US 6,271,252 B1Granted

Cyclic amino acid derivatives as cell adhesion inhibitors

AssigneeMerck & Co., Inc.

InventorsLinda Chang, William K. Hagmann, Malcolm MacCoss

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Abstract

Cyclic amino acid derivatives of Formula I are antagonists of VLA-4 and/or α4β7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of asthma, allergies, inflammation, multiple sclerosis, and other inflammatory and autoimmune disorders.

Claims14

Dependent claims

A compound of the formula I:

or a pharmaceutically acceptable salt thereof wherein:
X is —C(O)ORd;
Y is —S(O)2—;
R is a saturated or partially saturated monocyclic or bicyclic ring having 0 heteroatoms, optionally benzo-fused and optionally substituted with from 1-4 groups selected from Rb;
R1 is Cy optionally substituted with one to four substituents independently selected from Rb;
R2 and R3 are each hydrogen, or
R2 and R3 together with the atoms to which they are attached form a pyrrolidine ring, wherein said ring may be isolated or benzo-fused, and optionally substituted with one to four substituents independently selected from Rb;
R4 is
1) hydrogen,
2) C1-10alkyl,
3) C2-10alkenyl,
4) C2-10alkynyl,
5) aryl, or
6) aryl C1-10alkyl,
wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra, and aryl is optionally substituted with one to four substituents independently selected from Rb;
or
R3, R4 and the carbon to which they are attached form a 3-7 membered carbocyclic ring;
R5 is
1) hydrogen,
2) C1-10 alkyl,
3) Cy, or
4) Cy-C1-10 alkyl,
wherein alkyl is optionally substituted with one to four substituents independently selected from Ra;
and Cy is optionally substituted with one to four substituents independently selected from Rb;
R6 is selected from the group consisting of:
1) hydrogen,
2) C1-10alkyl,
3) C2-10alkenyl,
4) C2-10alkynyl,
5) Cy-(Cy1)p,
6) Cy-(Cy1)p-C1-10alkyl,
7) Cy-(Cy1)p-C2-10alkenyl,
8) Cy-(Cy1)p-C2-10alkynyl,
alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra;
and Cy and Cy1 are optionally substituted with one to four substituents independently selected from Rb;
or
R6 together with the carbon atom to which it is attached and another carbon atom of R form a carbocyclic ring having from 5-8 members optionally substituted with Rb;
R7 is
1) hydrogen
2) C1-10alkyl,
3) C2-10alkenyl,
4) C2-10alkynyl,
5) Cy,
6) Cy-C1-10alkyl,
7) Cy-C2-10alkenyl,
8) Cy-C2-10alkynyl,
9) C1-10alkoxy,
10) Cy-O,
11) Cy-C1-10alkoxy,
12) —S(O)mRd,
13) —SRd,
14) —S(O)2ORd,
15) —S(O)mNRdRe,
16) hydroxy,
17) —NRdRe,
18) —O(CRfRg)nNRdRe,
19) —OC(O)Rd,
20) —CN,
21) —C(O)NRdRe,
22) —NRdC(O)Re,
23) —OC(O)NRdRe,
24) —NRdC(O)ORe, or
25) —NRdC(O)NRdRe,
wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and Cy is optionally substituted with one to four substituents independently selected from Rb;
or
R7 together with the carbon atom to which it is attached and another carbon atom of R form a carbocyclic ring having from 5-8 members optionally substituted with Rb;
or
R6 and R7 together represents a double bond between the carbon atoms to which they are attached;
Ra is
1) —CF3;
2) —ORd,
3) —NO2,
4) halogen
5) —S(O)mRd,
6) —SRd,
7) —S(O)2ORd,
8) —S(O)mNRdRe,
9) —NRdRe,
10) —O(CRfRg)nNRdRe,
11) —C(O)Rd,
12) —CO2Rd,
13) —CO2(CRfRg)nCONRdRe,
14) —OC(O)Rd,
15) —CN,
16) —C(O)NRdRe,
17) —NRdC(O)Re,
18) —OC(O)NRdRe,
19) —NRdC(O)ORe, or
20) —NRdC(O)NRdRe;
21) —CRd(N—ORe), or
22) Cy optionally substituted with a group independently selected from Rc;
Rb is
1) a group selected from Ra,
2) C1-10 alkyl,
3) C2-10 alkenyl,
4) C2-10 alkynyl, or
5) Cy-C1-10 alkyl,
wherein alkyl, alkenyl, alkynyl, and Cy are optionally substituted with a group independently selected from Rc;
Rc is
1) halogen,
2) amino,
3) carboxy,
4) C1-4alkyl,
5) C1-4alkoxy,
6) aryl,
7) aryl C1-4alkyl, or
8) aryloxy;
Rd and Re are independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, Cy and Cy-C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from Rc;
Rf and Rg are independently selected from hydrogen, C1-10alkyl, Cy and Cy-C1-10alkyl;
m is 0, 1 or 2;
n is an integer from 1 to 10;
p is 0 or 1.

109 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of the formula I:

or a pharmaceutically acceptable salt thereof wherein:
X is —C(O)ORd;
Y is —S(O)2—;
R is a saturated or partially saturated monocyclic or bicyclic ring having 0 heteroatoms, optionally benzo-fused and optionally substituted with from 1-4 groups selected from Rb;
R1 is Cy optionally substituted with one to four substituents independently selected from Rb;
R2 and R3 are each hydrogen, or
R2 and R3 together with the atoms to which they are attached form a pyrrolidine ring, wherein said ring may be isolated or benzo-fused, and optionally substituted with one to four substituents independently selected from Rb;
R4 is
1) hydrogen,
2) C1-10alkyl,
3) C2-10alkenyl,
4) C2-10alkynyl,
5) aryl, or
6) aryl C1-10alkyl,
wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra, and aryl is optionally substituted with one to four substituents independently selected from Rb;
or
R3, R4 and the carbon to which they are attached form a 3-7 membered carbocyclic ring;
R5 is
1) hydrogen,
2) C1-10 alkyl,
3) Cy, or
4) Cy-C1-10 alkyl,
wherein alkyl is optionally substituted with one to four substituents independently selected from Ra;
and Cy is optionally substituted with one to four substituents independently selected from Rb;
R6 is selected from the group consisting of:
1) hydrogen,
2) C1-10alkyl,
3) C2-10alkenyl,
4) C2-10alkynyl,
5) Cy-(Cy1)p,
6) Cy-(Cy1)p-C1-10alkyl,
7) Cy-(Cy1)p-C2-10alkenyl,
8) Cy-(Cy1)p-C2-10alkynyl,
alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra;
and Cy and Cy1 are optionally substituted with one to four substituents independently selected from Rb;
or
R6 together with the carbon atom to which it is attached and another carbon atom of R form a carbocyclic ring having from 5-8 members optionally substituted with Rb;
R7 is
1) hydrogen
2) C1-10alkyl,
3) C2-10alkenyl,
4) C2-10alkynyl,
5) Cy,
6) Cy-C1-10alkyl,
7) Cy-C2-10alkenyl,
8) Cy-C2-10alkynyl,
9) C1-10alkoxy,
10) Cy-O,
11) Cy-C1-10alkoxy,
12) —S(O)mRd,
13) —SRd,
14) —S(O)2ORd,
15) —S(O)mNRdRe,
16) hydroxy,
17) —NRdRe,
18) —O(CRfRg)nNRdRe,
19) —OC(O)Rd,
20) —CN,
21) —C(O)NRdRe,
22) —NRdC(O)Re,
23) —OC(O)NRdRe,
24) —NRdC(O)ORe, or
25) —NRdC(O)NRdRe,
wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and Cy is optionally substituted with one to four substituents independently selected from Rb;
or
R7 together with the carbon atom to which it is attached and another carbon atom of R form a carbocyclic ring having from 5-8 members optionally substituted with Rb;
or
R6 and R7 together represents a double bond between the carbon atoms to which they are attached;
Ra is
1) —CF3;
2) —ORd,
3) —NO2,
4) halogen
5) —S(O)mRd,
6) —SRd,
7) —S(O)2ORd,
8) —S(O)mNRdRe,
9) —NRdRe,
10) —O(CRfRg)nNRdRe,
11) —C(O)Rd,
12) —CO2Rd,
13) —CO2(CRfRg)nCONRdRe,
14) —OC(O)Rd,
15) —CN,
16) —C(O)NRdRe,
17) —NRdC(O)Re,
18) —OC(O)NRdRe,
19) —NRdC(O)ORe, or
20) —NRdC(O)NRdRe;
21) —CRd(N—ORe), or
22) Cy optionally substituted with a group independently selected from Rc;
Rb is
1) a group selected from Ra,
2) C1-10 alkyl,
3) C2-10 alkenyl,
4) C2-10 alkynyl, or
5) Cy-C1-10 alkyl,
wherein alkyl, alkenyl, alkynyl, and Cy are optionally substituted with a group independently selected from Rc;
Rc is
1) halogen,
2) amino,
3) carboxy,
4) C1-4alkyl,
5) C1-4alkoxy,
6) aryl,
7) aryl C1-4alkyl, or
8) aryloxy;
Rd and Re are independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, Cy and Cy-C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from Rc;
Rf and Rg are independently selected from hydrogen, C1-10alkyl, Cy and Cy-C1-10alkyl;
m is 0, 1 or 2;
n is an integer from 1 to 10;
p is 0 or 1.

109 more elements