Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-06
2004-03-16
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S517000, C548S537000, C548S538000, C514S423000
Reexamination Certificate
active
06706753
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds useful as therapeutic, prophylactic or diagnostic agents having binding affinity to integrin receptors, in particular to &agr;
4
integrins.
BACKGROUND OF THE INVENTION
The integrins are &agr;/&bgr; heterodimeric cell surface receptors involved in numerous cellular processes from cell adhesion to gene regulation (Hynes, Cell 1992, 69, 11-25; Hemler, Annu. Rev. Immunol. 1990, 8, 365-368). Several integrins have been implicated in disease processes and have generated widespread interest as potential targets for drug discovery (Sharar et al, Springer Semin. Immunopathology 1995, 16, 359-378). In the immune system, integrins are involved in leukocyte trafficking, adhesion and infiltration during inflammatory processes (Nakajima et al, J. Exp. Med. 1994, 179, 1145-1154). Differential expression of integrins regulates the adhesive properties of cells and different integrins are involved in different inflammatory responses (Butcher et al, Science 1996, 272, 60-66). The &agr;
4
integrins, &agr;
4
&bgr;
1
(VLA-4) and &agr;
4
&bgr;
7
(LPAM), are expressed primarily on monocytes, lymphocytes, eosinophils, basophils, and macrophages but not on neutrophils (Elices et al, Cell 1990, 60, 577-584). The primary ligands for &agr;
4
integrins are the endothelial surface proteins mucosal addressin cell adhesion molecule (MAdCAM) and vascular cell adhesion molecule (VCAM) with lower affinity (Makarem et al, J. Biol. Chem. 1994, 269, 4005-4011). The binding of the &agr;
4
&bgr;
1
or &agr;
4
&bgr;
7
to MAdCAM and/or VCAM expressed on high endothelial venules (HEVs) at sites of inflammation results in firm adhesion of the leukocyte to the endothelium followed by extravasation into the inflamed tissue (Chuluyan et al, Springer Semin. Immunopathology 1995, 16, 391-404). Monoclonal antibodies directed against &agr;
4
&bgr;
1
, (&agr;
4
&bgr;
7
, MAdCAM or VCAM have been shown to be effective modulators in animal models of chronic inflammatory diseases such as asthma (Simmons et al, Blood 1992, 80, 388-395), rheumatoid arthritis (RA) (Juliano et al, Current Opinion Cell Biology 1993, 5, 812-818), and inflammatory bowel diseases (IBD) (Laberge et al, Am. J. Respir. Crit Care Med. 1995, 151, 822-829 and Barbadillo et al, Springer Semin. Immunopathology 1995, 16). While antibodies have shown efficacy they must be administered parenterally and are inherently cumbersome to produce. Accordingly, it would be desirable to provide small molecule compounds which inhibit the interaction between &agr;
4
integrins and ligands MAdCAM and/or VCAM which would be useful for treatment of chronic inflammatory diseases such as arthritis, asthma, multiple sclerosis, Chrohn's disease, ulcerative colitis, and hepatitis C.
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided compounds of formula (I)
wherein
A is a 5 or 6 member, saturated or unsaturated carbocycle or heterocycle optionally substituted by oxo and R
4
;
Q is alkyl, alkenyl or alkynyl optionally substituted with halogen, carboxyl, alkyl or aryl, and wherein one or more carbon atoms are optionally replaced with O, N, NR
6
, S, SO, or SO
2
;
X is —CR
5
— or —N—;
Y is H, —CHR
3
—, —CR
3
═, or a bond;
Z is H, —CHR
3
—, ═CR
3
—, —NR
3
—, ═N—, O, S, SO, SO
2
or a bond, provided that when one of Y and Z is H then the other is also H;
W is —C(O)NR
6
—, —NR
6
C(O)—, —C(S)NR
6
—, —NR
6
C(S)—, NR
6
, O, S, SO
2
, —CH
2
—, —C—, —NR
6
SO
2
—, —SO
2
NR
6
—, —OC(O)NR
6
—, —NR
6
C(O)O—, —OC(S)NR
6
—, —NR
6
C(S) O—, —S—C(S)NR
6
—, —C(O)—, —NR
6
C(O)NR
6
— or —NR
6
C(S)NR
6
—;
R
1
is hydrogen or is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with hydroxyl, halogen, amino, nitro, carboxyl, a carbocycle, or a heterocycle; or R
1
is a carbocycle or heterocycle optionally substituted with hydroxyl, oxo, halogen, amino, or nitro;
R
2
is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with halogen, hydroxyl, oxo alkoxy, amino, nitro, carboxyl, carboxamido, acyl, acyloxy, amidinyl, guanidinyl, thiol, alkylthio, or one or more carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino or carboxyl; or R
2
is a carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino, nitro, carboxyl, acyl, acyloxy, alkyl, alkenyl, alkynyl or a carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino or carboxyl;
R
3
and R
4
are independently selected from the group consisting of H, hydroxyl, halogen, amino, nitro, carboxyl, alkyl, alkenyl, alkynyl, a carbocycle and a heterocycle, wherein said alkyl, alkenyl, alkynyl, carbocycle and heterocycle groups are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, amino, oxo and carboxyl, and optionally one or more carbon atoms of said alkyl, alkenyl and alkynyl group is replaced with N, NR
6
, O, S, SO or SO
2
;
R
5
is H or alkyl, alkenyl or alkynyl optionally having a carbon atom replaced with O, N or NR
6
, and optionally substituted with COOR
1
; or R
5
together with the carbon atom from which it depends forms a double bond to an adjacent carbon or nitrogen atom of Q; or R
5
together with a non-adjacent carbon or nitrogen atom of Q form a carbocycle or heterocycle;
R
6
is hydrogen, alkyl, alkenyl or alkynyl;
m and n are independently 1, 2 or 3;
and salts, solvates and hydrates thereof.
In another aspect of the invention, there is provided pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, excipient or adjuvant.
In another aspect of the invention, there is provided a method of inhibiting binding of an &agr;
4
integrin to a protein ligand comprising contacting said &agr;
4
integrin with a compound of the invention.
In another aspect of the invention, there is provided a method of treating a disease or condition mediated by &agr;
4
integrin receptors or ligands of &agr;
4
integrin receptors in a mammal, the method comprising administering to said mammal an effective amount of a compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Compounds are provided having binding affinity for &agr;
4
integrins, having the general formula (I)
wherein A, Q, W, X, Y, Z, R
1
to R
4
, m and n are as defined herein.
Ring A is a 5 or 6 member, saturated or unsaturated carbocycle or heterocycle optionally substituted by oxo (═O) and R
4
. By “carbocycle” is meant herein to be a mono- bi- or tricyclic ring system containing a 4-16 carbon atom scaffold that is saturated, partially unsaturated or fully unsaturated including aromatic. In the context of ring A, suitable carbocycles include cycloalkyl, cycloalkenyl and aryl. In a preferred embodiment, ring A is a carbocycle selected from the group consisting of cyclopentyl, cyclohexyl and benzene. In a most preferred embodiment ring A is benzene. In another embodiment, ring A is a heterocycle. By “heterocycle” is meant herein to be a mono-, bi- or tricyclic ring system comprising a combination of 4-16 carbon and hetero atoms (i.e. N, O, and S, as well as SO and SO
2
) that is saturated, partially unsaturated or fully unsaturated including aromatic. In the context of ring A, preferred heterocycles are 5 and 6 member monocycles. Particularly preferred ring A heterocycles include pyridine, pyran, pyrimidine, pyrazine, pyridazine, pyrole, furan, thiophene, imidazole, pyrazole, thiazole and triazole. It is appreciated that ring A encompasses heterocycles in which the heteroatoms may be shared with the central ring, if present, and/or may be adjacent to X.
Q is a divalent alkyl, alkenyl or alkynyl linking group optionally substituted with halogen, carboxyl, alkyl or aryl, and wherein one or more carbon atoms are optionally replaced with O, N, NR
6
, S, SO, or SO
2
. In a preferred embodiment, Q is alkyl having 1 to 3 carbon atoms or methylene
Artis Dean R.
Jackson David Y.
Rawson Thomas E.
Reynolds Mark E.
Stanley Mark S.
Evans David W
Genentech Inc.
McKane Joseph K.
Shameem Golam M M
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