Urea derivatives as calcium channel blockers

1. A compound which has formula (1)

or is a pharmaceutically acceptable salt or pharmaceutically acceptable conjugate thereof,

R 1 is H or alkyl (1-8C), alkenyl (2-8C) or alkynyl (2-8C);

each R 3 is independently a substituent selected from the group consisting of ═O, alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), acyl, aryl, alkylaryl, halo, CHF 2 , CF 3 , OCF 3 , OCHF 2 , OCOR, CN, NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , SOR, SO 2 R, SO 3 R, NRCOR, NROR, NRCOOR, OCONR 2 , SONR 2 , SO 2 NR 2 , OOCR, NRSOR and NRSO 2 R, wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl, or alkylaryl, wherein two R on the same nitrogen may form a 5-7 membered ring, and wherein two substituents on adjacent carbons may form a 5-7 membered ring;

wherein each R 4 is independently H or alkyl (1-4C);

m is 0-3;

n is 0-2;

wherein each phenyl may independently be substituted by one or more substituents selected from the group consisting of alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), acyl, aryl, alkylaryl, halo, CHF 2 , CF 3 , OCF 3 , OCHF 2 , OCOR, CN, NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , SOR, SO 2 R, SO 3 R, NRCOR, NROR, NRCOOR, OCONR 2 , SONR 2 , SO 2 NR 2 , OOCR, NRSOR and NRSO 2 R, wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl, or alkylaryl, wherein two R on the same nitrogen may form a 5-7 membered ring, and wherein two substituents on adjacent carbons may form a 5-7 membered ring, and

wherein any alkyl, alkenyl, alkynyl or aryl set forth above may further be substituted by ═O, alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), acyl, aryl, alkylaryl, halo, CHF 2 , CF 3 , OCF 3 , OCHF 2 , OCOR, CN, NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , SOR, SO 2 R, SO 3 R, NRCOR, NROR, NRCOOR, OCONR 2 , SONR 2 , SO 2 NR 2 , OOCR, NRSOR and NRSO 2 R, wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl, or alkylaryl, wherein two R on the same nitrogen may form a 5-7 membered ring, and wherein two substituents on adjacent carbons may form a 5-7 membered ring,

with the proviso that if all R 4 are H, and m is 0 or 1 and at least one phenyl must be substituted.

2. The compound of claim 1 , wherein R 1 is H.

3. The compound of claim 1 , wherein n is 0.

4. The compound of claim 1 , wherein m is 0.

5. The compound of claim 1 , wherein n is 2 and R 3 is ═O or COOH.

6. The compound of claim 1 , wherein each R 4 is H.

7. The compound of claim 1 , wherein formula (1) is selected from the group consisting of

4-[(2,4-dichloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2,4-dimethyl-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(3-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2,3-dichloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-(benzo[1,3]dioxol-5-yl-phenyl-methyl)-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-methoxy-phenyl)-(4-trifluoromethyl-phenyl)-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-tert-butyl-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-methoxy-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-benzyloxy-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-hydroxy-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-benzhydryl-2,5-dioxo-piperazine-1-carboxylic acid benzhydryl-amide; and

4-[(4-tert-butyl-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-methyl-amide.

8. The compound of claim 1 , wherein formula (1) is selected from the group consisting of

4-[(2,4-dichloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2,4-dimethyl-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(3-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide; and

4-[(2,3-dichloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide.

9. A pharmaceutical composition which comprises the compound of claim 1 in admixture with a pharmaceutically acceptable excipient.

10. The compound of claim 1 , wherein formula (1) is conjugated to polyethylene glycol.

11. A method to treat chronic or acute pain, epilepsy, type II diabetes, prostate cancer, in a subject, which method comprises administering to a subject in need of such treatment an amount of the compound of claim 1 effective to ameliorate said condition.

12. The method of claim 11 wherein said treating is of chronic or acute pain.

13. The method of claim 11 , wherein R 1 is H.

14. The method of claim 11 , wherein n is 0.

15. The method of claim 11 , wherein m is 0.

16. The method of claim 11 , wherein n is 2 and R 3 is ═O or COOH.

17. The method of claim 11 , wherein each R 4 is H.

18. A method to treat chronic or acute pain, epilepsy, type II diabetes, prostate cancer, in a subject, which method comprises administering to a subject in need of such treatment an amount of a compound selected from the group consisting of

4-benzhydryl-piperazine-1 -carboxylic acid benzhydryl-amide;

4-[(2,4-dichloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2,4-dimethyl-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(3-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2,3-dichloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-(benzo [1,3]dioxol-5-yl-phenyl-methyl)-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-methoxy-phenyl)-(4-trifluoromethyl-phenyl)-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-tert-butyl-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-methoxy-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-benzyloxy-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-hydroxy-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl- amide;

4-benzhydryl-2,5-dioxo-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-tert-butyl-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-methyl-amide;

4-(diphenyl-methyl)-piperazine-1-carboxylic acid benzhydryl-methyl-amide; and

the pharmaceutically acceptable salt or pharmaceutically acceptable conjugate thereof.

19. The method of claim 18 , wherein the compound is

4-benzhydryl-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2,4-dichloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2,4-dimethyl-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(4-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(3-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2-chloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;

4-[(2,3-dichloro-phenyl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide; or

the pharmaceutically acceptable salt or pharmaceutically acceptable conjugate thereof.

20. The method of claim 19 , wherein the compound is 4-benzhydryl-piperazine-1-carboxylic acid benzhydryl-amide or the pharmaceutically acceptable salt or pharmaceutically acceptable conjugate thereof.

21. The method of claim 18 , wherein said treating is of chronic or acute pain.

22. The method of claim 18 , wherein said compound is in the form of a pharmaceutically acceptable conjugate.

23. The method of claim 22 , wherein said conjugate comprises said compound coupled to polyethylene glycol.