Cyclopenta[C]pyrrole-2-carboxylate derivatives, preparation thereof and therapeutic use thereof

• US 8,697,883 B2
• Filed: 05/11/2010
• Issued: 04/15/2014
• Est. Priority Date: 05/12/2009
• Status: Expired due to Fees

• Current Assignee: Sanofi
• Original Assignee: Sanofi
• Inventors: Abouabdellah, Ahmed, Even, Luc, Fayol, Aude, Vache, Julien, Yaiche, Philippe
• Primary Examiner(s): Chu, Yong
• Assistant Examiner(s): WRIGHT, SONYA N
• Application Number:
  US13/319,908
• Publication Number:
  US 20120095040A1
• Time in Patent Office: 1,435 Days
• Field of Search: 548/311, 548/204, 548/248, 514/274, 514/365
• US Class Current: 548/204
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 277/64 : with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The invention relates to cyclopenta[c]pyrrole-2-carboxylate derivatives, to their preparation and to their therapeutic use.

Claims

1. A compound corresponding to formula (I)

2. The compound of claim 1, wherein R₂ represents a hydrogen atom or a hydroxyl group;

or

in the form of a base or of an acid-addition salt.

3. The compound of claim 1 wherein m, n, o and p have the value 1, or alternatively m and o have the value 1, n has the value 0 and p has the value 2;

or

in the form of a base or of an acid-addition salt.

4. The compound of claim 1, wherein A represents a covalent bond or an oxygen atom;

or in the form of a base or of an acid-addition salt.

5. The compound of claim 1, wherein R₁ represents a group R₅ that is unsubstituted or substituted with one or more groups R₆ and/or R₇;

R₅ represents a phenyl, naphthyl, benzothiazolyl or isoquinolyl group;

R₆ represents a halogen atom or a group C_1-6-haloalkyl or a group C_1-6-alkoxy;

R₇ represents a phenyl that may be substituted with one or more groups R₆, which may be identical or different;

or in the form of a base or of an acid-addition salt.

6. The compound of claim 1, wherein R₃ represents a hydrogen atom;

or in the form of a base or of an acid-addition salt.

7. The compound of claim 1, wherein R₄ represents a group chosen from a thiazolyl, a thiadiazolyl, a triazolyl, an oxazolyl and an isoxazolyl;

this group being unsubstituted or substituted with one or more groups C_1-6-alkyl, CONR₈R₉ or CON(R₈)(C_1-3-alkylene-NR₁₀R₁₁);

R₈, R₉, R₁₀ and R₁₁ represent, independently of each other, a hydrogen atom or a group C_1-6-alkyl;

or

in the form of a base or of an acid-addition salt.

8. The compound of claim 1 selected from the group consisting of:

thiazol-2-ylmethyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

thiazol-2-ylmethyl (3aR,5s,6aS)-5-[4-(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

thiazol-2-ylmethyl (3aR,5s,6aS)-5-[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

thiazol-2-ylmethyl (3aR,5r,6aS)-5-[3-(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (endo)

thiazol-2-ylmethyl (3aR,5s,6aS)-5-[3-(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-2(1R)-carboxylate (exo)

thiazol-2-ylmethyl (3aR,5r,6aS)-5-[(4′

-ethoxybiphenyl-3-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (endo)

1,2,3-thiadiazol-4-ylmethyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(5-tert-butyl-1,3,4-thiadiazol-2-yl)methyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

1,2,3-thiadiazol-4-ylmethyl (3aR,5s,6aS)-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(1-methyl-1H-1,2,4-triazol-5-yl)methyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(4-carbamoylthiazol-2-yl)methyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[4-(methylcarbamoyl)thiazol-2-yl]methyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-[3-(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-5-[3-(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

thiazol-2-ylmethyl (3aR,5s,6aS)-5-[(4′

-ethoxybiphenyl-3-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(4-carbamoyloxazol-2-yl)methyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

thiazol-4-ylmethyl (3aR,4S,6aS)-4-[(6-methoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

thiazol-4-ylmethyl (3aR,4R,6aS)-4-[3-(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (endo)

(4-carbamoylthiazol-2-yl)methyl (3aR,5s,6aS)-5-[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[4-(methylcarbamoyl)thiazol-2-yl]methyl (3aR,5s,6aS)-5-[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-5-[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[4-(methylcarbamoyl)oxazol-2-yl]methyl (3aR,5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-[(4-chloro-1-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-5-[(4-chloro-1-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

thiazol-4-ylmethyl (3aR,4S,6aS)-4-[(4-chloro-1-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

thiazol-4-ylmethyl (3aR,4R,6aS)-4-[(4′

-ethoxybiphenyl-3-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (endo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-[(4′

-fluorobiphenyl-4-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-5-(4-chloro-2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-(4-chloro-2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-(4-chloro-3-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-5-(4-chloro-3-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-(2,4-dichlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-5-(2,4-dichlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-(isoquinolin-7-yloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-(isoquinolin-6-yloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-carbamoylisoxazol-5-yl)methyl (3aR,5r,6aS)-5-(4-fluoro-1,3-benzothiazol-2-yl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(4-carbamoyloxazol-2-yl)methyl (3aR,5s,6aS)-5-[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-{[2-(dimethylamino)ethyl]carbamoyl}isoxazol-5-yl)methyl (3aR,5s,6aS)-5-(4-fluorophenoxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo), and its hydrochloride

[4-(methylcarbamoyl)oxazol-2-yl]methyl (3aR,5s,6aS)-5-[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-dimethylcarbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)

(3-methylcarbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-[(4′

-fluorobiphenyl-4-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo).

9. A pharmaceutical composition comprising the compound of claim 1, in the form of the base or of a pharmaceutically acceptable acid-addition salt.

10. The pharmaceutical composition of claim 9, further comprising one or more pharmaceutically acceptable excipients.