Sulphonamide derivatives, their preparation and their therapeutic application

FIELD OF THE INVENTION

The present invention relates to sulfonamide derivatives, to the process for preparing them and to their therapeutic use.

BACKGROUND OF THE INVENTION

Orexins A and B (or hypocretins 1 and 2) are hypothalamus neuropeptides of 33 and 28 amino acids, respectively, recently identified as endogenous ligands of two seven-domain transmembrane receptors, known as orexin 1 and orexin 2 receptors (Sakurai T., Cell, Vol. 92, 573-585, 1998; De Lecea L., Proc. Natl. Acad. Sci., Vol. 95, 322-327, 1998).

The orexin 2 receptor has the property of recognizing the two forms of orexin A and B equivalently. In contrast, the orexin 1 receptor, which shows 64% homology with the orexin 2 receptor, is more selective and binds orexin A ten times better than orexin B (Sakurai T., Cell, Vol. 92, 573-585, 1998).

Via these receptors, the orexins control various central and peripheral functions, especially taking of food and drink, certain cardiovascular endochrine functions and the awake/sleep cycle (Sakurai T., Regulatory Peptides, Vol. 85, 25-30, 1999).

SUMMARY OF THE INVENTION

It has now been found that certain sulfonamide derivatives show strong affinity for the orexin 2 receptors and are powerful antagonists of these receptors.

Thus, one subject of the present invention is compounds corresponding to the general formula (I)

##STR00002## in which Ar.sub.1 represents an aryl group such as a phenyl group optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro(C.sub.1-C.sub.4)alkyl group, a cyano group, a group --CO--NR.sub.aR.sub.b, a group --NR.sub.aR.sub.b, with R.sub.a and R.sub.b being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, a heterocyclyl group chosen from pyridyl, pyrimidinyl, thiazolyl and thienyl, the said heterocyclyl groups being optionally substituted with a halogen atom, a (C.sub.1-C.sub.4) alkyl group or a (C.sub.1-C.sub.4) alkoxy group, a (C.sub.3-C.sub.6) cycloalkyl group; T represents a group --(CH.sub.2).sub.n-- with n=0, 1 or 2, a group

##STR00003## with R.sub.2 being a hydroxyl group or a (C.sub.1-C.sub.4) alkyl group, a group

##STR00004## with R.sub.3 being a (C.sub.1-C.sub.4) alkyl group, a group

##STR00005## with R.sub.4 being a (C.sub.1-C.sub.4) alkyl group; Ar.sub.2 represents an aryl group such as phenyl optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro(C.sub.1-C.sub.4)alkyl group, a fluoro(C.sub.1-C.sub.4)alkoxy group, or with a group --NR.sub.cR.sub.d with R.sub.c and R.sub.d being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, a heterocyclyl group such as pyridyl optionally substituted with a (C.sub.1-C.sub.4) alkyl group or a (C.sub.1-C.sub.4) alkoxy group; Ar.sub.3 represents an aryl group chosen from phenyl and naphthyl, the said aryl groups being optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro(C.sub.1-C.sub.4)alkyl group, a fluoro(C.sub.1-C.sub.4)alkoxy group, a nitro group, a hydroxyl group, or with a group --NR.sub.5R.sub.6 with R.sub.5 and R.sub.6 being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, a heterocyclyl group such as pyridyl optionally substituted with a (C.sub.1-C.sub.4) alkyl group or a (C.sub.1-C.sub.4) alkoxy group, or with a group --NR.sub.xR.sub.y with R.sub.x and R.sub.y being, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group or a (C.sub.1-C.sub.4) alkoxy group, a group chosen from

##STR00006## R.sub.1 represents a --C(O)--CF.sub.3 group, a group of formula

##STR00007## in which n=0, 1, 2 or 3 R.sub.7 represents a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group, a fluorine atom or a (C.sub.1-C.sub.4) alkoxy group, a group --(CH.sub.2).sub.m-aryl, with m=1 or 2 and the aryl group being a phenyl group optionally substituted with a halogen atom, a (C.sub.1-C.sub.4) alkyl group or a (C.sub.1-C.sub.4) alkoxy group, R.sub.8 represents a hydrogen atom, a fluorine atom or a (C.sub.1-C.sub.4) alkyl group, R.sub.9 represents a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.3-C.sub.6) cycloalkyl group, a hydroxyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro(C.sub.1-C.sub.4)alkyl group, a --C.ident.CH group, a --C.ident.N group, a phenoxy group or a (C.sub.1-C.sub.4) alkenyl group, a group --NR.sub.10R.sub.11 with R.sub.10 and R.sub.11 being, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkylcarbonyl group, a (C.sub.1-C.sub.4) alkylsulfonyl group, a benzyl group or a --(CH.sub.2).sub.2--N(CH.sub.3).sub.2 group, or alternatively R.sub.10 and R.sub.11 form, together with the nitrogen atom that bears them, a pyrrolidine, a pyrrolidinone, a morpholine or a piperidine, a group --CO--NR.sub.12R.sub.13 with R.sub.12 and R.sub.13 being, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group optionally substituted with a --C.ident.N group, an aryl group such as phenyl or a heterocyclyl group such as pyridyl, the said aryl and heterocyclyl groups being optionally substituted with a (C.sub.1-C.sub.4) alkyl group or a hydroxyl group, or alternatively R.sub.12 and R.sub.13 form, together with the nitrogen atom that bears them, a group

##STR00008## a group --COOR.sub.14 with R.sub.14 being a (C.sub.1-C.sub.4) alkyl group, a group --NH--CO--NR.sub.15R.sub.16 with R.sub.15 and R.sub.16 being, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group, a phenyl group or a benzyl group, the said phenyl and benzyl groups being optionally substituted with one or more substituents chosen from a halogen atom, a (C.sub.1-C.sub.4) alkyl group and a (C.sub.1-C.sub.4) alkoxy group, a group --SO.sub.2--NR.sub.17R.sub.18 with R.sub.17 and R.sub.18 being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, a group --SO.sub.2--R.sub.19 with R.sub.19 being a (C.sub.1-C.sub.4) alkyl group or an aryl group such as phenyl, a heterocyclyl group chosen from 1,3-dioxolanyl, imidazolyl, tetrazolyl, triazolyl optionally substituted with a (C.sub.1-C.sub.4) alkyl group, thiazolyl, pyrimidyl, oxadiazolyl or pyridyl, the imidazolyl being optionally substituted on the nitrogen atom with a (C.sub.1-C.sub.4) alkyl group or a benzyl, the tetrazolyl being optionally substituted with a (C.sub.1-C.sub.4) alkyl group or a benzyl, and the oxadiazolyl being optionally substituted with a (C.sub.1-C.sub.4) alkyl, a group --NH--CO--OR.sub.15, R.sub.15 corresponding to the above definition, in the form of base, of acid-addition salt, of hydrate or of solvate, in the form of enantiomers, diastereoisomers, rotamers or atropoisomers, or mixtures thereof.

DETAILED DESCRIPTION

Among the compounds that are the subject of the invention, mention may be made of a first group of compounds of general formula (I) in which Ar.sub.1 represents an aryl group such as a phenyl group optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro(C.sub.1-C.sub.4)alkyl group, a heterocyclyl group chosen from pyridyl, thiazolyl and thienyl, the thienyl being optionally substituted with a (C.sub.1-C.sub.4) alkyl group, a (C.sub.3-C.sub.6) cycloalkyl group; T represents a group --(CH.sub.2).sub.n-- with n=1 a group

##STR00009## with R.sub.2 being a hydroxyl group or a (C.sub.1-C.sub.4) alkyl group, a group

##STR00010## with R.sub.3 being a (C.sub.1-C.sub.4) alkyl group, a group

##STR00011## with R.sub.4 being a (C.sub.1-C.sub.4) alkyl group; Ar.sub.2 represents an aryl group such as phenyl optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro(C.sub.1-C.sub.4)alkoxy group, a group --NR.sub.cR.sub.d with R.sub.c and R.sub.d being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group; Ar.sub.3 represents an aryl group chosen from phenyl and naphthyl, the phenyl group being optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro (C.sub.1-C.sub.4)alkyl group, a fluoro(C.sub.1-C.sub.4)alkoxy group, a nitro group, or a group --NR.sub.5R.sub.6 with R.sub.5 and R.sub.6 being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, a group chosen from

##STR00012## R.sub.1 represents a --C(O)--CF.sub.3 group, a group of formula

##STR00013## in which n=0, 1 or 2, R.sub.7 represents a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group R.sub.8 represents a hydrogen atom, R.sub.9 represents a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group, a hydroxyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro(C.sub.1-C.sub.4)alkyl group, a --C.ident.CH group or a --C.ident.N group, a group --NR.sub.10R.sub.11 with R.sub.10 and R.sub.11 being, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkylcarbonyl group or a benzyl, or alternatively R.sub.10 and R.sub.11 form, together with the nitrogen atom that bears them, a pyrrolidine, a piperidine or a pyrrolidinone, a group --CO--NR.sub.12R.sub.13 with R.sub.12 and R.sub.13 being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, or alternatively R.sub.12 and R.sub.13 form, together with the nitrogen atom that bears them, a group

##STR00014## or a group --COOR.sub.14 with R.sub.14 being a (C.sub.1-C.sub.4) alkyl group, a group --NH--CO--NR.sub.15R.sub.16 with R.sub.15 and R.sub.16 being, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.4) alkyl group, a phenyl or a benzyl, a heterocyclyl group chosen from imidazolyl optionally substituted on the nitrogen atom with a (C.sub.1-C.sub.4) alkyl group, tetrazolyl optionally substituted with a (C.sub.1-C.sub.4) alkyl group, and triazolyl, in the form of base, of acid-addition salt, of hydrate or of solvate, in the form of enantiomers, diastereoisomers, rotamers or atropoisomers, or mixtures thereof.

Among the compounds that are the subject of the invention, mention may be made of a second group of compounds of general formula (I) in which Ar.sub.1 represents an aryl group such as phenyl optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro (C.sub.1-C.sub.4) alkyl group, a heterocyclyl group chosen from pyridyl, thiazolyl and thienyl, the thienyl being optionally substituted with a (C.sub.1-C.sub.4) alkyl group; T represents a group --(CH.sub.2).sub.n-- with n=1 a group

##STR00015## with R.sub.2 being a hydroxyl group; Ar.sub.2 represents an aryl group such as phenyl optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group; a group --NR.sub.cR.sub.d with R.sub.c and R.sub.d being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group; Ar.sub.3 represents an aryl group such as phenyl, the phenyl group being optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, or alternatively a group --NR.sub.5R.sub.6 with R.sub.5 and R.sub.6 being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group; R.sub.1 represents a group of formula

##STR00016## in which n=0, 1 or 2, R.sub.7 represents a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, R.sub.8 represents a hydrogen atom, R.sub.9 represents a hydrogen atom, a --C.ident.CH group or a --C.ident.N group, a group --CO--NR.sub.12R.sub.13 with R.sub.12 and R.sub.13 being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, a heterocyclyl chosen from imidazolyl optionally substituted on the nitrogen atom with a (C.sub.1-C.sub.4) alkyl group, tetrazolyl optionally substituted with a (C.sub.1-C.sub.4) alkyl group, and triazolyl, in the form of base, of acid-addition salt, of hydrate or of solvate, in the form of enantiomers, diastereoisomers, rotamers or atropoisomers, or mixtures thereof.

Among the compounds that are the subject of the invention, mention may be made of a third group of compounds of general formula (I) in which Ar.sub.1 represents an aryl group such as phenyl optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a heterocyclyl group such as thienyl, optionally substituted with a (C.sub.1-C.sub.4) alkyl group, T represents a group --(CH.sub.2).sub.n-- with n=1 Ar.sub.2 represents a phenyl group optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a group --NR.sub.cR.sub.d with R.sub.c and R.sub.d being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group; Ar.sub.3 represents a phenyl group optionally substituted with one or more groups chosen, independently of each other, from the following groups: a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, or alternatively a group --NR.sub.5R.sub.6 with R.sub.5 and R.sub.6 being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group; R.sub.1 represents a group of formula

##STR00017## in which n=0, 1 or 2, R.sub.7 represents a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group; R.sub.8 represents a hydrogen atom; R.sub.9 represents a group --CO--NR.sub.12R.sub.13 with R.sub.12 and R.sub.13 being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group, a heterocycle chosen from imidazolyl substituted on the nitrogen atom with a (C.sub.1-C.sub.4) alkyl group, tetrazolyl substituted with a (C.sub.1-C.sub.4) alkyl group, and triazolyl, in the form of base, of acid-addition salt, of hydrate or of solvate, in the form of enantiomers, diastereoisomers, rotamers or atropoisomers, or mixtures thereof.

When Ar.sub.2 is an optionally substituted phenyl group, the bonds T-Ar.sub.2, on the one hand, and Ar.sub.2--N, on the other hand, are in an ortho position. In other words, the nitrogen atom and the substituent T are on two adjacent carbon atoms.

Examples of compounds according to the invention that may be mentioned include the following compounds:

Compound 1:

Ethyl N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(3,4-dimet- hoxyphenyl)sulfonyl]glycinate

##STR00018## Compound 2:

Ethyl N-(2-benzyl-4-chlorophenyl)-N-[(3,4-dimethoxyphenyl)sulfonyl]glycina- te

##STR00019## Compound 3:

Ethyl N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(3-methoxyphenyl)sulfonyl]g- lycinate

##STR00020## Compound 4:

Ethyl N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(2-methoxyphenyl)sulfonyl]g- lycinate

##STR00021## Compound 5:

Ethyl N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(2,5-dimethoxyphenyl)sulfon- yl]glycinate

##STR00022## Compound 6:

Ethyl N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(2,4-dimethoxyphenyl)sulfon- yl]glycinate

##STR00023## Compound 7:

Ethyl N-{4-chloro-2-[hydroxy(phenyl)methyl]phenyl}-N-[(3,4-dimethoxyphenyl- )sulfonyl]glycinate

##STR00024## Compound 8:

Ethyl N-[(3,4-dimethoxyphenyl)sulfonyl]-N-{2-[hydroxy(phenyl)methyl]phenyl- }glycinate

##STR00025## Compound 9:

Ethyl N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(2,4-dimet- hoxyphenyl)sulfonyl]glycinate

##STR00026## Compound 10:

Ethyl N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-(phenylsulf- onyl)glycinate

##STR00027## Compound 11:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(2-ethyl-2H-tetr- azol-5-yl)methyl]-3,4-dimethoxybenzenesulfonamide

##STR00028## Compound 12:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(1-ethyl-1H-tetr- azol-5-yl)methyl]-3,4-dimethoxybenzenesulfonamide

##STR00029## Compound 13:

Ethyl N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(4-methoxy- phenyl)sulfonyl]glycinate

##STR00030## Compound 14:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[(2- -methyl-2H-tetrazol-5-yl)methyl]benzenesulfonamide

##STR00031## Compound 15:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[(1- -methyl-1H-tetrazol-yl)methyl]benzenesulfonamide

##STR00032## Compound 16:

Ethyl N-{4-chloro-2-[(3-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(3,4-dimet- hoxyphenyl)sulfonyl]glycinate

##STR00033## Compound 17:

Ethyl N-{4-chloro-2-[hydroxy(2-methoxyphenyl)methyl]phenyl}-N-[(3,4-dimeth- oxyphenyl)sulfonyl]glycinate

##STR00034## Compound 18:

Ethyl N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(3,4-dichl- orophenyl)sulfonyl]glycinate

##STR00035## Compound 19:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.about.2.abo- ut.-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00036## Compound 20:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-ethyl-3,4-dimetho- xybenzenesulfonamide

##STR00037## Compound 21:

Methyl N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(3,4-dime- thoxyphenyl)sulfonyl]glycinate

##STR00038## Compound 22:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[(1- -methyl-1H-imidazol-2-yl)methyl]benzenesulfonamide

##STR00039## Compound 23:

N-(4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl)-3,4-dimethoxy-N-(2-- methoxyethyl)benzenesulfonamide

##STR00040## Compound 24:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-(2-hydroxyethyl)-- 3,4-dimethoxybenzenesulfonamide

##STR00041## Compound 25:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-met- hylbenzenesulfonamide

##STR00042## Compound 26:

Ethyl N-{4-chloro-2-[hydroxy(2-methylphenyl)methyl]phenyl}-N-[(3,4-dimetho- xyphenyl)sulfonyl]glycinate

##STR00043## Compound 27:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3-methoxyphenyl)sulf- onyl]glycinamide

##STR00044## Compound 28:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,4- -dimethylphenyl)sulfonyl]glycinamide

##STR00045## Compound 29:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-(2-na- phthylsulfonyl)glycinamide

##STR00046## Compound 30:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(3-methoxy- phenyl)sulfonyl]glycinamide

##STR00047## Compound 31:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3-c- hlorophenyl)sulfonyl]glycinamide

##STR00048## Compound 32:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(4-m- ethoxyphenyl)sulfonyl]glycinamide

##STR00049## Compound 33:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2,4- -dimethoxyphenyl)sulfonyl]glycinamide

##STR00050## Compound 34:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,4- -dichlorophenyl)sulfonyl]glycinamide

##STR00051## Compound 35:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N N.sup.2-[(4-chlorophenyl)sulfonyl]glycinamide

##STR00052## Compound 36:

N.sup.2{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2,5-- dimethoxyphenyl)sulfonyl]glycinamide

##STR00053## Compound 37:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2-c- hlorophenyl)sulfonyl]glycinamide

##STR00054## Compound 38:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(4-c- hloro-2,5-dimethylphenyl)sulfonyl]glycinamide

##STR00055## Compound 39:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(4-methoxyphenyl)sulf- onyl]glycinamide

##STR00056## Compound 40:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2,5-dimethoxyphenyl)- sulfonyl]glycinamide

##STR00057## Compound 41:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2,3- -dimethoxyphenyl)sulfonyl]glycinamide

##STR00058## Compound 42:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-{[3-(trifluoromethyl)p- henyl]sulfonyl}-glycinamide

##STR00059## Compound 43:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-{[3-(trifluoromethoxy)- phenyl]sulfonyl}-glycinamide

##STR00060## Compound 44:

N.sup.2-{4-chloro-2-[(3-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,4- -dimethoxyphenyl)sulfonyl]glycinamide

##STR00061## Compound 45:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2-methoxyphenyl)sulf- onyl]glycinamide

##STR00062## Compound 46:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]-N.sup.1-methylglycinamide

##STR00063## Compound 47:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(4-chlorophenyl)sulfo- nyl]glycinamide

##STR00064## Compound 48:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dichlorophenyl)s- ulfonyl]glycinamide

##STR00065## Compound 49:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(4-chloro-2,5-dimethy- lphenyl)sulfonyl]glycinamide

##STR00066## Compound 50:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2-chlorophenyl)sulfo- nyl]glycinamide

##STR00067## Compound 51:

N.sup.2-{4-chloro-2-[hydroxy(3-methoxyphenyl)methyl]phenyl}-N.sup.2-[(3,4-- dimethoxyphenyl)sulfonyl]glycinamide

##STR00068## Compound 52:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-(phen- ylsulfonyl)glycinamide

##STR00069## Compound 53:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-(phenylsulfonyl)glycin- amide

##STR00070## Compound 54:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-3,4-dimethoxy-N-methylbenzenesulfona- mide

##STR00071## Compound 55:

N.sup.2-[4-chloro-2-(2-fluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide

##STR00072## Compound 56:

N.sup.2-[4-chloro-2-(2-methoxybenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl- )sulfonyl]glycinamide

##STR00073## Compound 57:

N.sup.2-{4-chloro-2-[(2-fluorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,4- -dimethoxyphenyl)sulfonyl]glycinamide

##STR00074## Compound 58:

N.about.2.about.-[4-chloro-2-(3-methoxybenzyl)phenyl]-N.about.2.about.-[(3- ,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00075## Compound 59:

N.sup.2-{4-chloro-2-[hydroxy(4-methoxyphenyl)methyl]phenyl}-N.sup.2-[(3,4-- dimethoxyphenyl)sulfonyl]glycinamide

##STR00076## Compound 60:

N.sup.2-[4-chloro-2-(4-methoxybenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl- )sulfonyl]glycinamide

##STR00077## Compound 61:

N.sup.2-{2-[(2-chlorophenyl)(hydroxy)methyl]-4-fluorophenyl}-N-.sup.2-[(3,- 4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00078## Compound 62:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3-methylphenyl)sulfo- nyl]glycinamide

##STR00079## Compound 63:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-(2,3-dihydro-1,4-benzo- dioxin-6-ylsulfonyl)glycinamide

##STR00080## Compound 64:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-(2,3-- dihydro-1,4-benzodioxin-6-ylsulfonyl)glycinamide

##STR00081## Compound 65:

N.sup.2-(2-benzyl-4-chlorophenyl)-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]g- lycinamide

##STR00082## Compound 66:

N.sup.2-{4-chloro-2-[hydroxy(phenyl)methyl]phenyl}-N.sup.2-[(3,4-dimethoxy- phenyl)sulfonyl]glycinamide

##STR00083## Compound 67:

N.sup.2-[2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]- glycinamide

##STR00084## Compound 68:

N.sup.2-{4-chloro-2-[hydroxy(2-methoxyphenyl)methyl]phenyl}-N.sup.2-[(3,4-- dimethoxyphenyl)sulfonyl]glycinamide

##STR00085## Compound 69:

N.sup.2-{2-[(2-chlorophenyl)(hydroxy)methyl]-4-methoxyphenyl}-N.sup.2-[(3,- 4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00086## Compound 70:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]-N.sup.1, N.sup.1-dimethylglycinamide

##STR00087## Compound 71:

N.sup.2-(1,3-benzodioxol-5-ylsulfonyl)-N.sup.2-[4-chloro-2-(2-chlorobenzyl- )phenyl]glycinamide

##STR00088## Compound 72:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,4- -dimethoxyphenyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00089## Compound 73:

N.sup.2-[4-chloro-2-(2-methylbenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide

##STR00090## Compound 74:

N.sup.2-{4-chloro-2-[(2,5-dichlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00091## Compound 75:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]-N.sup.1-ethylglycinamide

##STR00092## Compound 76:

N.sup.2-(1,3-benzodioxol-5-ylsulfonyl)-N.sup.2-{4-chloro-2-[(2-chloropheny- l)(hydroxy)methyl]phenyl}-glycinamide

##STR00093## Compound 77:

N.sup.2-[2-[(2-chlorophenyl)(hydroxy)methyl]-4-(trifluoromethoxy)phenyl]-N- .sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00094## Compound 78:

N.sup.2-[4-chloro-2-(2,6-dichlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00095## Compound 79:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2-m- ethylphenyl)sulfonyl]glycinamide

##STR00096## Compound 80:

N.sup.2-[4-chloro-2-(2,5-dichlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00097## Compound 81:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2-methylphenyl)sulfo- nyl]glycinamide

##STR00098## Compound 82:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethylphenyl)s- ulfonyl]glycinamide

##STR00099## Compound 83:

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[(3- -methyl-1,2,4-oxadiazol-5-yl)methyl]benzenesulfonamide

##STR00100## Compound 84:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-3,4-dimethoxy-N-[(3-methyl-1,2,4-oxa- diazol-5-yl)methyl]benzenesulfonamide

##STR00101## Compound 85:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2,6- -dichlorophenyl)sulfonyl]glycinamide

##STR00102## Compound 86:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,5- -dimethylphenyl)sulfonyl]glycinamide

##STR00103## Compound 87:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2,6-dichlorophenyl)s- ulfonyl]glycinamide

##STR00104## Compound 88:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-tetraz- ol-5-yl)methyl]benzenesulfonamide

##STR00105## Compound 89:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,5-dimethylphenyl)s- ulfonyl]glycinamide

##STR00106## Compound 90:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(1-ethyl-1H-tetrazol-5-yl)methyl]- -3,4-dimethoxybenzenesulfonamide

##STR00107## Compound 91:

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00108## Compound 92:

N.sup.2-{4-chloro-2-[methyl(phenyl)amino]phenyl}-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]glycinamide

##STR00109## Compound 93:

N.sup.2-[2-(2-chlorobenzyl)-4-ethylphenyl]-N.sup.2-[(3,4-dimethoxyphenyl)s- ulfonyl]glycinamide

##STR00110## Compound 94:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2,5- -dimethoxy-4-methylphenyl)sulfonyl]glycinamide

##STR00111## Compound 95:

N.sup.2-(2-benzyl-4-chlorophenyl)-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]-- N.sup.1, N.sup.1-dimethylglycinamide

##STR00112## Compound 96:

N.sup.2-(2-benzyl-4-chlorophenyl)-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]-- N.sup.1-methylglycinamide

##STR00113## Compound 97:

N.sup.2-[4-chloro-2-(2-fluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]-N.sup.1,N.sup.1-dimethylglycinamide

##STR00114## Compound 98:

N.sup.2-[4-chloro-2-(2-fluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]-N.sup.1-methylglycinamide

##STR00115## Compound 99:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2,5-dimethoxy-4-meth- ylphenyl)sulfonyl]glycinamide

##STR00116## Compound 100:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2,4-dichloro-5-methy- lphenyl)sulfonyl]glycinamide

##STR00117## Compound 101:

N.sup.2-{4-chloro-2-[(2,6-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00118## Compound 102:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}N.sup.2-[(2,4,- 5-trimethoxyphenyl)sulfonyl]glycinamide

##STR00119## Compound 103:

N.sup.2-[2-(2-chlorobenzyl)-4-ethylphenyl]-N.sup.2-[(3,4-dimethoxyphenyl)s- ulfonyl]-N.sup.1, N.sup.1-dimethylglycinamide

##STR00120## Compound 104:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2,4,5-trimethoxyphen- yl)sulfonyl]glycinamide

##STR00121## Compound 105:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(4-chloro-2,5-dimethy- lphenyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00122## Compound 106:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2,4- ,5-trimethylphenyl)sulfonyl]glycinamide

##STR00123## Compound 107:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-imidaz- ol-2-yl)methyl]benzenesulfonamide

##STR00124## Compound 108:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(1-isopropyl-1H-tetrazol-5-yl)met- hyl]-3,4-dimethoxybenzenesulfonamide

##STR00125## Compound 109:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.1-methyl-N.sup.2-[(2,4,5- -trimethoxyphenyl)sulfonyl]glycinamide

##STR00126## Compound 110:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.1-methy- l-N.sup.2-[(2,4,5-trimethylphenyl)sulfonyl]glycinamide

##STR00127## Compound 111:

N-[(1-benzyl-1H-tetrazol-5-yl)methyl]-N-[4-chloro-2-(2-chlorobenzyl)phenyl- ]-3,4-dimethoxybenzenesulfonamide

##STR00128## Compound 112:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-3,5-dimethyl-N-[(1-methyl-1H-imidazo- l-2-yl)methyl]benzenesulfonamide

##STR00129## Compound 113:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.1-methy- l-N.sup.2-[(2,4,5-trimethoxyphenyl)sulfonyl]glycinamide

##STR00130## Compound 114:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2,4,5-trimethylpheny- l)sulfonyl]glycinamide

##STR00131## Compound 115:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.1-methyl-N.sup.2-[(2,4,5- -trimethylphenyl)sulfonyl]glycinamide

##STR00132## Compound 116:

N.sup.2-[4-chloro-2-(3-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide

##STR00133## Compound 117:

N.sup.2-{4-chloro-2-[(2,6-dichlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00134## Compound 118:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(4-chloro-2,5-dimethy- lphenyl)sulfonyl]-N.sup.1, N.sup.1-dimethylglycinamide

##STR00135## Compound 119:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,5-dimethoxyphenyl) sulfonyl]glycinamide

##STR00136## Compound 120:

N.sup.2-{4-chloro-2-[hydroxy(1,3-thiazol-2-yl)methyl]phenyl}-N.sup.2-[(3,4- -dimethoxyphenyl)sulfonyl]glycinamide

##STR00137## Compound 121:

N.sup.2-{4-chloro-2-[hydroxy(1,3-thiazol-2-yl)methyl]phenyl}-N.sup.2-[(3,4- -dimethoxyphenyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00138## Compound 122:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(2-ethyl-2H-tetrazol-5-yl)methyl]- -3,5-dimethylbenzenesulfonamide

##STR00139## Compound 123:

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(1-ethyl-1H-tetrazol-5-yl)methyl]- -3,5-dimethylbenzenesulfonamide

##STR00140## Compound 124:

N.sup.2-{4-chloro-2-[methyl(phenyl)amino]phenyl}-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00141## Compound 125:

N.sup.2-(4-chloro-2-{hydroxy[2-(trifluoromethyl)phenyl]methyl}phenyl)-N.su- p.2[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00142## Compound 126:

N.sup.2-{4-chloro-2-[(2,3-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00143## Compound 127:

N.sup.2-{4-chloro-2-[(2,3-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]-N.sup.1-ethylglycinamide

##STR00144## Compound 128:

N.sup.2-{4-chloro-2-[(2,3-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]-N.sup.1, N.sup.1-dimethylglycinamide

##STR00145## Compound 129:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(2,4- -dichloro-5-methylphenyl)sulfonyl]-N.sup.1, N.sup.1-dimethylglycinamide

##STR00146## Compound 130:

N.sup.2-[4-chloro-2-(2,6-dichlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00147## Compound 131:

N.sup.2-{4-chloro-2-[hydroxy(2-methylphenyl)methyl]phenyl}-N.sup.2-[(3,4-d- imethoxyphenyl)sulfonyl]glycinamide

##STR00148## Compound 132:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,5- -dimethylphenyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00149## Compound 133:

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,5- -dimethylphenyl)sulfonyl]-N.sup.1, N.sup.1-dimethylglycinamide

##STR00150## Compound 134:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3-nitrophenyl)sulfon- yl]glycinamide

##STR00151## Compound 135:

N.sup.2-[(3-aminophenyl)sulfonyl]-N.sup.2-[4-chloro-2-(2-chlorobenzyl)phen- yl]glycinamide

##STR00152## Compound 136:

N.sup.2-{2-[(2-chlorophenyl)(hydroxy)methyl]-4-methylphenyl}-N.sup.2-[(3,4- -dimethoxyphenyl)sulfonyl]glycinamide

##STR00153## Compound 137:

N.sup.2-{4-chloro-2-[hydroxy(phenyl)methyl]phenyl}-N.sup.2-[(3,4-dimethoxy- phenyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00154## Compound 138:

N.sup.2-[2-(2-chlorobenzyl)-4-methoxyphenyl]-N.sup.2-[(3,4-dimethoxyphenyl- )sulfonyl]glycinamide

##STR00155## Compound 139:

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00156## Compound 140:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-propylbenzenesul- fonamide

##STR00157## Compound 141:

N.sup.2-[4-chloro-2-(2,3-difiluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00158## Compound 142:

N.sup.2-[4-chloro-2-(2,3-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00159## Compound 143:

N.sup.2-[4-chloro-2-(2,3-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-N.sup.1, N.sup.1-dimethylglycinamide

##STR00160## Compound 144:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-methylbenzenesul- fonamide

##STR00161## Compound 145:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-(dimethylamino)ethyl]-3,4-d- imethoxybenzenesulfonamide

##STR00162## Compound 146:

N.sup.2-{4-chloro-2-[hydroxy(2-thienyl)methyl]phenyl}-N.sup.2-[(3,4-dimeth- oxyphenyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00163## Compound 147:

N.sup.2-{4-chloro-2-[(2,6-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,5-dimethylphenyl)sulfonyl]glycinamide

##STR00164## Compound 148:

N.sup.2-[(3-aminophenyl)sulfonyl]-N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hy- droxy)methyl]phenyl}-glycinamide

##STR00165## Compound 149:

N.sup.2-{4-chloro-2-[(2-fluoro-6-methoxyphenyl)(hydroxy)methyl]phenyl-}-N.- sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00166## Compound 150:

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-N.sup.1,N.sup.1-dimethylglycinamide

##STR00167## Compound 151:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(2-methyl-2H-te- trazol-5-yl)methyl]benzenesulfonamide

##STR00168## Compound 152:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-te- trazol-5-yl)methyl]benzenesulfonamide

##STR00169## Compound 153:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(2-ethyl-2H-tetrazol-5-yl)met- hyl]-3,4-dimethoxybenzenesulfonamide

##STR00170## Compound 154:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(1-ethyl-1H-tetrazol-5-yl)met- hyl]-3,4-dimethoxybenzenesulfonamide

##STR00171## Compound 155:

N.sup.2-{4-chloro-2-[hydroxy(2-thienyl)methyl]phenyl}-N.sup.2-[(3,4-dimeth- oxyphenyl)sulfonyl]glycinamide

##STR00172## Compounds 156:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-(6,7-dimethoxy-3,4-dihydroi- soquinolin-2(1H)-yl)-2-oxoethyl]-3,4-dimethoxybenzenesulfonamide

##STR00173## Compound 157:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,5-dimethyl-N-[(2-methyl-2H-tet- razol-5-yl)methyl]benzenesulfonamide

##STR00174## Compound 158:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,5-dimethyl-N-[(1-methyl-1H-tet- razol-5-yl)methyl]benzenesulfonamide

##STR00175## Compound 159:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(2-ethyl-2H-tetrazol-5-yl)met- hyl]-3,5-dimethylbenzenesulfonamide

##STR00176## Compound 160:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(1-ethyl-1H-tetrazol-5-yl)met- hyl]-3,5-dimethylbenzenesulfonamide

##STR00177## Compound 161:

N.sup.2-[4,5-dichloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00178## Compound 162:

N.sup.2-{4-chloro-2-[hydroxy(2,4,6-trifluorophenyl)methyl]phenyl}-N.sup.2-- [(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00179## Compound 163:

N.sup.2-{4-chloro-2-[(2,4-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00180## Compound 164:

N.sup.2-{4,5-dichloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00181## Compound 165:

N.sup.2-[2-(2-chlorobenzyl)-4-methylphenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide

##STR00182## Compound 166:

N.sup.2-[4-chloro-2-(2,6-dichlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-N.sup.1, N.sup.1-dimethylglycinamide

##STR00183## Compound 167:

N.sup.2-{4-chloro-2-[(4-chloro-2-fluorophenyl)(hydroxy)methyl]phenyl}-N.su- p.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00184## Compound 168:

N.sup.2-[4-chloro-2-(4-chloro-2-fluorobenzyl)phenyl]-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

##STR00185## Compound 169:

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,5-dimethylphen- yl)sulfonyl]glycinamide

##STR00186## Compound 170:

N.sup.2-[4-chloro-2-(2-fluoro-6-methoxybenzyl)phenyl]-N.sup.2-[(3,4-dimeth- oxyphenyl)sulfonyl]glycinamide

##STR00187## Compound 171:

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,5-dimethylphen- yl)sulfonyl]-N.sup.1-methylglycinamide

##STR00188## Compound 172:

N.sup.2-{4-chloro-2-[1-(2-chlorophenyl)-1-hydroxyethyl]phenyl}-N.sup.2-[(3- ,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00189## Compound 173:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2,4-dichloro-5-methy- lphenyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00190## Compound 174:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(2,4-dichloro-5-methy- lphenyl)sulfonyl]-N.about.1.about., N.about.1.about.-dimethylglycinamide

##STR00191## Compound 175:

N.sup.2-{5-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.about.2.abo- ut.-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00192## Compound 176:

N.sup.2-{4-chloro-2-[(5-chloro-2-fluorophenyl)(hydroxy)methyl]phenyl}-N.su- p.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00193## Compound 177:

N.sup.2-[4-chloro-2-(2,5-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00194## Compound 178:

N.sup.2-{4-chloro-2-[(3,5-difluorophenyl)(hydroxy)methyl]phenyl}N.sup.2-[(- 3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00195## Compound 179:

N.sup.2-[5-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide

##STR00196## Compound 180:

N.sup.2-[4-chloro-2-(2-thienylmethyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl- )sulfonyl]glycinamide

##STR00197## Compound 181:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-im- idazol-2-yl)methyl]benzenesulfonamide

##STR00198## Compound 182:

N.sup.2-[4-chloro-2-(5-chloro-2-fluorobenzyl)phenyl]-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

##STR00199## Compound 183:

N.sup.2-[4-chloro-2-(3,5-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00200## Compound 184:

N.sup.2-{4-chloro-2-[hydroxy(pyridin-4-yl)methyl]phenyl}-N.sup.2-[(3,4-dim- ethoxyphenyl)sulfonyl]glycinamide

##STR00201## Compound 185:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-prop-2-yn-1-ylbe- nzenesulfonamide

##STR00202## Compound 186:

N.sup.2-{4-chloro-2-[1-(2-chlorophenyl)ethyl]phenyl}-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

##STR00203## Compound 187:

N.sup.2-{4-chloro-2-[1-(2-chlorophenyl)ethyl]phenyl}-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]-N.sup.1-methylglycinamide

##STR00204## Compound 188:

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-{[3-(dimethylamino- )phenyl]sulfonyl}-glycinamide

##STR00205## Compound 189:

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-{[3-(methylamino)p- henyl]sulfonyl}-glycinamide

##STR00206## Compound 190:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2,2,2-trifluoro- ethyl)benzenesulfonamide

##STR00207## Compound 191:

N.sup.2-{4-chloro-2-[(2-chloro-6-methoxyphenyl)(hydroxy)methyl]phenyl}-N.s- up.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00208## Compound 192:

N.sup.2-[4-chloro-2-(2-chloro-6-methoxybenzyl)phenyl]-N.sup.2-[(3,4-dimeth- oxyphenyl)sulfonyl]glycinamide

##STR00209## Compound 193:

N.sup.2-[2-(2,6-difluorobenzyl)-4-methoxyphenyl]-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]glycinamide

##STR00210## Compound 194:

N.sup.2-{4-chloro-2-[(2-fluoro-5-methylphenyl)(hydroxy)methyl]phenyl}-N.su- p.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00211## Compound 195:

N.sup.2-[3-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00212## Compound 196:

N.sup.2-[4-chloro-2-(2-fluoro-5-methylbenzyl)phenyl]-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

##STR00213## Compound 197:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[3-(dimethylamino)propyl]-3,4-- dimethoxybenzenesulfonamide

##STR00214## Compound 198:

N.sup.2-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-4-methylphenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00215## Compound 199:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-pyrrolidin-1-- ylethyl)benzenesulfonamide

##STR00216## Compound 200:

N.sup.2-[2-(2,6-difluorobenzyl)-4-methylphenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00217## Compound 201:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-(dimethylamino)-1-methyleth- yl]-3,4-dimethoxybenzenesulfonamide

##STR00218## Compound 202:

N.sup.2-[2-(2,6-difluorobenzyl)-5-(dimethylamino)phenyl]-N.sup.2-[(3,4-dim- ethoxyphenyl)sulfonyl]glycinamide

##STR00219## Compound 203:

N-{2-[benzyl(methyl)amino]ethyl}-N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]- -3,4-dimethoxybenzenesulfonamide

##STR00220## Compound 204:

4-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]a- mino}-butanamide

##STR00221##

##STR00222## Compound 205:

2-{[2-(2,6-difluorobenzyl)-4-methylphenyl)[(3,4-dimethoxyphenyl)sulfonyl]a- mino}-butanamide

Compound 206:

N.sup.2-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-4-fluorophenyl}-N.sup.2-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00223## Compound 207:

N.sup.2-{4-chloro-2-[2-(trifluoromethyl)benzyl]phenyl)-N.sup.2-[(3,4-dimet- hoxyphenyl)sulfonyl]glycinamide

##STR00224## Compound 208:

N.sup.2-[2-(2,6-difluorobenzyl)-4,6-dimethoxyphenyl]-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

##STR00225## Compound 209:

N.sup.2-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-4-methoxyphenyl}-N.sup.2-- [(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00226## Compound 210:

N.sup.2-[2-(2,6-difluorobenzyl)-3,6-dimethoxyphenyl]-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

##STR00227## Compound 211:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(cyanomethyl)-3,4-dimethoxyben- zenesulfonamide

##STR00228## Compound 212:

N.sup.2-{4-chloro-2-[(5-methyl-2-thienyl)methyl]phenyl}-N.sup.2-[(3,4-dime- thoxyphenyl)sulfonyl]glycinamide

##STR00229## Compound 213:

N.sup.2-{4-chloro-2-[(2-chloro-6-methylphenyl)(hydroxy)methyl]phenyl}-N.su- p.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00230## Compound 214:

N.sup.2-{2,4-dichloro-6-[(2,6-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup- .2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00231## Compound 215:

N-(2-aminoethyl)-N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxybe- nzenesulfonamide

##STR00232## Compound 216:

N.sup.2-{2,4-dichloro-6-[(2,6-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup- .2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00233## Compound 217:

N-{2-[(anilinocarbonyl)amino]ethyl}-N-[2-(2,6-difluorobenzyl)-4-methylphen- yl]-3,4-dimethoxybenzenesulfonamide

##STR00234## Compound 218:

N-(2-{[(benzylamino)carbonyl]amino}ethyl)-N-[2-(2,6-difluorobenzyl)-4-meth- ylphenyl]-3,4-dimethoxybenzenesulfonamide

##STR00235## Compound 219:

N-(2-{[2-(2,6-difluorobenzyl)-4-methylphenyl][(3,4-dimethoxyphenyl)sulfony- l]amino}ethyl)acetamide

##STR00236## Compound 220:

N.sup.2-[2-(2,6-difluorobenzyl)-4-fluorophenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

##STR00237## Compound 221:

N.sup.2-{4,5-dichloro-2-[(2,6-difluorophenyl)(hydroxy)methyl]phenyl}-N.sup- .2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00238## Compound 222:

N.sup.2-{4-chloro-2-[(2-chloro-6-fluorophenyl)(hydroxy)methyl]phenyl}-N.su- p.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00239## Compound 223:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl- ]-2,2,2-trifluoroacetamide

##STR00240## Compound 224:

N.sup.2-[4-chloro-2-(2-chloro-6-fluorobenzyl)phenyl]-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

##STR00241## Compound 225:

N.sup.2-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-6-methoxyphenyl}-N.sup.2-- [(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00242## Compound 226:

N.sup.2-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-6-methoxyphenyl}-N.sup.2-- [(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00243## Compound 227:

N.sup.2-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-5-methoxy-4-methylphenyl}- N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00244## Compound 228:

N.sup.2-[4,5-dichloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethox- yphenyl)sulfonyl]glycinamide

##STR00245## Compound 229:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-{3-[(diethylamino)sulfonyl]pro- pyl}-3,4-dimethoxybenzenesulfonamide

##STR00246## Compound 230:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-{3-[(dimethylamino)sulfonyl]pr- opyl}-3,4-dimethoxybenzenesulfonamide

##STR00247## Compound 231:

N-{(2-[(aminocarbonyl)amino]ethyl}-N-[4-chloro-2-(2,6-difluorobenzyl)pheny- l]-3,4-dimethoxybenzenesulfonamide

##STR00248## Compound 232:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(3-pyridin-3-ylp- ropyl)benzenesulfonamide

##STR00249## Compound 233:

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide

##STR00250## Compound 234:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[2-(2-oxopyrroli- din-1-yl)ethyl]benzenesulfonamide

##STR00251## Compound 235:

4-{([4-chloro-2-(2,6-difluorobenzyl)phenyl][(4-chloro-2,5-dimethylphenyl)s- ulfonyl]amino}-butanamide

##STR00252## Compound 236:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-methoxyethyl)- benzenesulfonamide

##STR00253## Compound 237:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(2-hydroxyethyl)-3,4-dimethoxy- benzenesulfonamide

##STR00254## Compound 238:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-({[(3-chlorophenyl)amino]ca- rbonyl}amino)-ethyl]-3,4-dimethoxybenzenesulfonamide

##STR00255## Compound 239:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(2}[(dimethylamino)carbonyl]am- ino}ethyl)-3,4-dimethoxybenzenesulfonamide

##STR00256## Compound 240:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-({[(2-chlorophenyl)amino]ca- rbonyl}amino)ethyl]-3,4-dimethoxybenzenesulfonamide

##STR00257## Compound 241:

N.about.2.about.-[5-bromo-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00258## Compound 242:

N.about.2.about.-[4-bromo-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-[- (3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00259## Compound 243:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[1-(2-methyl-2H-- tetrazol-5-yl)ethyl]benzenesulfonamide

##STR00260## Compound 244:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[1-(1-methyl-1H-- tetrazol-5-yl)ethyl]benzenesulfonamide

##STR00261## Compound 245:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(3-pyridin-3-ylp- ropyl)benzenesulfonamide

##STR00262## Compound 246:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(1-cyanoethyl)-3,4-dimethoxybe- nzenesulfonamide

##STR00263## Compound 247:

N.about.2.about.-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.about.2.about.- -[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00264## Compound 248:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(cyclopropylmethyl)-3,4-dimeth- oxybenzenesulfonamide

##STR00265## Compound 249:

N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(4-chloro-2,5-dimethylphenyl)sulfonyl]glycinamide

##STR00266## Compound 250:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-pyridin-2-yle- thyl)benzenesulfonamide

##STR00267## Compound 251:

N.about.2.about.-{4-chloro-2-[(2,6-difluorophenyl)(hydroxy)methyl]phenyl}-- N.about.2.about.-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00268## Compound 252:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-({[(3,4-dimethoxyphenyl)ami- no]carbonyl}amino)ethyl]-3,4-dimethoxybenzenesulfonamide

##STR00269## Compound 253:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-{[(methylamin- o)carbonyl]amino}ethyl)-benzenesulfonamide

##STR00270## Compound 254:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-pyridin-3-yle- thyl)benzenesulfonamide

##STR00271## Compound 255:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-pyridin-4-yle- thyl)benzenesulfonamide

##STR00272## Compound 256:

N-(2-aminoethyl)-N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybe- nzenesulfonamide

##STR00273## Compound 257:

N-(2-aminoethyl)-N-[2-(2,5-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxybe- nzenesulfonamide

##STR00274## Compound 258:

N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxy-N-[2-(methylamino)- ethyl]benzenesulfonamide

##STR00275## Compound 259:

N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(4-methoxy-3-methylphenyl)sulfonyl]glycinamide

##STR00276## Compound 260:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-phenoxyethyl)- benzenesulfonamide

##STR00277## Compound 261:

N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(3,4-dimethoxyphenyl)sulfonyl]alaninamide

##STR00278## Compound 262:

N-(2-aminoethyl)-N-[4-chloro-2-(2,5-difluorobenzyl)phenyl]-3,4-dimethoxybe- nzenesulfonamide

##STR00279## Compound 263:

N.about.2.about.-[(4-tert-butylphenyl)sulfonyl]-N.about.2.about.-[4-chloro- -2-(2,6-difluorobenzyl)phenyl]glycinamide

##STR00280## Compound 264:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(2-hydroxy-1-methylethyl)-3,4-- dimethoxybenzenesulfonamide

##STR00281## Compound 265:

N.about.2.about.-[2-(2-chlorobenzyl)-4-(dimethylamino)phenyl]-N.about.2.ab- out.-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00282## Compound 266:

4-{[4-chloro-2-(2,5-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]a- mino}-butanamide

##STR00283## Compound 267:

N.about.2.about.-[4-chloro-2-(2,5-difluorobenzyl)phenyl]-N.about.2.about.-- [(4-chloro-2,5-dimethylphenyl)sulfonyl]glycinamide

##STR00284## Compound 268:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-(1,3-dioxolan-2-yl)ethyl]-3- ,4-dimethoxybenzenesulfonamide

##STR00285## Compound 269:

phenyl (2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)su- lfonyl]amino}ethyl)-carbamate

##STR00286## Compound 270:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(3-hydroxypropyl)-3,4-dimethox- ybenzenesulfonamide

##STR00287## Compound 271:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-(1H-imidazol-1-yl)ethyl]-3,- 4-dimethoxybenzenesulfonamide

##STR00288## Compound 272:

4-{[2-(2,6-difluorobenzyl)-6-methoxyphenyl][(3,4-dimethoxyphenyl)sulfonyl]- amino}-butanamide

##STR00289## Compound 273:

N.about.3.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.3.about.-- [(3,4-dimethoxyphenyl)sulfonyl]-beta-alaninamide

##STR00290## Compound 274:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(2R)-pyrrolidin- -2-ylmethyl]benzenesulfonamide

##STR00291## Compound 275:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(2S)-pyrrolidin- -2-ylmethyl]benzenesulfonamide

##STR00292## Compound 276:

2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]a- mino}-2-ethoxyacetamide

##STR00293## Compound 277:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[2-(1H-1,2,4-tri- azol-1-yl)ethyl]benzenesulfonamide

##STR00294## Compound 278:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(2-{[2-(dimethylamino)ethyl]am- ino}ethyl)-3,4-dimethoxybenzenesulfonamide

##STR00295## Compound 279:

N.about.2.about.-[(4-aminophenyl)sulfonyl]-N.about.2.about.-[4-chloro-2-(2- ,6-difluorobenzyl)phenyl]glycinamide

##STR00296## Compound 280:

N.about.2.about.-[2-(2,5-difluorobenzyl)-4-methylphenyl]-N.about.2.about.-- [(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00297## Compound 281:

N-(2-aminoethyl)-N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-3,4-dimethoxyb- enzenesulfonamide

##STR00298## Compound 282:

N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-3,4-dimethoxy-N-[2-(methylamino- )ethyl]benzenesulfonamide

##STR00299## Compound 283:

N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(6-methoxypyridin-3-yl)sulfonyl]glycinamide

##STR00300## Compound 284:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[2-(methylamino)- ethyl]benzenesulfonamide

##STR00301## Compound 285:

N.about.2.about.-[2-(2,5-difluorobenzyl)-6-methoxyphenyl]-N.about.2.about.- -[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00302## Compound 286:

N.about.2.about.-[5-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00303## Compound 287:

N-(3-aminopropyl)-N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxyb- enzenesulfonamide

##STR00304## Compound 288:

N.about.2.about.-[2-(2,6-difluorobenzyl)-6-methylphenyl]-N.about.2.about.-- [(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00305## Compound 289:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-vinylbenzenesulf- onamide

##STR00306## Compound 290:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(1,3-thiazol-2-y- lmethyl)benzenesulfonamide

##STR00307## Compound 291:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(pyrimidin-2-ylm- ethyl)benzenesulfonamide

##STR00308## Compound 292:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-morpholin-4-y- lethyl)benzenesulfonamide

##STR00309## Compound 293:

N.about.2.about.-[2-chloro-6-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00310## Compound 294:

N-(2-aminoethyl)-N-[2-(2,5-difluorobenzyl)-6-methoxyphenyl]-3,4-dimethoxyb- enzenesulfonamide

##STR00311## Compound 295:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(pyridin-2-ylmet- hyl)benzenesulfonamide

##STR00312## Compound 296:

N.about.2.about.-[2-(2,6-difluorobenzyl)-5-methoxyphenyl]-N.about.2.about.- -[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00313## Compound 297:

N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-3,4-dimethoxy-N-methylbenzenesu- lfonamide

##STR00314## Compound 298:

3-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]a- mino}-butanamide

##STR00315## Compound 299:

4-{[2-(2,5-difluorobenzyl)-6-methoxyphenyl][(3,4-dimethoxyphenyl)sulfonyl]- amino}-butanamide

##STR00316## Compound 300:

N-(2-aminoethyl)-N-[4-chloro-2-(2,6-difluorobenzyl)-6-methoxyphenyl]-3,4-d- imethoxybenzenesulfonamide

##STR00317## Compound 301:

N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[2-(1H-imidazol-1-yl)ethyl]-3- ,4-dimethoxybenzenesulfonamide

##STR00318## Compound 302:

N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.about- .2.about.-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00319## Compound 303:

N.about.2.about.-[2-(2,6-difluorobenzyl)-6-methoxy-4-methylphenyl]-N.about- .2.about.-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

##STR00320## Compound 304:

(+)N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.abou- t.-[(3,4-dimethoxyphenyl)sulfonyl]alaninamide

##STR00321## Compound 305:

(-)N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.abou- t.-[(3,4-dimethoxyphenyl)sulfonyl]alaninamide

##STR00322## Compound 306:

N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-3,4-dimethoxy-N-[2-(1H-1,2,4-tr- iazol-1-yl)ethyl]benzenesulfonamide

##STR00323## Compound 307:

N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(3,5-dimethoxyphenyl)sulfonyl]glycinamide

##STR00324## Compound 308:

N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(3-methoxy-4-methylphenyl)sulfonyl]glycinamide

##STR00325## Compound 309:

N.about.2.about.-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.about.2.about.- -[(3,4-dimethoxyphenyl)sulfonyl]-N-ethylglycinamide

##STR00326## Compound 310:

N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(2-ethyl-2H-tetrazol-5-yl)me- thyl]-3,4-dimethoxybenzenesulfonamide

##STR00327## Compound 311:

N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(1-ethyl-1H-tetrazol-5-yl)me- thyl]-3,4-dimethoxybenzenesulfonamide

##STR00328## Compound 312:

N.about.2.about.-[(3,4-dimethoxyphenyl)sulfonyl]-N.about.2.about.-(3-metho- xybiphenyl-2-yl)glycinamide

##STR00329## Compound 313:

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-{2-[(methylsulfo- nyl)amino]ethyl}-benzenesulfonamide

##STR00330## Compound 314:

N.about.2.about.-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.about.2.about.-- [(2-fluoro-4,5-dimethoxyphenyl)sulfonyl]glycinamide

##STR00331## Compound 315:

methyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)- sulfonyl]-L-alaninate

##STR00332## Compound 316:

methyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)- sulfonyl]-L-alaninate

##STR00333## Compound 317:

methyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)- sulfonyl]-D-alaninate

##STR00334## Compound 318:

methyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)- sulfonyl]-D-alaninate

##STR00335## Compound 319:

N.about.2.about.-[(4-tert-butylphenyl)sulfonyl]-N.about.2.about.-[2-(2,6-d- ifluorobenzyl)-6-methoxyphenyl]glycinamide

##STR00336## Compound 320:

N.about.2.about.-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.about.2.about.- -[(3,4-difluorophenyl)sulfonyl]glycinamide

##STR00337## Compound 321:

N.sup.2-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.sup.2-[(3,4-dimethoxy phenyl)sulfonyl]-R-alaninamide

##STR00338## Compound 322:

N.sup.2-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]-S-alaninamide

##STR00339## Compound 323:

N.sup.2-[2-methoxy-6-(2-phenylethyl)phenyl]-N.sup.2-[(3,4-dimethoxy phenyl)sulfonyl]glycinamide

##STR00340##

In the context of the invention, the following meanings apply: a (C.sub.1-C.sub.4) alkyl group: a saturated, linear or branched aliphatic group containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; an optionally substituted (C.sub.1-C.sub.4) alkyl group: an alkyl group as defined above in which one or more hydrogen atoms have been substituted with a substituent; a (C.sub.3-C.sub.6) cycloalkyl group: a saturated cyclic alkyl group containing from 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkyl group may optionally be substituted with a (C.sub.1-C.sub.4) alkyl group, for example methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl or dimethylcyclohexyl; a (C.sub.1-C.sub.4) alkoxy group: a (C.sub.1-C.sub.4) alkyl-O-radical in which the (C.sub.1-C.sub.4) alkyl group is as defined above, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy; a (C.sub.1-C.sub.4) alkylcarbonyl group: a (C.sub.1-C.sub.4) alkyl-C(O)-group in which the (C.sub.1-C.sub.4) alkyl group is as defined above; a fluoro (C.sub.1-C.sub.4)alkyl group: a (C.sub.1-C.sub.4) alkyl group as defined above, one or more hydrogen atoms of which have been substituted with one or more fluorine atoms. Examples that may be mentioned include the --CF.sub.3 and --CH.sub.2--CF.sub.3 groups; a (C.sub.1-C.sub.4) alkenyl group: a linear or branched monounsaturated or polyunsaturated aliphatic group containing from 1 to 4 carbon atoms, for example having one or two ethylenic unsaturations; a fluoro (C.sub.1-C.sub.4)alkoxy group: a (C.sub.1-C.sub.4) alkoxy group as defined above, one or more hydrogen atoms of which have been substituted with one or more fluorine atoms. Examples that may be mentioned include the --O--CF.sub.3 and --O--CH.sub.2--CF.sub.3 groups; a halogen atom; a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an aryl group: a monocyclic or bicyclic aromatic group containing between 6 and 10 carbon atoms, for example phenyl or naphthyl. The aryl group may optionally be substituted with 1, 2, 3 or 4 substituents. Examples of substituents that may be mentioned include a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a fluoro (C.sub.1-C.sub.4)alkyl group, a fluoro (C.sub.1-C.sub.4)alkoxy group, a hydroxyl group, a --CN group, a nitro group and a group --CO--NR.sub.aR.sub.b with R.sub.a and R.sub.b being, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.4) alkyl group; a heterocyclyl group: a saturated, unsaturated or aromatic monocyclic or bicyclic group containing between 5 and 10 atoms and comprising from 1 to 4 hetero atoms chosen from nitrogen, oxygen and sulfur. Examples that may be mentioned include 1,3-dioxolanyl, imidazolyl, tetrazolyl, oxadiazolyl, pyridyl, thiazolyl, thienyl, pyrimidinyl and triazolyl. The heterocyclyl group may optionally be substituted with 1, 2, 3, 4 or 5 substituents. Examples of substituents that may be mentioned include a halogen atom, a (C.sub.1-C.sub.4) alkyl group, a (C.sub.1-C.sub.4) alkoxy group, a hydroxyl group and a --CN group.

As already indicated, the compounds of general formula (I) may comprise one or more asymmetric carbons. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

By virtue of their structure, the compounds of general formula (I) may also exist in the form of rotamers. In the context of the invention, the term "rotamers" means compounds that have identical structural formulae but different set spatial conformations. These differences in the set spatial conformations of these compounds can give them different physicochemical properties and even, in certain cases, different biological activities.

The compounds of general formula (I) may also exist in the form of atropoisomers. Atropoisomers are compounds of identical structural formulae, but which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance on either side of this single bond. Atropoisomerism is independent of the presence of stereogenic components, such as an asymmetric carbon.

The compounds of formula (I) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or separating the compounds of general formula (I) also form part of the invention.

The compounds of general formula (I) may also be in the form of hydrates or solvates, i.e. in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention.

In the text hereinbelow, the term "leaving group" means a group that may be readily cleaved from a molecule, with loss of an electron pair, by breaking a heterolytic bond. This group may thus be readily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, halogens, or an activated hydroxyl group such as a mesylate, tosylate, triflate, acetyl, etc. Examples of leaving groups and references for preparing them are given in "Advanced Organic Chemistry", J. March, 3.sup.rd Edition, Wiley Interscience, pp. 310-316.

A subject of the present invention is also the process for preparing the compounds of general formula (I).

Thus, the compounds of general formula (I) may be prepared via the processes illustrated in scheme 1. According to this scheme, the compounds of formula (I) may be obtained: either via alkylation of the compounds of general formula (II) with compounds of general formula (IV), in the presence of a base, according to an adaptation of the process described by Levin et al., Bioorg. Med. Chem., 2001, EN 11; 22; 2975-2978; or via a Mitsunobu reaction between the alcohols of formula (X) and the compounds of general formula (II).

In the compounds of general formulae (II), (IV) and (X), Ar.sub.1, Ar.sub.2, Ar.sub.3, T and R.sub.1 are as defined in formula (I) and Z is a leaving group such as a halogen atom chosen from bromine, chlorine and iodine; or alternatively a mesylate, a tosylate or a triflate.

The base may be an organic base, for instance potassium tert-butoxide, or a mineral base, for instance potassium carbonate, or alternatively a phase-transfer agent, for instance tetrabutylammonium bromide.

In the Mitsunobu reaction, diisopropyl azodicarboxylate (DIAD) may be replaced with analogues thereof, for instance diethyl azodicarboxylate and ditert-butyl azodicarboxylate, and the triphenylphosphine may be grafted onto a resin (R. G. Gentles et al., J. Comb. Chem. 2002, 4, 442-456).

##STR00341##

The compounds of structure (I) for which R.sup.1 is a sequence of the type --CR.sub.7R.sub.8--(CH.sub.2).sub.n--R.sub.9, with R.sub.9=--CONR.sub.12R.sub.13, may be obtained from the corresponding esters of formula --CR.sub.7R.sub.8--(CH.sub.2).sub.nCOOR.sub.14, according to the following reaction sequence: saponification of the carboxylate function --COOR.sub.14; activation of the carboxylic acid function generated, for example with chloroformates to form mixed anhydrides; amidation reaction with amines of the type NHR.sub.12R.sub.13 with n, R.sub.7, R.sub.8, R.sub.12, R.sub.13 and R.sub.14 as defined above.

The compounds of structure (I) for which R.sub.1 is a sequence of the type --CR.sub.7R.sub.8--(CH.sub.2).sub.n--R.sub.9 with R.sub.9=--NH--CO--NR.sub.15R.sub.16 may be obtained from compounds (I) for which R.sub.9.dbd.NH.sub.2 via the action of isocyanates of the type R.sub.15NCO or R.sub.16NCO with n, R.sub.7, R.sub.8, R.sub.15 and R.sub.16 as defined above.

The compounds of structure (I) for which R.sub.1 is a sequence of the type --CR.sub.7R.sub.8--(CH.sub.2).sub.n--R.sub.9, R.sub.9=--NR.sub.10R.sub.11 in which R.sub.10 and R.sub.11, independently of each other, represent a hydrogen atom and a (C.sub.1-C.sub.4) alkylcarbonyl group, may be obtained from compounds (I) for which R.sub.9.dbd.NH.sub.2 via the action of carboxylic acids of formula (C.sub.1-C.sub.4)alkyl-COOH or the acid chlorides thereof of formula (C.sub.1-C.sub.4)alkyl-COCl with n, R.sub.7, R.sub.8, R.sub.10 and R.sub.11, as defined above.

The compounds (I) for which R.sub.9 is a heterocyclyl group such as substituted tetrazolyl are obtained via standard chemical reactions known to those skilled in the art, from compounds (I) for which R.sub.9 is a cyano group.

The compounds of structure (I) for which T=--(CH.sub.2).sub.n with n=1 may be obtained, in certain cases, from compounds of structure (I) for which T=--CHOH, via the action of hydride, for example triethylsilane, in the presence of boron trifluoride etherate.

The compounds of structure (I) for which T=

##STR00342## with R.sub.2 being a hydroxyl group may be obtained, in certain cases, from the corresponding compounds for which

##STR00343## via the action of hydride, for example sodium borohydride.

The compounds of structure (II) are obtained beforehand according to scheme 2, via sulfonylation of the compound of formula (III) with sulfonyl chlorides of formula (V) in the presence of a base chosen from tertiary amines such as pyridine, according to the process described by Stauffer et al., Bioorg. Med. Chem., 2000, EN 8, 6, 1293-1316. Tertiary amines that may also be used include triethylamine and diisopropylethylamine.

In certain cases, it may even be envisaged to use a mixture of tertiary amines.

The compounds of formula (V) are commercial or may be obtained by adaptation of the processes described, for example, by A. J. Prinsen et al., Recl. Trav. Chim. Netherlands 1965, EN 84, 24.

In the compounds of formulae (III) and (V), Ar.sub.1, Ar.sub.2, Ar.sub.3 and T are as defined in formula (I).

##STR00344##

The compounds of formulae (IIIa), (IIIb) and (IIIf) are prepared according to schemes 3 to 5. The 2-nitroaldehyde derivatives of formula (VI) react with organometallic compounds of formula (VII) in which M represents an MgBr, MgI, ZnI or Li group to give the compounds of structure (VIII). The organometallic compounds of formula (VII) are commercial or are formed according to the standard processes described in the literature. The nitro alcohols of formula (VIII) are reduced via hydrogenation, for example under the action of tin metal and concentrated hydrochloric acid in ethanol, to give the compounds of structure (IIIb). The derivatives of formula (IIIb) are reduced via the action of hydrides, for example with a mixture of triethylsilane and trifluoroacetic acid in dichloromethane to give the derivatives of formula (IIIa).

The nitroaldehydes of formula (VI) are commercial or may be prepared, for example, according to an adaptation of the process described by J. Kenneth Horner et al., J. Med. Chem., 1968, 11; 5; 946.

##STR00345##

Other possibilities for synthesizing the compounds of general formula (IIIb) and (IIIf) are presented in scheme 4.

##STR00346##

The anilines of formula (IX) are condensed with nitriles of formula (XII), in the presence of a Lewis acid, for instance boron trichloride with aluminium trichloride or with gallium trichloride, to give the compounds of formula (IIIf), according to the process described by T. Sugasawa et al., J.A.C.S. 1978; 100; 4842. The compounds of formula (IIIf) may be obtained via condensation of aminonitriles (XI) with the organometallic derivatives (VII), according to the process described by R. Fryer et al., J. Heterocycl. Chem., 1991, EN 28; 7, 1661. The compounds of formula (IIIf) may also be obtained from the intermediate (XIV) according to an adaptation of the process described by D. Lednicer, J. Heterocyclic. Chem., 1971; 903.

The carbonyl function of the compounds (IIIf) is reduced via the action of a hydride, for example sodium borohydride in ethanol, to give the compounds of structure (IIIb).

Another method for preparing the compounds of formula (IIIb) consists in condensing the anilines of formula (IX) with benzaldehyde derivatives of formula (XIII) in the presence of phenyldichloroborane and triethylamine, according to the process described by T. Toyoda et al., Tet. Lett., 1980, 21, 173.

It should be noted that the compounds of formula (IIIf), under the action of triethylsilane and trifluoroacetic acid, for example, may give the compounds of formula (IIIa).

Another possibility for synthesizing the compounds of general formula (IIIa), in which Ar.sub.1 represents a heteroaryl, is presented in scheme 5.

##STR00347##

The nitrophenyls of formula (XVII) are condensed onto chloromethyl heteroaryls of formula (XVIII) in the presence of a base, for example potassium tert-butoxide, to give the derivatives (XIX) according to the process described by Florio S. et al., Eur. J. Org. Chem., 2004, 2118, which are reduced, for example, via the action of tin metal in the presence of 12M hydrochloric acid, to give the derivatives of formula (IIIa).

The compounds of formulae (IIIc) and (IIId) are prepared according to scheme 6.

The compounds of formula (IIIf), under the action of a (C.sub.1-C.sub.4) alkylmagnesium reagent, give the derivatives of formula (IIIc). These compounds are dehydroxylated under the action of aluminium trichloride and lithium aluminium hydride to give the compounds (IIId).

##STR00348##

The compounds of formula (IIIe) are prepared according to scheme 7. The derivatives (XV), under the action of a base, for example caesium carbonate and a C.sub.1-C.sub.4 alkyl halide, give the derivatives (XVI). The nitro group of these derivatives may be reduced, for example, in the presence of tin metal and hydrochloric acid in ethanol to give the compounds of formula (IIIe).

##STR00349##

The compounds of formula (IIIg) are prepared according to scheme 8. The nitroaldehydes (VI), via condensation with the derivatives (XX) according to a Wittig reaction, give the compounds (XXI). These derivatives are reduced, for example by catalytic hydrogenation with palladium, to give the compounds of formula (IIIg).

##STR00350##

In all the schemes and for all the compounds of formulae (II) to (XXI), the meanings of Ar.sub.1, T, Ar.sub.2, Ar.sub.3 and R.sub.1 are as defined for the compounds of general formula (I).

In schemes 1 to 8, the starting compounds and the reagents, when their mode of preparation is not described, are commercially available or described in the literature, or alternatively may be prepared via methods described therein or known to those skilled in the art.

When a compound comprises a reactive function, for example a hydroxyl group, it may necessitate prior protection before reaction. A person skilled in the art can determine the need for prior protection.

The compounds of formulae (II) to (XXI) are useful as synthetic intermediates for the preparation of the compounds of general formula (I) and form an integral part of the present invention.

The examples that follow describe the preparation of the compounds in accordance with the invention. These examples are not limiting and serve merely to illustrate the invention.

The numbers of the compounds given as examples refer to those given in the above table. The elemental microanalyses, the mass spectra and the NMR spectra confirm the structures of the compounds obtained.

The analysis conditions by liquid chromatography coupled to mass spectrometry LC/MS are the following: for the liquid chromatography part: C18 symmetry column (2.1.times.50 mm) 3-5 .mu.m. Eluent A=H.sub.2O+0.005% TFA, pH=3.14; eluent B=CH.sub.3CN+0.005% TFA, with a gradient of from 100% A to 90% B over 10 minutes, then 5 minutes at 90% B for the mass spectrometry part: positive electrospray ionization mode.

When the .sup.1H NMR spectrum reveals rotamers, only the interpretation corresponding to the major rotamer is described.

In the following tables: m.p. (.degree. C.) represents the melting point of the compound in degrees Celsius MH.sup.+ represents the mass peak of the ionized product the retention time is expressed in minutes n.d. means "not determined".

EXAMPLE 1

Ethyl N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(3,4-dimet- hoxyphenyl)sulfonyl]glycinate (compound 1)

EXAMPLE 1.1

N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3,4-dimethoxybenzene sulfonamide

To 5.3 g of (2-amino-5-chlorophenyl)(2-chlorophenyl)methanone dissolved in 50 ml of pyridine are added 5.29 g of 3,4-dimethoxybenzenesulfonyl chloride, and the mixture is left for 3 hours at room temperature. The reaction medium is concentrated, the residue is taken up in diisopropyl ether and the precipitate formed is filtered off to give, after drying, 5.2 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.75 (s, 3H); 3.83 (s, 3H); 7.06-7.69 (unresolved complex, 11H).

EXAMPLE 1.2

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzen- esulfonamide

16 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3,4-dimethoxybenzenesulfon- amide dissolved in 900 ml of ethanol are added portionwise 3.93 g of sodium borohydride, and the mixture is left for 18 hours at room temperature. The reaction medium is concentrated and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is solidified with diisopropyl ether; after filtering off and drying the precipitate, 14.66 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.77 (s, 3H); 3.84 (s, 3H); 6.27 (s, 1H); 6.96-7.44 (unresolved complex, 10H).

EXAMPLE 1.3

Ethyl N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(3,4-dimet- hoxyphenyl)sulfonyl]glycinate

To 6 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dime- thoxybenzenesulfonamide dissolved in 50 ml of DMF at 0.degree. C. is added portionwise 0.674 g of sodium hydride. After 1 hour at 0.degree. C., 1.4 ml of ethyl 2-bromoacetate are introduced and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 1.3 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.03 (t, 3H); 2.90 (d, 1H); 3.77 (s, 3H); 3.87 (t, 3H); 4.11 (d, 1H); 4.73 (q, 2H); 5.94 (d, 1H); 6.47 (s, 1H); 7.10-7.77 (unresolved complex, 10H). m.p.=86.degree. C.

Table I illustrates the chemical structures and physical properties of a number of compounds of the invention obtained according to this example.

TABLE-US-00001 TABLE I ##STR00351## Com- MH.sup.+/ pound Nature and position of the substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 8 H H CH.sub.2CO.sub.2Et 3,4-diOMe 58.8 486/8.15 7 H 4-Cl CH.sub.2CO.sub.2Et 3,4-diOMe 152 521/8.78 9 2-Cl 4-Cl CH.sub.2CO.sub.2Et 2,4-diOMe 155 555/9.34 10 2-Cl 4-Cl CH.sub.2CO.sub.2Et H 109.8 495/9.40 13 2-Cl 4-Cl CH.sub.2CO.sub.2Et 4-OMe 98.2 524/9.47 18 2-Cl 4-Cl CH.sub.2CO.sub.2Et 3,4-diCl 140 562/10.46 19 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 154.7 526/7.52 28 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-diMe 205 n.d. 31 2-Cl 4-Cl CH.sub.2CONH.sub.2 3-Cl 187 499/8.32 32 2-Cl 4-Cl CH.sub.2CONH.sub.2 4-OMe 207 495/7.86

EXAMPLE 2

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-ethyl-3,4-dimetho- xybenzenesulfonamide (compound 20)

To 1 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dime- thoxybenzenesulfonamide, obtained in Example 1.2, dissolved in 43 ml of acetonitrile are successively added 1.2 ml of triethylamine and 0.68 ml of iodoethane, and the mixture is refluxed for 8 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 4/6 (v/v) cyclohexane/ethyl acetate solvent mixture to obtain, after crystallization from cyclohexane, 0.418 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 0.12 (t, 3H); 2.94 (m, 1H); 3.21 (m, 1H); 3.75 (s, 3H); 3.88 (s, 3H); 6.02 (d, 1H); 6.51 (d, 1H); 6.80 (d, 1H); 6.96-7.49 (unresolved complex, 8H); 7.91 (d, 1H). m.p.=153.9.degree. C.

Table II illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this example.

TABLE-US-00002 TABLE II ##STR00352## Com- Nature and position of the substituents MH.sup.+/ pound m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 21 2-Cl 4-Cl CH.sub.2COCH.sub.3 3,4-diOMe 158.5 540/8.72 23 2-Cl 4-Cl (CH.sub.2).sub.2OMe 3,4-diOMe 112.2 526/8.77 29 2-Cl 4-Cl CH.sub.2CONH.sub.2 naphthyl 218 515/8.52 30 2-Cl 4-Cl CH.sub.2CONH.sub.2 3-OMe 114.8 495/7.87

EXAMPLE 3

N.sup.2-{4-chloro-2-[(2-chlorophenyl) (hydroxy)methyl]phenyl}-N.sup.2-[(2,4-dimethoxyphenyl)sulfonyl]-glycinami- de (compound 33)

To 1.5 g of N-{4-chloro-2-[(chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzene- sulfonamide, obtained in Example 1.2, dissolved in 15 ml of DMF are added at room temperature 1.25 g of caesium carbonate and 0.68 g of 2-bromoacetamide, and the mixture is maintained at 100.degree. C. for 2 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/methanol solvent gradient to give 0.601 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.85 (s, 6H); 4.40 (d, 1H); 4.66 (d, 1H); 6.45-7.62 (unresolved complex, 14H). m.p.=158.degree. C.

Table III illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this example.

TABLE-US-00003 TABLE III ##STR00353## Com- MH.sup.+/ pound Nature and position of the substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 36 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,5-diOMe 109 525/7.57 38 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,5-diMe, 126.3 527/9.16 4-Cl

EXAMPLE 4

N.sup.2-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2-[(3,4- -dichlorophenyl)sulfonyl]glycinamide (compound 34)

EXAMPLE 4.1

(2-amino-5-chlorophenyl)(2-chlorophenyl)methanol

To 20 g of (2-amino-5-chlorophenyl)(2-chlorophenyl)methanone dissolved in 80 ml of ethanol are introduced portionwise 8.6 g of sodium borohydride, and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 21.63 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 5.16 (s, 2H); 5.70 (d, 1H); 5.98 (d, 1H); 6.63 (d, 1H); 6.85-7.29 (unresolved complex, 6H).

EXAMPLE 4.2

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dichlorobenzene- sulfonamide

To 0.9 g of (2-amino-5-chlorophenyl)(2-chlorophenyl)methanol dissolved in 4 ml of pyridine is added 0.822 g of 3,4-dichlorobenzenesulfonyl chloride, and the mixture is left for 30 minutes at room temperature. The reaction medium is taken up in ethyl acetate and washed with water, and then with 1M hydrochloric acid solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.601 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 6,07 (s, 1H); 6.25 (s, 1H); 7.06-7.69 (unresolved complex, 11H).

EXAMPLE 4.3

N.sup.2-{4-chloro-2-[(2-chlorophenyl) (hydroxy)methyl]phenyl}-N.sup.2-[(3,4-dichlorophenyl)sulfonyl]glycinamide

To 1.315 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenze- nesulfonamide, obtained in Example 1.2, dissolved in 10 ml of tetrahydrofuran are added, at room temperature, 0.37 g of potassium tert-butoxide and 0.46 g of 2-bromoacetamide, and the mixture is refluxed for 3 hours. After 18 hours at room temperature, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/methanol solvent gradient to give 1.06 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 4.41 (q, 2H); 6.42 (d, 1H); 6.67 (s, 2H); 7.02 (m, 1H); 7.18-7.92 (unresolved complex, 10H) m.p.=135.degree. C.

Table IV illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this process.

TABLE-US-00004 TABLE IV ##STR00354## Compound Nature and position of the substituents m.p. MH.sup.+/retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 35 2-Cl 4-Cl CH.sub.2CONH.sub.2 4-Cl 130 499/8.41 37 2-Cl 4-Cl CH.sub.2CONH.sub.2 2-Cl 137 4997.75 41 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,3-diOMe 222 526/8.76 64 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,4- 102.1 523/7.64 ethylenedioxy 79 2-Cl 4-Cl CH.sub.2CONH.sub.2 2-Me 134 479/8.24 106 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,4,5-triMe 150.2 507/8.95 110 2-Cl 4-Cl CH.sub.2CONHMe 2,4,5-triMe 171.7 521/9.25 113 2-Cl 4-Cl CH.sub.2CONHMe 2,4,5-triOMe 119.6 569/7.67 129 2-Cl 4-Cl CH.sub.2CON(Me).sub.2 2,4-diCl-5-Me 204.8 557/10.35 132 2-Cl 4-Cl CH.sub.2CONHMe 3,5-diMe 109 489*/9.48 133 2-Cl 4-Cl CH.sub.2CON(Me).sub.2 3,5-diMe 142 520/9.85 52 2-Cl 4-Cl CH.sub.2CONH.sub.2 H 170.6 465/7.75 85 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,6-diCl 149 533/8.01 72 2-Cl 4-Cl CH.sub.2CONHMe 3,4-diOMe 88 539/7.89 86 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,5-diMe 137 493/8.60 94 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,5-diOMe, 4-Me 180.8 539/8.25 102 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,4,5-triOMe 123.5 555/7.36 83 2-Cl 4-Cl (3-methyl- 3,4-diOMe 90 564/9.15 1,2,4-oxadiazol- 5-yl) methyl 22 2-Cl 4-Cl (1-methyl- 3,4-diOMe 199 562/5.30 1H-imidazol- 2-yl) methyl 148 2-Cl 4-Cl CH.sub.2CONH.sub.2 3-NH2 189.6 462*/7.86 *the ion observed is the M-H.sub.2O + H.sup.+

Compound 83 is obtained by alkylation with the derivative 5-bromomethyl-3-methyl[1,2,4]oxadiazole, which is synthesized as follows:

Synthesis of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride

To 10.25 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid dissolved in 50 ml of dichloromethane are added, at room temperature, 4.6 ml of oxalyl chloride and 2 drops of DMF, and the mixture is left for 18 hours at room temperature. The resulting mixture is evaporated to dryness to give 11 g of the expected product.

Synthesis of 2-(3-methyl[1,2,4]oxadiazol-5-yl)isoindol-1,3-dione

To 4.4 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride in 20 ml of pyridine are added 1.48 g of acetamidoxime, and the mixture is refluxed for 1 hour. The reaction medium is concentrated and taken up in ethyl acetate and water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 7/3 (v/v) toluene/ethyl acetate mixture to give 1.2 g of expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.26 (s, 2H); 2.34 (s, 3H); 3.92 (s, 2H).

Synthesis of 1-(3-methyl[1,2,4]oxadiazol-5-yl)methanamine

To 5 g of 2-(3-methyl[1,2,4]oxadiazol-5-yl)isoindol-1,3-dione dissolved in 100 ml of ethanol are added 2 ml of hydrazine hydrate, and the mixture is refluxed for 2 hours. The insoluble material is filtered off and the filtrate is concentrated. The residue is taken up in diethyl ether, the insoluble material is filtered off and the filtrate is concentrated to give 2 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.39 (s, 3H); 4.88 (s, 2H).

Synthesis of 5-bromomethyl-3-methyl[1,2,4]oxadiazole

To 2.26 g of 1-(3-methyl[1,2,4]oxadiazol-5-yl)methanamine dissolved in 10 ml of water and 20 ml of 6M hydrobromic acid are added dropwise, at 70.degree. C., 2.76 g of sodium nitrite dissolved in 10 ml of water. After 1 hour at 80.degree. C., the medium is cooled to room temperature, taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 2.6 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.39 (s, 3H); 4.88 (s, 2H).

Compound 22 is obtained by alkylation with the derivative 2-chloromethyl-1-methylimidazole, which is synthesized as follows:

Synthesis of 1-methyl-2-imidazolemethanol

To 10 g of 1-methyl-2-imidazolecarboxaldehyde dissolved in 200 ml of methanol are added 5.2 g of sodium borohydride, and the mixture is left for 48 hours at room temperature. The solvents are evaporated off and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 6.5 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.67 (s, 3H); 4.49 (d, 2H); 5.36 (t, 1H); 6.78 (d, 1H); 7.08 (d, 1H). m.p.=108.2.degree. C.

Synthesis of 2-chloromethyl-1-methylimidazole

To 1.12 g of 1-methyl-2-imidazolemethanol are added dropwise 1.8 ml of thionyl chloride at 0.degree. C. After 18 hours at 20.degree. C., the mixture is heated at 70.degree. C. for 2 hours. The reaction medium is concentrated to give the expected product quantitatively.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.90 (s, 3H); 5.22 (s, 2H); 5.36 (t, 1H); 7.77 (d, 1H); 7.80 (d, 1H).

Compound 148 is obtained from the corresponding nitro derivative via a reduction reaction with nascent hydrogen.

EXAMPLE 5

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-met- hylbenzenesulfonamide (compound 25)

EXAMPLE 5.1

N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3,4-dimethoxy-N-methylbenzenesulfon- amide

To 1 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3,4-dimethoxybenzenesulf- onamide, obtained in Example 1.1, dissolved in 20 ml of dimethylformamide is added, at 0.degree. C., 0.094 g of sodium hydride; after one hour at this temperature, 0.16 ml of iodomethane is introduced and the mixture is left at room temperature for 18 hours. The precipitate is filtered off, taken up in ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The residue is washed with diethyl ether and filtered to give, after drying, 0.735 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.75 (s, 3H); 3.69 (s, 3H); 3.86 (s, 3H); 6.76-7.15 (unresolved complex, 4H); 7.51-7.75 (unresolved complex, 6H). m.p.=136.6.degree. C.

EXAMPLE 5.2

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-met- hylbenzenesulfonamide

To 0.152 g of the compound obtained in Example 5.1 dissolved in 5 ml of ethanol is added 0.036 g of sodium borohydride and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is taken up in a minimum amount of ethyl acetate and the precipitate formed is filtered off and dried to give 0.067 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.33 (s, 3H); 3.75 (s, 3H); 3.88 (s, 3H); 6.06 (d, 1H); 6.45 (d, 1H); 6.68 (m, 1H); 6.96-7.81 (unresolved complex, 9H). m.p.=173.2.degree. C.

Table V illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this process.

TABLE-US-00005 TABLE V ##STR00355## MH.sup.+/ Com- Nature and position of the reten- pound substituents m.p. tion No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 66 H 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 201.6 491/ 7.39 137 H 4-Cl CH.sub.2CONHMe 3,4-diOMe 111.5 487*/ 8.58 57 2-F 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 192.1 509/ 7.10 *the ion observed is the M-H.sub.2O + H.sup.+

EXAMPLE 6

Synthesis of N.sup.2-{4-chloro-2-[hydroxy(3-methoxyphenyl)methyl]phenyl}-N.sup.2-[(3,4- -dimethoxyphenyl)sulfonyl]glycinamide (compound 51)

EXAMPLE 6.1

(2-amino-5-chlorophenyl)(3-methoxyphenyl)methanone

To 5 g of 2-amino-5-chlorobenzonitrile dissolved in 100 ml of diethyl ether are added dropwise, at -5.degree. C., 100 ml of a molar solution in tetrahydrofuran of 3-bromobenzenemagnesium, and the mixture is left for 18 hours at room temperature. The reaction medium is hydrolysed with ice containing 6M hydrochloric acid. The resulting mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a gradient of from 100 cyclohexane to 60/40 cyclohexane/dichloromethane (v/v) to give 7.26 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.83 (s, 3H); 6.92 (d, 1H); 7.10-7.50 (unresolved complex, 8H).

EXAMPLE 6.2

(2-amino-5-chlorophenyl)(3-methoxyphenyl)methanol

To 3.66 g of (2-amino-5-chlorophenyl)(3-methoxyphenyl)methanone dissolved in 15 ml of ethanol are added, at 20.degree. C., 1.59 g of sodium borohydride. After 24 hours at 20.degree. C., the reaction medium is concentrated, taken up in ethyl acetate and washed twice with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is solidified with dichloromethane to give 2.37 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.74 (s, 3H); 5.14 (s, 2H); 5.70 (d, 1H); 5.94 (d, 1H); 6.61 (d, 1H); 6.81-7.27 (unresolved complex, 6H).

EXAMPLE 6.3

N-{4-chloro-2-[(3-methoxyphenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenze- nesulfonamide

To 1 g of (2-amino-5-chlorophenyl)(3-methoxyphenyl)methanol dissolved in 6 ml of pyridine are added, at room temperature, 1.08 g of 3,4-dimethoxybenzenesulfonyl chloride. After 18 hours, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 1.65 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.74 (s, 3H); 3.75 (s, 3H) 3.85 (s, 3H); 6.07 (s, 1H); 6.25 (s, 1H); 6.76-7.33 (unresolved complex, 10H); 9.43 (s, 1H).

EXAMPLE 6.4

N.sup.2-{4-chloro-2-[hydroxy(3-methoxyphenyl)methyl]phenyl}-N.sup.2-[(3,4-- dimethoxyphenyl)sulfonyl]glycinamide

To 0.7 g of N-{4-chloro-2-[(3-methoxyphenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenz- enesulfonamide dissolved in 5 ml of THF are added, at room temperature, 0.2 g of potassium tert-butoxide and 0.25 g of 2-bromoacetamide. After 48 hours at 20.degree. C., the reaction medium is concentrated, taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 0.4 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.76 (s, 3H); 3.78 (s, 3H); 3.90 (s, 3H); 4.12-4.53 (unresolved complex, 2H); 6.16 (d, 1H); 6.47 (d, 1H); 6.81-7.42 (unresolved complex, 11H); 7.76 (s, 1H). m.p.=100.degree. C.

Table VI illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this process.

TABLE-US-00006 TABLE VI ##STR00356## MH.sup.+/ Com- Nature and position of the reten- pound substituents m.p. tion No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 16 3-Cl 4-Cl CH.sub.2CO.sub.2Et 3,4-diOMe 149 554/ 9.48 17 2-OMe 4-Cl CH.sub.2CO.sub.2Et 3,4-diOMe 119.6 550/ 8.98 26 2-Me 4-Cl CH.sub.2CO.sub.2Et 3,4-diOMe 85.4 534/ 9.04 44 3-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 120.1 525/ 8.95 59 4-OMe 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 181 521/ 7.30 68 2-OMe 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 104.6 521/ 7.26 131 2-Me 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 144.6 487/ 8.42 76 3-Cl 4-Cl CH.sub.2CONH.sub.2 3,4- 229 509/ methylene- 7.73 dioxy

EXAMPLE 7

N.sup.2-{4-chloro-2-{hydroxy[2-(trifluoromethyl)phenyl]methyl}phenyl)-N.su- p.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide (compound 125)

EXAMPLE 7.1

6-chloro-2-methylbenzo[d][1,3]oxazin-4-one

To 15 g of 2-amino-5-chlorobenzoic acid are added 80 ml of acetic anhydride, and the mixture is refluxed for 2 hours. The reaction medium is concentrated and the residue is recrystallized from ethanol. After filtering off and rinsing the precipitate, 10.25 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.40 (s, 3H); 7.58 (d, 1H) 7.97 (m, 2H).

EXAMPLE 7.2

(2-amino-5-chlorophenyl)-(2-trifluoromethylphenyl)methanone

To 1.1 g of magnesium in 22 ml of diethyl ether are added dropwise 6.05 ml of 2-trifluoromethylbromobenzene. To the magnesium reagent formed are added over 15 minutes 8 g of 6-chloro-2-methylbenzo[d][1,3]oxazin-4-one dissolved in 60 ml of dichloromethane, and the mixture is left for 18 hours at room temperature. The reaction medium is hydrolysed with saturated ammonium chloride solution and extracted with diethyl ether. After concentrating the organic phase, 7 ml of ethanol and 7 ml of 3M sodium hydroxide solution are added to the residue and the mixture is refluxed for 1 hour 30 minutes. At room temperature, the medium is extracted with diethyl ether and the ether phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed to give 3.3 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 6.98 (d, 1H); 7.08-7.58 (unresolved complex, 8H).

EXAMPLE 7.3

N-[4-chloro-2-(2-trifluoromethylbenzoyl)phenyl]-3,4-dimethoxybenzenesulfon- amide

Starting with 3.295 g of (2-amino-5-chlorophenyl)(2-trifluoromethylphenyl)methanone according to the process described in Example 1.1, 1.22 g of the expected product are obtained.

EXAMPLE 7.4

N-{4-chloro-2-[(2-trifluoromethylphenyl)(hydroxy)methyl]phenyl}-3,4-dimeth- oxybenzenesulfonamide

Starting with 3 g of N-[4-chloro-2-(2-trifluoromethylbenzoyl)phenyl]-3,4-dimethoxybenzenesulfo- namide according to the process described in Example 1.2, 1.566 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.76 (s, 3H); 3.84 (s, 3H); 6.27 (s, 1H); 6.96-7.44 (unresolved complex, 12H).

EXAMPLE 7.5

N.sup.2-{4-chloro-2-{hydroxy[2-(trifluoromethyl)phenyl]methyl}phenyl}-N.su- p.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

Starting with 0.7 g of N-{4-chloro-2-[(2-trifluoromethylphenyl)(hydroxy)methyl]phenyl}-3,4-dimet- hoxybenzenesulfonamide according to the process described in Example 1.3, 0.265 g of expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.77 (s, 3H); 3.94 (s, 3H); 4.14-4.41 (unresolved complex, 2H); 6.50 (s, 1H); 6.80 (d, 1H); 6.80-7.88 (unresolved complex, 12H). m.p.=128.8.degree. C.

EXAMPLE 8

N.sup.2-{2-[(2-chlorophenyl) (hydroxy)methyl]-4-fluorophenyl}-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]g- lycinamide (compound 61)

EXAMPLE 8.1

(2-nitro-5-fluorophenyl)(2-chlorophenyl)methanone

To 2.6 g of chromium trichloride suspended in 50 ml of THF are successively added 30 ml of a 0.5M solution in THF of 2-chlorophenyliodozinc, 2.54 g of 2-nitro-5-fluorobenzaldehyde and 5.7 ml of trimethylsilyl chloride. The mixture is heated at 65.degree. C. for 1 hour and then left at room temperature for 18 hours. 1M hydrochloric acid solution is added to the reaction medium, the precipitate formed is filtered off and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with cyclohexane, to give 1 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 6.95 (d, 1H); 7.05-7.57 (unresolved complex, 8H)

EXAMPLE 8.2

(2-amino-5-fluorophenyl)-(2-chlorophenyl)methanol

To 0.5 g of (2-nitro-5-fluorophenyl)(2-chlorophenyl)methanone dissolved in 10 ml of ethanol are added 0.44 g of tin and 1.5 ml of 12M hydrochloric acid, and the mixture is left for 3 hours at room temperature. The reaction medium is concentrated and the residue is taken up in ethyl acetate and washed with 2M sodium hydroxide solution and then with saturated ammonium chloride solution. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 0.453 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 5.16 (s, 2H); 5.77 (d, 1H); 5.98 (d, 1H); 6.83-7.34 (unresolved complex, 7H).

EXAMPLE 8.3

N-{4-fluoro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzen- esulfonamide

Starting with 0.45 g of (2-amino-5-fluorophenyl)(2-chlorophenyl)methanol according to the process described in Example 1.1, 0.56 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): n.d.

EXAMPLE 8.4

N.sup.2-{2-[(2-chlorophenyl)(hydroxy)methyl]-4-fluorophenyl}-N.sup.2-[(3,4- -dimethoxyphenyl)sulfonyl]glycinamide

Starting with 0.56 g of N-{4-fluoro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenze- nesulfonamide, according to the process described in Example 4.3, 0.3 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.76 (s, 3H); 3.86 (s, 3H); 4.05-4.46 (unresolved complex, 2H); 6.31 (d, 1H); 6.63 (m, 1H); 6.95-7.80 (unresolved complex, 12H). m.p.=232.degree. C.

Table VII illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 8 (activation of the reaction by addition of trimethylsilane and chromium trichloride described in Example 8.1 was not used for compounds 69, 136 and 175).

TABLE-US-00007 TABLE VII ##STR00357## MH.sup.+/ Com- Nature and position of the reten- pound substituents m.p. tion No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 69 2-Cl 4-OMe CH.sub.2CONH.sub.2 3,4-diOMe 235.3 521/ 6.88 136 2-Cl 4-Me CH.sub.2CONH.sub.2 3,4-diOMe 189.2 487/ 7.90 175 2-Cl 5-Cl CH.sub.2CONH.sub.2 3,4-diOMe 197.1 507*/ 8.15 *the ion observed is the M-H.sub.2O + H.sup.+

EXAMPLE 9

N.sup.2-{4-chloro-2-[(2,6-dichlorophenyl) (hydroxy)methyl]phenyl}-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamid- e (compound 117)

EXAMPLE 9.1

(2-nitro-5-chlorophenyl)(2,6-dichlorophenyl)methanol

To 16.75 g of 1,3-dichlorobenzene dissolved in 250 ml of THF are added dropwise, at -70.degree. C., 68 ml of a 1.6M solution in hexane of n-butyllithium. After one hour at -70.degree. C., 10 g of 5-chloro-2-nitrobenzaldehyde dissolved in THF are introduced and the mixture is left for 3 hours at this temperature. The resulting mixture is hydrolysed by addition of 5 ml of acetic acid and is allowed to warm to room temperature. The resulting mixture is concentrated and the residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate mixture to give 7.975 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 6.82 (s, 2H); 7.32-7.46 (unresolved complex, 3H); 7.65 (d, 1H); 7.90 (m, 1H).

EXAMPLE 9.2

(2-amino-5-chlorophenyl)(2,6-dichlorophenyl)methanol

To 3.9 g of (2-nitro-5-chlorophenyl)(2,6-dichlorophenyl)methanol dissolved in 37 ml of methanol are added 5.25 g of ammonium formate and 0.374 g of platinum oxide. The mixture is left for 5 hours at room temperature and then heated at 50.degree. C. for 18 hours. The resulting mixture is filtered through Celite and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate mixture to give 1.378 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 5.16 (s, 2H); 6.17 (d, 1H); 6.35 (d, 1H); 6.64 (d, 1H); 6.72 (s, 1H); 7.01 (m, 1H); 7.38-7.55 (unresolved complex, 3H).

EXAMPLE 9.3

N-{4-chloro-2-[(2,6-dichlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybe- nzenesulfonamide

Starting with 1.9 g of (2-amino-5-chlorophenyl)(2,6-dichlorophenyl)methanol according to the process described in Example 4.2, 1.47 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.76 (s, 3H); 3.84 (s, 3H); 6.53 (s, 1H); 6.83-7.48 (unresolved complex, 10H); 9.29 (s, 1H).

EXAMPLE 9.4

N.sup.2-{4-chloro-2-[(2,6-dichlorophenyl) (hydroxy)methyl]phenyl}-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamid- e

Starting with 0.7 g of N-{4-chloro-2-[(2,6-dichlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxyb- enzenesulfonamide according to the process described in Example 4.3, 0.23 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.76 (s, 3H); 3.86 (s, 3H); 4.27 (q, 2H); 6.42 (s, 1H); 6.91-7.89 (unresolved complex, 9H); 8.02 (s, 1H). m.p.=128.3.degree. C.

Table VIII illustrates the chemical structures and physical properties of a number of compounds of the invention obtained according to Example 9 (for all the compounds, the reduction described in Example 9.2 is performed using tin metal and 12M hydrochloric acid instead of ammonium formate and platinum oxide).

TABLE-US-00008 TABLE VIII ##STR00358## Com- pound Nature and position of the substituents m.p. MH.sup.+/retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 147 2,6-diF 4-Cl CH.sub.2CONH.sub.2 3,5-diMe 108.7 477/8.59 198 2,6-diF 4-Me CH.sub.2CONH.sub.2 3,4-diOMe 175.7 439*/7.40 206 2,6-diF 4-F CH.sub.2CONH.sub.2 3,4-diOMe 178.8 511/6.65 209 2,6-diF 4-OMe CH.sub.2CONH.sub.2 3,4-diOMe 114.2 523/7.14 221 2,6-diF 4,5-diCl CH.sub.2CONH.sub.2 3,4-diOMe 149.9 543/8.15 222 2-Cl, 6-F 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 147 565**/8.20 225.sup.# 2,6-diF 6-OMe CH.sub.2CONH.sub.2 3,4-diOMe 228.7 523*/6.81 226.sup.# 2,6-diF 6-OMe CH.sub.2CONH.sub.2 3,4-diOMe 210.1 523*/7.25 101 2,6-diF 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 134.1 527/7.02 *the ion observed is the M-H.sub.2O + H.sup.+, **the ion observed is the MNa.sup.+, .sup.#rotamers Enantiomers of compound 101 Dextrorotatory Levorotatory enantiomer enantiomer compound 251 Optical rotation -64.4 +62.4 [.alpha.].sub.D* C = 0.5 g/100 ml in methanol, at 25.degree. C. and at 589 nm.

EXAMPLE 10

N.sup.2-{4-chloro-2-[(2,5-dichlorophenyl) (hydroxy)methyl]phenyl}-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamid- e (compound 74)

EXAMPLE 10.1

(2-amino-5-chlorophenyl)(2,5-dichlorophenyl)methanone

To 28 ml of a 1M solution of trichloroborane at -5.degree. C. are added 5.6 g of 4-chloroaniline dissolved in 30 ml of 1,2-dichloroethane. After 45 minutes at +15.degree. C., 3.8 g of 2,5-dichlorobenzonitrile and 5 g of gallium trichloride are introduced and the mixture is refluxed for 3 hours. At room temperature, the resulting mixture is hydrolysed with 2M hydrochloric acid solution and maintained at 80.degree. C. for 2 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a cyclohexane/dichloromethane gradient to give 6.38 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 6.90-6.96 (m, 2H); 7.37 (d, 1H); 7.60-7.72 (unresolved complex, 5H).

EXAMPLE 10.2

(2-amino-5-chlorophenyl)(2,5-dichlorophenyl)methanol

To 6.38 g of (2-amino-5-chlorophenyl)(2,5-dichlorophenyl)methanone dissolved in 50 ml of ethanol are added 2.4 g of sodium borohydride, and the mixture is left for 18 hours at room temperature. The resulting mixture is concentrated and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 2.016 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 5.27 (s, 2H); 5.89 (d, 1H); 6.15 (d, 1H); 6.51 (d, 1H); 6.73 (d, 1H); 7.03 (d, 1H); 7.42-7.51 (m, 2H); 7.66 (s, 1H).

EXAMPLE 10.3

N-{4-chloro-2-[(2,5-dichlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybe- nzenesulfonamide

Starting with 2 g of (2-amino-5-chlorophenyl)(2,5-dichlorophenyl)methanol according to the process described in Example 4.2, 1.389 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.77 (s, 3H); 3.84 (s, 3H); 6.29 (s, 2H); 6.91 (d, 1H); 7.06-7.50 (unresolved complex, 8H); 9.25 (s, 1H).

EXAMPLE 10.4

N.sup.2-{4-chloro-2-[(2,5-dichlorophenyl) (hydroxy)methyl]phenyl}-N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamid- e

Starting with 2.42 g of N-{4-chloro-2-[(2,5-dichlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxyb- enzenesulfonamide, according to the process described in Example 4.3, 1.5 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.77 (s, 3H); 3.88 (s, 3H); 4.30 (q, 2H); 6.57-6.63 (m, 2H); 6.94-7.78 (unresolved complex, 11H). m.p.=132.degree. C.

Table IX illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 10 (for all these compounds in Example 10.1, the gallium trichloride is replaced with aluminium trichloride).

TABLE-US-00009 TABLE IX ##STR00359## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 77 2-Cl 4-OCF.sub.3 CH.sub.2CONH.sub.2 3,4-diOMe 116 n.d. 120 2-thiazolyl 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 93 497/6.42 121 2-thiazolyl 4-Cl CH.sub.2CONHMe 3,4-diOMe 225 511/6.72 126 2,3-diF 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 184.9 531**/8.16 127 2,3-diF 4-Cl CH.sub.2CONHEt 3,4-diOMe 93.4 555/8.86 128 2,3-diF 4-Cl CH.sub.2CON(Me).sub.2 3,4-diOMe 100.5 537**/8.88 149 2-F, 6-OMe 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 197.3 521*/7.66 146 2-thienyl 4-Cl CH.sub.2CONHMe 3,4-diOMe 121.2 493**/8.20 155 2-thienyl 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 119 479**/7.87 162 2,4,6-triF 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 118.8 527*/7.96 163 2,4-diF 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 161.9 509*/8.28 164 2-Cl 4,5-diCl CH.sub.2CONH.sub.2 3,4-diOMe 146.7 541*/8.79 167 2-F, 4-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 205.1 525*/8.79 176 2-F, 5-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 195.2 525*/8.71 178 3,5-diF 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 205.7 509*/8.93 184 4-pyridyl 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 122 492/5.14 191 2-Cl, 6-Ome 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 143.6 537*/8.10 194 2-F, 5-Me 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 120.5 505*/8.40 *the ion observed is the M-H.sub.2O + H.sup.+, **the ion observed is the MNa.sup.+

EXAMPLE 11

N.sup.2-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-5-methoxy-4-methylphenyl}- -N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide (compound 227)

EXAMPLE 11.1

(2-amino-4-methoxy-5-methylphenyl) (2,6-difluorophenyl)methanol

To 6.05 g of dichlorophenylborane dissolved in 40 ml of dichloromethane, at -20.degree. C., are successively added 5.226 g of 3-methoxy-4-methylaniline dissolved in 50 ml of dichloromethane, and 13.4 ml of triethylamine dissolved in 25 ml of dichloromethane. After 30 minutes at -20.degree. C., 5.412 g of 2,6-difluorobenzaldehyde dissolved in 60 ml of dichloromethane are introduced. After 24 hours at room temperature, the mixture is hydrolysed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. To the oil obtained, dissolved in 80 ml of diethyl ether, are added 80 ml of 2M sodium hydroxide solution and the mixture is left stirring for 18 hours. The phases are separated by settling and the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is solidified with n-pentane to give 5.069 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.98 (s, 3H); 3.69 (s, 3H); 4.74 (s, 2H); 5.79 (d, 1H); 5.98 (d, 1H); 6.30 (s, 1H); 6.75 (s, 1H); 7.06 (m, 2H); 7.41 (m, 1H).

EXAMPLE 11.2

N-{2-[(2,6-difluorophenyl) (hydroxy)methyl]-5-methoxy-4-methylphenyl}-3,4-dimethoxybenzenesulfonamid- e

Starting with 5.06 g of (2-amino-4-methoxy-5-methylphenyl) (2,6-difluorophenyl)methanol according to the process described in Example 4.2, 8.5 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.03 (s, 3H); 3.38 (s, 3H); 3.78 (s, 3H); 3.84 (s, 3H); 5.99 (s, 1H); 6.17 (s, 1H); 6.42 (s, 1H); 6.98-7.40 (unresolved complex, 7H); 8.98 (s, 1H).

EXAMPLE 11.3

N.sup.2-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-5-methoxy-4-methylphenyl}- -N.sup.2-[(3,4-dimethoxyphenyl)sulfonyl]glycinamide

Starting with 4.5 g of N-{2-[(2,6-difluorophenyl)(hydroxy)methyl]-5-methoxy-4-methylphenyl}-3,4-- dimethoxybenzenesulfonamide, according to the process described in Example 4.3, 3.8 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.18 (s, 3H); 3.43 (s, 3H); 3.79 (s, 3H); 3.87 (s, 3H); 4.09-4.37 (unresolved complex, 2H); 6.60 (d, 1H); 6.77-7.75 (unresolved complex, 11H). m.p.=203.8.degree. C.

Table X illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 11.

TABLE-US-00010 TABLE X ##STR00360## Compound Nature and position of the substituents m.p. MH.sup.+/retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 213 2-Cl, 6-Me 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 130 521/8.67 214.sup.# 2,6-diF 2,4-diCl CH.sub.2CONH.sub.2 3,4-diOMe 160.6 583**/7.80 216.sup.# 2,6-diF 2,4-diCl CH.sub.2CONH.sub.2 3,4-diOMe 235.1 583**/8.24 **the ion observed is the MNa.sup.+, .sup.#rotamers

Physical characteristics of the rotamers 214 and 216

TABLE-US-00011 ##STR00361## Com- t.sub.R = 7.80 .quadrature. = 3.78, s, 3H, OCH.sub.323; .quadrature. = 3.85, s, pound min 3H, OCH.sub.324; .quadrature. = 3.82, q, 2H, CH.sub.221; 214 543 .quadrature. = 6.21, d, 1H, J.sub.H7OH = 5.2, OH; .quadrature. = 6.57, a.m.u. d, 1H, J.sub.H7OH = 5.2, H7; .quadrature. = 6.62, s, 1H, (M-H.sub.2O)H.sup.+ NH.sub.2; .quadrature. = 6.90, t, 2H, 583 J.sub.H3H4 = J.sub.H5H4 = J.sub.H3F = J.sub.H5F = 8.4Hz, H3 and H5; a.m.u. .quadrature. = 7.11, s, 1H, NH.sub.2; .quadrature. = 7.13, d, 1H, (MNa+) J.sub.H19H20 = 8.4, H19; .quadrature. = 7.29, m, 3H, H4, H16 and H20; .quadrature. = 7.51, s, 1H, JH.sub.11H13 = 2.8, H11; .quadrature. = 7.88, s, 1H, H13 Com- t.sub.R = 8.24 .quadrature. = 3.76, s, 3H, OCH.sub.323; .quadrature. = 3.86, s, pound min 3H, OCH.sub.324; .quadrature. = 4.04 and 4.53, d, 2H, 216 543 CH.sub.221; .quadrature. = 7.04, d, 1H, J.sub.H7OH = 5.6, H7; a.m.u. .quadrature. = 7.07, s, 1H, H13; .quadrature. = 7.13, m, 4H, (M-H.sub.2O)H.sup.+ H3, H5, H16, H19; .quadrature. = 7.30, dd, 1H, 583 J.sub.H20H19 = 8.8, J.sub.H20H16 = 1.6, H20; .quadrature. = 7.47, a.m.u. m, 1H, H4; .quadrature. = 7.58, s, 1H, NH.sub.2; .quadrature. = (MNa+) 7.63, d, 1H, J.sub.H11H13 = 2.4, H11; .quadrature. = 7.70, d, 1H, J.sub.OHH7 = 5.6, OH; .quadrature. = 8.05, s, 1H, NH.sub.2. .sup.1H NMR spectra acquired in DMSO, at a frequency of 400 Mz, the chemical shifts .quadrature. are expressed in ppm, the coupling constants J in hertz. Sample as a solution at 1 mg/ml of MeOH, 2 .mu.L injected. Mass spectrometry: positive electrospray, sweep from 120 to 1500 a.m.u.,

EXAMPLE 12

Ethyl N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(3-methoxyphenyl) sulfonyl]glycinate (compound 3)

EXAMPLE 12.1

[4-chloro-2-(2-chlorobenzyl)phenyl]amine

To 10 g of (2-amino-5-chlorophenyl) (2-chlorophenyl)methanone dissolved in 100 ml of dichloromethane are added at room temperature 18.7 ml of triethylsilane and 14.4 ml of trifluoroborane etherate, and the mixture is refluxed for 18 hours and then maintained at room temperature for 72 hours. The resulting mixture is hydrolysed with 2M sodium hydroxide solution, and the phases are separated by settling. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a cyclohexane/ethyl acetate solvent mixture to give 4.46 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.86 (s, 2H); 5.17 (s, 2H); 6.50 (d, 1H); 6.70 (d, 1H); 7.00-7.53 (unresolved complex, 5H).

EXAMPLE 12.2

N-[4-chloro-2-(2-chlorobenzyl)phenyl]-3-methoxybenzenesulfonamide

Starting with 0.71 g of [4-chloro-2-(2-chlorobenzyl)phenyl]amine dissolved in 5 ml of THF are added 0.4 ml of pyridine and 0.8 g of 3-methoxybenzenesulfonyl chloride, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate solvent mixture to give 0.666 g of expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.78 (s, 3H); 3.97 (s, 2H); 6.71 (d, 1H); 6.96 (m, 2H); 7.23-7.34 (unresolved complex, 6H); 7.46-7.54 (unresolved complex, 2H); 9.89 (s, 1H).

EXAMPLE 12.3

ethyl-N-[4-chloro-2-(2-chlorobenzyl)phenyl]-N-[(3-methoxyphenyl)sulfonyl]g- lycinate

To 0.525 g of N-[4-chloro-2-(2-chlorobenzyl)phenyl]-2-methoxybenzenesulfonamide dissolved in 6 ml of DMF is added, at 0.degree. C., 0.065 g of sodium hydride, after 40 minutes at this temperature 0.14 ml of ethyl 2-bromoacetate is introduced, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate solvent mixture to give 0.272 g of the expected product, in the form of an oil.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.18 (t, 3H); 3.82 (s, 3H); 3.98-4.12 (unresolved complex, 3H); 4.36 (s, 1H); 4.40 (q, 2H); 6.73 (d, 1H); 7.10-7.55 (unresolved complex, 10H).

Table XI illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 12.

TABLE-US-00012 TABLE XI ##STR00362## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 2 H 4-Cl CH.sub.2CO.sub.2Et 3,4-diOMe 139 504/9.06 4 2-Cl 4-Cl CH.sub.2CO.sub.2Et 2-OMe oil 508/10.03 5 2-Cl 4-Cl CH.sub.2CO.sub.2Et 2,5-diOMe 80 538/9.91 6 2-Cl 4-Cl CH.sub.2CO.sub.2Et 2,4-diOMe 80 538/9.98

EXAMPLE 13

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3-methoxyphenyl)sulf- onyl]glycinamide (compound 27)

To 1 g of N-[4-chloro-2-(2-chlorobenzyl)phenyl]-3-methoxybenzenesulfonami- de, obtained in Example 12.2, dissolved in 40 ml of acetonitrile are added at room temperature 1.34 ml of triethylamine, followed by 0.89 g of 2-bromoacetamide, and the mixture is refluxed for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate solvent mixture to give 0.58 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.82 (s, 3H); 4.08-4.58 (unresolved complex, 4H); 6.65 (s, 1H); 6.91 (d, 1H); 7.08-7.57 (unresolved complex, 11H). m.p.=65.7.degree. C.

EXAMPLE 14

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[(2- -methyl-2H-tetrazol-5-yl)methyl]benzenesulfonamide (compound 14) and N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[(- 1-methyl-1H-tetrazol-5-yl)methyl]benzenesulfonamide (compound 15)

EXAMPLE 14.1

N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-N-(cyanomethyl)3,4-dimethoxybenzene- sulfonamide

To 5.4 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3,4-dimethoxybenzenesulfonamide, obtained in Example 1.1, dissolved in 60 ml of DMF is added, at 0.degree. C., 0.57 g of sodium hydride; after 40 minutes at this temperature, 0.9 ml of 2-bromoacetonitrile is introduced and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 5.3 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.76 (s, 3H); 3.85 (s, 3H); 4.71 (m, 2H); 7.08-7.63 (unresolved complex, 9H); 7.81 (m, 1H). m.p.=164.degree. C.

EXAMPLE 14.2

N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3,4-dimethoxy-N-(1H-tetrazol-5-ylme- thyl)benzenesulfonamide

To 1 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-N-(cyanomethyl)-3,4-dime- thoxybenzenesulfonamide dissolved in 20 ml of THF are successively added 0.3 g of dibutyltin oxide and 2.6 ml of azidotrimethylsilane, and the mixture is refluxed for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by filtration on silica H, eluting with dichloromethane, to give 0.95 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.87 (s, 3H); 5.00 (s, 2H); 6.88-7.76 (unresolved complex, 10H).

EXAMPLE 14.3

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-(1H- -tetrazol-5-ylmethyl)benzenesulfonamide

To 0.95 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3,4-dimethoxy-N-(1H-tetrazol-5-ylm- ethyl)benzenesulfonamide dissolved in 40 ml of ethanol is added 0.38 g of sodium borohydride, and the mixture is refluxed for 18 hours. The solvents are evaporated off and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 0.93 g of the expected product.

EXAMPLE 14.4

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[(2- -methyl-2H-tetrazol-5-yl)methyl]benzenesulfonamide (compound 14) and N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[(- 1-methyl-1H-tetrazol-5-yl)methyl]benzenesulfonamide (compound 15)

To 0.93 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-(1- H-tetrazol-5-ylmethyl)benzenesulfonamide dissolved in 25 ml of DMF are successively added 0.2 ml of iodomethane and 0.32 g of potassium carbonate, and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol solvent mixture to give 0.34 g of compound 14.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.77 (s, 3H); 3.87 (s, 3H); 4.15 (s, 3H); 4.70 (d, 1H); 5.15 (d, 1H); 6.01 (d, 1H); 6.60-7.83 (unresolved complex, 11H). m.p.=94.8.degree. C.

0.19 g of compound 15 is obtained, the characteristics of which are as follows:

.sup.1H NMR .delta. in ppm (DMSO d6): 3.60 (s, 3H); 3.79 (s, 3H); 3.88 (s, 3H); 4.25 (d, 1H); 4.77 (d, 1H); 5.96 (d, 1H); 6.36 (d, 1H); 6.65-7.79 (unresolved complex, 10H). m.p.=118.3.degree. C.

The following compounds were synthesized according to this process: Compound 11: N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(2-ethyl-2H-tet- razol-5-yl)methyl]-3,4-dimethoxybenzenesulfonamide.

m.p.=113.degree. C. Compound 12: N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-[(1-ethyl-1H-tet- razol-5-yl)methyl]-3,4-dimethoxybenzenesulfonamide.

m.p.=75.degree. C.

EXAMPLE 15

N.sup.2-[4-chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(4-methoxyphenyl)sulf- onyl]glycinamide (compound 39)

To 0.766 g of N-[4-chloro-2-(2-chlorobenzyl)phenyl]-4-methoxybenzenesulfonamide, obtained according to Example 12.2, dissolved in 5 ml of THF are successively added 0.214 g of potassium tert-butoxide and 0.263 g of 2-bromoacetamide, and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/methanol gradient to give 0.50 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.89 (s, 3H); 4.02-4.29 (m, 3H); 4.58 (d, 1H); 6.66 (d, 1H); 6.89 (d, 1H); 7.14-7.65 (unresolved complex, 11H). m.p.=150.degree. C.

Table XII illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to an adaptation of Example 15.

TABLE-US-00013 TABLE XII ##STR00363## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 40 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,5-diOMe 125 509/8.93 42 2-Cl 4-Cl CH.sub.2CONH.sub.2 3-CF.sub.3 119 517/9.25 43 2-Cl 4-Cl CH.sub.2CONH.sub.2 3-OCF.sub.3 129 533/9.38 45 2-Cl 4-Cl CH.sub.2CONH.sub.2 2-OMe 114 479/8.18 46 2-Cl 4-Cl CH.sub.2CONHMe 3,4-diOMe 146 523/8.42 47 2-Cl 4-Cl CH.sub.2CONH.sub.2 4-Cl 205 483/9.06 48 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-diCl 166 517/9.64 49 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,5-diMe, 214.5 511/9.76 4-Cl 50 2-Cl 4-Cl CH.sub.2CONH.sub.2 2-Cl 97 483/8.44 53 2-Cl 4-Cl CH.sub.2CONH.sub.2 H 150 449/8.40 55 2-F 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 183.3 493/7.80 62 2-Cl 4-Cl CH.sub.2CONH.sub.2 3-Me 95 463/8.66 63 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-ethyl- 111.6 507/8.19 enedioxy 71 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-methyl- 89 493/8.29 enedioxy 75 2-Cl 4-Cl CH.sub.2CONHEt 3,4-diOMe 101 537/8.79 81 2-Cl 4-Cl CH.sub.2CONH.sub.2 2-Me 160 463/9.32 82 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,4-diMe 166 477/9.64 89 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,5-diMe 84 477/9.24 105 2-Cl 4-Cl CH.sub.2CONHMe 2,5-diMe, 172.6 525/10.24 4-Cl 109 2-Cl 4-Cl CH.sub.2CONHMe 2,4,5- 160.4 553/8.17 triOMe 104 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,4,5- 221.2 539/7.80 triOMe 119 2-Cl 4-Cl CH.sub.2CONH.sub.2 3,5-diOMe 110 509/8.71 118 2-Cl 4-Cl CH.sub.2CON(Me).sub.2 2,5-diMe, 166.4 539/10.71 4-Cl 134 2-Cl 4-Cl CH.sub.2CONH.sub.2 3-NO.sub.2 91 494/8.72 173 2-Cl 4-Cl CH.sub.2CONHMe 2,4-diCl, 108 545/10.74 5-Me 174 2-Cl 4-Cl CH.sub.2CON(Me).sub.2 2,4-diCl, 204 559/11.27 5-Me 54 2-Cl 4-Cl Me 3,4-diOMe 106.6 466/9.73 65 H 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 184 475/7.75 70 2-Cl 4-Cl CH.sub.2CON(Me).sub.2 3,4-diOMe 157.6 537/8.88 87 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,6-diCl 163 517/8.70 95 H 4-Cl CH.sub.2CON(Me).sub.2 3,4-diOMe 144.2 503/8.67 96 H 4-Cl CH.sub.2CONHMe 3,4-diOMe 89.6 489/8.25 97 2-F 4-Cl CH.sub.2CON(Me).sub.2 3,4-diOMe oil 521/8.63 98 2-F 4-Cl CH.sub.2CONHMe 3,4-diOMe 107.5 507/8.23 99 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,5-diOMe, 172.5 523/8.70 4-Me 114 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,4,5-triMe 184.9 491/9.48 115 2-Cl 4-Cl CH.sub.2CONHMe 2,4,5-triMe 188.5 505/9.82 84 2-Cl 4-Cl (3-methyl- 3,4-diOMe 111.4 548/10.20 1,2,4- oxadiazol- 5-yl)methyl 107 2-Cl 4-Cl (1-methyl-1H- 3,4-diOMe 105 546/6.32 imidazol-2- yl)methyl 112 2-Cl 4-Cl (1-methyl-1H- 3,5-diMe 112 514/6.98 imidazol-2- yl)methyl 135 2-Cl 4-Cl CH.sub.2CONH.sub.2 3-NH.sub.2 103 464/8.44 188 2,6- 4-Cl CH.sub.2CONH.sub.2 3-NMe.sub.2 190 494/9.17 diF 189 2,6- 4-Cl CH.sub.2CONH.sub.2 3-NHMe 195 480/8.65 diF 249 2,6- 4-Cl CH.sub.2CONH.sub.2 2,5-diMe, 196.8 513/9.50 diF 4-Cl 263 2,6- 4-Cl CH.sub.2CONH.sub.2 4-tBut 161.4 507/10.74 diF 279 2,6- 4-Cl CH.sub.2CONH.sub.2 4-NH.sub.2 111 n.d. diF 307 2,6- 4-Cl CH.sub.2CONH.sub.2 3,5-diOMe 170.2 511/9.48 diF 319 2,6- 6- CH.sub.2CONH.sub.2 4-tBut 173 503/10.1 diF OMe 320 2,6- 6- CH.sub.2CONH.sub.2 3,4-diF 259 483/9.13 diF OMe

Compound 84 is obtained by alkylation with the derivative 5-bromomethyl-3-methyl-[1,2,4]oxadiazole (synthesis described according to Example 4.3).

Compound 135 is obtained from 1.25 g of compound 134 by reduction of the nitro function as described in Example 8.2.

Compounds 188 and 189 are obtained by alkylation reaction with iodomethane in the presence of caesium carbonate in THF of N.sup.2-[3-aminophenyl)sulfonyl]-N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)- phenyl]glycinamide.

For compounds 54, 65, 95, 96, 97 and 98, the potassium tert-butoxide is replaced with sodium hydride.

Compound 312 is obtained according to this process, starting with 3-methoxybiphenyl-2-amine.

MH.sup.+=457; the retention time is 8.04 minutes m.p.=86.8.degree. C.

EXAMPLE 16

N.sup.2-[4-chloro-2-(2-methoxybenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl- )sulfonyl]glycinamide (compound 56)

EXAMPLE 16.1

(2-amino-5-chlorophenyl)(2-methoxyphenyl)methane

To 1.438 g of (2-amino-5-chlorophenyl)(2-methoxyphenyl)methanone, obtained according to the process described in Example 10.1, dissolved in 16 ml of dichloromethane are successively added 2.61 ml of triethylsilane and 4 ml of boron trifluoride etherate, and the mixture is refluxed for 18 hours. The cooled reaction medium is poured onto ice containing 2M sodium hydroxide solution, and, after separation of the phases by settling, the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel to give 0.571 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.70 (s, 2H); 3.80 (s, 3H); 5.05 (s, 2H); 6.65 (m, 2H); 6.88-7.29 (unresolved complex, 5H).

EXAMPLE 16.2

N-[4-chloro-2-(2-methoxybenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide

To 0.57 g of (2-amino-5-chlorophenyl)(2-methoxyphenyl)methane dissolved in 5 ml of THF are successively added 0.2 ml of pyridine and 0.547 g of 3,4-dimethoxybenzenesulfonyl chloride, and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.832 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.70 (s, 2H); 3.76 (s, 3H); 3.85 (s, 3H); 6.77-7.28 (unresolved complex, 10H) 9.52 (s, 1H).

EXAMPLE 16.3

N.sup.2-[4-chloro-2-(2-methoxybenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl- )sulfonyl]glycinamide

To 0.83 g of N-[4-chloro-2-(2-methoxybenzyl)phenyl]-3,4-methoxybenzenesulfonamide dissolved in 10 ml of DMF is added, at 0.degree. C., 0.081 g of sodium hydride. After 40 minutes at this temperature, 0.28 g of 2-bromoacetamide is introduced and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.77 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.80 (s, 6H); 3.88 (s, 3H); 3.91 (d, 1H); 4.18 (s, 2H); 4.30 (d, 1H); 6.75 (d, 1H); 6.91-7.28 (s, 11H).

Table XIII illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 16.

TABLE-US-00014 TABLE XIII ##STR00364## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 58 3-OMe 4-Cl CH.sub.2CONH.sub.2 3,4- 109 505/7.79 phenyl diOMe 60 4-OMe 4-Cl CH.sub.2CONH.sub.2 3,4- 214 505/7.73 phenyl diOMe 73 2-Me 4-Cl CH.sub.2CONH.sub.2 3,4- 88 489/8.12 phenyl diOMe 116 3-Cl 4-Cl CH.sub.2CONH.sub.2 3,4- 181.8 509/8.39 phenyl diOMe 212 2-Me 4-Cl CH.sub.2CONH.sub.2 3,4- 100.1 495/8.86 thienyl diOMe

EXAMPLE 17

N.sup.2-[4-chloro-2-(2,6-dichlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide (compound 78)

EXAMPLE 17.1

(2-amino-5-chlorophenyl)(2,6-dichlorophenyl)methane

To 4.85 g of (2-nitro-5-chlorophenyl)(2,6-dichlorophenyl)methanol, obtained in Example 9.1, dissolved in 58 ml of ethanol are added 5.042 g of tin and 19 ml of 12M hydrochloric acid, and the mixture is refluxed overnight. The reaction medium is concentrated and the residue is taken up in ethyl acetate and washed with water containing 2M sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 3.71 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.99 (s, 2H); 6.00 (d, 1H); 6.73 (d, 1H); 6.98 (d, 1H); 7.39-7.61 (unresolved complex, 3H).

EXAMPLE 17.2

N-[4-chloro-2-(2,6-dichlorobenzyl)phenyl]-3,4-methoxybenzenesulfonamide

Starting with 2 g of (2-amino-5-chlorophenyl)(2,6-dichlorophenyl)methane according to the process described in Example 12.2, 0.389 g of the expected product is obtained.

EXAMPLE 17.3

N.sup.2-[4-chloro-2-(2,6-dichlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

To 0.38 g of N-[4-chloro-2-(2,6-dichlorobenzyl)phenyl]-3,4-methoxybenzenesulfonamide dissolved in 4 ml of DMF is added, at 0.degree. C., 0.035 g of sodium hydride; after 40 minutes at this temperature, 0.121 g of 2-bromoacetamide is added and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 98/2 (v/v) dichloromethane/methanol mixture to give 0.225 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.80 (s, 3H); 3.88 (s, 3H); 4.10-4.70 (unresolved complex, 4H); 6.30 (d, 1H); 7.03-7.61 (unresolved complex, 10H). m.p.=195.3.degree. C.

Table XIV illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 17.

TABLE-US-00015 TABLE XIV ##STR00365## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 130 2,6- 4-Cl CH.sub.2CONHMe 3,4- 149.3 557/9.13 diCl diOMe 166 2,6- 4-Cl CH.sub.2CON(Me).sub.2 3,4- 102.7 571/9.63 diCl diOMe 67 2-Cl H CH.sub.2CONH.sub.2 3,4- 240.2 475/7.45 diOMe 91 2,6- 4-Cl CH.sub.2CONH.sub.2 3,4- 231.6 511/8.48 diF diOMe 242 2,6- 4-Br CH.sub.2CONH.sub.2 3,4- 209.7 555/8.31 diF diOMe 280 2,6- 4-Me CH.sub.2CONH.sub.2 3,4- 180.4 490/8.80 diF diOMe 286 2,6- 4-Cl CH.sub.2CONH.sub.2 3,4- 165.3 511/8.89 diF diOMe 297 2,6- 6- CH.sub.3 3,4- 116 464/9.92 diF OMe diOMe 308 2,6- 4-Cl CH.sub.2CONH.sub.2 3,4- 169 495/9.84 diF diOMe 314 2,6- 4-Cl CH.sub.2CONH.sub.2 2-F; 212.3 525/8.96 diF 4,5- diOMe

EXAMPLE 18

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-N.sup.1-methylglycinamide (compound 139)

EXAMPLE 18.1

(2-amino-5-chlorophenyl)(2,6-fluorophenyl)methane

To 1 g of (2-amino-5-chlorophenyl)(2,6-fluorophenyl)methanol, obtained according to Example 9.2, dissolved in 10 ml of dichloromethane are added 1.8 ml of triethylsilane and 0.86 ml of trifluoroacetic acid, and the mixture is maintained at 50.degree. C. for 6 hours. The reaction medium is added to ice and taken up in dichloromethane and 100 ml of 2M sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/cyclohexane mixture to give 0.997 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.77 (s, 2H); 5.26 (s, 2H); 6.36 (s, 1H); 6.70 (d, 1H); 6.99 (m, 1H); 7.18 (t, 2H); 7.48 (m, 1H).

EXAMPLE 18.2

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide

Starting with 0.97 g of (2-amino-5-chlorophenyl)(2,6-fluorophenyl)methane according to an adaptation of the process described in Example 12.2, 1.58 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.76 (s, 3H); 3.85 (s, 3H); 3.96 (s, 2H); 6.64 (s, 1H); 6.90 (d, 1H); 7.10-7.50 (unresolved complex, 7H); 9.69 (s, 1H). m.p.=144.degree. C.

EXAMPLE 18.3

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-N.sup.1-methylglycinamide

Starting with 0.7 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide according to an adaptation of process 15 (presence of co-solvent such as DMF and of sodium iodide), 0.669 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.53 (s, 3H); 3.81 (s, 3H); 3.89 (s, 3H); 4.02-4.61 (unresolved complex, 4H); 6.62 (s, 1H); 6.86 (d, 1H); 7.15-7.31 (unresolved complex, 6H); 7.47 (m, 1H); 7.90(m, 1H). m.p.=92.9.degree. C.

Table XV illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 18.

TABLE-US-00016 TABLE XV ##STR00366## Nature and position of the MH.sup.+/ Compound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 140 2,6-diF 4-Cl propyl 3,4-diOMe 135.1 496/10.82 150 2,6-diF 4-Cl CH.sub.2CON(Me).sub.2 3,4-diOMe 130.2 539/9.2 145 2,6-diF 4-Cl (CH.sub.2).sub.2N(Me).sub.2 3,4-diOMe 121.2 525/6.47 144 2,6-diF 4-Cl Me 3,4-diOMe 191.8 468/10.05 156 2,6-diF 4-Cl ##STR00367## 3,4-diOMe 128.2 687/9.78 169 2,6-diF 4-Cl CH.sub.2CONH.sub.2 3,5-diMe 146 479/9.49 171 2,6-diF 4-Cl CH.sub.2CONHMe 3,5-diMe 196 493/9.80 185 2,6-diF 4-Cl prop-2-yn-1-yl 3,4-diOMe 172 492/10.13 193 2,6-diF 4-OMe CH.sub.2CONH.sub.2 3,4-diOMe 189.7 507/7.93 195 2,6-diF 3-Cl CH.sub.2CONH.sub.2 3,4-diOMe 193.5 511/8.33 285 2,5-diF 6-OMe CH.sub.2CONH.sub.2 3,4-diOMe 193 507/8.58 200 2,6-diF 4-Me CH.sub.2CONH.sub.2 3,4-diOMe 196 491/8.20 202 2,6-diF 5-N(Me).sub.2 CH.sub.2CONH.sub.2 3,4-diOMe 141 520/7.84 205 2,6-diF 4-Me CH(Et)CONH.sub.2 3,4-diOMe 197.6 519/8.84 211 2,6-diF 4-Cl CH.sub.2CN 3,4-diOMe 61.7 493/9.84 220 2,6-diF 4-F CH.sub.2CONH.sub.2 3,4-diOMe 184.7 495/8.16 224 2-Cl, 4-Cl CH.sub.2CONH.sub.2 3,4-diOMe 230 527/8.77 6-F 181 2,6-diF 4-Cl (1-methyl-1H-imidazol- 3,4-diOMe 87 547/6.65 2-yl)methyl 210 2,6-diF 3,6-diOMe CH.sub.2CONH.sub.2 3,4-diOMe 242.9 537/7.88 246 2,6-diF 4-Cl CH(CH.sub.3)CN 3,4-diOMe 143.4 507/10.82 288 2,6-diF 6-Me CH.sub.2CONH.sub.2 3,4-diOMe 225.6 491/8.61 293 2,6-diF 6-Cl CH.sub.2CONH.sub.2 3,4-diOMe 227.4 511/8.63

For compounds 193, 195 and 220, the potassium tert-butoxide is replaced with sodium hydride.

EXAMPLE 19

N.sup.2-[4-chloro-2-(2,5-dichlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide (compound 80)

EXAMPLE 19.1

(2-amino-5-chlorophenyl)(2,5-dichlorophenyl)methane

Starting with 1.72 g of (2-amino-5-chlorophenyl)(2,5-dichlorophenyl)methanol, obtained in Example 10.2 according to the process described in Example 18.1, 1.41 g of the expected product are obtained.

EXAMPLE 19.2

N-[4-chloro-2-(2,5-chlororobenzyl)phenyl]-3,4-methoxybenzenesulfonamide

Starting with 1.41 g of (2-amino-5-chlorophenyl)(2,5-dichlorophenyl)methane according to an adaptation of the process described in Example 12.2, 2.3 g of the expected product are obtained.

EXAMPLE 19.3

N.sup.2-[4-chloro-2-(2,5-dichlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide

Starting with 2.3 g of N-[4-chloro-2-(2,5-chlororobenzyl)phenyl]-3,4-methoxybenzenesulfonamide according to an adaptation of the process described in Example 15, 1 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.80 (s, 3H); 3.89 (s, 3H); 4.01-4.69 (unresolved complex, 4H); 6.72 (s, 1H); 6.89 (d, 1H); 7.15-7.61 (unresolved complex, 9H). m.p.=200.degree. C.

Table XVI illustrates the chemical structures and physical properties of a number of compounds of the invention obtained according to Example 19.

TABLE-US-00017 TABLE XVI ##STR00368## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 142 2,3- 4-Cl CH.sub.2CONH.sub.2 3,4- 172.2 511/8.70 diFphenyl diOMe 143 2,3- 4-Cl CH.sub.2CON(Me).sub.2 3,4- 88.2 539/9.43 diFphenyl diOMe 141 2,3- 4-Cl CH.sub.2CONHMe 3,4- 150.9 525/9.01 diFphenyl diOMe 170 2-F, 6- 4-Cl CH.sub.2CONH.sub.2 3,4- 160 523/8.56 OMe diOMe phenyl 180 2-thienyl 4-Cl CH.sub.2CONH.sub.2 3,4- 183.9 481/8.41 diOMe 192 2-Cl, 6- 4-Cl CH.sub.2CONH.sub.2 3,4- 180.6 539/8.82 OMe diOMe phenyl

EXAMPLE 20

N.sup.2-[4,5-dichloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]glycinamide (compound 161)

To 0.9 g of (N.sup.2-{4,5-dichloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N.sup.2- [(phenyl)sulfonyl]glycinamide, obtained according to Example 10.4, dissolved in 10 ml of dichloromethane are added 0.77 ml of triethylsilane and 1.2 ml of trifluoroborane etherate, and the mixture is maintained at 40.degree. C. for 3 hours. The reaction medium is taken up in dichloromethane and 100 ml of 2M sodium hydroxide solution. After separation of the phases by settling, the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/ethyl acetate mixture to give 0.622 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.81 (s, 3H); 3.90 (s, 3H); 4.07-4.19 (unresolved complex, 3H); 4.51 (d, 1H); 6.87 (s, 1H); 7.14-7.57 (unresolved complex, 10H). m.p.=163.degree. C.

Table XVII illustrates the chemical structures and physical properties of a number of compounds of the invention obtained according to Example 20.

TABLE-US-00018 TABLE XVII ##STR00369## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 177 2,5-diF 4-Cl CH.sub.2CONH.sub.2 3,4- 216.5 511/8.75 diOMe 182 2-F, 5- 4-Cl CH.sub.2CONH.sub.2 3,4- 210.3 527/9.09 Cl diOMe 183 3,5-diF 4-Cl CH.sub.2CONH.sub.2 3,4- 184 511/8.96 diOMe 196 2-F, 5- 4-Cl CH.sub.2CONH.sub.2 3,4- 231.6 507/8.98 Me diOMe 100 2-Cl 4-Cl CH.sub.2CONH.sub.2 2,4- 228.3 531/9.72 diCl, 5-Me 168 2-F, 4- 4-Cl CH.sub.2CONH.sub.2 3,4- 195.2 527/9.32 Cl diOMe 208 2,6-diF 4,6- CH.sub.2CONH.sub.2 3,4- 191 537/7.98 diOMe diOMe 228 2,6-diF 4,5- CH.sub.2CONH.sub.2 3,4- 181.1 545/8.98 diCl diOMe 103 2-Cl 4-Et CH.sub.2CONMe.sub.2 3,4- 142.7 531/8.99 diOMe 93 2-Cl 4-Et CH.sub.2CONH.sub.2 3,4- 86 503/8.21 diOMe

Compound 247 is prepared from (N.sup.2-{2-[{2,6-difluorophenyl)(hydroxy)methyl]-6-methoxyphenyl}-N.sup.- 2-[(3,4-dimethoxyphenyl}sulfonyl]glycinamide obtained according to Example 9.4.

m.p.=244.9; MH.sup.+=507; the retention time is 8.37 minutes.

EXAMPLE 21

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-te- trazol-5-yl)methyl]benzenesulfonamide (compound 152) and N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(2-methyl-2H-t- etrazol-5-yl)methyl]benzenesulfonamide (compound 151)

EXAMPLE 21.1

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1H-tetrazol-5-- yl)methyl]benzenesulfonamide

To 8.7 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(cyanomethyl)-3,4-dimethoxybe- nzenesulfonamide (compound 211), obtained in Example 18, dissolved in 100 ml of THF are added, at room temperature, 10 g of azidotrimethylsilane and 2.29 g of dibutyltin oxide, and the mixture is refluxed for 8 hours. The reaction medium is concentrated and the residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture to give 7 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.82 (s, 3H); 3.90 (s, 3H); 4.05 (q, 2H); 4.88 (d, 1H); 5.29 (d, 1H); 6.60 (s, 1H); 6.85 (d, 1H); 7.12-7.49 (unresolved complex, 7H).

EXAMPLE 21.2

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-te- trazol-5-yl)methyl]benzenesulfonamide

To 2.7 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1H-tetrazol-5- -yl)methyl]benzenesulfonamide dissolved in 50 ml of DMF are added, at room temperature, 1.07 g of iodomethane and 1.04 g of potassium carbonate. After 48 hours at room temperature, the medium is poured into water and then extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) toluene/ethyl acetate mixture to give 1 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-t- etrazol-5-yl)methyl]benzenesulfonamide (compound 152) .sup.1H NMR .delta. in ppm (DMSO d6): 3.81 (s, 3H); 3.90 (s, 3H); 3.93 (q, 1H); 4.05 (m, 4H); 4.93 (d, 1H); 5.42 (d, 1H); 6.58 (s, 1H); 7.00 (d, 1H); 7.10-7.46 (unresolved complex, 7H). m.p.=180.8.degree. C. and 0.71 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(2-methyl-2H-t- etrazol-5-yl)methyl]benzenesulfonamide (compound 151) .sup.1H NMR .delta. in ppm (DMSO d6): 3.81 (s, 3H); 3.89 (s, 3H); 4.13 (s, 2H); 4.26 (s, 3H); 4.77 (d, 1H); 5.25 (d, 1H); 6.57 (s, 1H); 6.86 (d, 1H); 7.11-7.47 (unresolved complex, 7H). m.p.=136.3.degree. C.

Table XVIII illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 21.

TABLE-US-00019 TABLE XVIII ##STR00370## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 153 2,6-diF 4-Cl (2-ethyl-2H- 3,4- 139.7 564/9.81 tetrazol-5- diOMe yl)methyl 154 2,6-diF 4-Cl (1-ethyl-1H- 3,4- 150.9 564/9.48 tetrazol-5- diOMe yl)methyl 159 2,6-diF 4-Cl (2-ethyl-2H- 3,5- 105.5 532/10.84 tetrazol-5- diMe yl)methyl 160 2,6-diF 4-Cl (1-ethyl-1H- 3,5- 134 532/10.46 tetrazol-5- diMe yl)methyl 157 2,6-diF 4-Cl (2-methyl- 3,5- 159 518/10.53 2H-tetrazol- diMe 5-yl)methyl 158 2,6-diF 4-Cl (1-methyl- 3,5- 240 518/10.20 1H-tetrazol- diMe 5-yl)methyl 122 2-Cl 4-Cl (2-ethyl-2H- 3,5- oil 530/10.65 tetrazol-5- diMe yl)methyl 123 2-Cl 4-Cl (1-ethyl-1H- 3,5- 158 530/10.27 tetrazol-5- diMe yl)methyl 108 2-Cl 4-Cl (1-isopropyl- 3,4- 79 576/9.52 1H-tetrazol- diOMe 5-yl)methyl 111 2-Cl 4-Cl (1-benzyl- 3,4- 98 624/9.89 1H-tetrazol- diOMe 5-yl)methyl 90 2-Cl 4-Cl (1-ethyl-1H- 3,4- 168.3 562/9.25 tetrazol- diOMe 5-yl)methyl 88 2-Cl 4-Cl (1-methyl- 3,4- 200.6 548/8.96 1H-tetrazol- diOMe 5-yl)methyl 243 2,6-diF 4-Cl 1-(2-methyl- 3,4- 259.3 564/9.85 2H-tetrazol- diOMe 5-yl)ethyl 244 2,6-diF 4-Cl 1-(1-methyl- 3,4- 178.1 564/10.44 1H-tetrazol- diOMe 5-yl)ethyl 310 2,6-diF 6- (2-ethyl-2H- 3,4- 136.3 560/9.61 OMe tetrazol-5- diOMe yl)methyl 311 2,6-diF 6- (1-ethyl-1H- 3,4- 161.4 560/9.30 OMe tetrazol-5- diOMe yl)methyl

EXAMPLE 22

N.sup.2-[2-(2-chlorobenzyl)-4-methylphenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide (compound 165)

EXAMPLE 22.1

N-[4-methyl-2-(2-chlorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide

Starting with 1 g of N-{4-methyl-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenze- nesulfonamide, obtained according to Example 8, according to an adaptation of the process described in Example 18.1, 0.47 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.14 (s, 3H); 3.73 (s, 3H); 3.84 (s, 3H); 4.04 (s, 2H); 6.60 (s, 1H); 6.81-7.47 (unresolved complex, 9H); 9.43 (s, 1H).

EXAMPLE 22.2

N.sup.2-[2-(2-chlorobenzyl)-4-methylphenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide

To 0.47 g of N-{4-methyl-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenze- nesulfonamide dissolved in 5.7 ml of DMF is added, at 0.degree. C., 0.048 g of sodium hydride. After 1 hour at this temperature, 0.166 g of 2-bromoacetamide is introduced and the mixture is left for 18 hours at room temperature. The medium is poured into water and then extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate mixture to give 0.4 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.16 (s, 3H); 3.79 (s, 3H); 3.88 (s, 3H); 4.05-4.25 (unresolved complex, 3H); 4.52 (d, 1H); 6.54 (s, 1H); 6.76 (d, 1H); 6.94-7.53 (unresolved complex, 10H). m.p.=140.6.degree. C.

N.sup.2-[5-Chloro-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl- )sulfonyl]glycinamide (compound 179) is synthesized according to this process starting with N-{5-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenze- nesulfonamide obtained according to Example 9.3, m.p.=86.4.degree. C.

N.sup.2-[2-(2-Chlorobenzyl)-4-methoxyphenyl]-N.sup.2-[(3,4-dimethoxypheny- l)sulfonyl]glycinamide (compound 138) is synthesized according to this process.

m.p.=184.6.degree. C.

EXAMPLE 23

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[3-(dimethylamino)propyl]-3,4-- dimethoxybenzenesulfonamide (compound 197)

To 0.45 g of [4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide (prepared according to Example 18.2) are successively added 0.207 g of potassium carbonate, 0.1 g of tetrabutylammonium bromide, 20 ml of toluene and 0.237 g of 3-dimethylamino-1-bromopropane, and the mixture is refluxed for 24 hours. 0.168 g of potassium tert-butoxide and 0.237 g of 3-dimethylamino-1-bromopropane are added and the mixture is refluxed for 4 hours. The reaction medium is poured into water and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture. The oil obtained is dissolved in methanol and poured into a 0.5M sodium hydroxide solution, and the precipitate formed is filtered off and dried under vacuum to give 0.504 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.34-1.48 (unresolved complex, 2H); 2.01 (s, 6H); 2.14 (t, 2H); 3.13 (m, 1H); 3.75 (s, 3H); 3.78 (m, 1H); 3.85 (s, 3H); 4.13 (d, 1H); 4.31 (d, 1H); 6.72-7.51 (unresolved complex, 9H). m.p.=134.degree. C.

Table XIX illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 23.

TABLE-US-00020 TABLE XIX ##STR00371## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 199 2,6- 4-Cl 2-pyrrolidin-1- 3,4- 131.4 551/6.61 diF ylethyl diOMe 201 2,6- 4-Cl 2-(dimethylamino)- 3,4- 128.6 539/6.44 diF 1-methylethyl diOMe 203 2,6- 4-Cl 2-[benzyl(methyl)- 3,4- 104.8 601/7.18 diF amino]ethyl diOMe 231 2,6- 4-Cl (CH.sub.2).sub.2NHCONH.sub.2 3,4- 124.5 539/8.27 diF diOMe 229 2,6- 4-Cl (CH.sub.2).sub.3SO.sub.2NEt.sub.2 3,4- 71.2 630/10.27 diF diOMe 230 2,6- 4-Cl (CH.sub.2).sub.3SO.sub.2NMe.sub.2 3,4- 76.8 602/9.71 diF diOMe 234 2,6- 4-Cl 2-(2-oxopyrrolidin- 3,4- 138.6 565/8.80 diF 1-yl)ethyl diOMe 236 2,6- 4-Cl 2-methoxyethyl 3,4- 83.8 512/9.38 diF diOMe 241 2,6- 5-Br CH.sub.3CONH.sub.2 3,4- 93.5 555/8.99 diF diOMe 248 2,6- 4-Cl cyclopropylmethyl 3,4- 163.4 508/11.42 diF diOMe 259 2,6- 4-Cl CH.sub.3CONH.sub.2 3-Me, 156.6 495/9.07 diF 4-OMe 268 2,6- 4-Cl 2-(1,3-dioxolan- 3,4- 288.8 554/10.50 diF 2-yl)ethyl diOMe 283 2,6- 4-Cl CH.sub.3CONH.sub.2 6-OMe 164 482/9.27 diF pyrid- 3-yl

EXAMPLE 24

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-(2-hydroxyethyl)-- 3,4-dimethoxybenzenesulfonamide (compound 24)

EXAMPLE 24.1

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[2-- (tetrahydro-2H-pyran-2-yloxy)ethyl]benzenesulfonamide

To 1 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dime- thoxybenzenesulfonamide, obtained in Example 1.2, dissolved in 40 ml of acetonitrile are successively added 1.2 ml of triethylamine and 1.29 ml of 2-(2-bromoethoxytetrahydro-2H-pyran, and the mixture is refluxed for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a cyclohexane/ethyl acetate solvent mixture to give 0.479 g of the expected product.

EXAMPLE 24.2

N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-N-(2-hydroxyethyl)-- 3,4-dimethoxybenzenesulfonamide

To 0.479 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[2- -(tetrahydro-2H-pyran-2-yloxy)ethyl]benzenesulfonamide dissolved in 4.7 ml of THF are added 9.15 ml of acetic acid and 2.25 ml of water, and the mixture is maintained at 40.degree. C. for 48 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a cyclohexane/ethyl acetate solvent mixture to give 0.209 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.02 (m, 2H); 3.40 (m, 2H); 3.75 (s, 3H); 3.88 (s, 3H); 4.40 (t, 1H); 6.01 (d, 1H); 6.70-7.51 (unresolved complex, 10H); 7.86 (s, 1H). m.p.=86.2.degree. C.

In the same manner, compound 237 is prepared, the physical properties of which are as follows:

MH.sup.+=498, the retention time is 8.99 minutes m.p.=165.3.degree. C.

EXAMPLE 25

N.sup.2-{4-chloro-2-[1-(2-chlorophenyl)-1-hydroxyethyl]phenyl}-N.sup.2-[(3- ,4-dimethoxyphenyl)sulfonyl]glycinamide (compound 172)

EXAMPLE 25.1

1-(2-amino-5-chlorophenyl)-1-(2-chlorophenyl)ethanol

To 5 g of 2-amino-2',5-dichlorobenzophenone dissolved in 100 ml of diethyl ether, at -30.degree. C., are added 12.5 ml of 3M methylmagnesium bromide solution, and the mixture is maintained at room temperature for 18 hours. 6 ml of 3M methylmagnesium bromide solution are added and the mixture is left at room temperature for 1 hour. The resulting mixture is hydrolysed with 2M hydrochloric acid solution and washed with water. The organic phase is dried over anhydrous sodium sulfate to give 4.3 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.99 (s, 3H); 4.91 (s, 2H); 6.11 (s, 1H); 6.53 (d, 1H); 6.97-7.42 (unresolved complex, 5H); 7.97 (d, 1H).

EXAMPLE 25.2

N-{4-chloro-2-[1-(2-chlorophenyl)-1-hydroxyethyl]phenyl}-3,4-dimethoxybenz- enesulfonamide

To 1.5 g of 1-(2-amino-5-chlorophenyl)-1-(2-chlorophenyl)ethanol according to an adaptation of the process described in Example 1.1, 2.9 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.78 (s, 3H); 3.75 (s, 3H); 3.83 (s, 3H); 4.05 (q, 1H); 6.87 (s, 1H); 7.04-7.54 (unresolved complex, 5H); 7.82 (m, 2H); 8.60 (d, 2H); 10.00 (s, 1H).

EXAMPLE 25.3

N-{4-chloro-2-[1-(2-chlorophenyl)-1-hydroxyethyl]phenyl}N-[(3,4-dimethoxyp- henyl)sulfonyl]glycinamide

To 1.3 g of N-{4-chloro-2-[1-(2-chlorophenyl)-1-hydroxyethyl]phenyl}-3,4-dimethoxyben- zenesulfonamide dissolved in diethyl ether are successively added, at -5.degree. C., 1.3 ml of a 2M solution of lithium diisopropylamine in hexane, and 0.45 g of 2-bromoacetamide. After 18 hours at room temperature, 0.5 g of 2-bromoacetamide and 1.4 g of sodium iodide are successively added and the mixture is refluxed for 4 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 95/5 (v/v) dichloromethane/methanol mixture to give 0.51 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.11 (s, 3H); 3.74-3.98 (unresolved complex, 8H); 6.25 (s, 1H); 6.96-7.97 (unresolved complex, 12H).

EXAMPLE 26

N.sup.2-{4-chloro-2-[1-(2-chlorophenyl)ethyl]phenyl}-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide (compound 186)

EXAMPLE 26.1

4-chloro-2-[1-(2-chlorophenyl)ethyl]phenylamine

To 54 ml of a 1M solution of lithium aluminium hydride in THF are added portionwise 7.1 g of aluminium trichloride. To this solution are added 4 g of 1-(2-amino-5-chlorophenyl)-1-(2-chlorophenyl)ethanol, obtained in Example 25.1, dissolved in diethyl ether, and the mixture is stirred for 18 hours at room temperature and then refluxed for 4 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 40/60 (v/v) dichloromethane/cyclohexane mixture to give 0.9 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.45 (d, 3H); 4.43 (q, 1H); 4.96 (s, 2H); 6.65 (m, 2H); 6.94 (d, 1H); 7.30-7.47 (unresolved complex, 4H).

EXAMPLE 26.2

N-{4-chloro-2-[1-(2-chlorophenyl)ethyl]phenyl}-3,4-dimethoxybenzenesulfona- mide

Starting with 0.9 g of 4-chloro-2-[1-(2-chlorophenyl)ethyl]phenylamine according to the process described in Example 1.1, 1.7 g of the expected product are obtained.

EXAMPLE 26.3

N.sup.2-{4-chloro-2-[1-(2-chlorophenyl)ethyl]phenyl}-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

Starting with 0.9 g of N-(4-chloro-2-[1-(2-chlorophenyl)ethyl]phenyl}-3,4-dimethoxybenzenesulfon- amide according to the process described in Example 12.3, 0.9 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.35 (d, 3H); 2.75 (d, 1H); 3.79 (s, 3H); 3.86 (s, 3H); 4.25 (d, 1H); 4.74 (q, 1H); 6.92-7.64 (unresolved complex, 12H). m.p.=150.degree. C.

Compound 187 is obtained according to this process. m.p.=151.degree. C.

EXAMPLE 27

N-(2-aminoethyl)N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxyben- zenesulfonamide (compound 215)

To 1 g of N-[4-methyl-2-(2,6-difluorobenzyl)phenyl]-N-[2-(phthalimido)eth- yl]-3,4-dimethoxybenzenesulfonamide, obtained according to an adaptation of the process described in Example 18, dissolved in 15 ml of ethanol is added 0.4 g of hydrazine hydrate, and the mixture is refluxed for 3 hours. At room temperature, the insoluble material is filtered off and the filtrate is concentrated. The residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture to give 0.26 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.62 (s, 2H); 2.17 (s, 3H); 2.40-2.67 (unresolved complex, 2H); 3.12 (m, 1H); 3.69 (m, 1H); 3.75 (s, 3H); 3.88 (s, 3H); 4.09 (d, 1H); 4.26 (d, 1H); 6.56 (m, 2H); 6.97-7.43 (unresolved complex, 7H). m.p.=251.8.degree. C.

Table XX illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 28.

TABLE-US-00021 TABLE XX ##STR00372## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 256 2,6-diF 4-Cl 2-aminoethyl 3,4- 163.4 497/6.82 diOMe 257 2,5-diF 4-Me 2-aminoethyl 3,4- 61.1 477/6.69 diOMe 262 2,5-diF 4-Cl 2-aminoethyl 3,4- 141.1 497/6.88 diOMe 281 2,6-diF 6-OMe 2-aminoethyl 3,4- 137.8 493/6.47 diOMe 287 2,6-diF 4-Cl 3-aminopropyl 3,4- 149.1 511/6.91 diOMe 294 2,5-diF 6-OMe 2-aminoethyl 3,4- 114.8 493/6.47 diOMe 300 2,6-diF 4-Cl, 2-aminoethyl 3,4- 185.4 527/6.82 6-OMe

EXAMPLE 28

N-(2-{[(benzylamino)carbonyl]amino}ethyl)-N-[2-(2,6-difluorobenzyl)-4-meth- ylphenyl]-3,4-dimethoxybenzenesulfonamide (compound 218)

To 1 g of N-(2-aminoethyl)-N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-- dimethoxybenzenesulfonamide (compound 215) dissolved in 20 ml of THF is added 0.266 g of benzyl isocyanate, and, after refluxing for 3 hours, the medium is evaporated to dryness. The residue is chromatographed on a column of silica gel, eluting with an 8/2 (v/v) toluene/ethyl acetate mixture to give 0.65 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.17 (s, 3H); 3.05 (m, 2H); 3.24 (m, 1H); 3.74 (s, 3H); 3.78 (m, 1H); 3.87 (s, 3H); 4.07-4.25 (unresolved complex, 4H); 5.99 (t, 1H); 6.50 (t, 1H); 6.58 (d, 2H); 6.98-7.43 (unresolved complex, 12H). m.p.=100.4.degree. C.

Table XXI illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to Example 28.

TABLE-US-00022 TABLE XXI ##STR00373## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 217 2,6- 4-Me 2-[(anilino- 3,4- 163.4 n.d diF carbonyl)amino]- diOMe ethyl 238 2,6- 4-Cl 2-({[(3- 3,4- 149.3 650/10.87 diF chlorophenyl)- diOMe amino]-carbonyl}- amino)-ethyl 240 2,6- 4-Cl 2-({[(2- 3,4- 136.3 650/10.77 diF chlorophenyl)- diOMe amino]-carbonyl}- amino)-ethyl 252 2,6- 4-Cl 2-({[(3,4- 3,4- 169.7 676/9.80 diF dimethoxyphenyl)- diOMe amino] carbonyl}- amino) ethyl

EXAMPLE 29

N-(2-{[2-(2,6-difluorobenzyl)-4-methylphenyl][(3,4-dimethoxyphenyl)sulfony- l]amino}ethyl)acetamide (compound 219)

To 1 g of N-(2-aminoethyl)N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-d- imethoxybenzenesulfonamide (compound 215) dissolved in 25 ml of THF are added 0.167 ml of pyridine and 0.22 g of acetic anhydride. After 48 hours at room temperature, the reaction medium is concentrated. The residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture to give 0.505 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.74 (s, 3H); 2.17 (s, 3H); 3.05-3.28 (m, 3H); 3.72 (m, 1H); 3.76 (s, 3H); 3.87 (s, 3H); 4.05 (d, 1H); 4.22 (d, 1H); 6.60 (d, 2H); 6.99-7.46 (unresolved complex, 7H); 7.85 (t, 1H). m.p.=79.7.degree. C.

EXAMPLE 30

N.sup.2-{4-chloro-2-[methyl(phenyl)amino]phenyl}-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]-N.sup.1-methylglycinamide (compound 124)

EXAMPLE 30.1

5-chloro-2-nitro-N-diphenyl-N-methylamine

To 10 g of 5-chloro-2-nitrodiphenylamine dissolved in 20 ml of DMF are successively added 2.8 ml of iodomethane and 14.71 g of caesium carbonate, and the mixture is stirred for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with 97/3 (v/v) cyclohexane/ethyl acetate mixture to give 10.51 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.32 (s, 3H); 6.78-6.93 (unresolved complex, 3H); 7.19-7.26 (m, 2H); 7.40 (d, 1H); 7.65 (d, 1H); 7.93(d, 1H).

EXAMPLE 30.2

2-amino-5-chloro-N-diphenyl-N-methylamine

To 10.49 g of 5-chloro-2-nitro-N-diphenyl-N-methylamine dissolved in 100 ml of ethanol are successively added 14.22 g of tin metal and 50 ml of 12M hydrochloric acid solution, and the mixture is refluxed for 1 hour. After evaporating off the ethanol, the reaction medium is taken up in ethyl acetate, basified and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 9.37 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.11 (s, 3H); 5.07 (s, 2H) 6.57-7.21 (unresolved complex, 8H).

EXAMPLE 30.3

N-{4-chloro-2-[methyl(phenyl)amino]phenyl}-3,4-dimethoxybenzenesulfonamide

Starting with 1.5 g of 2-amino-5-chloro-N-diphenyl-N-methylamine, the process is performed according to Example 1.1 to give 1.122 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.93 (s, 3H); 3.67 (s, 3H); 3.84 (s, 3H); 6.37 (d, 2H); 6.74 (t, 1H); 7.05-7.37 (unresolved complex, 7H); 7.54 (d, 1H); 9.46 (s, 1H).

EXAMPLE 30.4

N.sup.2-{4-chloro-2-[methyl(phenyl)amino]phenyl}-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]-N.sup.1-methylglycinamide

Starting with 0.8 g of N-{4-chloro-2-[methyl(phenyl)amino]phenyl}-3,4-dimethoxybenzenesulfonamid- e according to the process described in Example 4.3, 0.766 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.41 (d, 3H); 3.16 (s, 3H); 3.77 (s, 3H); 3.88 (s, 3H); 4.12 (s, 2H); 6.66-6.84 (unresolved complex, 3H); 7.10-7.43 (unresolved complex, 8H); 7.72 (t, 1H). m.p.=148.6.degree. C.

Compound 92 is obtained by this process:

m.p.=192.5.degree. C.

EXAMPLE 31

4-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]-- amino}butanamide (compound 204)

EXAMPLE 31.1

4-{[4-chloro-2-{[2-(2,6-difluorobenzyl)phenyl][((3,4-dimethoxyphenyl}sulfo- nyl]amino}butanoic acid

To 2.6 g of ethyl 4-{[4-chloro-2-{[2-(2,6-difluorobenzyl)phenyl][((3,4-dimethoxyphenyl}sulf- onyl]amino}butanoate, obtained according to Example 18, dissolved in 50 ml of ethanol are added 22.8 ml of sodium hydroxide, and the mixture is left for 18 hours at room temperature. The solvent is evaporated off and the residue is taken up in 40 ml of 1M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is solidified with diisopropyl ether to give 1.7 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.54 (m, 2H); 2.27 (t, 2H); 3.27 (m, 1H); 3.76 (s, 3H); 3.85 (s, 3H); 4.23 (m, 2H); 6.75-7.51 (unresolved complex, 10H); 12.09 (s, 1H).

EXAMPLE 31.2

{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]ami- no}butanamide

To 1.7 g of 4-{[4-chloro-2-{[2-(2,6-difluorobenzyl)phenyl][((3,4-dimethoxyphenyl}sulf- onyl]amino}butanoic acid dissolved in 30 ml of THF, at 0.degree. C., are added 0.42 ml of N-ethylmorpholine and 0.42 ml of ethyl chloroformate; after 30 minutes at this temperature, a solution of ammonia in THF is introduced dropwise and the mixture is left for 1 hour at 20.degree. C. The resulting mixture is poured into saturated sodium hydrogencarbonate solution and taken up in ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated, and the residue is solidified with diethyl ether to give, after drying, 1.41 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.51 (m, 2H); 2.07 (t, 2H); 3.21 (m, 1H); 3.74 (m, 1H); 3.78 (s, 3H); 3.89 (s, 3H); 4.23 (q, 2H); 6.75 (m, 3H); 7.04-7.51 (unresolved complex, 8H). m.p.=197.degree. C.

Table XXII illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this example.

TABLE-US-00023 TABLE XXII ##STR00374## MH.sup.+/ Com- Nature and position of the reten- pound substituents m.p. tion No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 235 2,6- 4-Cl CH.sub.2CH.sub.2CH.sub.2CONH.sub.2 2,5- n.d 541/ diF diMe, 10.03 4-Cl 266 2,5- 4-Cl CH.sub.2CH.sub.2CH.sub.2CONH.sub.2 3,4- 150 539/ diF diOMe 9.15 272 2,6- 6- CH.sub.2CH.sub.2CH.sub.2CONH.sub.2 3,4- 207.8 535/ diF OMe diOMe 8.42 299 2,5- 6- CH.sub.2CH.sub.2CH.sub.2CONH.sub.2 3,4- 189.3 535/ diF OMe diOMe 8.54

EXAMPLE 32

N.sup.2-{4-chloro-2-[2-(trifluoromethyl)benzyl]phenyl}-N.sup.2-[(3,4-dimet- hoxyphenyl)sulfonyl]glycinamide (compound 207)

EXAMPLE 32.1

(2-amino-5-chlorophenyl)(2-trifluoromethylphenyl)methanol

To 1.9 g of (2-amino-5-chlorophenyl)(2-trifluoromethylphenyl)methanone, obtained in Example 7.2, dissolved in 87 ml of ethanol is added 0.775 g of sodium borohydride, and the mixture is left at 20.degree. C. for 18 hours. The solvent is evaporated off and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 1.96 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 5.15 (s, 2H); 5.97 (d, 1H); 6.11 (d, 1H); 6.35 (d, 1H); 6.72 (d, 1H); 6.99 (d, 1H); 7.53-7.81 (unresolved complex, 4H).

EXAMPLE 32.2

N-{4-chloro-2-[(2-trifluoromethylphenyl)(hydroxy)methyl]phenyl}-3,4-dimeth- oxybenzenesulfonamide

Starting with 1.28 g of (2-amino-5-chlorophenyl)(2-trifluoromethylphenyl)methanol according to the process described in Example 1.1, 2.06 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.76 (s, 3H); 3.85 (s, 3H); 6.34 (s, 2H); 6.89 (d, 1H); 6.98 (s, 1H); 7.08 (d, 1H); 7.23-7.33 (unresolved complex, 4H); 7.53-7.77 (unresolved complex, 3H); 9.25 (s, 1H).

EXAMPLE 32.3

N-[4-chloro-2-(2-trifluoromethylbenzyl)phenyl]-3-methoxybenzenesulfonamide

Starting with 2.06 g of N-{4-chloro-2-[(2-trifluoromethylphenyl)(hydroxy)methyl]phenyl}-3,4-dimet- hoxybenzenesulfonamide according to the method described in Example 22.1, 0.94 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.73 (s, 3H); 3.85 (s, 3H); 4.06 (s, 2H); 6.64 (s, 1H); 6.89-7.28 (unresolved complex, 6H); 7.48-7.60 (m, 2H); 7.75 (d, 1H); 9.72 (s, 1H).

EXAMPLE 32.4

N.sup.2-{4-chloro-2-[2-(trifluoromethyl)benzyl]phenyl}-N.sup.2-[(3,4-dimet- hoxyphenyl)sulfonyl]glycinamide

Starting with 0.94 g of N-[4-chloro-2-(2-trifluoromethylbenzyl)phenyl]-3-methoxybenzenesulfonamid- e according to Example 16.3, 0.723 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.80 (s, 3H); 3.89 (s, 3H); 4.03 (d, 1H); 4.27 (q, 2H); 4.74 (d, 1H); 6.55 (s, 1H); 6.88 (d, 1H); 7.12-7.63 (unresolved complex, 9H); 7.82 (d, 1H). m.p.=133.degree. C.

EXAMPLE 33

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl- ]-2,2,2-trifluoroacetamide (compound 223)

To 2.2 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide- , obtained in Example 18.2, dissolved in 40 ml of dichloromethane are added 0.8 ml of triethylamine and 1.46 g of trifluoroacetyl triflate, and, after 10 minutes, the medium is hydrolysed and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/cyclohexane mixture to give 1.1 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.86 (s, 3H); 3.93 (s, 3H); 4.19 (s, 2H); 6.92 (s, 1H); 7.17-7.54 (unresolved complex, 7H); 7.71 (d, 1H). m.p.=79.7.degree. C.

EXAMPLE 34

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2,2,2-trifluoro- ethyl)benzenesulfonamide (compound 190)

To 1.48 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide- , obtained in Example 18.2, dissolved in 40 ml of xylene are added 2.3 g of 2,2,2-trifluoroethyl trichloromethanesulfonate, 0.44 g of potassium tert-butoxide and 20 ml of N-methylpyrrolidone, and the mixture is maintained at 150.degree. C. for 8 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.455 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.82 (s, 3H); 3.90 (s, 3H); 4.14-4.35 (unresolved complex, 3H); 4.82 (m, 1H); 6.63 (s, 1H); 6.80 (d, 1H); 7.17-7.54 (unresolved complex, 7H). m.p.=70.degree. C.

EXAMPLE 35

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(3-pyrid-3-ylpro- pyl)benzenesulfonamide (compound 232)

To 1.5 g of triphenylphosphine dissolved in 25 ml of THF is added 0.909 g of diisopropyl azodicarboxylate. After 15 minutes at room temperature, 0.61 g of 3-pyrid-3-ylpropan-1-ol is introduced and the mixture is left at 20.degree. C. for 15 minutes. 1.36 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide are introduced and the mixture is left at room temperature for 18 hours. The medium is concentrated and the residue is chromatographed on a column of silica gel, eluting with a toluene/ethyl acetate mixture passing from a ratio of 9/1 to 5/5 (v/v). 5 ml of 2M hydrochloric acid are added to the product obtained, dissolved in diethyl ether, and the solvents are then evaporated off. The residue is taken up in diisopropyl ether to give, after filtration, 0.55 g of the expected product.

m.p.=102.8.degree. C.

Table XXIII illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this example.

TABLE-US-00024 TABLE XXIII ##STR00375## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 245 2,6- 4-Cl 3-pyrid-3- 3,4- 102.8 573/8.10 diF ylpropyl diOMe 250 2,6- 4-Cl 2-pyrid-2- 3,4- 75.1 559/8.24 diF ylethyl diOMe 254 2,6- 4-Cl 2-pyrid-3- 3,4- 90.3 559/7.14 diF ylethyl diOMe 255 2,6- 4-Cl 2-pyrid-4- 3,4- 164.3 559/8.29 diF ylethyl diOMe 260 2,6- 4-Cl 2-phenoxyethyl 3,4- 64.3 574/10.88 diF diOMe 274 2,6- 4-Cl (2R)-pyrrolidin- 3,4- 204.8 537/7.07 diF 2-ylmethyl diOMe 275 2,6- 4-Cl (2S)-pyrrolidin- 3,4- 214.1 537/7.07 diF 2-ylmethyl diOMe 278 2,6- 4-Cl {[2- 3,4- 103 568/6.29 diF (dimethylamino)- diOMe ethyl]- amino}ethyl 290 2,6- 4-Cl 1,3-thiazol-2- 3,4- 184 551/10.26 diF ylmethyl diOMe 291 2,6- 4-Cl pyrimid-2- 3,4- 104 546/9.89 diF ylmethyl diOMe 292 2,6- 4-Cl 2-morpholino-4- 3,4- 185.3 567/7.35 diF ylethyl diOMe 295 2,6- 4-Cl pyrid-2-ylmethyl 3,4- 200.8 545/16.9 diF diOMe 315 2,6- 6- CH(CH.sub.3)COOEt 3,4- 94.3 536/9.98 diF OMe diOMe 316 2,6- 6- CH(CH.sub.3)COOEt 3,4- 130.2 536/9.89 diF OMe diOMe 317 2,6- 6- CH(CH.sub.3)COOEt 3,4- 73.3 536/9.98 diF OMe diOMe 318 2,6- 6- CH(CH.sub.3)COOEt 3,4- 130.8 536/9.89 diF OMe diOMe ##STR00376## ##STR00377## ##STR00378## ##STR00379##

Compounds 315/316 and 317/318 are pairs of atropoisomers. Each atropoisomer is characterized by its optical rotation (.alpha..sub.D). The centre of atropoisomerism is generated by the steric hindrance around the N-aromatic bond.

EXAMPLE 36

ethyl N-[(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxy-N-[2-(methylam- ino)ethyl]benzenesulfonamide (compound 258)

EXAMPLE 36.1

ethyl N-(2-bromoethyl)-N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimet- hoxybenzenesulfonamide

To 1 g of N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxybenzenes- ulfonamide dissolved in 1.1 ml of dimethylformamide are successively added 0.38 g of potassium carbonate and 0.48 ml of 1,2-dibromoethane, and the mixture is maintained at 100.degree. C. for 4 hours. After cooling to room temperature, the reaction medium is hydrolysed and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 1.24 g of expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.17 (s, 3H); 3.42 (m, 2H); 3.73 (m, 1H); 3.76 (s, 3H); 3.88 (s, 3H); 4.03-4.15 (unresolved complex, 2H); 4.45 (d, 1H); 6.63 (d, 1H); 6.98-7.48 (unresolved complex, 8H).

EXAMPLE 36.2

ethyl N-[(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxy-N-[2-(methylam- ino)ethyl]benzenesulfonamide hydrobromide

To 1.24 g of N-(2-bromoethyl)-N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxyb- enzenesulfonamide are added 10.7 ml of 2M solution of methylamine in methanol and the mixture is maintained at 105.degree. C. for 4 hours. The reaction is completed by addition of 10 ml of 2M solution of methylamine in methanol with refluxing for 8 hours. After cooling to room temperature, the medium is concentrated and the residue is chromatographed to give 0.849 g of the expected product.

m.p.=208.5.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 2.20 (s, 3H); 2.58 (s, 3H); 2.85 (m, 1H); 3.06 (m, 1H); 3.52 (m, 1H); 3.77 (s, 3H); 3.90 (s, 3H); 3.99-4.07 (unresolved complex, 2H); 4.27 (d, 1H); 6.58-6.64 (unresolved complex, 2H); 7.01-7.49 (unresolved complex, 2H); 8.48 (s, 2H).

Table XXIV illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this example.

TABLE-US-00025 TABLE XXIV ##STR00380## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 277 2,6- 4-Cl 2-(1H-1,2,4- 3,4- 129.1 n.d. diF triazol-1-yl)ethyl diOMe 282 2,6- 6- methylaminoethyl 3,4- 262.9 507/6.54 diF OMe diOMe 284 2,6- 4-Cl methylaminoethyl 3,4- 54 511/6.94 diF diOMe 306 2,6- 6- 2-(1H-1,2,4- 3,4- 132.1 545/8.76 diF OMe triazol-1-yl)ethyl diOMe

EXAMPLE 37

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(3-hydroxypropyl)-3,4-dimethox- ybenzenesulfonamide (compound 270)

EXAMPLE 37.1

N-(3-{[tertbutyl(dimethyl)silyl]oxy}propyl)-N-[4-chloro-2-(2,6-difluoroben- zyl)phenyl]-3,4-dimethoxybenzenesulfonamide

To 4.3 g of triphenylphosphine in 20 ml of tetrahydrofuran are added, at room temperature, 3.25 ml of diisopropyl azodicarboxylate. After 30 minutes, 3.5 ml of 3-[tert-butyl(dimethyl)silyloxy]propanol dissolved in 30 ml of tetrahydrofuran are introduced. The mixture is left at room temperature for 30 minutes, and 5 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide are then introduced. After 48 hours at room temperature, the reaction medium is concentrated and then chromatographed on a column of silica gel to give 8.09 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): -0.04 (s, 3H); -0.02 (s, 3H); 0.82 (s, 9H); 1.40-1.56 (unresolved complex, 2H); 3.18 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 3.82 (m, 1H); 3.90 (s, 3H); 4.13 (d, 1H); 4.26 (d, 1H); 6.72-7.23 (unresolved complex, 9H).

EXAMPLE 37.2

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(3-hydroxypropyl)-3,4-dimethox- ybenzenesulfonamide

To 8 g of N-(3-{[tertbutyl(dimethyl)silyl]oxy}propyl)-N-[4-chloro-2-(2,6-- difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide in 80 ml of tetrahydrofuran at 0.degree. C. are added 2.98 g of tetrabutylammonium fluoride trihydrate. After 40 minutes at 25.degree. C., the reaction medium is concentrated and then chromatographed on a column of silica gel, eluting with dichloromethane, to give 3.28 g of the expected product.

m.p.=138.3.degree. C. .sup.1H NMR 6 in ppm (DMSO d6): 1.35-1.55 (unresolved complex, 2H); 3.18 (m, 1H); 3.41 (m, 1H); 3.77 (s, 3H); 3.85 (m, 2H); 3.88 (s, 3H); 4.13 (d, 1H); 4.29 (d, 1H); 4.48 (t, 1H); 6.71-7.50 (unresolved complex, 9H)

EXAMPLE 38

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(2-hydroxy-1-methylethyl)-3,4-- dimethoxybenzenesulfonamide (compound 264)

To 1.1 g of methyl N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfony- l]alaninate in 15 ml of tetrahydrofuran are added, at room temperature, 158 mg of lithium aluminium hydride. After refluxing for 5 hours, the mixture is cooled to room temperature and hydrolysed with 15% sodium hydroxide solution. The medium is taken up in ethyl acetate and washed with water, the phases are separated by settling and the organic phase is dried over anhydrous sodium sulfate. The organic phase is concentrated and the residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) toluene/ethyl acetate mixture to give 0.215 g of the expected product.

m.p.=169.2.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 1.18 (d, 3H); 3.47 (m, 2H); 3.77 (s, 3H); 3.88 (s, 3H); 4.07-4.52 (unresolved complex, 3H); 4.98 (t, 1H); 6.61-7.49 (unresolved complex, 9H)

EXAMPLE 39

2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]a- mino}-2-ethoxyacetamide (compound 276)

EXAMPLE 39.1

ethyl {[4-chloro-2-{2,6-difluorobenzyl}phenyl][(3,4-dimethoxyphenyl}sulfon- yl]amino(fluoro)acetate

To 2 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenes- ulfonamide in 15 ml of tetrahydrofuran are successively added, at room temperature, 0.742 g of potassium tert-butoxide and 0.78 ml of ethyl bromo(fluoro) acetate, and the mixture is left at room temperature for 18 hours. To complete the reaction, 0.742 g of potassium tert-butoxide and 0.6 ml of ethyl bromo(fluoro) acetate are added. After 24 hours at room temperature, the reaction medium is concentrated and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a toluene/ethyl acetate mixture (100% toluene to 80% toluene/20% ethyl acetate) to give 0.825 g of product (HPLC purity 77%).

.sup.1H NMR .delta. in ppm (DMSO d6): 0.92 (t, 3H); 3.78 (s, 3H); 3.87 (s, 3H); 4.12-4.38 (unresolved complex, 5H); 6.73-7.33 (unresolved complex, 9H).

EXAMPLE 39.2

5-chloro-3-(2,6-difluorophenyl)-1-[(3,4-dimethoxyphenyl)sulfonyl]indoline-- 2-carboxylic acid

To 0.825 g of ethyl {[4-chloro-2-(2,6-difluorobenzyl}phenyl][(3,4-dimethoxyphenyl)sulfonyl]am- ino(fluoro)acetate in 10 ml of ethanol and 10 ml of 1,4-dioxane is added, at room temperature, 0.062 g of lithium hydroxide hydrate, and the mixture is left at room temperature for 6 hours. The reaction medium is concentrated and the residue is taken up in ethyl acetate and washed with 1M hydrochloric acid solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/methanol mixture (100% dichloromethane to 90% dichloromethane/10% methanol) to give 0.345 g of product (50% HPLC purity).

.sup.1H NMR .delta. in ppm (DMSO d6): 3.74 (s, 3H); 3.84 (s, 3H); 4.17 (d, 1H); 4.40 (d, 1H); 5.57 (s, 1H); 6.49 (s, 1H); 6.78-7.47 (unresolved complex, 8H).

EXAMPLE 39.3

2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxy phenyl)sulfonyl]amino}-2-ethoxyacetamide

To 0.34 g of 5-chloro-3-(2,6-difluorophenyl)-1-[(3,4-dimethoxyphenyl)sulfonyl]indoline- -2-carboxylic acid in 10 ml of tetrahydrofuran are successively added, at 0.degree. C., 90 .mu.l of N-ethylmorpholine and 68 .mu.l of ethyl chloroformate, the mixture is left at this temperature for 30 minutes, and 0.5 ml of 6M aqueous ammonia solution is introduced. The reaction medium is concentrated and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/methanol mixture (100% dichloromethane to 98% dichloromethane/2% methanol) to give 0.256 g of product (99.6% HPLC purity).

m.p.=153.6.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 1.25 (t, 3H); 3.57 (m, 2H); 3.84 (s, 3H); 3.87 (s, 3H); 4.31 (q, 2H); 6.53 (s, 1H); 6.52-7.55 (unresolved complex, 11H)

EXAMPLE 40

phenyl (2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl) sulfonyl]amino}ethylcarbamate (compound 269)

To 1.4 g of ethyl N-[2,6-difluorobenzyl)-4-chlorophenyl]-3,4-dimethoxy-N-[2-(methylamino)et- hyl]benzenesulfonamide in 6 ml of tetrahydrofuran are successively added, at 0.degree. C., 0.29 ml of pyridine and 0.37 ml of phenyl chloroformate, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed successively with 1M hydrochloric acid solution, sodium hydrogen carbonate solution, and water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel to give 1.07 g of the expected product.

m.p.=137.5.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 3.05-3.24 (unresolved complex, 4H); 3.76 (s, 3H); 3.87 (s, 3H); 4.09 (d, 1H); 4.30 (d, 1H); 6.78-7.46 (unresolved complex, 14H); 7.77 (t, 1H).

EXAMPLE 41

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-(2-{[(methylamin- o)carbonyl]amino}ethyl)benzenesulfonamide (compound 253)

To 0.42 g of phenyl(2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)su- lfonyl]amino}ethylcarbamate in 1.2 ml of dimethyl sulfoxide is added, at room temperature, 0.053 ml of an aqueous solution of methylamine, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel to give 0.326 g of the expected product.

m.p.=105.7.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 2.48 (s, 3H); 3.18 (q, 2H); 3.24 (m, 1H); 3.68 (m, 1H); 3.76 (s, 3H); 3.88 (s, 3H); 4.20 (q, 2H); 5.75-5.94 (unresolved complex, 2H); 6.73-7.51 (unresolved complex, 9H).

In the same manner, compound 239 is prepared, the physical properties of which are as follows:

MH+=568; the retention time is 9.44 minutes m.p.=99.5.degree. C.

EXAMPLE 42

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[2-(1H-imidazol-1-yl)ethyl]-3,- 4-dimethoxybenzenesulfonamide (compound 271)

To 2 ml of dimethylformamide are added, at room temperature, 51 mg of sodium hydride at 50% in oil, followed by 72 mg of imidazole. After 30 minutes at this temperature, 0.4 g of ethyl N-(2-bromoethyl)-N-[2-(2,6-difluorobenzyl)-4-chlorophenyl]-3,4-dimethoxyb- enzenesulfonamide dissolved in 5 ml of dimethylformamide is introduced. The reaction medium is left for 18 hours at room temperature and then taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 97/3 (v/v) toluene/ethyl acetate mixture to give 0.082 g of the expected product.

m.p.=159.5.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 3.66 (m, 1H); 3.76 (s, 3H); 3.89 (s, 3H); 3.99-4.15 (unresolved complex, 5H); 6.72-7.56 (unresolved complex, 12H).

In the same manner, compound 301 is prepared, the physical properties of which are as follows:

MH+=544; the retention time is 6.62 minutes m.p.=153.6.degree. C.

EXAMPLE 43

N.sup.3-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.3- [(3,4-dimethoxyphenyl)sulfonyl]-.beta.-alaninamide (compound 273)

EXAMPLE 43.1

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl- ]-.beta.-alanine

To 2.63 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(3-hydroxypropyl)-3,4-dimetho- xybenzenesulfonamide (Example 37) dissolved in 35 ml of acetonitrile are added, at room temperature, 0.069 g of ruthenium trichloride, 1.65 g of sodium periodate and 2.7 ml of water. The mixture is left for 10 hours at room temperature. The reaction medium is filtered through talc and then concentrated. The residue is taken up in dichloromethane and washed with 1M hydrochloric acid solution. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 3.13 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.3 (m, 2H); 3.45 (m, 1H); 3.71 (s, 3H); 3.86 (m, 1H); 3.90 (s, 3H); 4.1-4.35 (unresolved complex, 2H); 6.74-7.47 (unresolved complex, 9H); 12.3 (s, 1H).

EXAMPLE 43.2

N.sup.3-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.3-[(3,4-dimethoxyphe- nyl)sulfonyl]-.beta.-alaninamide

To 0.8 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfony- l]-.beta.-alanine dissolved in 16 ml of tetrahydrofuran are added, at 0.degree. C., 0.21 ml of N-ethylmorpholine and 0.16 ml of ethyl chloroformate. The mixture is left at room temperature for 1 hour, and 1.36 ml of ammonia (20%) in water are then introduced. After 48 hours at room temperature, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated, and the residue is chromatographed on a column of silica gel, eluting with a 98/2 (v/v) dichloromethane/methanol mixture to give 0.295 g of the expected product.

m.p.=189.4.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 2.08-2.25 (unresolved complex, 2H); 3.42 (m, 1H); 3.76 (s, 3H); 3.88 (s, 3H) 3.92 (m, 1H); 4.13 (d, 1H); 4.27 (d, 1H); 6.75-7.51 (unresolved complex, 11H)

In the same manner, compound 298 is prepared, the physical properties of which are as follows:

MH+=539; the retention time is 9.15 minutes m.p.=189.3.degree. C.

EXAMPLE 44

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-.beta.-alaninamide (compound 261)

EXAMPLE 44.1

methyl N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)s- ulfonyl]alaninate

By reaction of 2 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide with methyl lactate according to process 35, 1.393 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.12 (t, 3H); 1.25 (d, 3H); 3.75 (s, 3H); 3.86 (s, 3H); 3.98 (d, 1H); 4.19 (q, 2H); 4.65 (d, 1H); 4.87 (q, 1H); 6.55 (s, 1H) 7.04-7.48 (unresolved complex, 8H).

EXAMPLE 44.2

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl- ]alanine

To 1.373 g of methyl N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfony- l]alaninate dissolved in 20 ml of ethanol is added 0.52 g of lithium hydroxide monohydrate, and the mixture is left at room temperature for 18 hours. The medium is concentrated and the residue is taken up in ethyl acetate and washed with 5% potassium hydrogen sulfate solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) dichloromethane/methanol mixture to give 0.494 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.17 (d, 3H); 3.76 (s, 3H); 3.87 (s, 3H); 3.92 (d, 1H); 4.19 (d, 1H); 4.75 (q, 1H); 6.53-7.52 (unresolved complex, 9H); 12.9 (s, 1H).

EXAMPLE 44.3

N.sup.2-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphe- nyl)sulfonyl]-.beta.-alaninamide

To 0.47 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfony- l]alanine dissolved in 20 ml of tetrahydrofuran are added, at 0.degree. C., 0.13 ml of N-ethylmorpholine and 0.094 ml of ethyl chloroformate. The mixture is left at room temperature for 1 hour, and 0.75 ml of ammonia (20%) in water is then introduced. After 24 hours at room temperature, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated, and the residue is chromatographed on a column of silica gel, eluting with a 95/5 (v/v) dichloromethane/methanol mixture to give 0.295 g of the expected product.

m.p.=108.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 1.04 (d, 3H); 3.77 (s, 3H); 3.84 (s, 3H); 3.93 (d, 1H); 4.19 (d, 1H); 4.85 (q, 1H); 4.89 (d, 1H); 6.53-7.52 (unresolved complex, 9H).

The enantiomers of compound 261 are separated by chiral chromatography.

Laevorotatory enantiomer, compound 305

[.alpha.].sub.D (C=0.5 g/100 ml in methanol)=-28.2 Dextrorotatory enantiomer, compound 304 [.alpha.].sub.D (C=0.5 g/100 ml in methanol)=+25.4

Table XXV illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this example.

TABLE-US-00026 TABLE XXV ##STR00381## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 304 2,6- 4-Cl CH(CH.sub.3)CONH.sub.2 3,4- 105.3 525/9.29 diF diOMe 305 2,6- 4-Cl CH(CH.sub.3)CONH.sub.2 3,4- 94.1 525/9.29 diF diOMe

EXAMPLE 45

N.sup.2-[2-(2-chlorobenzyl)-4-(dimethylamino)phenyl]-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide (compound 265)

EXAMPLE 45.1

N.sup.2-[4-amino-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)s- ulfonyl]glycinamide

To 2 g of N.sup.2-[2-(2-chlorobenzyl)-4-nitrophenyl]-N.sup.2-[(3,4-dimeth- oxyphenyl)sulfonyl]glycinamide, obtained according to Example 15, dissolved in 150 ml of ethanol are successively added, at room temperature, 0.91 g of tin and 3.2 ml of 12M hydrochloric acid. After 18 hours, the medium is concentrated, taken up in ethyl acetate and washed with sodium hydroxide solution (pH 14). The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 95/5 (v/v) dichloromethane/methanol mixture to give 0.287 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.79 (s, 3H); 3.88 (s, 3H); 3.94-4.40 (unresolved complex, 4H); 5.15 (s, 2H); 5.94 (d, 1H); 6.22 (d, 1H); 6.50 (d, 1H); 7.04-7.49 (unresolved complex, 9H).

EXAMPLE 45.2

N.sup.2-[2-(2-chlorobenzyl)-4-(dimethylamino)phenyl]-N.sup.2-[(3,4-dimetho- xyphenyl)sulfonyl]glycinamide

To 0.6 g of N.sup.2-[4-amino-2-(2-chlorobenzyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide dissolved in N-methylpyrrolidine are added 0.42 g of caesium carbonate and 0.9 ml of iodomethane, and the mixture is left at room temperature for 18 hours. The medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 100% to 90%/10% dichloromethane/acetone gradient to give the expected product.

m.p.=130.4.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 2.73 (s, 6H); 3.78 (s, 3H); 3.84 (s, 3H); 3.98-4.08 (unresolved complex, 3H); 4.40 (d, 1H); 6.04 (d, 1H); 6.43 (d, 1H); 6.70 (d, 1H); 7.02-7.51 (unresolved complex, 9H).

EXAMPLE 46

ethyl N-[4-chloro-2-(2-chlorophenyl)]-3,4-dimethoxy-N-vinylbenzenesulfonam- ide (compound 289)

To 0.18 g of 1-methyl-2-imidazolidone dissolved in N-methylpyrrolidone is added 0.086 g of sodium hydride at 50% in oil, the mixture is left at room temperature for 15 minutes, and 1 g of ethyl N-(2-bromoethyl)-N-[2-(2,6-difluorobenzyl)-4-chlorophenyl]-3,4-dimethoxyb- enzenesulfonamide is introduced. After 18 hours, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated, and the residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.67 g of the expected product.

m.p.=153.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 3.54 (d, 1H); 3.79 (s, 3H); 3.89 (s, 3H); 3.94-4.20 (unresolved complex, 2H); 4.22 (d, 1H); 6.50 (d, 1H); 7.06-7.45 (unresolved complex, 9H).

EXAMPLE 47

N.sup.2-[2-(2,6-difluorobenzyl)-5-methoxyphenyl]-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]glycinamide (compound 296)

EXAMPLE 47.1

(2-amino-4-methoxyphenyl)(2,6-difluorophenyl)methane

To 6.22 g of (2-amino-4-methoxyphenyl)(2,6-difluorophenyl)methanol, obtained according to Example 11.1, dissolved in 95 ml of dichloromethane are successively added, at room temperature, 11.7 ml of triethylsilane and 10.7 ml of trifluoroacetic acid. After refluxing for 4 hours, the medium is hydrolysed with 6M sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 1.505 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.69 (s, 3H); 4.93 (s, 2H); 6.04 (d, 1H); 6.21 (s, 1H); 6.48 (d, 1H); 7.01-7.35 (unresolved complex, 3H).

EXAMPLE 47.2

N-[2-(2,6-difluorobenzyl)-5-methoxyphenyl]-3,4-dimethoxybenzenesulfonamide

Starting with 1.5 g of (2-amino-4-methoxyphenyl)(2,6-difluorophenyl)methane according to Example 12.2, 0.32 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.55 (s, 3H); 3.74 (s, 3H); 3.82 (s, 3H); 3.85 (d, 2H); 6.42 (d, 1H); 6.56-7.42 (unresolved complex, 8H); 9.54 (s, 1H).

EXAMPLE 47.3

N.sup.2-[2-(2,6-difluorobenzyl)-5-methoxyphenyl]-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]glycinamide

Starting with 0.312 g of N-[2-(2,6-difluorobenzyl)-5-methoxyphenyl]-3,4-dimethoxybenzenesulfonamid- e according to Example 12.3, 0.219 g of the expected product is obtained.

m.p.=188.2.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 3.55 (s, 3H); 3.78 (s, 3H); 3.88 (s, 3H); 4.10-4.24 (unresolved complex, 3H); 4.43 (d, 1H); 6.41 (d, 1H); 6.57 (d, 1H); 6.83 (d, 1H); 7.05-7.48 (unresolved complex, 8H).

Table XXVI illustrates the chemical structures and the physical properties of a number of compounds of the invention obtained according to this example.

TABLE-US-00027 TABLE XXVI ##STR00382## Com- Nature and position of the MH.sup.+/ pound substituents m.p. retention No. Ar.sub.1 Ar.sub.2 R.sub.1 Ar.sub.3 (.degree. C.) time 302 2,6-diF 4-Cl, CH.sub.2CONH.sub.2 3,4- 238.5 541/8.89 6-OMe diOMe 303 2,6-diF 4-Cl, CH.sub.2CONH.sub.2 3,4- 217 521/8.61 6-Me diOMe

EXAMPLE 48

N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-{2-[(methylsulfo- nyl)amino]ethyl}-benzenesulfonamide (compound 313)

To 0.543 g of compound 256 dissolved in 10 ml of tetrahydrofuran are added 106 .mu.l of pyridine and 102 .mu.l of methanesulfonyl chloride, and the mixture is left at room temperature for 18 hours. The reaction medium is concentrated and the residue is chromatographed on a column of silica gel, eluting with a dichloromethane/methanol mixture to give 0.425 g of the expected product.

m.p.=133.2.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 2.85 (s, 3H); 2.90 (m, 1H); 3.12 (m, 1H); 3.35 (m, 1H); 3.78 (s, 3H); 3.83 (m, 1H); 3.86 (s, 3H); 4.09 (d, 1H); 4.31 (d, 1H); 6.78-7.51 (unresolved complex, 10H).

EXAMPLE 49

N.sup.2-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]-N-ethylglycinamide (compound 309)

EXAMPLE 49.1

N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfony- l]glycine

To 1.8 g of ethyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfon- yl]-glycinate dissolved in 50 ml of ethanol are added 10 ml of 2M sodium hydroxide solution. After 18 hours at room temperature, the medium is extracted with diethyl ether and the aqueous phase is acidified and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then concentrated to give 1.8 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.18 (s, 3H); 3.72 (s, 3H); 3.82 (d, 1H); 3.90 (s, 3H); 4.29 (d, 1H); 4.53 (d, 1H); 5.01 (d, 1H); 6.26 (d, 1H); 6.78 (d, 1H); 7.01-7.47 (unresolved complex, 7H); 12.75 (s, 1H).

EXAMPLE 49.2

N.sup.2-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.sup.2-[(3,4-dimethoxyph- enyl)sulfonyl]-N-ethylglycinamide

To 1.8 g of N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfon- yl]glycine dissolved in 30 ml of tetrahydrofuran at 0.degree. C. are introduced 0.5 ml of N-ethylmorpholine and 0.38 ml of ethyl chloroformate. After 15 minutes at 10.degree. C., 0.8 g of ethylamine dissolved in tetrahydrofuran is added and the mixture is left at room temperature for 30 minutes. The medium is taken up in ethyl acetate and washed with water, and the organic phase is dried over anhydrous sodium sulfate and concentrated to give 1.4 g of the expected product.

m.p.=180.degree. C. .sup.1H NMR .delta. in ppm (DMSO d6): 0.98 (t, 3H); 3.07 (m, 2H); 3.26 (s, 3H); 3.76 (s, 3H); 3.79 (m, 1H); 3.87 (s, 3H); 4.26 (d, 1H); 4.43 (d, 1H); 4.94 (d, 1H); 6.20 (d, 1H); 6.81 (d, 1H); 7.09-7.45 (unresolved complex, 7H); 7.88 (t, 1H).

EXAMPLE 50

N.sup.2-[4-chloro-2-(2,5-difluorobenzyl)phenyl]-N.sup.2-[(4-chloro-2,5-dim- ethylphenyl)sulfonyl]glycinamide (compound 267)

EXAMPLE 50.1

(2-nitro-5-chlorophenyl)(2,5-difluorophenyl)methanol

To 15 g of 2,5-difluorobenzene dissolved in 150 ml of tetrahydrofuran are added, at -70.degree. C., 50 ml of 1.6M butyllithium solution. After 2 hours at -70.degree. C., 9.616 g of 2-nitro-5-chlorobenzaldehyde are introduced and the mixture is left at this temperature for 3 hours and then at room temperature for 18 hours. The medium is hydrolysed with ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is filtered through silica, eluting with dichloromethane, to give 8.89 g of the expected product.

EXAMPLE 50.2

(2-amino-5-chlorophenyl)(2,5-difluorophenyl)methanol

Starting with 8.55 g of (2-nitro-5-chlorophenyl)(2,5-difluorophenyl)methanol according to process 8.2, 2.7 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 5.18 (s, 2H); 5.89 (d, 1H); 6.15 (d, 1H); 6.68-7.36 (unresolved complex, 6H)

EXAMPLE 50.3

(2-amino-5-chlorophenyl)(2,5-difluorophenyl)methane

Starting with 2.7 g of (2-amino-5-chlorophenyl)(2,5-difluorophenyl)methanol according to process 18.1, 1.947 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.80 (s, 2H); 5.18 (s, 2H); 6.60 (unresolved complex, 6H)

EXAMPLE 50.4

N-[4-chloro-2-(2,5-difluorobenzyl)phenyl]-2,5-dimethyl-4-chlorobenzenesulf- onamide

Starting with 0.484 g of (2-amino-5-chlorophenyl)(2,5-difluorophenyl)methane according to the process described in Example 12.2, 0.837 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.28 (s, 3H); 2.45 (s, 3H); 3.98 (s, 2H); 6.60 (m, 1H); 6.94-7.61 (unresolved complex, 8H), 9.93 (s, 1H)

EXAMPLE 50.5

N.sup.2-[4-chloro-2-(2,5-difluorobenzyl)phenyl]-N.sup.2-[(4-chloro-2,5-dim- ethylphenyl)sulfonyl]glycinamide

Starting with 0.83 g of N-[4-chloro-2-(2,5-difluorobenzyl)phenyl]-2,5-dimethyl-4-chlorobenzenesul- fonamide according to Example 15, 0.424 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.16 (s, 3H); 2.36 (s, 3H); 3.92 (d, 1H); 4.23 (d, 1H); 4.40 (d, 1H); 6.87 (s, 1H) 6.96-7.75 (unresolved complex, 8H) m.p.=169.7.degree. C.

EXAMPLE 51

N.sup.2-[4-chloro-2-(pyrid-2-ylmethyl)phenyl]-N.sup.2-[(3,4-dimethoxypheny- l)sulfonyl]glycinamide

EXAMPLE 51.1

2-(5-chloro-2-nitrobenzyl)pyridine

To 22.44 g of potassium tert-butoxide in 500 ml of dimethyl sulfoxide are slowly added 8.66 g of 4-chloronitrobenzene and 8.2 g of 2-chloromethylpyridine dissolved in 100 ml of dimethyl sulfoxide. After 18 hours at room temperature, the mixture is hydrolysed with saturated ammonium chloride solution and extracted three times with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is filtered through silica H, eluting with dichloromethane, to give 10.695 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 4.49 (s, 2H); 7.20-7.31 (unresolved complex, 2H); 7.60-7.78 (unresolved complex, 3H); 8.03 (d, 1H); 8.41 (d, 1H) m.p.=69.degree. C.

EXAMPLE 51.2

4-chloro-2-(pyrid-2-ylmethyl)aniline

Starting with 5 g of 2-(5-chloro-2-nitrobenzyl)pyridine according to Example 8.2, 3.86 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.93 (s, 2H); 5.33 (s, 2H); 6.66 (d, 1H); 6.93-7.06 (unresolved complex, 2H); 7.21-7.38 (unresolved complex, 2H); 7.76 (m, 1H); 8.47 (d, 1H)

EXAMPLE 51.3

N-[4-chloro-2-(pyrid-2-ylmethyl)phenyl]-3,4-dimethoxybenzenesulfonamide

Starting with 1.86 g of 4-chloro-2-(pyrid-2-ylmethyl)aniline according to Example 12.2, 2.12 g of the expected product are obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.71 (s, 3H); 3.83 (s, 3H); 3.94 (s, 2H); 7.07-7.32 (unresolved complex, 8H); 7.74 (m, 1H); 8.54 (d, 1H)

EXAMPLE 51.4

N.sup.2-[4-chloro-2-(pyrid-2-ylmethyl)phenyl]-N.sup.2-[(3,4-dimethoxy]phen- yl)sulfonyl]glycinamide

Starting with 0.5 g of N-[4-chloro-2-(pyrid-2-ylmethyl)phenyl]-3,4-dimethoxybenzenesulfonamide according to Example 12.3, 0.257 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.79 (s, 3H); 3.88 (s, 3H); 4.03-4.48 (unresolved complex, 4H)); 6.93-7.37 (unresolved complex, 10H); 7.74 (t, 1H); 8.54 (d, 1H) m.p.=88.degree. C.

EXAMPLE 52

N.sup.2-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.sup.2[(3,4-dimethoxyphe- nyl)sulfonyl]-(R)-alaninamide (compound 321)

##STR00383##

EXAMPLE 52.1

N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfony- l]-(R)-alanine

To 0.164 g of methyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfon- yl]-(R)-alaninate dissolved in 8 ml of a 1,4-dioxane/water mixture (4/1) is added, at room temperature, 0.015 g of lithium hydroxide monohydrate. The mixture is left at room temperature for 48 hours. The reaction medium is washed with 1M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/ethanol mixture to give 0.08 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.64 (d, 3H); 3.22 (s, 3H); 3.70 (s, 3H); 3.85 (s, 3H); 4.11 (d, 1H); 4.22 (q, 1H); 4.77 (d, 1H); 6.31 (d, 1H); 6.78 (d, 1H); 7.02-7.44 (unresolved complex, 7H), 12.5 (s, 1H).

EXAMPLE 52.2

N.sup.2-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.sup.2[(3,4-dimethoxyphe- nyl)sulfonyl]-(R)-alaninamide

Starting with 0.098 g of N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfon- yl]-(R)-alanine according to Example 43.2, 0.08 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.34 (d, 3H); 3.32 (s, 3H); 3.74 (s, 3H); 3.85 (s, 3H); 4.22 (d, 2H); 4.41 (q, 1H); 6.27 (d, 1H); 6.88 (d, 1H); 7.07-7.44 (unresolved complex, 9H).

According to this process, N.sup.2-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N.sup.2-[(3,4-dimethoxyp- henyl)sulfonyl]-(S)-alaninamide (compound 322) is synthesized.

.sup.1H NMR .delta. in ppm (DMSO d6): 1.34 (d, 3H); 3.32 (s, 3H); 3.74 (s, 3H); 3.85 (s, 3H); 4.22 (d, 2H); 4.41 (q, 1H); 6.27 (d, 1H); 6.88 (d, 1H); 7.07-7.44 (unresolved complex, 9H).

##STR00384##

EXAMPLE 53

N.sup.2-[2-methoxy-6-(2-phenylethyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide (compound 323)

##STR00385##

EXAMPLE 53.1

1-methoxy-2-nitro-3-[(E)-2-phenylvinyl]benzene

To 10 ml of ethanol is added, at room temperature, 0.31 g of sodium. The mixture is left at room temperature for 15 minutes, and 4.05 g of benzyltriphenylphosphonium chloride and 2 g of 2-nitro-3-methoxybenzaldehyde are successively introduced. After 18 hours at room temperature, the reaction medium is taken up in dichloromethane and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel to give 2.254 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 3.92 (s, 3H); 6.55-7.56 (unresolved complex, 10H).

EXAMPLE 53.2

2-methoxy-6-(2-phenylethyl)aniline

2.25 g of 1-methoxy-2-nitro-3-[(E)-2-phenylvinyl]benzene are added to 0.18 g of palladium-on-charcoal (10%) suspended in 90 ml of methanol, and placed under 4 bar of hydrogen. After 18 hours, the reaction medium is filtered through talc and the filtrate is concentrated to give 2.115 g of the expected product.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.74-2.88 (unresolved complex, 4H); 3.78 (s, 3H); 4.55 (s, 2H); 6.55-7.31 (unresolved complex, 8H).

EXAMPLE 53.3

N-[2-methoxy-6-(2-phenylethyl)phenyl](3,4-dimethoxyphenyl)sulfonamide

Starting with 2.11 g of 2-methoxy-6-(2-phenylethyl)aniline according to Example 12.2, 0.5 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.83 (m, 2H); 3.01 (m, 2H); 3.22 (s, 3H); 3.73 (s, 3H); 3.84 (s, 3H); 6.71-7.33 (unresolved complex, 11H); 8.99 (s, 1H).

EXAMPLE 53.4

N.sup.2-[2-methoxy-6-(2-phenylethyl)phenyl]-N.sup.2-[(3,4-dimethoxyphenyl)- sulfonyl]glycinamide

Starting with 0.5 g of N-[2-methoxy-6-(2-phenylethyl)phenyl](3,4-dimethoxyphenyl)sulfonamide according to Example 12.3, 0.187 g of the expected product is obtained.

.sup.1H NMR .delta. in ppm (DMSO d6): 2.83 (m, 3H); 3.26 (s, 3H); 3.40 (m, 1H); 3.73 (s, 3H); 3.84 (s, 3H); 6.76 (d, 1H); 7.03-7.36 (unresolved complex, 12H). m.p.=243.9.degree. C.

The compounds of the invention underwent pharmacological trials that demonstrated their advantage as therapeutically active substances.

They were in particular tested as regards their effects. More particularly, the affinity of the compounds of the invention for the orexin 2 receptors was determined in a test of in vitro binding according to the technique described below. This method consists in studying the displacement of radio-iodinated orexin A bound to human orexin 2 receptors expressed in CHO cells. The test is performed on membranes in a Hepes 50 mM, MgCl.sub.2 1 mM, CaCl.sub.2 25 mM, NaN.sub.3 0.025%, bovine serum albumin (BSA) 1% incubation buffer and 100 pM of ligand, for 30 minutes at 25.degree. C. The reaction is quenched by filtration and washing on a Whatman GF/C filter. The non-specific binding is measured in the presence of 10.sup.-6M of human orexin B. The IC.sub.50 values (concentration that inhibits 50% of the binding of the radio-iodinated orexin A to its receptors) are low, less than 300 nM, in particular less than 100 nM and more particularly less than 30 nM.

The affinity of the compounds according to the invention for the orexin 1 receptors was also studied in a test of in vitro binding according to the same technique using radio-iodinated orexin A as ligand in a membrane preparation of CHO cells expressing the human orexin 1 receptors. The compounds according to the invention show little or no affinity for the orexin 1 receptors.

The agonist or antagonist nature of the compounds is determined in vitro in a test of measurement of intracellular calcium (FLIPR) on a cell preparation expressing the orexin 2 receptors, according to the general technique described in Sullivan et al., Methods Mol. Biol., 1999, vol. 114, 125-133, using 1 .mu.M of Fluo-4 AM as fluorescent calcium indicator. For the antagonist test, the compounds are preincubated for 30 minutes before addition of 0.25 nM or orexin B. The IC.sub.50 values for the orexin 2 receptors measured in these studies are low and more particularly less than 100 nM.

The table below illustrates the affinity of a number of compounds according to the invention for the orexin receptors in a test of in vitro binding according to the technique described above, and also their antagonist nature determined in vitro in a test of measurement of intracellular calcium (FLIPR) according to the general technique mentioned above.

TABLE-US-00028 Measurement of Compound IC.sub.50 OX 2 IC.sub.50 OX 1 [Ca.sup.2+]i IC.sub.50 OX 2 No. (nM) (nM) (nM) - FLIPR 1 13 446 5 28 62 1500 19 30 82 966 26 44 85 >10 .mu.M 54 107 20 899 11 124 50 >10 .mu.M 65 137 19 >10 .mu.M 10 138 8 4760 11 202 9 1870 7

The biological results show that the compounds according to the invention are quite clearly specific antagonists of the orexin 2 receptors.

Thus, the compounds according to the present invention, as orexin 2 receptor antagonists, may be used in the prophylaxis and treatment of all diseases involving dysfunction associated with these receptors.

The compounds of the invention may be used for the preparation of a medicament for the prophylaxis or treatment of all diseases involving dysfunction associated with the orexin 2 receptor, and more particularly in the prophylaxis or treatment of pathologies in which an orexin 2 receptor antagonist affords therapeutic benefit. Such pathologies are, for example, obesity, appetite or taste disorders including cachexia, anorexia and bulimia (Smart et al., Eur. J. Pharmacol., 2002, 440, 2-3, 199-212), diabetes (Ouedraogo et al., Diabetes, 2002, 52, 111-117), metabolic syndromes (Sakurai, Curr. Opin. Nutr. Metab. Care, 2003, 6, 353-360), vomiting and nausea (U.S. Pat. No. 6,506,774), depression and anxiety (Salomon et al., Biol. Psychiatry, 2003, 54, 96-104; Jaszberenyi et al., J. Neuroendocrinol., 2000, 12, 1174-1178), addictions (Georgescu et al., J. Neurosci., 2003, 23, 8, 3106-3111; Kane et al., Endocrinology, 2000, 141, 10, 3623-3629), mood and behaviour disorders, schizophrenia (Nishino et al., Psychiatry Res., 2002, 110, 1-7), sleep disorders (Sakurai, Neuroreport, 2002, 13, 8, 987-995), restless legs syndrome (Allen et al., Neurology, 2002, 59, 4, 639-641), memory learning disorders (van den Pol et al., 2002, J. Physiol., 541(1), 169-185; Jaeger et al., Peptides, 2003, 23, 1683-1688; Telegdy et Adamik, Regul. Pept., 2002, 104, 105-110), sexual and psychosexual dysfunctions (Gulia et al., Neuroscience, 2003, 116, 921-923), pain, visceral or neuropathic pain, hyperalgesia, allodynia (U.S. Pat. No. 6,506,774; Suyama et al., In vivo, 2004, 18, 2, 119-123), digestive disorders (Takakashi et al., Biochem. Biophy. Res. Comm., 1999, 254, 623-627; Matsuo et al., Eur. J. Pharmacol., 2002, 105-109), irritable bowel syndrome (U.S. Pat. No. 6,506,774), neuronal degenerescence (van den Pol, Neuron, 2000, 27, 415-418), ischaemic or haemorrhagic attacks (Irving et al., Neurosci. Lett., 2002, 324, 53-56), Cushing's disease, Guillain-Barre syndrome (Kanbayashi et al., Psychiatry Clin. Neurosci., 2002, 56, 3, 273-274), myotonic dystrophy (Martinez-Rodriguez et al., Sleep, 2003, 26, 3, 287-290), urinary incontinence (Blackstone et al., AGS Annual Meeting, poster P491, 2002), hyperthyroidism (Malendowicz et al., Biomed. Res., 2001, 22, 5, 229-233), pituitary function disorders (Voisin et al., Cell. Mol. Life. Sci., 2003, 60, 72-78) and hypertension or hypotension (Samson et al., Brain Res., 1999, 831, 1-2, 248-253).

The use of the compounds according to the invention for the preparation of a medicament for preventing or treating the pathologies mentioned above forms an integral part of the invention.

A subject of the invention is also medicaments comprising a compound of formula (I). These medicaments find their therapeutic use especially in the prophylaxis or treatment of the pathologies mentioned above.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention and optionally one or more pharmaceutically acceptable excipients.

The said excipients are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or the possible salt, solvate or hydrate thereof, may be administered in a unit administration form, as a mixture with standard pharmaceutical excipients, to man and animals for the prophylaxis or treatment of the above disorders or diseases.

The appropriate unit forms of administration include oral forms such as tablets, soft or hard gel capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, forms for administration by inhalation, subcutaneous, intramuscular or intravenous administration forms, and rectal or vaginal administration forms. For topical application, the compounds according to the invention may be used in creams, ointments or lotions.

For example, when a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets may be coated with sucrose, a cellulose derivative or other materials. The tablets may be made via various techniques, direct compression, dry granulation, wet granulation or hot-melting.

In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle may range between 0.1 mg and 200 mg per kg of body weight and per day. Although these dosages are examples of an average situation, there may be particular cases in which higher or lower dosages are appropriate, and such dosages also form part of the invention. According to the usual practice, the dosage that is appropriate to each patient is determined by the doctor according to the mode of administration, the weight and the response of the said patient.

Each unit dose may contain from 0.1 to 1000 mg and preferably from 0.1 to 500 mg of active principle in combination with one or more pharmaceutical excipients. This unit dose may be administered 1 to 5 times a day so as to administer a daily dosage of from 0.5 to 5000 mg and preferably from 0.5 to 2500 mg.

According to another of its aspects, the present invention also relates to a method for preventing or treating the pathologies indicated above, which comprises the administration of a compound according to the invention, a pharmaceutically acceptable salt, a solvate or a hydrate of the said compound.