Modulator
The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is OR 1 or NR 1 R 2 wherein each of R 1 and R 2 is independently H, or a hydrocarbyl group; X is an alkylene, alkenylene, or alkynylene group, each of which may be optionally substituted by one or more substituents selected from alkyl, COOH, CO 2 -alkyl, alkenyl, CN, NH 2 , hydroxy, halo, alkoxy, CF 3 and nitro; Y is a polar functional group selected from OH, NO 2 , CN, COR 3 , COOR 3 , NR 3 R 4 , CONR 3 R 4 , SO 3 H, SO 2 —R 3 , SO 2 NR 3 R 4 and CF 3 , where each of R 3 and R 4 is independently H or a hydrocarbyl group; A is an aryl or heteroaryl group, each of which may be optionally substituted; and B is (CH2) n where n is 0, 1, 2, 3, 4 or 5; with the proviso that: (i) when A is phenyl, n is 0, and Z is OH, X—Y is other than meta-C≡—C—(CH 2 ) 2 CO 2 H, meta-C≡—C—(CH 2 ) 2 OH, meta-C≡C—(CH 2 ) 2 CO 2 Me, meta-(CH 2 ) 4 CO 2 H, ortho-CH 2 CO 2 H, ortho-(CH 2 ) 2 CO 2 H and ortho-(CH 2 ) 4 CO 2 H; and (ii) when A is phenyl, n is 0, and Z is OMe, X—Y is other than meta-C≡C—(CH 2 ) 4 OH. Further aspects of the invention relate to the use of such compounds in the preparation of a medicament for the treatment of a muscular disorder, a gastrointestinal disorder, or for controlling spasticity or tremors.
1. A compound of formula I, or a pharmaceutically acceptable salt thereof,
wherein
Z is NR 1 R 2 wherein each of R 1 and R 2 is independently H, or a hydrocarbyl group;
X-Y is selected from
—C≡C—(CH 2 ) p —Y
—C(R 5 )═C(R 6 )—(CH 2 ) q —Y; and
—C(R 5 )(R 6 )C(R 7 )(R 8 )—(CH 2 ) r —Y;
wherein each of R 5 , R 6 , R 7 , and R 8 is independently H or alkyl, and each of p, q and r is independently 2, 3, or 4;
Y is a polar functional group selected from OH, NO 2 , CN, COR 3 , COOR 3 , NR 3 R 4 ,
CONR 3 R 4 , SO 3 H, SO 2 —R 3 , SO 2 NR 3 R 4 and CF 3 , where each of R 3 and R 4 is independently H or a hydrocarbyl group;
A is phenyl; and
B is (CH 2 ) n where n is 0.
2. A compound according to claim 1 wherein Y is selected from CN, OH, COOR 3 , SO 2 NR 3 R 4 , CONR 3 R 4 , where each of R 3 and R 4 is independently H or a hydrocarbyl group.
3. A compound according to claim 1 wherein each of R 1 , R 2 , R 3 and R 4 is independently H, an alkyl group, an aryl group, or a cycloalkyl group, each of which may be optionally substituted.
4. A compound according to claim 1 wherein Y is selected from OH, CN, COOR 3 , CONR 3 R 4 , where each of R 3 and R 4 is independently H or an optionally substituted alkyl group.
5. A compound according to claim 1 wherein Y is selected from OH, CN, COOMe, COOH, CONH 2 , CONHMe and CONMe 2 .
6. A compound according to claim 1 wherein X-Y is selected from
—C≡C—(CH 2 ) p —Y; and
—CH═CH—(CH 2 ) q —Y;
wherein each of p and q is independently 2, 3 or 4.
7. A compound according to claim 1 wherein X-Y is —cis—C(R 5 )═C(R 6 )—(CH 2 ) q —Y and q is 2, 3 or 4.
8. A compound according to claim 1 wherein X-Y is —C(Me) 2 —CH 2 —(CH 2 ) r —Y and r is 2, 3 or 4.
9. A compound according to claim 1 wherein Z is NR 1 R 2 and each of R 1 and R 2 is independently H, an alkyl or a cycloalkyl group, each of which may be optionally substituted by one or more OH or halogen groups.
10. A compound according to claim 1 wherein Z is selected from NHCH 2 CH 2 F, NH-cyclopropyl, NHCH(Me)CH 2 OH and NHCH 2 CH 2 OH.
11. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 which is
13. The compound of claim 12 which is in the form of a racemic mixture.
14. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. A method according to claim 14 wherein the muscular disorder is a neuromuscular disorder.
16. A method according to claim 14 wherein Y is selected from NO 2 , CN, OR 3 , COR 3 , COOR 3 , NR 3 R 4 , CONR 3 R 4 , SO 3 H, SO 2 —R 3 , SO 2 NR 3 R 4 and CF 3 , where each of R 3 and R 4 is independently H or a hydrocarbyl group.
17. A method compound according to claim 14 wherein Y is selected from CN, COOR 3 , SO 2 NR 3 R 4 , CONR 3 R 4 , where each of R 3 and R 4 is independently H or a hydrocarbyl group.
18. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, admixed with pharmaceutically acceptable diluent, excipient or carrier.
19. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 2 , or a pharmaceutically acceptable salt thereof.
20. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 3 , or a pharmaceutically acceptable salt thereof.
21. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 4 , or a pharmaceutically acceptable salt thereof.
22. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
23. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 6 , or a pharmaceutically acceptable salt thereof.
24. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 7 , or a pharmaceutically acceptable salt thereof.
25. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 8 , or a pharmaceutically acceptable salt thereof.
26. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 9 , or a pharmaceutically acceptable salt thereof.
27. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 10 , or a pharmaceutically acceptable salt thereof.
28. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 11 , or a pharmaceutically acceptable salt thereof.
29. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 12 , or a pharmaceutically acceptable salt thereof.
30. A method of treating a muscular disorder in a subject in need thereof, said method comprising administering to the subject a compound of claim 13 , or a pharmaceutically acceptable salt thereof.