Aryl spirolactam CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula (I): where variables A 1 , A 2 , B, J, K, m, n, R 4 , R 5a , R 5b , R 5c and X are as defined herein useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
1. A compound of formula I:
wherein:
B is a selected from the group consisting of: C 3-10 cycloalkyl, phenyl, indanyl, indolinyl, indolyl, isoquinolinyl, tetrahydroisoquinolinyl and tetrahydroquinolinyl, where
B is linked to A 1 via a carbon atom in B, and where
B is unsubstituted or substituted with 1-5 substituents, each substituent independently selected from C 1-6 alkyl, halo, acetyl and oxo;
R 9 is selected from: hydrogen, —C 5-6 cycloalkyl, benzyl, phenyl, and —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
R 10 is selected from: hydrogen, —C 5-6 cycloalkyl, benzyl, phenyl, —COR 9 , —SO 2 R 12 , and —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
R 12 is selected from: —C 5-6 cycloalkyl, benzyl, phenyl and —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
A 1 and A 2 are each independently selected from:
(1) a bond,
(2) —CR 13 R 14 —, wherein R 13 and R 14 are independently selected from: hydrogen, hydroxyl and C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
(3) —NR 10 —,
(4) —CR 13 R 14 —NR 10 —,
(5) —CR 13 R 14 —CH 2 —,
(6) —CH 2 —CR 13 R 14 —,
(7) —O—CR 13 R 14 —,
(8) —CR 13 R 14 —O—, and
(9) —C≡C—,
(10) —C(R 13 )═C(R 14 )—, and
(11) —C(═O)—,
or wherein one of A 1 and A 2 is absent;
J is ═C(R 6a )—;
K is ═C(R 6b )—;
X is —CO— or —SO 2 —;
R 4 is selected from: hydrogen, C 5-6 cycloalkyl, benzyl, phenyl and C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro;
R 5a , R 5b and R 5c are each independently selected from: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, —OCF 3 , trifluoromethyl, halo, hydroxy and —CN;
R 6a and R 6b and the atom(s) to which they are attached are joined together to form a ring selected from phenyl, pyridyl and pyrimidinyl, where said ring is unsubstituted;
m is 1;
n is 1;
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
2. The compound of claim 1 of the formula Ib:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
3. The compound of claim 1 of the formula Ic:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
4. The compound of claim 1 of the formula Id:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
5. The compound of claim 1 of the formula Ie:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
6. The compound of claim 1 of the formula If:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
7. The compound of claim 1 of the formula Ig:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
8. The compound of claim 1 of the formula Ii:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
9. The compound of claim 1 , wherein A 1 is selected from a bond, —CH 2 —, —OCH 2 —, —C≡C—, —CH 2 —NR 10 , —NR 10 and —C(H)═C(H)—.
10. The compound of claim 1 , wherein A 2 is selected from a bond, —CH 2 , —NH— and —CH 2 —NH—.
11. The compound of claim 1 , wherein R 5a , R 5b and R 5c are each independently selected from hydrogen, C 1-6 alkyl and halo.
12. The compound of claim 1 , wherein R 6a and R 6b and the atom(s) to which they are attached join together to form pyridyl, where said pyridyl is unsubstituted.
13. A compound selected from:
and pharmaceutically acceptable salts and individual diastereomers thereof.
14. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
15. A method for antagonism of CGRP receptor activity in a mammal which comprises the administration of an effective amount of the compound of claim 1 .