Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
申请人：——
公开号：US20020049236A1
公开（公告）日：2002-04-25
There is disclosed a genus of non-peptidyl compounds, wherein said compounds are VLA-4 inhibitors useful in treating inflammatory, autoimmune, and respiratory diseases, and wherein said compounds comprise a compound of Formula (1.0.0):
1
and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein:
A is (C
1
-C
6
) alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted with 0 to 3 R
9
; or is a member selected from the group consisting of the following radicals: A
1
-NHC(═O)NH-A
2
-, A
1
-NHC(═O)O-A
2
-, A
1
-OC(═O)NH-A
2
-, A
1
-NHSO
2
NH-A
2
-, A
1
-NHC(═O)-A
2
-, A
1
-C(═O)NH-A
2
-, A
1
-NHSO
2
-A
2
-, A
1
-SO
2
NH-A
2
-, A
1
-(CH
2
)
r
-A
2
-, where A
1
and A
2
are each independently selected from the group consisting of hydrogen, aryl, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
2
-C
6
) alkynyl, cycloalkyl, heteroaryl, and heterocyclyl substituted with 0 to 3 R
9
;
B is a member independently selected from the group consisting of the following:
2
E is a single bond; —O—; —NR
10
—; —CH═CH—; —CC—; —S(═)
q
; —CR
11
R
12
NR
10
—; or —CR
11
R
12
;
X is —O—; —C(═O)—; —S(═O)
q
—; or —NR
10
—; X
1
, X
2
and X
3
are each independently selected from the group consisting of CH, CR
9
or N; Y is a single bond; —C(═O)—; —C(═S)—; or —S(═O)
2
—; R
7
is (C
1
-C
6
) alkyl; (CH
2
)
k
OR
5
; (CH
2
)
k
NR
6
C(═O)R
5
; (CH
2
)
k
NR
6
C(═O)OR
5
; (CH
2
)
k
NR
6
SO
2
R
5
; (CH
2
)
k
NR
6
R
5
; F; CF
3
; OCF
3
; aryl, substituted with 0 to 3 R
9
; heterocyclyl, substituted with 0 to 3 R
9
; heteroaryl, substituted with 0 to 3 R
9
; cycloalkyl, substituted with 0 to 3 R
9
; or R
7
may be taken together with R
8
to form a cycloalkyl or heterocyclyl ring; or R
7
may be taken together with R
11
to form a cycloalkyl or heterocyclyl ring; and R
8
is hydrogen; F; (C
1
-C
6
) alkyl or (C
1
-C
6
) alkoxy.
本发明涉及一类非肽类化合物，其中这些化合物是VLA-4抑制剂，用于治疗炎症性、自身免疫和呼吸道疾病，这些化合物包括如下式（1.0.0）的化合物：
1
以及其药学上可接受的盐和其他前药衍生物，其中：
A为（C
1
-C
6
）烷基，环烷基，芳基，杂芳基或杂环烷基，可选地取代为0至3个R
9
；或者是从以下基团中选择的成员：A
1
-NHC(═O)NH-A
2
-，A
1
-NHC(═O)O-A
2
-，A
1
-OC(═O)NH-A
2
-，A
1
-NHSO
2
NH-A
2
-，A
1
-NHC(═O)-A
2
-，A
1
-C(═O)NH-A
2
-，A
1
-NHSO
2
-A
2
-，A
1
-SO
2
NH-A
2
-，A
1
-(CH
2
)
r
-A
2
-，其中A
1
和A
2
各自独立地选择自氢，芳基，（C
1
-C
6
）烷基，（C
2
-C
6
）烯基，（C
2
-C
6
）炔基，环烷基，杂芳基和杂环烷基，取代为0至3个R
9
；
B是独立地从以下成员中选择的：
2
E是单键；—O—；—NR
10
—；—CH═CH—；—CC—；—S(═)
q
；—CR
11
R
12
NR
10
—；或—CR
11
R
12
；
X是—O—；—C(═O)—；—S(═O)
q
—；或—NR
10
—；X
1
，X
2
和X
3
各自独立地选择自CH，CR
9
或N；Y是单键；—C(═O)—；—C(═S)—；或—S(═O)
2
—；R
7
是（C
1
-C
6
）烷基；（CH
2
）
k
OR
5
；（CH
2
）
k
NR
6
C(═O)R
5
；（CH
2
）
k
NR
6
C(═O)OR
5
；（CH
2
）
k
NR
6
SO
2
R
5
；（CH
2
）
k
NR
6
R
5
；F；CF
3
；OCF
3
；芳基，取代为0至3个R
9
；杂环烷基，取代为0至3个R
9
；杂芳基，取代为0至3个R
9
；环烷基，取代为0至3个R
9
；或R
7
可以与R
8
一起形成环烷基或杂环烷基环；或R
7
可以与R
11
一起形成环烷基或杂环烷基环；而R
8
是氢；F；（C
1
-C
6
）烷基或（C
1
-C
6
）烷氧基。
