Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-07
2003-12-30
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S183000, C544S112000, C540S553000, C540S575000, C514S243000, C514S233200
Reexamination Certificate
active
06670357
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of treating conditions associated with p38&agr; and &bgr; kinases and to pyrrolotriazine compounds, more particularly, to pyrrolotriazine carboxamide and benzamide compounds useful for treating p38 kinase-associated conditions.
BACKGROUND OF THE INVENTION
A large number of cytokines participate in the inflammatory response, including IL-1, IL-6, IL-8 and TNF-&agr;. Overproduction of cytokines such as IL-1 and TNF &agr; are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others [Henry et al.,
Drugs Fut.,
24:1345-1354 (1999); Salituro et al.,
Curr. Med. Chem.,
6:807-823 (1999)]. Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases, such as, for example, monoclonal antibody to TNF-&agr; (Enbrel) [Rankin et al.,
Br. J. Rheumatol.,
34:334-342 (1995)], and soluble TNF-&agr; receptor-Fc fusion protein (Etanercept) [Moreland et al.,
Ann. Intern. Med.,
130:478-486 (1999)].
The biosynthesis of TNF-&agr; occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TNF-&agr; production are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase. These kinases are activated in response to various stress stimuli, including but not limited to proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Activation of p38 requires dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes.
There are four known isoforms of p38, i.e., p38&agr;, p38&bgr;, p38&ggr;, and p38&dgr;. The &agr; and &bgr; isoforms are expressed in inflammatory cells and are key mediators of TNF-&agr; production. Inhibiting the p38&agr; and &bgr; enzymes in cells results in reduced levels of TNF-&agr; expression. Also, administering p38&agr; and &bgr; inhibitors in animal models of inflammatory disease has proven that such inhibitors are effective in treating those diseases. Accordingly, the p38 enzymes serve an important role in inflammatory processes mediated by IL-1 and TNF-&agr;. Compounds that reportedly inhibit p38 kinase and cytokines such as IL-1 and TNF-&agr; for use in treating inflammatory diseases are disclosed in U.S. Pat. Nos. 6,277,989 and 6,130,235 to Scios, inc; U.S. Pat. Nos. 6,147,080 and 5,945,418 to Vertex Pharmaceuticals Inc; U.S. Pat. Nos. 6,251,914, 5,977,103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Pat. Nos. 5,932,576 and 6,087,496 to G.D. Searle & Co.; WO 00/56738 and WO 01/27089 to Astra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazoline derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship between p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors).
The present invention provides methods of treating conditions associated with p38 kinase activity comprising administering to a patient in need thereof certain pyrrolotriazine compounds. The invention further provides select pyrrolotriazine compounds, including 5-methyl and 5-trifluoromethyl pyrrolotriazine-6-carboxamide compounds useful as kinase inhibitors, particularly kinases p38&agr; and &bgr;. Pyrrolotriazine compounds useful as tyrosine kinase inhibitors are disclosed in U.S. patent application Ser. No. 09/573,829 filed May 18, 2000, assigned to the present assignee. Pyrrolotriazine compounds substituted with an acidic group reportedly having sPLA
2
-inhibitory activity are disclosed in WO 01/14378 A1 to Shionogi & Co., Ltd, published Mar. 1, 2001 in Japanese. Each of the patent applications, patents, and publications referred to herein is incorporated herein by reference.
SUMMARY OF THE INVENTION
The instant invention is directed to methods of treating one or more conditions associated with p38 kinase activity comprising administering to a patient in need thereof one or more pharmaceutically-active compounds having the Formula (I):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R
3
is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, or NH
2
;
X is selected from —O—, —OC(═O)—, —S—, —S(═O)—, —SO
2
—, —C(═O)—, —CO
2
—, —NR
10
—, —NR
10
C(═O)—, —NR
10
C(═O)NR
11
—, —NR
10
CO
2
—, —NR
10
SO
2
—, —NR
10
SO
2
NR
11
—, —SO
2
NR
10
—, —C(═O)NR
10
—, halogen, nitro, and cyano, or X is absent;
Z is selected from O, S, N, and CR
20
, wherein when Z is CR
20
, said carbon atom may form an optionally-substituted bicyclic aryl or heteroaryl with R
4
and R
5
;
R
1
is hydrogen, —CH
3
, —OH, —OCH
3
, —SH, —SCH
3
, —OC(═O)R
21
, —S(═O)R
22
, —SO
2
R
22
, —SO
2
NR
24
R
25
, —CO
2
R
21
, —C(═O)NR
24
R
25
, —NH
2
, —NR
24
R
25
, —NR
21
SO
2
NR
24
R
25
, —NR
21
SO
2
R
22
, —NR
24
C(═O)R
25
, —NR
24
CO
2
R
25
, —NR
21
C(═O)NR
24
R
25
, halogen, nitro, or cyano;
R
2
is selected from:
a) hydrogen, provided that R
2
is not hydrogen if X is —S(═O)—, —SO
2
—, —NR
10
CO
2
—, or —NR
10
SO
2
—;
b) alkyl, alkenyl, and alkynyl optionally substituted with up to four R
26
;
c) aryl and heteroaryl optionally substituted with up to three R
27
; and
d) heterocyclo and cycloalkyl optionally substituted with keto (═O), up to three R
27
, and/or having a carbon—carbon bridge of 3 to 4 carbon atoms; or
e) R
2
is absent if X is halogen, nitro, or cyano;
(i) R
4
is substituted aryl, aryl substituted with NHSO
2
alkyl, substituted heteroaryl, or an optionally-substituted bicyclic 7-11 membered saturated or unsaturated carbocyclic or heterocyclic ring, and R
5
is hydrogen, alkyl, or substituted alkyl, except when Z is O or S, R
5
is absent, or alternatively,
(ii) R
4
and R
5
taken together with Z form an optionally-substituted bicyclic 7-11 membered aryl or heteroaryl;
R
6
is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, —NR
7
R
8
, —OR
7
, or halogen;
R
10
and R
11
are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo, and substituted heterocyclo;
R
7
, R
8
, R
21
, R
24
, and R
25
are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocylco, and substituted heterocyclo;
R
20
is hydrogen, lower alkyl, or substituted alkyl, or R
20
may be absent if the carbon atom to which it is attached together with R
4
and R
5
is part of an unsaturated bicyclic aryl or heteroaryl;
R
22
is alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo;
R
26
is selected from halogen, trifluoromethyl, haloalkoxy, keto (═O), nitro, cyano, —SR
28
, —OR
28
, —NR
28
R
29
, —NR
28
SO
2
, —NR
28
SO
2
R
29
, —SO
2
R
28
, —SO
2
NR
28
R
29
, —CO
2
R
28
, —C(═O)R
28
, —C(═O)NR
28
R
29
, —OC(═O)R
28
, —OC(═O)NR
28
R
29
, —NR
28
C(═O)R
29
, —NR
28
CO
2
R
29
, ═N—OH, ═N—O-alkyl; aryl optionally substituted with one to three R
27
; cycloalkyl optionally substituted with keto(═O), one to three R
27
, or having a carbon—carbon bridge of 3 to 4 carbon atoms; and heterocyclo optionally substituted with keto (═O), one to three R
27
, or having a carbon—carbon bridge of 3 to 4 carbon atoms; wherein R
28
and R
29
are each independently selected from hydrogen, alkyl, alkenyl, aryl, aralkyl, C
3-7
cycloalkyl, and C
3-7
heterocycle, or may be taken together to form a C
3-7
heterocycle; and wherein each R
28
and R
29
in turn is optionally substituted with up to two of alkyl, alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy; and
R
2
Barrish Joel
Hynes John
Leftheris Katerina
Wrobleski Stephen T.
Berch Mark L.
Bristol--Myers Squibb Company
Habte Kahsay
Winslow Anastasia P.
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