Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-07-28
2004-05-11
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...
C546S082000
Reexamination Certificate
active
06734190
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, 389418.; 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 ant-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
X is CO or SO
2
;
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
8
, CONR
9
R
10
, 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
11
, NR
12
R
13
or CN groups;
R
3
is H, F, Cl, Br or I;
R
4
and R
5
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
14
, NR
15
R
16
, CO
2
R
17
or C
3
-C
7
cycloalkyl group,
phenyl optionally substituted with one or two halogen, CN, OR
14
, NR
15
R
16
, CO
2
R
17
, COR
18
, an optionally substituted C
1
-C
6
alkyl or an optionally substituted C
2
-C
6
alkenyl group,
benzyl optionally substituted with one or two halogen, OR
14
, COR
18
, or a C
1
-C
3
alkyl group optionally substituted with one OR
14
group, or
pyridinyl optionally substituted with one or two halogen, OR
14
, NR
15
R
16
or CO
2
R
17
groups, or
R
4
and R
5
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, NR
19
or S;
R
6
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
20
, 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
20
, 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
20
, SO
2
NR
21
R
22
, CO
2
R
23
or NR
24
R
25
groups;
R
8
, R
11
, R
17
, R
18
and R
23
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;
R
9
, R
10
, R
12
, R
13
, R
15
, R
16
, R
21
, R
22
, 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
9
and R
10
or R
12
and R
13
or R
15
and R
16
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;
n is 0 or an integer of 1 or 2;
R
14
is H, C
1
-C
3
alkyl or C
1
-C
3
haloalkyl;
R
19
is H or C
1
-C
3
alkyl; and
R
20
is a C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
6
haloalkyl, phenyl, C
5
-C
7
cyloheteroalkyl or heteroaryl group each optionally substituted; 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.
DETAILED DESCRIPTION OF THE INVENTION
Full T cell activation requires both an antigen-specific and a second co-stimulatory signal. Co-stimulation 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 (Greenfield, E. A., Nguyen, K. A. and Kuchroo, V. K. (1998) Critical Review of Immunology, 18, 389-418 and Lenschow, D. J., Walunas, T. L. and Bluestone, J. A. (1996) Annual Review of Immunology, 14, 233-258). Animal studies and clinical trials with protein antagonists of these interactions indicate considerable promise for immunotherapy in transplantation and autoimmune disease.
Surprisingly, it has now been found that dihydrodipyrazolopyridinylbenzamide and -sulfonamide compounds of formula I are effective inhibitors of B7-1/CD28 binding. Equilibrium dialysis demonstrates that compounds of formula I bind specifically to human B7-1 at a common site. Occupancy of this site by said inhibitors blocked B7-1 binding not only to CD28, but also to CTLA-4 (although at much higher concentrations of inhibitor). Accordingly, the present invention provides dihydrodipyrazolopyridinylbenzamide or -sulfonamide B7-1 inhibitors of formula I
wherein
X is CO or SO
2
;
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
8
, CONR
9
R
10
, 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
11
, NR
12
R
13
or CN groups;
R
3
is H, F, Cl, Br or I;
R
4
and R
5
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
14
, NR
15
R
16
, CO
2
R
17
or C
3
-C
7
cycloalkyl group,
phenyl optionally substituted with one or two halogen, CN, OR
14
, NR
15
R
16
, CO
2
R
17
, COR
18
, an optionally substituted C
1
-C
6
alkyl or an optionally substituted C
2
-C
6
alkenyl group,
benzyl optionally substituted with one or two halogen, OR
14
, COR
18
, or a C
1
-C
3
alkyl group optionally substituted with one OR
14
group, or
pyridinyl optionally substituted with one or two haloge
Chen Lihren
Davies Audrey Molina
Green Neal Jeffrey
Xiang Jason Shaoyun
Aulakh Charanjit S.
Lences Barbara L.
Wyeth
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