IP Library › Granted Patent US 7,053,089

Granted Patent B2

US 7,053,089 · App. 10/079,452 · Granted May 30, 2006

N-substituted nonaryl-heterocyclic NMDA/NR2B antagonists

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Quick Facts

Patent No.: US 7,053,089
App. No.: 10/079,452
Granted: May 30, 2006
Kind: B2

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Abstract

Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are effective as NMDA NR2B antagonists useful for relieving pain.

Claims (85)

1. A compound having the formula (I):

or pharmaceutically acceptable salts thereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring;

HetAr is a 5 or 6 membered heteroaromatic ring containing 1–3 nitrogen ring atoms, or isoxazolyl, thiazolyl, thiadiazolyl, quinolinyl, quinazolinyl, purinyl, pteridinyl, benzimidazolyl, pyrrolopyrimidinyl, or imidazopyridinyl;

HetAr is optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—;

A is —C 1-4 alkyl-;

B is aryl(CH 2 ) 0-3 —O—C(O)—, heteroaryl(CH 2 ) 1-3 —O—C(O)—, indanyl(CH 2 ) 0-3 —O—C(O)—, aryl(CH 2 ) 1-3 —C(O)—, aryl-cyclopropyl-C(O)—, heteroaryl-cyclopropyl-C(O)—, heteroaryl(CH 2 ) 1-3 —C(O)—, aryl(CH 2 ) 1-3 —, —NH—C(O)—, aryl(CH 2 ) 1-3 —NH—C(NCN)—, aryl(CH 2 ) 1-3 —SO 2 —, heteroaryl(CH 2 ) 1-3 —SO 2 —, wherein any of the aryl or heteroaryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , or X taken with an adjacent bond is ═O.

2. The compound according to claim 1 , or a pharmaceutically acceptable salts thereof, wherein

B is aryl(CH 2 ) 0-3 —O—C(O)—, wherein the aryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro.

3. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is a 6 membered heteroaromatic ring containing 1 nitrogen ring atom;

4. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is an isoxazolyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

5. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is a thiadiazolyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

6. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is a 5 membered heteroaromatic ring containing 2 nitrogen ring atoms;

7. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is quinolinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

8. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is purinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

9. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is a 6 membered heteroaromatic ring containing 2 nitrogen ring atoms;

10. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is thiazolyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

11. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is pteridinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

12. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is pyrrolopyrimidinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

13. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is a imidazopyridinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

14. The compound according to claim 2 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is benzimidazolyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

15. The compound according to claim 1 , or a pharmaceutically acceptable salts thereof, wherein

B is aryl(CH 2 ) 1-3 —SO 2 —, wherein the aryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro.

16. The compound according to claim 15 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is a 6 membered heteroaromatic ring containing 2 nitrogen ring atoms;

17. The compound according to claim 15 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is quinazolinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

18. The compound according to claim 15 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is purinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl,hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

19. The compound according to claim 15 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is imidazopyridinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

20. The compound according to claim 15 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is a 6 membered heteroaromatic ring containing 1 nitrogen ring atom; and

21. The compound according to claim 1 , or a pharmaceutically acceptable salts thereof, wherein

B is heteroaryl(CH 2 ) 1-3 —C(O)—, wherein the heteroaryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro.

22. The compound according to claim 1 , or a pharmaceutically acceptable salts thereof, wherein

B is aryl(CH 2 ) 1-3 —C(O)—, wherein the aryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro.

23. The compound according to claim 1 , or a pharmaceutically acceptable salts thereof, wherein

B is aryl-cyclopropyl-C(O)—, wherein the aryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro.

24. The compound according to claim 23 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is pyridyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

25. The compound according to claim 23 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is pyrazinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

26. The compound according to claim 23 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is pyridazinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

27. The compound according to claim 23 , or a pharmaceutically acceptable salts thereof, wherein

HetAr is pyrimidinyl optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, trifluoromethyl, hydroxy, hydroxyC 1-4 alkyl, fluoro, chloro, bromo, iodo, cyano, methylsulfanyl, cyclopropylethynyl-, phenylethynyl-, heteroarylethynyl-,—N(C 0-4 alkyl)(C 0-4 alkyl), nitro, (C 1-2 alkyl)(C 1-2 alkyl)NCH 2 —, (C 1-2 alkyl)HNCH 2 —, Si(CH 3 ) 3 —C—, or NH 2 C(O)—.

28. The compound according to claim 1 , or a pharmaceutically acceptable salts thereof, wherein

B is heteroaryl(CH 2 ) 1-3 —O—C(O)—, wherein the heteroaryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro.

29. The compound according to claim 1 , or a pharmaceutically acceptable salts thereof, wherein

B is aryl(CH 2 ) 1-3 —NH—C(NCN)—, wherein the aryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro.

30. The compound according to claim 1 , wherein said compound is

31. The compound according to claim 1 , wherein said compound is