Cyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase

• US 20020052370A1
• Filed: 06/28/2001
• Published: 05/02/2002
• Est. Priority Date: 07/06/2000
• Status: Abandoned Application

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Cook, Andrew Simon, Pryde, David Cameron, Barber, Christopher Gordon, Maw, Graham Nigel, Stobie, Alan
• Application Number:
  US09/893,585
• Publication Number:
  US 20020052370A1
• Time in Patent Office: Days
• US Class Current: 514/237.5
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 233/58 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 233/60 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 235/40 having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 237/24 having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 275/52 Y being a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/13 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/18 to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07C 311/51 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 207/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 209/14 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 211/40 : Oxygen atoms
• CPC Class Codes: C07D 213/64 : attached in position 2 or 6
• CPC Class Codes: C07D 213/70 : Sulfur atoms
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 285/12 : 1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
• CPC Class Codes: C07D 285/135 : Nitrogen atoms
• CPC Class Codes: C07D 307/81 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52

Abstract

The invention provides compounds of formula I wherein R¹ is optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; n is 0, 1 or 2; and Y is —NR¹⁸S(O)_uR¹⁹ or a group shown below.

Claims

1. A method of treating female sexual dysfunction comprising administering a therapeutically effective amount of a compound of formula (I), pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof:

2. A compound of formula (I), pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R¹, n and Y are as defined in claim 1 with the proviso that Y is not the group —

C(O)NR¹¹R¹² and when R¹ is propyl or phenylethyl, R¹⁴ is not —

CH₂OH.

3. A compound of formula (I), pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R¹, n and Y are as defined in claim 1 with the proviso that Y is not the group —

C(O)NR¹¹R¹² and R¹⁴ is not H or —

CH₂OH.

4. A compound according to claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R¹ is C_1-6alkyl, C_1-6alkoxy, C_1-6alkoxy(C_1-3)alkyl, C_1-6alkoxyC_1-6alkoxyC_1-3alkyl or C_1-6alkyl substituted with aryl.

5. A compound according to claim 4, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R¹ is C_1-6alkyl, C_1-6alkoxy, C_1-6alkoxy(C_1-3)alkyl or C_1-6alkoxyC_1-6alkoxyC_1-3alkyl.

6. A compound according to claim 5, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R¹ is C_1-4alkyl or C_1-6alkoxy(C_1-3)alkyl.

7. A compound according to claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein when Y is the group

8. A compound according to claim 7, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein the carbocyclic ring is 5, 6 or 7 membered wherein one of R⁹ or R¹⁰, is —

C(O)NR¹¹R¹², with the other being C_1-6alkyl;

phenyl optionally substituted by C_1-4alkyl;

or phenyl(C_1-4alkyl) wherein the phenyl group is optionally substituted by C_1-4alkyl.

9. A compound according to claim 7, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R⁹ and R¹⁰ are attached to adjacent carbon atoms in the ring.

10. A compound according to claim 7 pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R⁸ is CH₂OH.

11. A compound according to claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein when Y is the group —

NR¹⁸S(O)_uR¹⁹, preferably R¹⁸ is H.

12. A compound according to claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R¹⁹ is benzyl or phenyl.

13. A compound according to claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein u is 2.

14. A compound according to claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein Y is an optionally substituted 5-7 membered heterocyclic ring.

15. A compound according to claim 14, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein the 5-7 membered heterocyclic ring is an optionally substituted aromatic ring.

16. A compound according to claim 15, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein said aromatic ring is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, indolyl, isoindolinyl, quinolyl, isoquinolyl, pyridonyl, quinoxalinyl or quinazolinyl each of which may be substituted as defined in claim 1.

17. A compound according to claim 16, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein the aromatic ring is oxadiazole, pyridone or thiadiazole each of which may be substituted as defined in claim 1.

18. A compound according to claim 17, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein the aromatic ring is 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-pyridone or 1,3,4-thiadiazole each of which may be substituted as defined in claim 1.

19. A compound according to claim 14 , pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein the 5-7 membered heterocyclic ring is substituted by one or more C_1-6alkyl, phenyl or phenylC_1-4alkyl.

20. A compound according to claim 19, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein the 5-7 membered heterocyclic ring is substituted by C_1-4alkyl or benzyl.

21. A compound according to claim 17, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein when Y is a pyridone said pyridone is N-substituted pyridone.

22. A compound according to claim 14, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein Y is a lactam linked at the nitrogen.

23. A compound according to any claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein Y is

24. A compound according to claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein R¹⁶ and R¹⁷ are hydrogen.

25. A compound according to claim 2, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, wherein t is 0.

26. A compound of formula Ie, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof,

28. The method according to claim 1 wherein the female sexual dysfunction treated includes at least female sexual arousal dysfunction (FSAD).

29. The method according to claim 1 wherein the medicament is administered systemically.

30. The method according to claim 1 wherein the medicament is administered orally.

31. A method of treatment or prophylaxis of a condition for which a beneficial therapeutic response can be obtained by the inhibition of neutral endopeptidase comprising administration of a therapeutically effective amount of a compound as defined in claim 2.

32. A medicine comprising the compound of claim 2.

33. A pharmaceutical formulation including a compound as defined in claim 2 together with a pharmaceutically acceptable excipient.

34. A method for the treatment or prophylaxis of female sexual dysfunction including administering to the patient a therapeutically effective amount of a compound as defined in claim 2.

35. A female sexual dysfunction pharmaceutical formulation including a therapeutically effective amount of a compound as defined in claim 2 together with a pharmaceutically acceptable excipient.

36. A process for preparing a compound of formula I or salts thereof

37. A compound of formula IV

27. A compound, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, selected from the group consisting of:

2-[(1-{[(1-benzyl-6-oxo-1 ,6-dihydro-3-pyridinyl)amino]carbonyl}cyclopentyl)-methyl]-4-methoxybutanoic acid;

2-{[1-({[3-(2-oxo-1-pyrrolidinyl)propyl]amino}carbonylcyclopentyl]-methyl}-4-phenylbutanoic acid);

(+)-2-{[1-({[2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)cyclopentyl]methyl}-4-phenylbutanoic acid;

2-[(1-{[(5-methyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]-4-phenylbutanoic acid;

cis-3-(2-methoxyethoxy)-2-[(1-{[(4-{[(phenylsulfonyl)amino]carbonyl}cyclohexyl)-amino]carbonyl}cyclopentyl)methyl]propanoic acid;

(+)-2-{[1-({[2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)cyclopentyl]-methyl}pentanoic acid;

(2R)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)-methyl]pentanoic acid or (−

)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)-methyl]pentanoic acid;

(2S)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)-methyl]pentanoic acid or (+)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)-methyl]pentanoic acid;

2-({1-[(3-benzylanilino)carbonyl]cyclopentyl}methyl)pentanoic acid;

2-[(1-{[(1-benzyl-6-oxo-1 ,6-dihydro-3-pyridinyl)amino]carbonyl}cyclopentyl)-methyl]pentanoic acid;

2-{[1-({[(1R,3S,4R)-4-(aminocarbonyl)-3-butylcyclohexyl]amino}carbonyl)-cyclopentyl]methyl}pentanoic acid;

trans-3-[1-({[2-(4-chlorophenyl)cyclopropyl]amino}carbonyl)cyclopentyl]-2-(methoxymethyl)propanoic acid;

trans-3-[1-({[2-(4-methoxyphenyl)cyclopropyl]amino}carbonyl)cyclopentyl]-2-(methoxyethyl)propanoic acid;

trans-3-[l -({[2-pentylcyclopropyl]amino}carbonyl)cyclopentyl]-2-(methoxyethyl)propanoic acid;

3-[1-({[5-benzyl-[1,3,4]-thiadiazol-2-yl]amino}carbonyl)cyclopentyl]-2-(methoxyethyl)propanoic acid;

3-[1-({[4-butylpyridin-2-yl]amino}carbonyl)cyclopentyl]-2-(methoxyethyl)propanoic acid;

3-[1-({[4-phenylpyridin-2-yl]amino}carbonyl)cyclopentyl]-2-(methoxyethyl)propanoic acid

3-[1-({[1-hydroxymethyl-3-phenylcyclopentyl]amino}carbonyl)cyclopentyl]-2-(methoxyethyl)propanoic acid;

2-{[1-({[2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)-cyclopentyl]methyl}-4-methoxybutanoic acid

trans-3-[1-({[2-phenylcyclopropyl]amino}carbonyl)cyclopentyl]-2-(methoxyethyl)propanoic acid;

(R)-2-{[l-({[2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)-cyclopentyl]methyl}-4-methoxybutanoic acid; and

(S)-2-{[1-({[2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)-cyclopentyl]methyl}-4-methoxybutanoic acid.