4-arylmorpholin-3-one derivatives, their preparation and therapeutic use thereof

1. A compound corresponding to formula (I):

in which:

Ar represents a phenyl mono- or di-substituted with a halogen atom;

R 1 represents a phenyl that is un-substituted or substituted once or twice with one or two substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl and a (C 1 -C 4 )alkoxy;

R 2 represents:

a pyridyl;

a phenyl that is un-substituted or substituted once or twice with one or two substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethyl group and a trifluoromethoxy group;

a benzyl that is un-substituted or substituted on the phenyl once or twice with one or two substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethyl group and a trifluoromethoxy group;

R 2 may also represent:

a heterocyclic radical chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or perhydroazepine when R 3 represents a cyano or a group —CONR 11 R 12 ;

R 3 represents a group chosen from:

(1) a hydrogen atom;

(2) (C 1 -C 4 ) alkyl;

(3) (C 1 -C 4 ) alkylcarbonyl;

(4) cyano;

(5) —(CH 2 ) q —OH;

(6) —(CH 2 ) q —O—(C 1 -C 4 )alkyl;

(7) —(CH 2 ) q —O—CO—R 4 ;

(8) —(CH 2 ) q —O—CO—NH—(C 1 -C 4 )alkyl;

(9) —NR 5 R 6 ;

(10) —(CH 2 ) q —NR 7 COR 8 ;

(11) —(CH 2 ) q —NR 7 COOR 9 ;

(12) —(CH 2 ) q —NR 7 SO 2 R 10 ;

(13) —(CH 2 ) q —NR 7 CONR 11 R 12 ;

(14) —CH 2 NR 13 R 14 ;

(15) —CH 2 —CH 2 NR 13 R 14 ;

(16) —COOH;

(17) —COO—(C 1 -C 4 ) alkyl;

(18) —CONR 11 R 12 ;

(19) —CH 2 —COOH;

(20) —CH 2 —COO—(C 1 -C 4 )alkyl;

(21) —CH 2 —CONR 11 R 12 ;

(22) —O—CH 2 CH 2 OR 15 ;

(23) —NR 7 COCOR 16 ;

(24) —CONR 7 —NR 17 R 18 ;

q is 0, 1 or 2;

R 4 represents a (C 1 -C 4 )alkyl; a (C 3 -C 7 )cycloalkyl that is un-substituted or substituted with one or more methyl groups; a phenyl, or a pyridyl;

R 5 and R 6 each independently represent a hydrogen atom or a (C 1 -C 4 )alkyl; R 6 may also represent a (C 3 -C 7 )cycloalkylmethyl, a benzyl or a phenyl; or R 5 and R 6 , together with the nitrogen atom to which they are attached, constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine thiomorpholine, perhydroazepine or piperazine that is un-substituted or substituted in position 4 with a (C 1 -C 4 )alkyl;

R 7 represents a hydrogen atom or a (C 1 -C 4 )alkyl;

R 8 represents a hydrogen atom; a (C 1 -C 4 )alkyl; a vinyl; a phenyl; a benzyl; a pyridyl; or a (C 3 -C 7 )cycloalkyl that is un-substituted or substituted with one or more methyl groups; a furyl; a thienyl; a pyrrolyl; an imidazolyl;

or R 7 and R 8 together represent a group —(CH 2 ) p —;

p is 3 or 4;

R 9 represents a (C 1 -C 4 ) alkyl or a phenyl;

or R 7 and R 9 together represent a group —(CH 2 ) n —;

n is 2 or 3;

R 10 represents a (C 1 -C 4 ) alkyl or an amino that is free or substituted with one or two (C 1 -C 4 )alkyls; a phenyl that is un-substituted or substituted one or more times with a substituent chosen from: a halogen atom, a (C 1 -C 4 )alkyl, a trifluoromethyl, a hydroxyl, a (C 1 -C 4 )alkoxy, a carboxyl, a (C 1 -C 4 )alkoxycarbonyl, a (C 1 -C 4 )alkylcarbonyloxy, a cyano, a nitro, an amino that is free or substituted with one or two (C 1 -C 4 )alkyls, the said substituents being identical or different;

R 11 and R 12 each independently represent a hydrogen or a (C 1 -C 4 ) alkyl; R 12 may also represent a (C 3 -C 7 )cycloalkyl, a (C 3 -C 7 )cycloalkylmethyl, a hydroxyl, a (C 1 -C 4 )alkoxy, a benzyl or a phenyl; or R 11 and R 12 , together with the nitrogen atom to which they are attached, constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine thiomorpholine and perhydroazepine;

or R 7 and R 12 together represent a group —(CH 2 ) m —;

m is 2 or 3;

R 13 and R 14 each independently represent a hydrogen atom or a (C 1 -C 4 )alkyl; R 14 may also represent a (C 3 -C 7 )cycloalkylmethyl or a benzyl;

R 15 represents a hydrogen atom; a (C 1 -C 4 )alkyl; a formyl; a (C 1 -C 4 )alkylcarbonyl;

R 16 represents a (C 1 -C 4 )alkoxy;

R 17 and R 18 each independently represent a hydrogen atom or a (C 1 -C 4 )alkyl;

or alternatively R 17 and R 18 , together with the nitrogen atom to which they are attached, constitute a heterocycle chosen from pyrrolidine, piperidine and morpholine;

R 19 represents a hydrogen atom or a (C 1 -C 4 )alkyl;

R 20 and R 21 each independently represent a hydrogen atom or a (C 1 -C 4 ) alkyl; R 21 may also represent a formyl or a (C 1 -C 4 )alkylcarbonyl;

in the form of its' acid-addition salt or hydrate or a solvate of said compound.

2. The compound of formula (I) as recited in to claim 1 , wherein:

Ar represents a phenyl di-substituted with a halogen atom;

R 1 represents a phenyl that is un-substituted or substituted once or twice with a halogen atom;

R 2 represents:

a pyridyl;

a phenyl that is un-substituted or substituted once or twice with one or two substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethyl group and a trifluoromethoxy group;

R 2 may also represent a heterocyclic radical chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazetidine when R 3 represents a group —CONR 11 R 12 ;

R 3 represents a group chosen from:

(5) —(CH 2 ) q —OH in which q is 0;

(10) —(CH 2 ) q —NR 7 COR 8 in which q is 0;

(11) —(CH 2 ) q —NR 7 COOR 9 in which q is 0;

(18) —CONR 11 R 12 ;

R 7 , R 8 , R 9 , R 11 and R 12 being as defined for a compound of formula (I) in claim 1 ; also in

in the form of its' acid-addition salt, or a hydrate or a solvate of said compound.

3. The compound of formula (I) as recited in claim 1 , wherein:

Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl;

R 1 represents a phenyl, a 4-chlorophenyl, a 4-fluorophenyl or a 3,4-difluorophenyl;

R 2 represents:

a 2-pyridyl;

a phenyl, a 4-chlorophenyl, a 3-fluorophenyl, a 4-fluorophenyl, a 3,4-difluorophenyl, a 3-methylphenyl, a 3,4-dimethylphenyl, a 4-methoxyphenyl, a 3-(trifluoromethyl)phenyl, a 4-(trifluoromethyl)phenyl or a 4-(trifluoromethoxy)phenyl;

R 2 may also represent a 1-piperidyl when R 3 represents a —CONH 2 group or a —CON(CH 3 ) 2 group;

R 3 represents a group chosen from:

a hydroxyl;

DPP-IV exists as both a membrane-spanning form present in cells throughout the body and a soluble circulating form. Both forms of DPP-IV have identical enzymatic activity (9) and cleave a wide range of bioactive peptides in vitro, including hormones, neuropeptides, and chemokines (12). One potential regulatory role of DPP-IV is the inactivation of GHRH through cleavage of the active form, GHRH(1-44)-NH 2 , to the N-terminally shortened inactive form, GHRH(3-44)-NH 2 , in the form of its' acid-addition salts, or a hydrate or a solvate of said compound.

4. The compound as recited in claim 1 , selected from the group consisting of:

-6-(3,4-dichlorophenyl)-6-[2-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-phenyl-4-piperidyl]-acetamide, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-(3-fluorophenyl)-4-piperidyl]acetamide, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-(3,4-difluorophenyl)-4-piperidyl]acetamide, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-(4-methylphenyl)-4-piperidyl]acetamide, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-(4-methoxyphenyl)-4-piperidyl]acetamide, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-[4-(trifluoromethoxy)-phenyl]-4-piperidyl]acetamide, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(3-fluoro-phenyl)-4-(2-oxopyrrolidin-1-yl)-1-piperidyl]ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(3,4-di-fluorophenyl)-4-(2-oxopyrrolidin-1-yl)-1-piperidyl]-ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(4-methyl-phenyl)-4-(2-oxopyrrolidin-1-yl)-1-piperidyl]ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

-1′-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4′-(4-methylphenyl)-1,4′-bipiperidin-2-one, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(3-methyl-phenyl)-4-(2-oxopyrrolidin-1-yl)-1-piperidyl]ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(3-fluoro-phenyl)-4-(2-oxo-1,3-oxazolidin-3-yl)-1-piperidyl]-ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(4-fluoro-phenyl)-4-(2-oxo-1,3-oxazolidin-3-yl)-1-piperidyl]-ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(3,4-dimethyl-phenyl)-4-(2-oxo-1,3-oxazolidin-3-yl)-1-piperidyl]-ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

-3-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-phenyl-4-piperidyl]-1,3-oxazinan-2-one, dextrorotatory isomer;

-3-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-(4-fluorophenyl)-4-piperidyl]-1,3-oxazinan-2-one, dextrorotatory isomer;

-3-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-(3,4-difluorophenyl)-4-piperidyl]-1,3-oxazinan-2-one, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(morpholin-4-ylcarbonyl)-4-phenyl-1-piperidyl]ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

-1′-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-1,4′-bipiperidin-4′-carboxamide, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-[4-(3,4-di-fluorophenyl)-4-(2-oxo-1,3-oxazolidin-3-yl)-1-piperidyl]ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-difluorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-phenyl-4-piperidyl]-acetamide, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-[4-(trifluoromethyl)-phenyl]-4-piperidyl]acetamide, dextrorotatory isomer;

-1′-[2-[2-(3,4-difluorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-1,4′-bipiperidine-4′-carboxamide, dextrorotatory isomer;

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-[3-(trifluoromethyl)-phenyl]-4-piperidyl]acetamide, dextrorotatory isomer;

-6-(3,4-dichlorophenyl)-6-[2-(4-hydroxy-4-pyridin-2-yl-1-piperidyl)ethyl]-4-phenylmorpholin-3-one, dextrorotatory isomer;

—N-[1-[2-[4-(4-chlorophenyl)-2-(3,4-dichloro-phenyl)-5-oxomorpholin-2-yl]ethyl]-4-phenyl-4-piperidyl]acetamide;

-4-(4-chlorophenyl)-6-[2-[4-(4-chlorophenyl)-4-(2-oxo-1,3-oxazolidin-3-yl)-1-piperidyl]ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one;

-1′-[2-[4-(4-chlorophenyl)-2-(3,4-dichloro-phenyl)-5-oxomorpholin-2-yl]ethyl]-N,N-dimethyl-1,4′-bipiperidine-4′-carboxamide;

—N-[1-[2-[2-(3,4-dichlorophenyl)-4-(4-fluoro-phenyl)-5-oxomorpholin-2-yl]ethyl]-4-phenyl-4-piperidyl]acetamide;

—N-[1-[2-[2-(3,4-dichlorophenyl)-4-(4-fluoro-phenyl)-5-oxomorpholin-2-yl]ethyl]-4-(3,4-difluoro-phenyl)-4-piperidyl]acetamide;

-1′-[2-[2-(3,4-dichlorophenyl)-4-(4-fluoro-phenyl)-5-oxomorpholin-2-yl]ethyl]-N,N-dimethyl-1,4′-bipiperidine-4′-carboxamide;

—N-[1-[2-[2-(3,4-dichlorophenyl)-4-(3,4-di-fluorophenyl)-5-oxomorpholin-2-yl]ethyl]-4-phenyl-4-piperidyl]acetamide;

in the form of its' acid-addition salt or hydrate or a solvate of said compound.

5. The compound as recited in claim 1 selected from the group comprising:

—N-[1-[2-[2-(3,4-dichlorophenyl)-5-oxo-4-phenylmorpholin-2-yl]ethyl]-4-(3-fluorophenyl)-piperid-4-yl]acetamide, dextrorotatory isomer; in the form of its' acid-addition salt or hydrate or a solvate of said compound.

6. A process for the preparation of a compound of formula (I) as recited in claim 1 wherein the compound of formula II:

and Ar and R 1 are as defined in claim 1 , is reacted with a compound of formula III in which R 2 and R 3 are as defined in claim 1 :

in the presence of an acid in a solvent, and the intermediate aminium salt formed thereby is then reduced using a reducing agent.

7. A process for preparing a compound of formula (I) as recited in claim 1 wherein a compound of formula IV:

in which Ar and R 1 are as defined for a compound of formula (I) in claim 1 , and Y represents a methyl, phenyl, tolyl or trifluoromethyl group, is reacted with a compound of formula:

in which R 2 and R 3 are as defined for a compound of formula (I) in claim 1 .

8. A pharmaceutical composition comprising a compound of formula (I) according to claim 5 , or a pharmaceutically acceptable salt, hydrate or a solvate thereof in combination with at least one pharmaceutically acceptable excipient.