Benzodiazepine CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula I: I (where variables R 1?, R 2?, R 3?, R 6?, R 7?, G, J, Q, T, U, V, W, X and Y 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:
R 1 is selected from:
1) H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -6 cycloalkyl, and heterocycle, unsubstituted or substituted with one or more substituents independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) s OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 )SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 , and
v) O(CO)R 4 ; and
2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) s OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 )SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 , and
v) O(CO)R 4 ; and
R 2 is independently selected from H and:
1) C 1-6 alkyl,
2) C 3-6 cycloalkyl,
3) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
4) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
5) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
6) (F) p C 1-3 alkyl,
7) halogen,
8) OR 4 ,
9) O(CH 2 ) s OR 4 ,
10) CO 2 R 4 ,
11) (CO)NR 10 R 11 ,
12) O(CO)NR 10 R 11 ,
13) N(R 4 )(CO)NR 10 R 11 ,
14) N(R 10 )(CO)R 11 ,
15) N(R 10 )(CO)OR 11 ,
16) SO 2 NR 10 R 11 ,
17) N(R 10 )SO 2 R 11 ,
18) S(O) m R 10 ,
19) CN,
20) NR 10 R 11 ,
21) N(R 10 )(CO)NR 4 R 1 , and
22) O(CO)R 4 ;
R 7 is selected from:
1) H, C 0 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) s OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 )SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 ,
v) O(CO)R 4 ; and
2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) s OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 )SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 , and
v) O(CO)R 4 ;
R 4 is selected from: H, C 1-6 alkyl, (F) p C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C 1 -C 6 alkoxy;
R 5 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, OR 4 , N(R 4 ) 2 , CO 2 R 4 and (F) p C 1-6 alkyl;
W is O, NR 4 or C(R 4 ) 2 ;
X is C or S;
Y is O, (R 4 ) 2 , NCN, NSO 2 CH 3 or NCONH 2 , or Y is O 2 when X is S;
R 3 is independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl, CN and CO 2 R 4 ;
R 6 is independently selected from H and:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) s OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 )SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 , and
v) O(CO)R 4 ;
R 10 and R 11 are independently selected from: H, C 1-6 alkyl, (F) p C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C 1 -C 6 alkoxy, where R 10 and R 11 may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ;
G-J is selected from: N, N—C(R 5 ) 2 , C═C(R 5 ), C═N; C(R 5 ), C(R 5 )—C(R 5 ) 2 , C(R 5 )—C(R 5 ) 2 —C(R 5 ) 2 , C═C(R 5 )—C(R 5 ) 2 , C(R 5 )—C(R 5 )═C(R 5 ), C(R 5 )—C(R 5 ) 2 —N(R 5 ), C═C(R 5 )—N(R 5 ), C(R 5 )—C(R 5 )═N, C(R 5 )—N(R 5 )—C(R 5 ) 2 , C═N—C(R 5 ) 2 , C(R 5 )—N═C(R 5 ), C(R 5 )—N(R 5 )—N(R 5 ), C═N—N(R 5 ), N—C(R 5 ) 2 —C(R 5 ) 2 , N—C(R 5 )═C(R 5 ), N—C(R 5 ) 2 —N(R 5 ), N—C(R 5 )═N, N—N(R 5 )—C(R 5 ) 2 and N—N═C(R 5 );
Q, T, U and V are each independently a carbon atom or a nitrogen atom wherein at least one but no more than three of Q, T, U and V are nitrogen atoms, and wherein when any of Q, T, U, or V is a carbon atom it is unsubstituted or substituted where the substituents are independently selected from R 6 ;
p is 0 to 2q+1, for a substituent with q carbons;
m is 0, 1 or 2;
n is 0 or 1;
s is 1, 2 or 3;
“heterocyclic” is a stable 5- to 7- membered monocyclic- or stable 8- to 11- membered bicyclic heterocyclic ring system, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quarternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring;
“heteroaryl” is a stable 5- to 7- membered monoclcylic stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated;
or a pharmaceutically acceptable salt or individual diastereomer thereof.
2. The compound of claim 1 of the formula Ia:
or a pharmaceutically acceptable salt or individual diastereomer thereof.
3. The compound of claim 2 , wherein R 7 is phenyl, unsubstituted or substituted with one or substituents independently selected from:
a) C 1-6 alkyl,
b) OH,
c) OR 5 ,
d) halogen,
e) CO 2 R 4 ,
f) S(O) m R 5 ,
g) N(R 4 ) 2 , and
j) CN,
or a pharmaceutically acceptable salt or individual diastereomer thereof.
4. The compound of claim 2 , wherein R 7 is heteroaryl, unsubstituted or substituted with one or substituents independently selected from:
a) C 1-6 alkyl,
b) OH,
c) OR 5 ,
d) halogen,
e) CO 2 R 4 ,
f) S(O) m R 5 ,
g) N(R 4 ) 2 , and
j) CN,
or a pharmaceutically acceptable salt or individual diastereomer thereof.
5. The compound of claim 2 , wherein R 7 is selected from H and C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 6 cycloalkyl, unsubstituted or substituted with one or substituents independently selected from:
a) C 1-6 alkyl,
b) C 1-6 alkoxy,
c) fluorine,
d) HO,
e) OR 5 ,
f) CO 2 R 4 ,
g) CON(R 4 ) 2 ,
h) S(O) m R 5 , and
i) N(R 4 ) 2 ; and
or a pharmaceutically acceptable salt or individual diastereomer thereof.
6. The compound of claim 2 , wherein R 7 is heterocycle, unsubstituted or substituted with one or substituents independently selected from:
a) C 1-6 alkyl,
b) C 1-6 alkoxy,
c) fluorine,
d) HO,
e) OR 5 ,
f) CO 2 R 4 ,
g) CON(R 4 ) 2 ,
h) S(O) m R 5 , and
i) N(R 4 ) 2 ; and
or a pharmaceutically acceptable salt or individual diastereomer thereof.
7. The compound of claim 1 of the formula Ib:
or a pharmaceutically acceptable salt or individual diastereomer thereof.
8. The compound of claim 1 of the formula Ic:
or a pharmaceutically acceptable salt or individual diastereomer thereof.
9. The compound of claim 1 of the formula Id:
or a pharmaceutically acceptable salt or individual diastereomer thereof.
10. A compound selected from:
or a pharmaceutically acceptable salt or individual diastereomer thereof.
11. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
12. A method for treating headache in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 .
13. The method of claim 12 wherein the headache is a migraine headache or cluster headache.