Cell adhesion inhibitors
View Patent ↗A cell adhesion inhibitor of the general formula: R 3 -L-L′-R 1 is disclosed. An inhibitor of the present invention interacts with VLA-4 molecules and inhibits VLA-4 dependent cell adhesion. Also disclosed are methods for preparing and using such a cell adhesion inhibitor, as well as pharmaceutical compositions containing the same.
1. A compound of the formula:
R 3 -L-L′-R 1
wherein
R 1 is piperidinyl N-substituted with —SO 2 —R 14 , where R 14 is
1) C 1-10 alkyl,
2) C 2-10 alkenyl,
3) C 2-10 alkynyl,
4) Cy,
5) Cy-C 1-10 alkyl,
6) Cy-C 2-10 alkenyl, or
7) Cy-C 2-10 alkynyl;
L′ is
in which
Y 1 is —NR c —C(O)—,
R 2 is
1) H,
2) C 1-10 alkyl,
3) C 2-10 alkenyl,
4) C 2-10 alkynyl,
5) Cy,
6) Cy-C 1-10 alkyl,
7) Cy-C 1-10 alkenyl, or
8) Cy-C 1-10 alkynyl;
Y 2 is a bond;
X is —C(O)OR c ,
L is
in which
Y 3 is C 1-5 alkylene,
Y 4 is —C(O)—NR c —,
R 3 is a moiety of the following formula:
wherein:
Y 5 is —CO—;
R 4 is Z 5 -L c -Z 6 , where Z 5 is aryl, L c is —NH—C(O)—NH—, and Z 6 is aryl-C 1-10 alkyl;
R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl, or an amino acid side chain selected from the group consisting of arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, cyclohexylalanine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, phenylglycine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, norvaline, valine, threonine, serine, beta-cyanoalanine, 2-aminobutyric acid and allothreonine; and
R 5 is hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl-substituted alkyl; and
each R c , independently, is
1) H,
2) C 1-10 alkyl,
3) C 2-10 alkenyl,
4) C 2-10 alkynyl,
5) Cy, or
6) Cy-C 1-10 alkyl;
wherein each of alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R g ;
R g is
1) halogen,
2) amino,
3) carboxy,
4) —COO—C 1-4 alkyl,
5) —P(O)(OH) 2 ,
6) —P(O)(OH)(O—C 1-4 alkyl),
7) —P(O)(C 1-4 alkyl) 2 ,
8) —P(O)(OH)(C 1-4 alkyl),
9) —P(O)(O—C 1-4 alkyl)(C 1-4 alkyl),
10) —SO 2 —C 1-4 alkyl,
11) —CO—NH 2 ,
12) —CO—NH(C 1-4 alkyl),
13) —CO—N(C 1-4 alkyl)2,
14) —C 1-4 alkyl,
15) C 1-4 alkoxy,
16) aryl,
17) aryl-C 1-4 alkoxy,
18) hydroxy,
19) CF 3 , or
20) aryloxy;
or a pharmaceutically acceptable salt thereof.
2. A compound of the formula:
wherein
Y 7 is SO 2 ;
R 14 is
1) C 1-10 alkyl,
2) C 2-10 alkenyl,
3) C 2-10 alkynyl,
4) Cy,
5) Cy-C 1-10 alkyl,
6) Cy-C 2-10 alkenyl, or
7) Cy-C 2-10 alkynyl;
wherein Cy is optionally substituted with one to four substituents independently selected from R b or one of the following groups:
1) —NR c C(O)NR c SO 2 R d ,
2) —NR c S(O) m R d ,
3) —OS(O) 2 OR c , or
4) —OP(O)(OR c ) 2 ;
R 2 is
1) H,
2) C 1-10 alkyl,
3) C 2-10 alkenyl,
4) C 2-10 alkynyl,
5) Cy,
6) Cy-C 1-10 alkyl,
7) Cy-C 1-10 alkenyl, or
8) Cy-C 1-10 alkynyl;
wherein each of said alkyl, alkenyl and alkynyl is optionally substituted with one to four substituents independently selected from R a , each of said aryl and heteroaryl is optionally substituted with one to four substituents independently selected from R b ;
Y 2 is a bond;
X is COOH;
Y 3 is C 1-5 alkylene;
Y 4 is —C(O)NH—;
Y 5 is CO;
R 4 is Z 5 -L c -Z 6 , where
Z 5 is aryl;
L c is —NH—C(O)—NH—; and
Z 6 is aryl-C 1-10 alkyl;
R 5 is hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl-substituted alkyl; and
R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl, or an amino acid side chain selected from the group consisting of arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, cyclohexylalanine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, phenylglycine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, norvaline, valine, threonine, serine, beta-cyanoalanine, 2-aminobutyric acid and allothreonine;
each of said Cy is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
R a is
1) Cy,
2) —OR c ,
3) —NO 2 ,
4)-halogen,
5) —S(O) m R c ,
6) —SR c ,
7) —S(O) 2 OR c ,
8) —S(O) 2 NR c R d ,
9) —NR c R d ,
10) —O(CR e R f ) n NR c R d ,
11) —C(O)R d ,
12) —CO 2 R c ,
13) —P(O)(OR c )(OR d ),
14) —P(O)(R c )(OR d ),
15) —S(O) m OR c ,
16) —C(O)NR c R j ,
17) —CO 2 (CR e R f ) n CONR c R d ,
18) —OC(O)R c ,
19) —CN,
20) —NR c C(O)R d ,
21) —OC(O)NR c R d ,
22) —NR c C(O)OR d ,
23) —NR c C(O)NR d R e ,
24) —CR c (NOR d ),
25) —CF 3 ,
26) —OCF 3 , or
27) oxo;
wherein Cy is optionally substituted with one to four substituents independently selected from R b ;
R b is
1) a group selected from R a ,
2) C 1-10 alkyl,
3) C 2-10 alkenyl,
4) C 2-10 alkynyl,
5) aryl-C 1-10 alkyl, or
6) heteroaryl-C 1-10 alkyl,
wherein each of alkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with a group independently selected from R g ;
each of R c , R d , R e , and R f , independently, is
1) H,
2) C 1-10 alkyl,
3) C 2-10 alkenyl,
4) C 2-10 alkynyl,
5) Cy, or
6) Cy-C 1-10 alkyl;
wherein each of alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R g ;
R g is
1) halogen,
2) amino,
3) carboxy,
4) —COO—C 1-4 alkyl,
5) —P(O)(OH) 2 ,
6) —P(O)(OH)(O—C 1-4 alkyl),
7) —P(O)(C 1-4 alkyl) 2 ,
8) —P(O)(OH)(C 1-4 alkyl),
9) —P(O)(O—C 1-4 alkyl)(C 1-4 alkyl),
10) —SO 2 —C 1-4 alkyl,
11) —CO—NH 2 ,
12) —CO—NH(C 1-4 alkyl),
13) —CO—N(C 1-4 alkyl) 2 ,
14) C 1-4 alkyl,
15) C 1-4 alkoxy,
16) aryl,
17) aryl-C 1-4 alkoxy,
18) hydroxy,
19) CF 3 , or
20) aryloxy;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , where said compound is compound no.:
8555 in which R 1 is 1-(3,5-dichloro-benzenesulfonyl)-2-piperidinyl, L′ is a hydrocarbon linker moiety having 1 carbon chain atom and is (i) terminally attached to R 1 by —NHC(═O)— and (ii) substituted with —COOH, L is C 2 alkyl terminally attached to R 3 by —C(═O)NH—, R 4 is 4—[N′-(2-methylphenyl)ureido]benzyl, Y 5 is —C(═O)—, R 5 is methyl, and R 6 is 2-methylpropyl;
8628 in which R 1 is 1-benzenesulfonyl-3-piperidinyl, L′ is a hydrocarbon linker moiety having 1 carbon chain atom and is (i) terminally attached to R 1 by —NHC(═O)— and (ii) substituted with —COOH, L is C 2 alkyl terminally attached to R 3 by —C(═O)NH—, R 4 is 4-[N′-(2-methylphenyl)ureido]benzyl, Y 5 is —C(═O)—, R 5 is methyl, and R 6 is 2-methylpropyl; or
8674 in which R 1 is 1-benzenesulfonyl-4-piperidinyl, L′ is a hydrocarbon linker moiety having 1 carbon chain atom and is (i) terminally attached to R 1 by —NHC(═O)— and (ii) substituted with —COOH, L is C 2 alkyl terminally attached to R 3 by —C(═O)NH—, R 4 is 4-[N′-(2-methylphenyl)ureido]benzyl, Y 5 is —C(═O)—, R 5 is methyl, and R 6 is 2-methylpropyl.
4. A composition comprising a pharmaceutical carrier and an effective amount of a compound of the following formula:
wherein
Y 7 is SO 2 ;
R 14 is
1) C 1-10 alkyl,
2) C 2-10 alkenyl,
3) C 2-10 alkynyl,
4) Cy,
5) Cy-C 1-10 alkyl,
6) Cy-C 2-10 alkenyl, or
7) Cy-C 2-10 alkynyl;
wherein Cy is optionally substituted with one to four substituents independently selected from R b or one of the following groups:
1) —NR c C(O)NR c SO 2 R d ,
2) —NR c S(O) m R d ,
3) —OS(O) 2 OR c , or
4) —OP(O)(OR c ) 2 ;
R 2 is
1) H,
2) C 1-10 alkyl,
3) C 2-10 alkenyl,
4) C 2-10 alkynyl,
5) Cy,
6) Cy-C 1-10 alkyl,
7) Cy-C 1-10 alkenyl, or
8) Cy-C 1-10 alkynyl;
wherein each of said alkyl, alkenyl and alkynyl is optionally substituted with one to four substituents independently selected from R a , each of said aryl and heteroaryl is optionally substituted with one to four substituents independently selected from R b;
Y 2 is a bond;
X is COOH;
Y 3 is C 1-5 alkylene;
Y 4 is —C(O)NH—;
Y 5 is CO;
R 4 is Z 5 -L c -Z 6 , where
Z 5 is aryl;
L c is —NH—C(O)—NH—; and
Z 6 is aryl-C 1-10 alkyl;
R 5 is hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl-substituted alkyl; and
R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl, or an amino acid side chain selected from the group consisting of arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, cyclohexylalanine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, phenylglycine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, norvaline, valine, threonine, serine, beta-cyanoalanine, 2-aminobutyric acid and allothreonine;
each of said Cy is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
R a is
1) Cy,
2) —OR c ,
3) —NO 2 ,
4)-halogen,
5) —S(O) m R c ,
6) —SR c ,
7) —S(O) 2 OR c ,
8) —S(O) 2 NR c R d ,
9) —NR c R d ,
10) —O(CR e R f )—NR c R d ,
11) —C(O)R d ,
12) —CO 2 R c ,
13) —P(O)(OR c )(OR d ),
14) —P(O)(R c )(OR d ),
15) S(O) m OR c ,
16) —C(O)NR c R j ,
17) —CO 2 (CR e R f ) n CONR c R d ,
18) —OC(O)R c ,
19) —CN,
20) —NR c C(O)R d ,
21) —OC(O)NR c R d ,
22) —NR c C(O)OR d ,
23) —NR c C(O)NR d R e ,
24) —CR c (NOR d ),
25) —CF 3 ,
26) —OCF 3 , or
27) oxo;
wherein Cy is optionally substituted with one to four substituents independently selected from R b ;
R b is
1) a group selected from R a ,
2) C 1-10 alkyl,
3) C 2-10 alkenyl,
4) C 2-10 alkynyl,
5) aryl-C 1-10 alkyl, or
6) heteroaryl-C 1-10 alkyl,
wherein each of alkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with a group independently selected from R g ;
each of R c , R d , R e , and R f , independently, is
1) H,
2) C 1-10 alkyl,
3) C 2-10 alkenyl,
4) C 2-10 alkynyl,
5) Cy, or
6) Cy-C 1-10 alkyl;
wherein each of alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R g ;
R g is
1) halogen,
2) amino,
3) carboxy,
4) —COO—C 1-4 alkyl,
5) —P(O)(OH) 2 ,
6) —P(O)(OH)(O—C 1-4 alkyl),
7) —P(O)(C 1-4 alkyl) 2 ,
8) —P(O)(OH)(C 1-4 alkyl),
9) —P(O)(O—C 1-4 alkyl)(C 1-4 alkyl),
10) —SO 2 —C 1-4 alkyl,
11) —CO—NH 2 ,
12) —CO—NH(C 1-4 alkyl),
13) —CO—N(C 1-4 alkyl) 2 ,
14) C 1-4 alkyl,
15) C 1-4 alkoxy,
16) aryl,
17) aryl-C 1-4 alkoxy,
18) hydroxy,
19) CF 3 , or
20) aryloxy;
or a pharmaceutically acceptable salt thereof.
5. The composition of claim 4 , wherein said compound is compound no.
8555 in which R 1 is 1-(3,5-dichloro-benzenesulfonyl)-2-piperidinyl, L′ is a hydrocarbon linker moiety having 1 carbon chain atom and is (i) terminally attached to R 1 by —NHC(═O)— and (ii) substituted with —COOH, L is C 2 alkyl terminally attached to R 3 by —C(═O)NH—, R 4 is 4-[N′-(2-methylphenyl)ureido]benzyl, Y 5 is —C(═O)—, R 5 is methyl, and R 6 is 2-methylpropyl;
8628 in which R 1 is 1-benzenesulfonyl-3-piperidinyl, L′ is a hydrocarbon linker moiety having 1 carbon chain atom and is (i) terminally attached to R 1 by —NHC(═O)— and (ii) substituted with —COOH, L is C 2 alkyl terminally attached to R 3 by —C(═O)NH—, R 4 is 4-[N′-(2-methylphenyl)ureido]benzyl, Y 5 is —C(═O)—, R 5 is methyl, and R 6 is 2-methylpropyl; or
8674 in which R 1 is 1-benzenesulfonyl-4-piperidinyl, L′ is a hydrocarbon linker moiety having 1 carbon chain atom and is (i) terminally attached to R 1 by —NHC(═O)— and (ii) substituted with —COOH, L is C 2 alkyl terminally attached to R 3 by —C(═O)NH—, R 4 is 4-[N′-(2-methylphenyl)ureido]benzyl, Y 5 is —C(═O)—, R 5 is methyl, and R 6 is 2-methylpropyl.