US 6,306,887 B1 · Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases

Abstract

Compounds of Formula (1.0.0): are described wherein A is for example aryl, heteroaryl or heterocyclyl, Y is preferably —C(═O)—; B is independently selected from a group of moieties, the most preferred of which are those of partial Formulas (1.1.2) and (1.1.6): and E is a single bond; oxygen; 1,1-cyclopropyl; C(CH3)2; CF2; or a bridging moiety of partial Formula (1.9.0): where R1a is hydrogen when R1 has the meaning of a mono-valent substituent; and R1a is a single bond when R1 has the meaning of a di-valent substituent. Said compounds are useful in methods of treating or preventing an inflammatory, autoimmune or respiratory diseases by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4.

A compound of Formula (1.0.0):

and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein:
A is phenyl, substituted with 0 to 3 R10;
or is a member selected from the group consisting of —A1—NHC(═O)NH—A2—, —A1—NHC(═O)O—A2—, and —A1—NH(NCN)NH—A2—, where A1 and A2 is each independently selected from the group consisting of hydrogen, provided that A1 and A2 may not both be hydrogen, and phenyl substituted wish 0 to 3 R10;
B is a member independently selected from the group consisting of the following:
where the symbol “*” indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.12) to the moiety “Y” in Formula (1.0.0);
and the symbol “→” indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.12) to the moiety “E” in Formula (1.0.0);
E is a single bond;
—O—;
—CH═CH—;
or a moiety of Formula (1.9.0):
where R1a is hydrogen when R1 has the meaning of a mono-valent substituent;
and R1a is a single bond when R1 has the meaning of a di-valent substituent;
X is —O—;
—S(═O)q—;
or —N(R14)—;
Y is —C(═O)—;
—C(═S)—;
—S(═O)2—;
or —CH(Ra)—;
m is an integer independently selected from 0, 1 and 2;
n is an integer independently selected from 1 and 2;
p is an integer independently selected from 1 and 2, provided that p must be selected as 1 where B is selected as partial Formula (1.1.2), (1.1.3), (1.1.5);
(1.1.6), (1.1.7), (1.1.8), (1.1.9), (1.1.10), (1.1.11), or (1.1.12);
q is an integer independently selected from 0 and 2;
R is independently selected from the group consisting of -tetrazolyl;
—C(═O)OR5;
—C(═O)(CH2)kC(═O)OR5;
—C(═O)NO.;
—C(═O)NH—S(═O)2R5;
—S(═O)2—NR14R5;
—C(═O)NHS(═O)2R6;
and a moiety of partial Formulas (3.0.0):
where:
k is an integer independently selected from 0, 1 and 2;
R1 is independently selected from the group consisting of hydrogen;
═O;
═S;
F;
(C1-C6) alkyl substituted with 0 to 3 R10;
(C2-C6) alkenyl substituted with 0 to 3 R10;
(C2—C6) alkynyl substituted with 0 to 3 R10;
a (C3—C14) carbocyclic ring system substituted with 0 to 3 R12;
aryl substituted with 0 to 3 R12;
and aryl(C1-C1) alkyl wherein said aryl and alkyl are substituted with 0 to 3 R12;
heterocyclyl as defined herein, substituted with 0 to 3 R12;
and heterocyclyl(C1-C1) alkyl as defined herein, wherein said heterocyclyl and alkyl are substituted with 0 to 3 R12;
C(═O)NR8R9;
and C(═O)R8;
R2 and R3 are each independently selected from the group consisting of hydrogen;
(C1-C1) alkyl substituted with 0 to 3 R13;
(C2—C6) alkenyl substituted with 0 to 3 R13;
a (C3—C14) carbocyclic ring system substituted with 0 to 3 R13;
(C1-C1) alkoxycarbonylamino-(C1-C1)alkyl-;
(C1-C1)alkylthio-(C1-C1)alkyl-;
(C1-C1) alkylsulfonyl-(C1-C1)alkyl-;
hydroxy(C1-C1) alkylthio-(C1-C1)alkyl-;
(C1-C1) alkylcarbonylamino-(C1-C1)alkyl-;
(C1-C4) alkylsulfonylamino-(C1-C4) alkyl-;
(C1-C1) alkylsulfonylaminocarbonyl-(C1-C1) alkyl-;
and a heterocyclyl ring as defined herein, substituted with 0 to 3 R13;
provided that
R2 and R3 are each defined as above;
or they are taken together as defined below;
or one of them is taken together with R4 as defined below, in which case the other has the meaning of hydrogen or methyl;
R2 and R3 are taken together to form a spirocyclic (C3-C14) carbocyclic ring substituted with 0 to 3 R13;
or
R2 or R3 is taken together with R4 and the carbon and nitrogen atoms to which they are respectively attached to form a heteroaryl or heterocyclyl group as defined herein, substituted with 0 to 3 R12;
R5 is hydrogen;
(C1-C1) alkyl;
(C3-C6) cycloalkyl;
or aryl;
R6 is hydrogen;
(C1-C1) alkyl;
(CH2)r—(C3-C6)cycloalkyl;
or (CH2)s-aryl;
where:
r and s are each independently an integer selected from 0, 1, and 2;
R8 and R9 are each independently selected from the group consisting of hydrogen;
(C1-C1) alkyl substituted with 0 to 3 R10;
a (C3-C14) carbocyclic ring system substituted with 0 to 3 R12;
aryl substituted with 0 to 3 R12;
and aryl-(C1-C1) alkyl wherein said aryl and alkyl are substituted with 0 to 3 R12;
heterocyclyl as defined herein, substituted with 0 to 3 R12;
and heterocyclyl-(C1-C4) alkyl as defined herein, wherein said heterocyclyl and alkyl are substituted with 0 to 3 R12;
R10 is independently selected from the group consisting of F;
Cl;
—C(═O)OR14;
—OH;
nitro;
cyano;
amino;
di(C1-C1) alkylamino;
(C1-C1) alkyl;
(C1-C4) alkoxy;
(C1-C4) alkylthio;
and (C1-C1) alkyl and (C1-C1) alkoxy each substituted with 1 to 3 substituents independently selected from F and Cl;
R12 when a substituent on a carbon atom, is independently selected from the group consisting of F;
Cl;
(C1-C1) alkyl;
(C3-C6) cycloalkyl;
(C1-C4) alkoxy;
—C(═O)OR14;
—OH;
(C1-C1) alkyl and (C1-C1) alkoxy each substituted with 1 to 3 substituents independently selected from F and Cl;
or
R12 when R12 is attached to a saturated carbon atom, may be ═O or ═S;
or when R12 is attached to a sulfur atom, may be ═O;
R12 when a substituent on a nitrogen atom, is independently selected from the group consisting of hydroxy;
hydroxy(C1-C1) alkyl;
(C1-C1) alkoxy;
(C3-C6) cycloalkyl;
(C1-C4) alkylcarbonyl;
and phenyl
R13 is (C1-C1) alkoxy;
and
R14 is hydrogen;
hydroxy;
(C1-C1) alkyl;
(C3-C6) cycloalkyl;
or aryl.

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Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases

Life of this patent

Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases

Life of this patent

Abstract

Claims19