Dihydropyrazolo[3,4-d]thieno[2,3-B]pyrid...

Details Dihydropyrazolo[3,4-d]thieno[2,3-B]pyrid... Dihydropyrazolo[3,4-d]thieno[2,3-B]pyrid...

2003-07-28

2004-12-21

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S083000

Reexamination Certificate

active

06833374

ABSTRACT:

BACKGROUND OF THE INVENTION
Regulation of T cell responses plays a primary role in determining the outcome of auto-immune disease, the development of tumor immunity, and graft survival following transplantation (Bluestone, et.al.
Annu, Rev. Immunol
. 1996, 14, 233-258.; Kuchroo, et. al.
Crit. Rev. Immunol
. 1998, 18, 389-418.; Guinan, et. al.
N. Engl. J. Med
. 1999, 340,1704-1714.; Abrams et. al.
J. Exp. Med
. 2000, 192, 681-694). These immune responses are controlled by the interaction of molecules on T cell and antigen presenting cell surfaces. Activation of T cells requires two signals, an antigen-specific signal delivered through T cell antigen receptor, and a second co-stimulatory signal. This co-stimulatory signal dictates the outcome for T cells through the binding of B7-1 and B7-2 expressed on antigen presenting cells to CD28 and CTLA-4 on T cells. CD28 engagement by B7-1 or B7-2 amplifies T cell receptor signaling and stimulates production of cytokines required for T-cell proliferation. On the other hand, CTLA-4 engagement by B7-1 or B7-2 down regulates the immune response (Allison, et. al.
Nature
1992, 356, 607-609.; Bluestone, et. al.
Immunity
1994, 1, 405-413.; Thompson, et. al.
Science
1995, 270, 985-988). In experimental disease models, altering these co-stimulatory signals has profound effects on immunity. Blocking B7/CD28 interactions with monoclonal antibodies or soluble receptors results in immunosuppression and enhanced allograft survival, while B7/CTLA-4 blockade results in enhanced anti-tumor immune responses (Larsen, et. al.
Nature
1996, 381, 434-438). Consequently, agents, such as small molecules, which act as inhibitors of cell-cell interactions may be useful in the development of effective immunomodulatory medicines.
Therefore, it is an object of this invention to provide compounds which are useful as immunotherapeutic agents in the treatment of transplant rejection, autoimmune disease or graft vs host disease.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of transplant rejection, autoimmune disease or graft vs host disease.
It is a feature of this invention that the compounds provided may be used to further study and elucidate the interactions of B7-1 with the CD28 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I:
wherein
R
1
and R
2
are each independently H, C
1
-C
10
alkyl optionally substituted with one or more halogen, hydroxy, C
1
-C
4
alkoxy, CO
2
R
6
, CONR
7
R
8
, C
3
-C
7
cycloalkyl or optionally substituted phenyl groups, or
phenyl optionally substituted with one to three halogen, hydroxy, C
1
-C
6
haloalkyl, C
1
-C
4
alkoxy, CO
2
R
9
, NR
10
R
11
or CN groups;
R
3
is H, C
1
-C
6
alkyl optionally substituted with a phenyl, naphthyl or heteroaryl group each group optionally substituted with one to three C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
4
alkoxy, hydroxy, CHO, NO
2
, CN, CO
2
R
12
or NR
13
R
14
groups,
phenyl optionally substituted with one to three halogen, NO
2
, CN, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
6
alkoxy, phenyl, phenoxy, benzyl, benzyloxy, CONR
15
R
16
, SO
2
NR
15
R
16
, CO
2
R
17
, NR
18
R
19
or CH
2
CO
2
R
20
groups,
naphthyl optionally substituted with one to three halogen, NO
2
, CN, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
6
alkoxy, phenyl, phenoxy, benzyl, benzyloxy, CO
2
R
17
, NR
18
R
19
or CH
2
CO
2
R
20
groups,
C
5
-C
7
cycloheteroalkyl optionally substituted with one to three halogen, NO
2
, CN, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
4
alkoxy, CO
2
R
17
or NR
18
R
19
groups, or
heteroaryl optionally substituted with one to three halogen, NO
2
, CN, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
4
alkoxy, CO
2
R
17
or NR
18
R
19
groups;
R
4
is phenyl optionally substituted with one to three halogen, NO
2
, CN, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkylthio, C
1
-C
6
haloalkyl, C
1
-C
6
alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO
n
R
26
, SO
2
NR
21
R
22
, CO
2
R
23
or NR
24
R
25
groups,
cycloheteroalkyl optionally substituted with one or more halogen, NO
2
, CN, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkylthio, C
1
-C
6
haloalkyl, C
1
-C
6
alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO
n
R
26
, SO
2
NR
21
,R
22
, CO
2
R
23
or NR
24
R
25
groups, or
heteroaryl optionally substituted with one or more halogen, NO
2
, CN, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkylthio, C
1
-C
6
haloalkyl, C
1
-C
6
alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO
n
R
26
, SO
2
NR
21
R
22
, CO
2
R
23
or NR
24
R
25
groups;
R
5
is H, C
1
-C
3
alkyl or haloalkyl;
R
6
, R
9
, R
12
, R
17
, R
20
, R
26
and R
27
are each independently H or a C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
6
haloalkyl, phenyl, C
5
-C
7
cycloheteroalkyl or heteroaryl group each optionally substituted;
n is 0 or an integer of 1 or 2;
R
7
, R
8
, R
10
, R
11
, R
13
, R
14
, R
18
, R
19
, R
21
, R22, R
24
and R
25
are each independently H or a C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
6
haloalkyl, phenyl, C
5
-C
7
cycloheteroalkyl or heteroaryl group each optionally substituted or each of R
7
and R
8
or R
10
and R
11
or R
13
and R
14
or R
18
and R
19
or R
21
and R
22
or R
24
and R
25
may be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, N or S; and
R
15
and R
16
are each independently H, NH
2
, CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
NH
2
or a C
1
-C
6
alkyl group optionally substituted with one or two CN, OR
5
, NR
13
R
14
, CO
2
R
17
or C
3
-C
7
cycloalkyl group;
phenyl optionally substituted with one or two halogen, OR
5
, CN, NR
13
R
14
, CO
2
R
17
, COR
27
, an optionally substituted C
1
-C
8
alkyl group or an optionally substituted C
2
-C
6
alkenyl group;
benzyl optionally substituted with one or two halogen, OR
5
, COR
27
or a C
1
-C
6
alkyl group optionally substituted with one OR
5
or
pyridinyl optionally substituted with one or two halogen, OR
5
, NR
13
R
14
or CO
2
R
17
groups or
R
15
and R
16
may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one double bond, a benzofused ring or an additional heteroatom selected from O, N or S; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
The present invention also provides methods and compositions useful for the immunotherapeutic treatment of transplant rejection, autoimmune disease or graft vs host disease.


REFERENCES:
patent: 4560689 (1985-12-01), Yokoyama
patent: 4814450 (1989-03-01), Yokoyama
patent: 6107304 (2000-08-01), Luengo
Ian T. Forbes et al., Journal of Medicinal Chemistry, 1990, vol. 33, 2640-2645.

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