluorophenyl)-1-pentyl-3-(5,6,7,8-tetrahydro-2-naphthoxymethyl)-piper idine, HCl. m.p. 55.3.degree. C. (hard glass). Reaction time 2h. The crude product was purified on a silicagel column, CHCl.sub.3 /CH.sub.3 OH (9/1) as eluent.
(-) trans 3-(2-Benzothiazolylthiomethyl)-4-(4-fluorophenyl)-1-pentylpiperidine, HCl. m.p. 199.9.degree. C. Reaction time 7h.
(-) trans 4-(-Fluorophenyl)-3-(2-naphthoxymethyl)-1-pentylpiperidine, HCl. m.p. 54.6.degree. C. (hard glass). Reaction time 4.5h. The crude product was purified on a silicagel column with CHCl.sub.3 /CH.sub.3 OH (9/1) as eluent.
(-) trans 1-Butyl-4-(4-fluorophenyl)-3-(5,6,7,8-tetrahydro2-naphthoxymethyl)-piperid ine, HCl. M.p. 154.3.degree. C. Reaction time 2.5 h.
(-) trans 4-(4-Fluorophenyl)-1-propyl-3-(5,6,7,8-tetrahydro2-naphthoxymethyl)-piperi dine, HCl. M.p. 186.6.degree. C. Reaction time 3.5 h.
(-) trans 4-(4-Fluorophenyl)-1-hexyl-3-(5,6,7,8-tetrahydro2-naphthoxymethyl)-piperid ine, HCl. M.p. 146.7.degree. C. Reaction time 4 h. The crude product was purified on a silicagel column with CHCl.sub.3 /CH.sub.3 OH (9/1) as eluent.
(-) trans 1-Ethyl-4-(4-Fluorophenyl)-3-(5,6,7,8-tetrahydro2-naphthoxymethyl)-piperid ine, HCl. M.p. 217.0.degree. C. Reaction time 24 h. The crude product was purified on a silicagel column with CHCl.sub.3 /CH.sub.3 OH (9/1) as eluent.
Example 6
(-) trans 3-(2-Benzothiazolylthiomethyl)-4-(4-fluorophenyl)-1-methylpiperidine,HCl was prepared by refluxing a mixture of 5g benzothiazol-2-thiol, 7.1g (-) trans-(3-chloromethyl) 4-(4-fluoromethyl)-1-methylpiperidine and 5g potassium carbonate in ethanol for 24h. Acetone/ether was added, the mixture filtered and the filtrate evaporated to drynes. The residue was extracted from NaOH/ether, the ether layer dried with K.sub.2 CO.sub.3, acidified with conc. HCl to pH2, and evaporated to dryness. The resulting oil was crystallized from acetone/ether. m.p. 204.2.degree. C. p In conclusion, from the foregoing it is apparent that the present invention provides novel effective calcium overload blocking piperidine compounds and salts thereof, having advantageous and unpredictable properties, as well as novel pharmaceutical compositions thereof and a method of treating therewith, all possessed of the foregoing more specifically-enumerated characteristics and advantages.
It is to be understood that the invention is not to be limited to the exact details of operation, or to the exact compositions, methods, procedures, or embodiments shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art and the invention is therefore to be limited only by the full scope of the appended claims.
