p38 MAP kinase inhibitors

Details p38 MAP kinase inhibitors p38 MAP kinase inhibitors

2001-04-19

2002-11-12

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S301000, C546S114000, C546S115000

Reexamination Certificate

active

06479507

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to compounds 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 heteroaryl;
------ represents a bond between either B and CR
1
or Q and CR
1
such that:
(i) when ------ is between Q and —CR
1
— then:
B is nitrogen;
R
2
is aryl; and
Q is —CR— wherein:
R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, nitro, cyano, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, —OR
5
(where R
5
is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —COOR
7
(where R
7
is hydrogen or alkyl) or —CONR′R″ (where R′ and R″ independently represent hydrogen, alkyl or heteroalkyl); and
(ii) when ------ is between B and —CR
1
— then:
B is carbon;
R
2
is aryl or heteroaryl; and
Q is —NR
4
—, —O—, or —S— wherein:
R
4
is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, —OR
5
(where R
5
is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —SO
2
R″ (where R″ is alkyl, amino, monosubstituted amino or disubstituted amino), —CONR′R″ (where R′ and R″ independently represent hydrogen, alkyl or heteroalkyl), -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein:
Z is cyano;
—COOR
7
where R
7
is hydrogen or alkyl;
—CONR
8
R
9
where R
8
is hydrogen or alkyl, R
9
is alkoxy or -(alkylene)-COOR
7
, or R
8
and R
9
together with the nitrogen atom to which they are attached form a heterocycle;
—C(═NR
10
)(NR
11
R
12
) where R
10
, R
11
and R
12
independently represent hydrogen or alkyl, or R
10
and R
11
together are —(CH
2
)
n
— where n is 2 or 3 and R
12
is hydrogen or alkyl; or
—COR
13
where R
13
is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and
 is a group represented by formula (S), (T), (U), (V) or (W);
 where:
R
6
is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, —COOR
14
, -(alkylene)-COOR
14
(where R
14
is hydrogen or alkyl), —CON R
15
R
16
(where R
15
and R
16
independently represent hydrogen or alkyl, or R
15
and R
16
together with the nitrogen atom to which they are attached form a heterocycle), —S(O)
n
R
17
(where n is an integer from 0 to 2 and R
17
is alkyl, amino, monosubstituted amino or disubstituted amino), —OR
18
(where R
18
is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —NRC(O)R″ [where R is hydrogen, alkyl or: hydroxyalkyl and R″ is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or
—S(O)
n
R′ (where n is 0 to 2 and R′ is alkyl)], —NRSO
2
R″ [where R is hydrogen or alkyl and R″ is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —S(O)
n
R′ (where n is 0 to 2 and R′ is alkyl)]; and R
3
is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, —OR
19
(where R
19
is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —COOR
20
(where R
20
is hydrogen or alkyl), —CONR
21
R
22
(where R
21
and R
22
independently represent hydrogen, alkyl or heteroalkyl, or R
21
and R
22
together with the nitrogen atom to which they are attached form a heterocycle),
—S(O)
n
R
23
(where n is an integer from 0 to 2 and R
23
is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino), -(alkylene)-Z″ or -(alkylene)-CO-(alkylene)-Z″ wherein:
Z″ is cyano;
—COOR
24
where R
24
is hydrogen or alkyl;
—CONR
25
R
26
where R
25
and R
26
independently represent hydrogen or alkyl, or R
25
and R
26
together with the nitrogen atom to which they are attached form a heterocycle;
—C(═NR
27
)(NR
28
R
29
) where R
27
, R
28
and R
29
independently represent hydrogen or alkyl, or R
27
and R
28
together are —(CH
2
)
n
— where n is 2 or 3 and R
29
is hydrogen or alkyl; or
—COR
30
where R
30
is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl,
heteroaryl or heteroaralkyl; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that both R
3
and R
6
are not either amino, monosubstituted amino or disubstituted amino.
In a second aspect, this invention provides compounds selected from the group of compounds represented by Formula (IIa):
wherein:
One of Z
1
and Z
2
is nitrogen and the other is —CR
6
— wherein R
6
is hydrogen, alkyl, or alkoxy; or both Z
1
and Z
2
are nitrogen such that:
(a) when Z
1
or Z
2
is nitrogen and the other is —CR
6
— then:
(i) when Y is halo, then —Q—R is —NH—C(R
1
)═CH(R
2
) or —N═C(CH
3
)(R
1
);
(ii) when Y is —C(R
2
)═C(R
1
)OX (where X is p-CH
3
C
6
H
4
SO
2
—, CH
3
SO
2
—, or CF
3
SO
2
—), then —Q—R is nitro or amino; and
(iii)

Affiliated with

Also associated with

Rating

p38 MAP kinase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with p38 MAP kinase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and p38 MAP kinase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2935830