VLA-4 Antagonists
4-Thio, 4-sulfinyl and 4-sulfonyl proline derivatives of the present invention are antagonists of the VLA-4 integrin and are useful in the treatment, prevention and suppression of diseases mediated by VLA-4-binding and cell adhesion and activation. Moreover, the compounds of the present invention demonstrate significant receptor occupancy of VLA-4 bearing cells after oral administration and are suitable for once-, twice-, or thrice-a-day oral administration. This invention also relates to compositions containing such compounds and methods of treatment using such compounds.
1 . A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
q is 0 or 1;
V and W are independently chosen from (1) C 1-3 alkyl, (2) halogen, and (3) C 1-3 alkoxy;
X and Y may independently be oxygen or not present;
Z is N or N + O − ;
R 1 is selected from (1) hydrogen, (2) C 1-10 alkyl, (3) —(C 1-10 alkyl)-aryl, (4) —(C 1-10 alkyl)-O—C 1-10 alkyl, (5) —(C 1-10 alkyl)-OC(O)—C 1-10 alkyl, (6) —(C 1-10 alkyl)-OC(O)-aryl, (7) —(C 1-10 alkyl)-OC(O)O—C 1-10 alkyl, and (8) —(C 1-10 alkyl)-N + (C 1-3 alkyl) 3 ; wherein alkyl is optionally substituted with one to three substituents independently selected from R a , and aryl is optionally substituted with one to three substituents independently selected from R b ;
R 2 and R 3 are independently selected from H, —SO 2 —C 1-3 alkyl, CN, CF 3 , OCF 3 , and halogen;
R 4 is selected from the group consisting of: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, Cy and Cy-C 1-10 alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R c ;
R a is selected from (1) —OR d , (2) —NR d S(O) m R e , (3) —NO 2 , (4) halogen, (5) —S(O) m R d , (6) —SR d , (7) —S(O) 2 OR d , (8) —S(O) m NR d R e , (9) —NR d R e , (10) —O(CR f R g ) n NR d R e , (11) —C(O)R d , (12) —CO 2 R d , (13) —CO 2 (CR f R g ) n CONR d R e , (14) —OC(O)R d , (15) —CN, (16) —C(O)NR d R e , (17) —NR d C(O)R e , (18) —OC(O)NR d R e , (19) —NR d C(O)OR e , (20) —NR d C(O)NR d R e , (21) —CR d (N—OR e ), (22) CF 3 , (23) —OCF 3 , (24) C 3-8 cycloalkyl, and (25) heterocyclyl; wherein cycloalkyl and heterocyclyl are optionally substituted with one to three groups independently selected from R c ;
R b is selected from (1) a group selected from R a , (2) C 1-10 alkyl, (3) C 2-10 alkenyl (4) C 2-10 alkynyl, (5) aryl, and (6) —(C 1-10 alkyl)-aryl, wherein alkyl, alkenyl, alkynyl, and aryl are optionally substituted with one to three substituents selected from a group independently selected from R c ;
R c is (1) halogen, (2) amino, (3) carboxy, (4) C 1-4 alkyl, (5) C 1-4 alkoxy, (6) aryl, (7) —(C 1-4 alkyl)-aryl, (8) hydroxy, (9) CF 3 , (10) OC(O)C 1-4 alkyl, (11) —CN, and (12) —SO 2 C 1-10 alkyl;
R d and R e are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, Cy and Cy-C 1-10 alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R c ; or
R d and R e together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from O, S and N—R h ; wherein said ring is optionally substituted with one to four substituents independently selected from R c ;
R f and R g are independently selected from hydrogen, C 1-10 alkyl, Cy and Cy-C 1-10 alkyl; or
R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
R h is selected from R f and —C(O)R f ;
Cy is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl;
each m is independently 0, 1 or 2; and
each n is independently 1, 2, 3, or 4.
2 . The compound according to claim 1 wherein one of V and W is halogen and the other is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy.
3 . The compound according to claim 2 wherein one of V and W is chloro and the other is chloro or methoxy.
4 . The compound according to claim 3 wherein V and W are each chloro.
5 . The compound according to claim 1 wherein R 1 is selected from the group consisting of: hydrogen, C 1-4 alkyl, —(C 1-4 alkyl)OC(O)—C 1-4 alkyl, and —(C 1-4 alkyl)OC(O)—C 1-4 alkyl.
6 . The compound according to claim 1 wherein R 1 is hydrogen.
7 . The compound according to claim 1 wherein R 1 is C 1-4 alkyl.
8 . The compound according to claim 1 wherein R 2 is hydrogen and R 3 is CN.
9 . The compound according to claim 1 wherein R 4 is selected from the group consisting of: C 1-6 alkyl, cycloalkyl and aryl.
10 . The compound according to claim 1 of formula Ia:
or a pharmaceutically acceptable salt thereof, wherein
q is 0 or 1;
X and Y may independently be oxygen or not present;
R 1 is selected from hydrogen and ethyl; and
R 4 is selected from C 1-6 alkyl, cyclopentyl, cyclohexyl and phenyl.
11 . The compound according to claim 10 wherein q is 0.
12 . The compound according to claim 10 wherein q is 1.
13 . The compound according to claim 10 wherein X and Y are not present.
14 . The compound according to claim 10 wherein X is oxygen and Y is not present.
15 . The compound according to claim 10 wherein X and Y are oxygen.
16 . A compound according to claim 10 selected from one of the following tables:
X
Y
q
R 1
R 4
not present
not present
0
ethyl
cyclopentyl
not present
not present
0
hydrogen
cyclopentyl
oxygen
not present
0
hydrogen
cyclopentyl
not present
not present
0
ethyl
tert-butyl
not present
not present
0
hydrogen
tert-butyl
oxygen
oxygen
0
hydrogen
cyclopentyl
not present
not present
0
hydrogen
cyclohexyl
not present
not present
0
ethyl
cyclohexyl
not present
not present
0
ethyl
phenyl
not present
not present
0
hydrogen
phenyl
not present
not present
0
hydrogen
1,2-dimethylpropyl
not present
not present
0
ethyl
1,2-dimethylpropyl
not present
not present
1
hydrogen
cyclopentyl
not present
not present
1
ethyl
cyclopentyl
X
Y
q
R 1
R 4
not present
not present
0
ethyl
cyclopentyl
not present
not present
0
hydrogen
cyclopentyl
oxygen
not present
0
hydrogen
cyclopentyl
oxygen
not present
0
ethyl
cyclopentyl
oxygen
oxygen
0
hydrogen
cyclopentyl
oxygen
oxygen
0
ethyl
cyclopentyl
or a pharmaceutically acceptable salt of any of the above.
17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
18 . Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by cell adhesion.
19 . The use of claim 18 wherein said disease is selected from asthma, multiple sclerosis, inflammatory bowel disease, chronic obstructory pulmonary disease, sickle cell anemia, leukemia, multiple myeloma, and rheumatoid arthritis.
20 . A method for preventing the action of VLA-4 in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1 .