Pyrazole derivatives P-38 MAP kinase inhibitors

Details Pyrazole derivatives P-38 MAP kinase inhibitors Pyrazole derivatives P-38 MAP kinase inhibitors

1999-09-22

2001-11-13

Stockton, Laura L. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S404000, C546S168000, C548S365700

Reexamination Certificate

active

06316466

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to certain pyrazole derivatives that inhibit p38 MAP kinase, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
BACKGROUND INFORMATION AND RELATED DISCLOSURES
TNF and IL-1 have been shown to be central players in the pathological processes underlying many chronic inflammatory and autoimmune diseases. IL-1 is implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Arend, W. P.
Arthritis & Rheumatism
38(2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, tuberculosis, atherosclerosis, diabetes, Hodgkin's disease (see., Benharroch, D.; et. al.
Euro. Cytokine Network
7(1): 51-57) and Alzheimer's disease. Excessive or unregulated TNF production has been implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Maini, R. N.; et. al.
APMIS
. 105(4): 257-263, (1997); Feldmann, M.,
J. of the Royal College of Physicians of London
30(6): 560-570, (1996); Lorenz, H. M.; et. al.
J. of Immunology
156(4): 1646-1653, (1996)) osteoarthritis, spondylitis, sepsis, septic shock ((see., Abraham, E.; et. al.
JAMA
. 277(19):1531-1538, (1997), adult respiratory distress syndrome, asthma ((see., Shah, A.; et. al.
Clin. & Exp. Allergy
1038-1044, (1995) and Lassalle, P., et. al.
Clin
. &
Exp. Immunol
. 94(1): 105-110, (1993)), bone resorption diseases, fever ((see., Cooper, A. L., et. al.
Am. J. of Physiology
267(6 Pt. 2): 1431-1436)), encephalomyelitis, demyelination ((see., Klindert, W. E.; et al.
J. of Neuroimmunol
. 72(2): 163-168, (1997)) and periodontal diseases.
Clinical trials with IL-1 and TNF receptor antagonists have shown that blocking the ability of these cytokines to signal through their receptors leads to significant improvement, in humans, in inflammatory diseases. Therefore, modulation of these inflammatory cytokines is considered one of the most effective strategies to block chronic inflammation and have positive therapeutic outcomes. It has also been shown that p38 MAP kinase plays an important role in the translational control of TNF and IL-1 and is also involved in the biochemical signaling of these molecules ((see., Lee, J. C., et al.
Nature
. 372 (6508): 739-46, (1994)). Compounds that bind to p38 MAP are effective in inhibiting bone resorption, inflammation, and other immune and inflammation-based pathologies. The characterization of the p38 MAP kinase and its central role in the biosynthesis of TNF and IL-1 have made this kinase an attractive target for the treatment of diseases mediated by these cytokines.
It would therefore be desirable to provide p38 MAP kinase inhibitors and thereby provide a means of combating diseases mediated by pro-inflammatory cytokines such as TNF and IL-1. This invention fulfills this and related needs.
SUMMARY OF THE INVENTION
In a first aspect, this invention provides compounds selected from the group of compounds represented by Formula (I):
wherein:
R
1
is hydrogen or acyl;
R
2
is hydrogen or alkyl;
A is an aryl or heteroaryl ring;
B is an aryl or heteroaryl ring;
R
3
is selected from the group consisting of:
(a) amino, alkylamino or dialkylamino;
(b) acylamino;
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl;
(h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
(l) optionally substituted heterocyclylalkynyl;
(m) optionally substituted cycloalkoxy, cycloalkylalkyloxy, heterocyclylalkoxy, or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) optionally substituted cycloalkylamino;
(r) —NHSO
2
R
6
where R
6
is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;
(s) —NHSO
2
NR
7
R
8
where R
7
and R
8
are, independently of each other, hydrogen, alkyl or heteroalkyl;
(t) —Y—(alkylene)-R
9
where:
Y is a single bond, —O—, —NH— or —S(O)
n
— (where n is an integer from 0 to 2); and R
9
is cyano, optionally substituted heteroaryl, —COOH, —COR
10
, —COOR
11
, —CONR
12
R
13
, —SO
2
R
14
, —SO
2
NR
15
R
16
, —NHSO
2
R
17
or —NHSO
2
NR
18
R
9
, where R
10
is alkyl or optionally substituted heterocycle, R
11
is alkyl, and R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
and R
19
are, independently of each other, hydrogen, alkyl or heteroalkyl;
(u) —C(═NR
20
)(NR
21
R
22
) where R
20
, R
21
and R
22
independently represent hydrogen, alkyl or hydroxy, or R
20
and R
21
together are —(CH
2
)
n
— where n is 2 or 3 and R
22
is hydrogen or alkyl;
(v) —NHC(X)NR
23
R
24
where X is —O— or —S—, and R
23
and R
24
are, independently of each other, hydrogen, alkyl or heteroalkyl;
(w) —CONR
25
R
26
where R
25
and R
26
independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R
25
and R
26
together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;
(x) —S(O)
n
R
27
where n is an integer from 0 to 2, and R
27
is alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, or —NR
28
R
29
where R
28
and R
29
are, independently of each other, hydrogen, alkyl or heteroalkyl;
(y) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(z) arylaminoalkylene or heteroarylaminoalkylene;
(aa) Z-alkylene—NR
30
R
31
or Z-alkylene-OR
32
where Z is —NH—, —N(alkyl)— or —O—, and R
30
, R
31
and R
32
are independently of each other, hydrogen, alkyl or heteroalkyl;
(bb) —OC(O)-alkylene-CO
2
H or —OC(O)—NR′R″ (where R′ and R″ are independently hydrogen or alkyl);
(cc) heteroarylalkenylene or heteroarylalkynylene;
(dd) X-(alkylene)CH[(CR′R″)
m
OR
40
][(CR′R″)
n
OR
40
] where:
X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)
p
— (where p is an integer from 0 to 2);
R
40
is acyl; C(O)OR
41
(where R
41
is hydrogen, alkyl, or cycloalkyl);
C(O)ONR
41
R
42
(where R
41
is as defined above and R
42
is hydrogen or alkyl); or C(O)NR
41
R
42
(where R
41
and R
42
are as defined above);
R′ and R″, independently, are hydrogen or alkyl; and
m and n, independently, are an integer from 0 to 3 provided that m and n are not both zero;
(ee) X-(alkylene)-CH(OH)CH
2
NHR
50
where:
X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)
n
— (where n is an integer from 0 to 2); and
R
50
is C(O)OR
51
and C(O)NR
51
R
52
(where R
51
is hydrogen, alkyl, or cycloalkyl and R
52
is hydrogen or alkyl); and
(ff) X-(alkylene)-CH(NR
50
)-CH
2
OH where:
X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)
n
— (where n is an integer from 0 to 2); and
R
50
is C(O)OR
51
and C(O)NR
51
R
52
(where R
51
is hydrogen, alkyl, or cycloalkyl and R
52
is hydrogen or alkyl);
R
4
is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) alkoxy; and
(e) hydroxy;
R
5
is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino;
(i) dialkylamino;
(j) heteroalkyl;
(k) optionally substituted heterocycle;
(l) optionally substituted heterocyclylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaminosulfonyl;
(p) heteroalkoxy; and
(q) carboxy;
R
6
is selected from a group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl; and
(d) alkoxy; and
prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a third aspect, this invention provides a method of treatment of a disease in a mammal treatable b

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