Preferentially substituted calcium channel blockers
View Patent ↗Compounds of the formula and their salts, wherein Cy represents cyclohexyl; Y is CH═CHΦ, CHΦ 2 , Φ or Cy, X is trivalent straight-chain alkylene (3–10C) or trivalent straight-chain 1-alkenylene (3–10C) optionally substituted by oxo at the C adjacent N when n is 0 and Y is Φ 2 CH; and is otherwise trivalent straight-chain alkylene (5–10C) or trivalent straight-chain 1-alkenylene (5–10C) optionally substituted by oxo at the C adjacent N; Z is N, NCO, CHNCOR 1 or CHNR 1 , wherein R 1 is alkyl (1–6C); and n is 0–5; wherein each Φ and Cy independently may optionally be substituted by alkyl (1–6C) or by halo, CF 3 , OCF 3 , NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , NROCR or OOCR where R is H or alkyl (1–4C), or two substituents may form a 5–7 membered ring with the proviso that the compounds of formula (1) contain at least one aromatic moiety, are useful as calcium channel blockers.
1. A method to treat pain in a subject which method comprises administering to a subject in need of such treatment a compound of the formula
or the salts thereof,
wherein Cy represents cyclohexyl and Φ represents phenyl;
Y is CH═CHΦ, CHΦ 2 , Φ or Cy,
X is trivalent straight-chain alkylene (3–10C) or trivalent straight-chain 1-alkenylene (3–10C) optionally substituted by oxo at the C adjacent N when n is 0 and Y is CHΦ 2 ; and is otherwise trivalent straight-chain alkylene (5–10C) or trivalent straight-chain 1-alkenylene (5–10C) optionally substituted by oxo at the C adjacent N;
Z is N, or CHNR 1 wherein R 1 is alkyl (1–6C); and
n is 0–5;
wherein each Φ and Cy independently may optionally be substituted by alkyl (1–6C) or by halo, CF 3 , OCF 3 , NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , NROCR or OOCR where R is H or alkyl (1–4C), or two substituents may form a 5–7 membered ring
with the proviso that the compounds of formula (1) contain at least one aromatic moiety.
2. The method of claim 1 wherein the compound of formula (1) is of the formula
wherein X, Y, Z and n are as defined, and each Φ may optionally be substituted as set forth, in claim 1 .
3. The method of claim 2 wherein Y is CH═CHΦ.
4. The method of claim 3 wherein X is CH(CH 2 ) m CO or CH(CH 2 ) m+1 wherein m is 4–8.
5. The method of claim 4 wherein m is 4.
6. The method of claim 3 wherein Z is N and n is 1–3.
7. The method of claim 6 wherein the compound of formula (1) is MC-34D as shown in FIG. 1A or a substituted form thereof.
8. The method of claim 2 wherein Y is Cy.
9. The method of claim 8 wherein X is CH(CH 2 ) m CO or CH(CH 2 ) m+1 wherein m is 4–8.
10. The method of claim 9 wherein m is 4.
11. The method of claim 2 wherein Z is CHNH and n is 1.
12. The method of claim 11 wherein the compound of formula (1) is JM-G-10 as shown in FIG. 1A or a substituted form thereof.
13. The method of claim 2 wherein Y is CHΦ 2 .
14. The method of claim 13 wherein X is CH(CH 2 ) 1 CO or CH(CH 2 ) l+1 , wherein l is 4–8.
15. The method of claim 14 wherein l is 1.
16. The method of claim 13 wherein Z is N.
17. The method of claim 16 wherein the compound of formula (1) is 39-1-B4 as shown in FIG. 1A or a substituted form thereof.
18. The method of claim 2 wherein n is 0 or 1 and Y is Φ.
19. The method of claim 18 wherein X is CH(CH 2 ) m+1 or CH(CH 2 ) m CO wherein m is 4–8.
20. The method of claim 19 wherein m is 4.
21. The method of claim 20 wherein the compound of formula (1) is compound 39-45-3 as shown in FIG. 1A or a differently substituted or unsubstituted form thereof.
22. A pharmaceutical composition for use in treating pain which composition comprises, in admixture with a pharmaceutically acceptable excipient, a dosage amount of at least one compound of the formula
or salts thereof,
wherein Cy represents cyclohexyl and Φ represents phenyl;
Y is CH═CHΦ or Φ,
X is trivalent straight-chain alkylene (3–10C) or trivalent straight-chain 1-alkenylene (3–10C) optionally substituted by oxo at the C adjacent N when n is 0 and Y is CHΦ 2 ; and is otherwise trivalent straight-chain alkylene (5–10C) or trivalent straight-chain 1-alkenylene (5–10C) optionally substituted by oxo at the C adjacent N;
Z is N or CHNR 1 , wherein R 1 is alkyl (1–6C); and
n is 0–5;
wherein each Φ and Cy independently may optionally be substituted by alkyl (1–6C) or by halo, CF 3 , OCF 3 , NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , NROCR or OOCR where R is H or alkyl (1–4C), or two substituents may form a 5–7 membered ring
with the proviso that the compounds of formula (1) contain at least one aromatic moiety.
23. The composition of claim 22 wherein the compound of formula (1) is of the formula
wherein X, Y, Z and n are as defined in claim 22 .
24. The composition of claim 23 wherein Y is CH═CHΦ.
25. The composition of claim 24 wherein X is CH(CH 2 ) m CO or CH(CH 2 ) m+1 wherein m is 4–8.
26. The composition of claim 25 wherein m is 4.
27. The composition of claim 26 wherein Z is N and n is 1–3.
28. The composition of claim 27 wherein the compound of formula (1) is MC-34D as shown in FIG. 1A or a substituted form thereof.
29. The composition of claim 23 wherein Z is CHNH and n is 1.
30. The composition of claim 29 wherein the compound of formula (1) is JM-G-10 as shown in FIG. 1A or a substituted form thereof.
31. The composition of claim 23 wherein n is 0 or 1 and Y is Φ.
32. The composition of claim 31 wherein X is CH(CH 2 ) m+1 or CH(CH 2 ) m CO wherein m is 4–8.
33. The composition of claim 32 wherein m is 4.
34. The composition of claim 33 wherein the compound of formula (1) is compound 39-45-3 as shown in FIG. 1A or a differently substituted or unsubstituted form thereof.