Benodiazepine spirohydantoin CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds that are antagonists of CGRP receptors and that are 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 the formula I
wherein:
R 1 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl or heterocycle, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO 2 R 9 wherein R 9 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1–6 fluoro,
(iii) —C 5-6 cycloalkyl,
(iv) benzyl, and
(v) phenyl,
(g) —NR 9 R 10 , wherein R 10 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1–6 fluoro,
(iv) benzyl, and
(v) phenyl,
or where R 9 and R 10 may be joined together to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) phenyl, and
(VI) benzyl,
(h) —CONR 9 R 10 , and
(i) —SO 2 R 10 ,
(j) trifluoromethyl
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl,
(4) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) trifluoromethyl,
(e) phenyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
R 2a , R 2b and R 2c are independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl or —C 3-6 cycloalkyl which are unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) trifluoromethyl,
(3) halo,
(4) hydroxy,
(5) —O—C 1-6 alkyl which are unsubstituted or substituted with 1–6 fluoro
(6) —OCF 3
(7) trifluoromethyl,
(8) —CO 2 R 9 ,
(9) —CONR 9 R 10 , and
(10) —SO 2 R 10 ;
R 3 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, or —C 3-6 cycloalkyl which are unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) trifluoromethyl,
(e) phenyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO 2 R 9 ,
(g) —NR 9 R 10 ,
(h) —CONR 9 R 10 , and
(i) —SO 2 R 10 ,
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —CO 2 R 9 ,
(g) —NR 9 R 10 ,
(h) —CONR 9 R 10 ,
(i) —SO 2 R 10 ,
(j) —CN, and
(k) —OCF 3 ;
R 4 is selected from:
(1) hydrogen,
(2) C 1-6 alkyl, which is unsubstituted or substituted with 1–6 fluoro,
(3) C 5-6 cycloalkyl,
(4) benzyl , and
(5) phenyl;
R 6 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl or —C 3-6 cycloalkyl which are unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —C 2 R 9 ,
(g) —NR 9 R 10 ,
(h) —CONR 9 R 10 ,
(i) —SO 2 R 10 , and
(j) trifluoromethyl
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl;
X is a bond or is —N(R 4a )—, where R 4a is independently selected from the definitions of R 4 ;
m is 1 or 2;
n is 1 or 2;
or a pharmaceutically acceptable salt or diastereomer thereof.
2. The compound of claim 1 of the formula Ia:
or a pharmaceutically acceptable salt or diastereomer thereof.
3. The compound of claim 1 of the formula Ib:
or a pharmaceutically acceptable salt or diastereomer thereof.
4. The compound of claim 1 wherein:
R 1 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidyl, pyrazinyl, thienyl, or morpholinyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO 2 R 9 , wherein R 9 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1–6 fluoro,
(iii) —C 5-6 cycloalkyl,
(iv) benzyl, and
(v) phenyl,
(g) —NR 9 R 10 , wherein R 10 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1–6 fluoro,
(iii) —C 5-6 cycloalkyl,
(iv) benzyl, and
(v) phenyl,
(h) —CONR 9 R 10 , and
(i) —SO 2 R 10 ,
(j) trifluoromethyl
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidyl, pyrazinyl, or thienyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl,
(4) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) trifluoromethyl,
(e) phenyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
R 2a , R 2b and R 2c are independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl or —C 3-6 cycloalkyl which are unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) trifluoromethyl,
(3) halo,
(4) hydroxy,
(5) —O—C 1-6 alkyl,
(6) —OCF 3
(7) trifluoromethyl,
(8) —C 2 R 9 ,
(9) —CONR 9 R 10 , and
(10) —SO 2 R 10 ;
R 3 is selected from:
(1) hydrogen,
( 2 ) —C 1-6 alkyl or —C 3-6 cycloalkyl which are unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) trifluoromethyl,
(e) phenyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO 2 R 9 ,
(g) —NR 9 R 10 ,
(h) —CONR 9 R 10 , and
(i) —SO 2 R 10 ,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, or thienyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —CO 2 R 9 ,
(g) —NR 9 R 10 ,
(h) —CONR 9 R 10 ,
(i) —SO 2 R 10 ,
(j) —CN, and
(k) —OCF 3 ;
R 4 is selected from:
(1) hydrogen,
(2) C 1-6 alkyl, which is unsubstituted or substituted with 1–6 fluoro,
(3) C 5-6 cycloalkyl,
(4) benzyl, and
(5) phenyl;
R 6 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl or —C 3-6 cycloalkyl which are unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —C 2 R 9 ,
(g) —NR 9 R 10 ,
(h) —CONR 9 R 10 ,
(i) —SO 2 R 10 , and
(j) trifluoromethyl
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidyl, pyrazinyl, or thienyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl;
X is a bond or is —N(R 4a )—, where R 4a is independently selected from the definitions of R 4 ;
m is 1;
n is 1;
or a pharmaceutically acceptable salt or diastereomer thereof.
5. The compound of claim 1 wherein R 1 is selected from hydrogen and —C 1-6 alkyl, which is unsubstituted or substituted with 1–4 substituents where the substituents are independently selected from: halo, hydroxy, —O—C 1-6 alkyl, —C 3-6 cycloalkyl and phenyl.
6. The compound of claim 1 wherein R 2a , R 2b and R 2c are independently selected from: hydrogen, halo, —C 1-6 alkyl, —O—C 1-6 alkyl and trifluoromethyl.
7. The compound of claim 1 wherein R 3 is selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, phenyl, pyridyl and thienyl.
8. The compound of claim 1 wherein R 4 is selected from: hydrogen and —C 1-6 alkyl, which is unsubstituted or substituted with fluoro.
9. The compound of claim 1 wherein R 6 is selected from: hydrogen, phenyl and —C 1-6 alkyl.
10. The compound of claim 1 wherein X is a bond or —NH—.
11. A compound which is selected from the group consisting of:
or a pharmaceutically acceptable salt or diastereomer thereof.
12. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
13. A method of treating migraine headaches or cluster headaches, said method comprising the administration, to a person in need of such treatment, of a therapeutically effective amount of the compound of claim 1 .