Spirolactam bicyclic CGRP receptor antagonists
View Patent ↗Compounds of formula I: (wherein variables A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , B, E 1 , E 2 , E 3 , E 4 , E 5 , G 1 , G 2 , J and K are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. 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 the formula I:
wherein:
B is a bicycloheterocycle selected from the group consisting of:
where T, U, V, W, X and Y are each independently a carbon atom or a nitrogen atom, wherein no more than two of T, U, V and W, or no more than three of T, U, V, W, X and Y, are a nitrogen atom,
where B is unsubstituted or substituted with 1 to 2 methyl, hydroxymethyl, trifluoromethyl, halogen, benzyl, benzyl alcohol, methoxy, CH 2 C(═O)N(CH 3 ) 2 , CN, SO 2 N(CH 3 ) 2 , N,N-dimethylcarbamide or a 1-(benzylcarboxylate)piperidene-4-spiro group;
A 1 , A 2 and A 3 are each independently selected from:
(1) a bond,
(2) —CR 13 R 14 —, wherein R 13 and R 14 are each hydrogen, and
(3) —C(═O)—;
A 5 and A 6 are each —CH 2 —;
both of A 4 and A 7 are absent;
E 1 is ═N—, E 2 is ═C—, E 3 is ═C(H)—, E 4 is absent, E 5 is ═C(H)—, or E 1 is —N(H)—, E 3 and E 4 are absent, E 2 is ═C—, E 5 is ═N—;
G 1 and G 2 are each ═C(R 4 )—;
J is ═C(R 6a )—;
K is —N(R 6b )—;
R 4 is hydrogen;
R 6a and R 6b and the atom(s) to which they are attached may be joined together to form a pyridyl ring, which is unsubstituted
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
2. The compound of claim 1 having the formula Ia:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
3. The compound of claim 1 having the formula Ib:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
4. The compound of claim 1 , wherein B is selected from:
where B is unsubstituted or substituted with 1 to 2 methyl, hydroxymethyl, trifluoromethyl, halogen, benzyl, benzyl alcohol, methoxy, CH 2 C(═O)N(CH 3 ) 2 , CN; SO 2 N(CH 3 ) 2 , N,N-dimethylcarbamide, or a 1-(benzylcarboxylate)piperidene-4-spiro group.
5. The compound of claim 1 , wherein B is selected from 2-oxobenzimidazolinyl, indolyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 2-oxoindolinyl, 2-oxobenzoxazolinyl, azaindolinyl, 2-oxoazabenzimidazolinyl, phthalimidyl, 2-oxotetrahydroquinolinyl and benzimidazolyl.
6. The compound of claim 1 , wherein A 1 is selected from CH 2 , —C(═O)— and a bond; A 2 is selected from CH 2 and a bond; and A 3 is bond.
7. A compound selected from:
or a pharmaceutically acceptable salt and individual stereoisomers thereof.
8. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof and individual enantioners and diasteromers thereof.