CYCLOPENTA[C]PYRROLE-2-CARBOXYLATE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

• US 20120095040A1
• Filed: 05/11/2010
• Published: 04/19/2012
• Est. Priority Date: 05/12/2009
• Status: Active Grant

• Current Assignee: Sanofi
• Original Assignee: Sanofi
• Inventors: Abouabdellah, Ahmed, Even, Luc, Fayol, Aude, Vache, Julien, Yauche, Philippe
• Granted Patent: US 8,697,883 B2
• Time in Patent Office: Days
• US Class Current: 514/307
• 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 compounds of the general formula (I) where: R₂ is a hydrogen or fluorine atom or a hydroxyl, cyano, trifluoromethyl, C_1-6-alkyl, C_1-6-alkoxy, or NR₈R₉ group; m, n, o and p independently are a number from 0 to 3; A is a covalent bond, an oxygen atom, a C_1-6-alkylene group or a —O—C_1-6-alkylene group in which the end that is an oxygen atom is bonded to the R₁ group while the end that is an alkylene group is bonded to the carbon of the bicyclic compound; R₁ is an optionally substituted aryl or heteroaryl group; R₃ is a hydrogen or fluorine atom or a C_1-6-alkyl or trifluoromethyl group; R₄ is an optionally substituted 5-membered heterocyclic compound; wherein the compounds can be in the state of a base or an acid addition salt. The invention can be used in therapeutics.

Claims

1. A compound corresponding to formula (I)

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

in the form of the 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;

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

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

in the form of the 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;

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

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

in the form of the 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;

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

8. The compound of claim 1 chosen from:

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(1H)-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)-5-(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 process for preparing the compound of claim 1, comprising the step of reacting either an amine of general formula (II),

10. A process for preparing the compound of claim 1, comprising the step of reacting a compound of general formula (Ia)

11. A process for preparing the compound of claim 1, in which R₁ represents a group R₅ substituted especially with a group R₆ of the type C_1-6-alkyl, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-alkylene, or with a group R₇ as defined in the general formula (I) according to claim 1, comprising the step of performing a coupling reaction, catalysed with a transition metal, on the compound of general formula (Ib),

12. A compound of general formula (Ia)

13. A compound of general formula (II),

14. A compound of general formula (IIe):

15. A pharmaceutical composition comprising the compound of claim 1, in the form of the base or of a pharmaceutically acceptable acid-addition salt, for its use as a medicament.

16. The pharmaceutical composition of claim 15, further comprising one or more pharmaceutically acceptable excipients.

17. A method of preventing or treating a pathology in which the endogenous cannabinoids and/or any substrate metabolized by the enzyme FAAH are involved in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 15.

18. A method of preventing or treating acute or chronic pain of neurogenic type, acute or chronic pain associated with inflammatory diseases, acute or chronic peripheral pain, vertigo, vomiting, nausea, eating behaviour disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleeping disorders, cardiovascular diseases, renal ischaemia, cancer, immune system disorders, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular complaints, pulmonary complaints, gastrointestinal diseases, urinary incontinence or bladder inflammation in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 15.