N-type calcium channel blockers

1. A compound of the formula

or the salts thereof, including all stereoisomeric forms thereof wherein:

Y is (X 2 ) l A or (X 1 ) m CR 4 A 2 ;

W is CR 4 or N;

n is 0-3;

l and m are independently 0 or 1;

each X 1 and X 2 is independently optionally substituted alkylene (1-10C) or alkenylene (2-10C) wherein one or more said C may optionally be replaced by N or O;

each A is independently a 5-7 membered optionally substituted carbocyclic aromatic or aliphatic ring;

wherein each R 1 is independently optionally substituted lower alkyl (1-6C), optionally substituted lower alkenyl (2-6C), or optionally substituted lower alkynyl (2-6C), each optionally including one or more heteroatoms selected from O, N and S or is an inorganic substituent;

wherein each R 2 is independently H, lower alkyl, lower alkenyl or halo;

wherein R 3 is H, lower alkyl, lower alkenyl, or lower acyl, wherein one or more carbons of each of the foregoing is replaced with a heteroatom; and

wherein R 4 is H, alkyl, alkenyl, arylalkyl, arylalkenyl, hydroxy, alkoxy, sulfhydryl, alkylsulfhydryl, amino or alkylamino.

2. The compound of claim 1 , wherein each R 1 and each said optional substituent is independently halo, NO 2 , SO 2 , SO, NO, ═O, ═NOH and n is 0-3.

3. The compound of claim 1 , wherein each R 2 is independently H or lower alkyl.

4. The compound of claim 3 , wherein at least one R 2 is H.

5. The compound of claim 1 , wherein R 3 is H or CONCH 2 CH 3 .

6. The compound of claim 1 , wherein R 4 is H, hydroxy or alkoxy.

7. The compound of claim 6 , wherein R 4 is H.

8. The compound of claim 1 , wherein X 1 is alkylene or alkenylene unsubstituted or substituted by ═O.

9. The compound of claim 8 , wherein said ═O is at the carbon adjacent the nitrogen to which X 1 is coupled.

10. The compound of claim 1 , wherein X 2 is alkylene or alkenylene unsubstituted or substituted by ═O.

11. The compound of claim 10 , wherein said ═O is at the carbon adjacent the nitrogen to which X 2 is coupled.

12. The compound of claim 1 , wherein each A is independently optionally substituted phenyl, or optionally substituted cyclohexyl.

13. The compound of claim 12 , wherein substituted phenyl or substituted cyclohexyl is substituted by substituents selected from the group consisting of inorganic substituents, alkyl, alkenyl, alkynyl, aryl, alkylaryl, and alkenylaryl, in each case optionally substituted, wherein said alkyl, alkenyl or alkynyl may optionally contain one or more heteroatoms in place of carbon.

14. The compound of claim 13 , wherein each of said substituents is independently halo, alkoxy or alkyl.

15. A compound of claim 1 which is of the formula

wherein:

each Z 1 and Z 2 is independently H 2 or ═O;

R 5 =H, optionally substituted alkyl, (CR 2 ) n CONR 7 2 , (CR 2 ) n NR 7 2 where each R 7 is H, lower alkyl or aryl;

n=0-1;

V is alkyl or phenyl, each optionally substituted;

W is CR 2 or NR;

X 4 is O, S, N or NCO; and

R 6 represents 0-3 substituents wherein said substituents are independently alkyl (1 -6C), optionally containing 1-4 heteroatoms (halo, N, O, or S), or aryl (6-10C) or arylalkyl (7-16C) and/or said substituents are halo, CF 3 , OCF, NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , NROCR, or OOCR;

and wherein each R═H or alkyl (1-8C).

16. The compound of claim 1 which is

N-(1-benzhydryl-pyrrolidin-3-ylmethyl)-3,3-diphenyl-propionamide;

1-{3-[(benzhydryl-amino)-methyl]-pyrrolidin-1-yl}-3,3-diphenyl-propan-1-one;

N-{1-[6,6-Bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,4,5-trimethoxy-benzamide;

{1-[6,6-bis-(4-fluoro-phenyl)-hexyl]-pyrrolidin-3-ylmethyl}-(3,4,5-trimethoxy-benzyl)-amine;

6,6-bis-(4-fluoro-phenyl)-hexanoic acid [1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-ylmethyl]-amide;

[6,6-bis-(4-fluoro-phenyl)-hexyl]-[1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-ylmethyl]-amine;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-4-hydroxy-benzmide;

4-[({1-[6,6-bis-(4-fluoro-phenyl)-hexyl]-pyrrolidin-3-ylmethyl}-amino)-methyl]-2,6-di-tert-butyl-phenol;

6,6-bis-(4-fluoro-phenyl)-hexanoic acid [1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-pyrrolidin-3-ylmethyl]-amide;

4-(3-{[6,6-bis-(4-fluoro-phenyl)-hexylamino]-methyl}-pyrrolidin-1-ylmethyl)-2,6-di-tert-butyl-phenol;

6,6-bis-(4-fluoro-phenyl)-hexanoic acid [1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidin-3-ylmethyl]-amide;

[6,6-bis-(4-fluoro-phenyl)-hexyl]-[1-(3,5-di-tert-butyl-4-methoxy-benzyl)-pyrrolidin-3-ylmethyl]-amine;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-4-methoxy-benzamide;

{1-[6,6-bis-(4-fluoro-phenyl)-hexyl]-pyrrolidin-3-ylmethyl}-(3,5-di-tert-butyl-4-methoxy-benzyl)-amine;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-dibromo-4-hydroxy-benzamide;

4-[({1-[6,6-bis-(4-fluoro-phenyl)-hexyl]-pyrrolidin-3-ylmethyl}-amino)-methyl]-2,6-dibromo-phenol;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-benzamide;

{1-[6,6-bis-(4-fluoro-phenyl)-hexyl]-pyrrolidin-3-ylmethyl}-(3,5-di-tert-butyl-benzyl)-amine;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-4-methoxy-benzamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexyl]-pyrrolidin-3-ylmethyl}-3,4,5-trimethoxy-benzamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexyl]-pyrrolidin-3-ylmethyl}-3,5-bis-trifluoromethyl-benzamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-4-(2-dimethylamino-ethoxy)-benzamide;

6,6-bis-(4-fluoro-phenyl)-hexanoic acid {1-[3,5-di-tert-butyl-4-(2-dimethylamino-ethoxy)-benzoyl]-pyrrolidin-3-ylmethyl}-amide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-bis-trifluoromethyl-benzamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-4-tert-butyl-benzamide;

N-{1-[(4-chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-ylmethyl}-3,3-diphenyl-propionamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-2-phenoxy-acetamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-2-phenylsulfanyl-acetamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-2-phenylamino-acetamide;

N-[2-({1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-amino)-ethyl]-3,4,5-trimethoxy-benzamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-2-(2,4-difluoro-phenoxy)-acetamide;

1-(1-benzhydryl-pyrrolidin-3-ylmethyl)-1-(3,3-diphenyl-propionyl)-3-ethyl-urea;

1-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3-ethyl-1-(2-phenylsulfanyl-acetyl)-urea;

1-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3-ethyl-1-(2-phenylamino-acetyl)-urea;

1-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-1-[2-(2,4-difluoro-phenoxy)-acetyl]-3-ethyl-urea;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-2-(4-chloro-phenoxy)-acetamide;

N-{1-[(2-chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-ylmethyl}-3,3-diphenyl-propionamide;

N-{1-[(3-chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-ylmethyl}-3,3-diphenyl-propionamide;

3,3-diphenyl-N-{1-[phenyl-(4-trifluoromethyl-phenyl)-methyl]-pyrrolidin-3-ylmethyl}-propionamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-2-(3,5-dimethyl-phenylamino)-acetamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-2-(3,5-dimethyl-phenylamino)-acetamide;

R-N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-4-methoxy-benzamide;

S-N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-4-methoxy-benzamide;

R-N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-benzamide;

S-N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-di-tert-butyl-benzamide;

N-(1-benzhydryl-pyrrolidin-3-ylmethyl)-2-diphenylamino-acetamide;

2-{(1-benzhydryl-pyrrolidin-3-ylmethyl)-[(diphenylcarbamoyl)-methyl]-amino}-N,N-diphenyl-acetamide;

1-benzhydryl-3-(1-benzhydryl-pyrrolidin-3-ylmethyl)-urea;

S-N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-bis-trifluoromethyl-benzamide;

R-N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3,5-bis-trifluoromethyl-benzamide;

3,3-bis-(4-fluoro-phenyl)-N-{1-[(4-fluoro-phenyl)-phenyl-methyl]-pyrrolidin-3-ylmethyl}-propionamide;

N-(1-benzhydryl-pyrrolidin-3-ylmethyl)-3,3-bis-(4-fluoro-phenyl)-propionamide;

N-{1-[(4-tert-butyl-phenyl)-phenyl-methyl]-pyrrolidin-3-ylmethyl}-3,3-bis-(4-fluoro-phenyl)-propionamide;

N-(1-benzhydryl-pyrrolidin-3-ylmethyl)-N-methyl-3,3-diphenyl-propionamide;

2-[(1-benzhydryl-pyrrolidin-3-ylmethyl)-methyl-amino]-N,N-diphenyl-acetamide;

N-(1-benzhydryl-pyrrolidin-3-ylmethyl)-N-methyl-N′,N′-diphenyl-ethane-1,2-diamine;

(1-benzhydryl-pyrrolidin-3-ylmethyl)-(3,3-diphenyl-propyl)-methyl-amine;

1-(3-{[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;

6,6-bis-(4-fluoro-phenyl)-1-(3-{[methyl-(3,4,5-trimethoxy-benzyl)-amino]-methyl}-pyrrolidin-1-yl)-hexan-1-one;

N-(1-benzhydryl-pyrrolidin-3-ylmethyl)-N-(2-diphenylamino-ethyl)-N′,N′-diphenyl-ethane-1,2-diamine;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-3-fluoro-5-trifluoromethyl-benzamide;

N-{1-[6,6-bis-(4-fluoro-phenyl)-hexanoyl]-pyrrolidin-3-ylmethyl}-4-fluoro-3-trifluoromethyl-benzamide; or

[3-({[6,6-bis-(4-fluoro-phenyl)-hexyl]-methyl-amino}-methyl)-pyrrolidin-1-yl]-(3,4,5-trimethoxy-phenyl)-methanone.

17. A pharmaceutical composition for use in treating stroke or pain which composition comprises, in admixture with a pharmaceutically acceptable excipient, a dosage amount of the compound of claim 1 .

18. A method to treat stroke or pain in a subject which method comprises administering to a subject in need of such treatment an effective amount of the compound of claim 1 or a pharmaceutical composition thereof.