Phenyl carbamates and their use as inhibitors of the fatty acid amide hydrolase (FAAH) enzyme and modulators of the D3 dopamine receptor (D3DR)

Patent metadata

Field	Value
Publication number	US-9828352-B2
Application number	US-201414905727-A
Country	US
Kind code	B2
Filing date	Jul 10, 2014
Priority date	Jul 18, 2013
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

The invention provides compounds of Formula (I) or pharmaceutically acceptable salts thereof

wherein Ar′, R 1 , R 2 , R 3 , R 4 , X, Y are as defined in the description of invention, as multi-target directed ligands (MTDLs) that are at the same time inhibitors of the fatty acid amide hydrolase (FAAH) enzyme and modulators of the D3 dopamine receptor (D3DR), their methods of preparation, formulations and therapeutic applications thereof.

First claim

The invention claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof

wherein:
Ar′ is a benzene, indole, naphthyl or pyridine ring;
R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, C 1-6 alkoxy, OH, CF 3 ; R 1 and R 2 can be attached in any position of the Ar′ group;
X is N;
Y is an alkylene or alkenylene group selected from the group consisting of

where n is 0 or an integer from 1 to 3 and wherein Y is optionally substituted by up to two same or different substituents B attached to any position of the Y group;
B is selected in the group consisting of F, OH, and CH 2 OH;
R 3 is a phenyl, benzyl, benzoyl or a pyridine ring attached to phenyl ring in the meta or para position and optionally substituted by up to two same or different substituents R 5 , wherein R 5 is halogen, C 1-6 alkyl or a group CONH 2 or CONHCH 3 attached to R 3 in the meta or para position;
or R 3 is a 5- to 7-membered heterocyclic ring comprising up to 2 heteroatoms selected from N, O and S attached to the phenyl ring in the meta or para position and optionally substituted by up to two same or different substituents R 6 , wherein R 6 is gem-difluoro, gem-dimethyl, COMe, attached to R 3 in any position of the ring;
and wherein the group R 3 can be attached to any position of the phenyl ring;
R 4 is hydrogen, halogen, linear or branched C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, CF 3 ; the group R 4 can be attached to any position of the phenyl ring;
or R 3 and R 4 together with the phenyl ring to which they are connected may form a 9H-carbazole ring.

2. A compound of Formula (I) according to claim 1 wherein:
R 1 and R 2 are, independently, hydrogen, halogen, C 1-6 alkoxy, CF 3 ;
X is N;
Y is CH 2 —(CH 2 ) n —CH 2 , where n is 0 or an integer from 1 to 2, or a group CH 2 —CH═CH—CH 2 , CH 2 CH(OH)CH 2 CH 2 , CH 2 CH(F)CH 2 , CH 2 CH(F)CH 2 CH 2 , CH 2 CH(OH)CH 2 , CH(CH 2 F)CH 2 , CH(CH 2 F) CH 2 CH 2 , CH(CH 2 OH)CH 2 ;
R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, CF 3 ; the group R 4 can be attached to the phenyl ring in any position of the ring;
or R 3 and R 4 together with the phenyl ring to which they are connected may form a 9H-carbazole ring.

3. A compound of Formula (I) according to claim 2 , wherein:
Ar′ is a benzene ring;
R 1 and R 2 are, independently, H, Cl, or OMe, Me, CF 3 ;
X is N;
Y is CH 2 —(CH 2 ) n —CH 2 , where n is 0 or an integer from 1 to 2, or a group CH 2 —CH═CH—CH 2 , a group CH(CH 2 F)CH 2 , or a group CH 2 CH(F)CH 2 CH 2 ;
R 3 is a phenyl, benzyl, benzoyl or pyridine ring attached to the phenyl ring in the meta or para position and optionally substituted with a group CONH 2 or CONHCH 3 attached to R 3 in the meta or para position;
or R 3 is a 1-pyrrolidinyl or 1-piperidinyl or 1-piperazinyl or 4-morpholinyl ring attached to the phenyl ring in the meta or para position and optionally substituted with gem-difluoro;
R 4 is hydrogen, F, Me or OMe; the group R 4 can be attached to the phenyl ring in any position of the ring;
or R 3 and R 4 together with the phenyl ring to which they are connected may form a 9H-carbazole ring.

4. Compounds according to claim 1 , selected from the group consisting of:
[3-(3-carbamoylphenyl)phenyl] N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl] carbamate;
[3-(3-carbamoylphenyl)phenyl] N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl] carbamate;
[3-(3-carbamoylphenyl)phenyl] N-[3-[4-(2,3-dichlorophenyl)piperazin-1-yl]propyl] carbamate;
[3-(3-carbamoylphenyl)phenyl] N-[3-(4-phenylpiperazin-1-yl)propyl] carbamate;
(3-phenylphenyl) N-[3-(4-phenylpiperazin-1-yl)propyl] carbamate;
[4-(3-carbamoylphenyl)phenyl] N-[3-[4-(2,3-dichlorophenyl)piperazin-1-yl]propyl] carbamate;
[4-(3-carbamoylphenyl)phenyl] N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl] carbamate;
(3-morpholinophenyl) N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl] carbamate hydrochloride;
[3-(4,4-difluoro-1-piperidinyl)phenyl] N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl] carbamate hydrochloride;
[4-(3-carbamoylphenyl)phenyl] N-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl] carbamate;
[4-(4,4-difluoro-1-piperidinyl)phenyl] N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl] carbamate hydrochloride;
(3-morpholinophenyl) N-[3-[4-(o-tolyl)piperazin-1-yl]propyl] carbamate hydrochloride;
(4-phenylphenyl) N-[3-[4-(o-tolyl)piperazin-1-yl]propyl] carbamate;
(4-phenylphenyl) N-[3-[4-[2-(trifluoromethyl)phenyl]piperazin-1-yl]propyl] carbamate;
9H-carbazol-2-yl N-[3-[4-(2,3-dichlorophenyl)piperazin-1-yl]propyl]carbamate;
[4-(4,4-difluoro-1-piperidinyl)phenyl] N-[3-[4-[2-(trifluoromethyl)phenyl] piperazin-1-yl]propyl] carbamate hydrochloride;
[4-(3-carbamoylphenyl)phenyl] N-[(E)-4-[4-(2,3-dichlorophenyl)piperazin-1-yl] but-2-enyl] carbamate;
[4-(3-carbamoylphenyl)-3-fluoro-phenyl] N-[(E)-4-[4-(2,3-dichlorophenyl) piperazin-1-yl]but-2-enyl] carbamate.

5. A pharmaceutical composition containing an effective amount of a compound of Formula (I) according to claim 1 or a pharmaceutically salt thereof and at least one pharmaceutically acceptable excipient.

Assignees

• Fondazione St Italiano Tecnologia
• Univ California

Inventors

• Bottegoni Giovanni
• De Simone Alessio
• Ruda Gian Filippo
• Cavalli Andrea
• Bandiera Tiziano
• Piomelli Daniele

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/34

  Tobacco-abuse · CPC title

• A61P25/36

  Opioid-abuse · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title