Inhibitors of p38

Details Inhibitors of p38 Inhibitors of p38

2002-06-11

2003-04-22

Ramsuer, Robert W. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S310000, C540S575000, C544S128000, C544S363000, C546S023000, C546S143000, C546S144000

Reexamination Certificate

active

06552019

ABSTRACT:

BACKGROUND OF THE INVENTION
Protein kinases are involved in various cellular responses to extracellular signals. Recently, a family of mitogen-activated protein kinases (MAPK) has been discovered. Members of this family are Ser/Thr kinases that activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98 (1996)]. MAPKs are themselves activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents.
One particularly interesting MAPK is p38. p38, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK, was isolated from murine pre-B cells that were transfected with the lipopolysaccharide (LPS) receptor, CD14, and induced with LPS. p38 has since been isolated and sequenced, as has the cDNA encoding it in humans and mouse. Activation of p38 has been observed in cells stimulated by stress, such as treatment of lipopolysaccharides (LPS), UV, anisomycin, or osmotic shock, and by cytokines, such as IL-1 and TNF.
Inhibition of p38 kinase leads to a blockade on the production of both IL-1 and TNF. IL-1 and TNF stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8 and have been implicated in acute and chronic inflammatory diseases and in post-menopausal osteoporosis [R. B. Kimble et al., Endocrinol., 136, pp. 3054-61 (1995)].
Based upon this finding, it is believed that p38, along with other MAPKs, have a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia. In addition, MAPKs, such as p38, have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders. Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. Other diseases associated with IL-1, IL-6, IL-8 or TNF overproduction are set forth in WO 96/21654.
Others have already begun trying to develop drugs that specifically inhibit MAPKs. For example, PCT publication WO 95/31451 describes pyrazole compounds that inhibit MAPKs, and, in particular, p38. However, the efficacy of these inhibitors in vivo is still being investigated.
Other p38 inhibitors have been produced, including those described in WO 98/27098, WO 99/00357, WO 99/10291, WO 99/58502, WO 99/64400, WO 00/17175 and WO 00/17204.
Accordingly, there is still a great need to develop new potent inhibitors of p38, including p38-specific inhibitors, that are useful in treating various conditions associated with p38 activation.
SUMMARY OF THE INVENTION
The present invention addresses this need by providing compounds, and pharmaceutically acceptable derivatives thereof, that demonstrate strong inhibition of p38. These compounds can be used alone or in combination with other therapeutic or prophylactic agents.
It is a principal object of this invention to provide novel classes of compounds which are inhibitors of p38. These compounds have the general formulae:
wherein each of Q
1
and Q
2
are independently selected from a phenyl or 5-6 membered aromatic heterocyclic ring system, or an 8-14 membered saturated, partially unsaturated, or aromatic bicyclic or tricyclic ring system containing 0-4 heteroatoms.
The rings that make up Q
1
are substituted with 1 to 4 substituents, each of which is independently selected from halo; C
1
-C
3
aliphatic optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′ or CON(R′)
2
; O—(C
1
-C
3
)-aliphatic optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′ or CON(R′)
2
; R′; N(R′)
2
; OCF
3
; CF
3
; NO
2
; CO
2
R′; CON(R′)
2
; SR′; S(O
2
)N(R′)
2
; SCF
3
; CN; N(R′)C(O)R
4
; N(R′)C(O)OR
4
; N(R′)C(O)C(O)R
4
; N(R′)S(O
2
)R
4
; N(R′)R
4
; N(R
4
)
2
; OR
4
; OC(O)R
4
; OP(O)
3
H
2
; N═CR′—N(R′)
2
; SO
2
R′; or C(O)R′.
The rings that make up Q
2
are optionally substituted with up to 4 substituents, each of which is independently selected from halo; C
1
-C
3
aliphatic optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′, S(O
2
)N(R′)
2
, N═CR′—N(R′)
2
, R
3
, O—P(O
3
)H
2
or CON(R′)
2
; O—(C
1
-C
3
)-aliphatic optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′, S(O
2
)N(R′)
2
, N═CR′—N(R′)
2
, R
3
, OP(O
3
)H
2
, or CON(R′)
2
; R′; N(R′)
2
; OCF
3
; CF
3
; NO
2
; CO
2
R′; CON(R′)
2
; R
3
; OR
3
; N(R
3
)
2
; SR
3
; C(O)R
3
; C(O)N(R′)R
3
; C(O)OR
3
; SR′; S(O
2
)N(R′)
2
; SCF
3
; N═CR′—N(R′)
2
; R
4
; O—CO
2
R
4
; N(R′)C(O)R
4
; N(R′)C(O)OR
4
; N(R′)C(O)C(O)R
4
; N(R′)S(O
2
)R
4
; N(R′)R
4
; N(R
4
)
2
; OR
4
; OC(O)R
4
; OP(O)
3
H
2
; or CN.
Each R′ is independently selected from hydrogen; (C
1
-C
3
)-aliphatic; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5-8 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl.
Each R
3
is independently selected from a 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring system each optionally substituted with halo, R′, R
4
, —C(O)R′, —C(O)R
4
, —C(O)OR
4
, —J or —K; or an 8-10 membered saturated, partially unsaturated, or aromatic bicyclic ring system containing 0-4 heteroatoms, said ring system optionally substituted with halo, R′, R
4
, —C(O)R′, —C(O)R
4
, —C(O)OR
4
, —J or —K.
Each R
4
is independently selected from —N(R′)
2
; —NR′C(O)—(C
1
-C
4
)-aliphatic optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′, CON(R′)
2
, SO
2
N(R′)
2
, SO
2
N(R
5
)
2
, —J or —K; —NR′—(C
1
-C
4
)-aliphatic optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′, CON(R′)
2
, SO
2
N(R′)
2
, SO
2
N(R
5
)
2
, —J or —K; —OC(O)—N(R′)
2
; a (C
1
-C
4
)-aliphatic, wherein up to two saturated carbon atoms of the aliphatic chain are each optionally and independently replaced by —C(O)—, —C(O)NR′—, —C(O)NR′NR′—, —CO
2
—, —NR′C(O)NR′—, —OC(O)—, —C(O)C(O)—, —OC(O)NR′—, —NR′NR′—, —NR′CO—, —NR′O—, —O—, —S—, —SO—, —SO
2
—, —NR′—, —SO
2
NR′—, —NR′SO
2
—, and wherein the aliphatic chain is optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′, CON(R′)
2
, SO
2
N(R′)
2
, SO
2
N(R
5
)
2
, —J or —K; a (C
1
-C
7
)-aliphatic optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′, CON(R′)
2
, SO
2
N(R′)
2
, SO
2
N(R
5
)
2
, —J or —K; —J; —K; or a 5-6 membered aromatic or non-aromatic carbocyclic or heterocyclic ring system optionally substituted with halo, R′, N(R′)
2
, OR′, CO
2
R′, C(O)N(R′)
2
, SO
2
N(R′)
2
SO
2
N(R
5
)
2
, —J or —K.
R
5
is selected from hydrogen; a (C
1
-C
3
)-aliphatic optionally substituted with halo, —R′, —N(R′)
2
, —OR′, SR′, —C(O)N(R′)
2
, —S(O)
2
N(R′)
2
, —C(O)OR′, —N(R′)S(O)
2
(R′), —N(R′)SO
2
R
6
, —C(O)N(R′)(R
6
), —N(R′)C(O)R′, —N(R′)(R
6
), —C(O)R
6
, —C(O)N═C(NHR′)
2
or R
6
.
R
6
is selected from 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring systems each optionally substituted with halo, R′, —C(O)R′ or —C(O)OR′; or an 8-10 membered saturated, partially unsaturated, or aromatic bicyclic ring system containing 0-4 heteroatoms, said ri

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