6-substituted pyrido-pyrimidines

Details 6-substituted pyrido-pyrimidines 6-substituted pyrido-pyrimidines

2002-02-11

2004-02-24

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Pteroyl per se or having -c-, wherein x is chalcogen, bonded...

Reexamination Certificate

active

06696566

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to pyridopyrimidines and derivatives thereof. In particular, the present invention provides 2,6-disubstituted 7-oxo-pyrido[2,3-d]pyrimidines, a process for their manufacture, pharmaceutical preparations comprising the same, and methods for using the same.
BACKGROUND OF THE INVENTION
Mitogen-activated protein kinases (MAP) is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. One group of MAP kinases is the p38 kinase group that includes various isoforms (e.g., p38&agr;, p39&bgr;, p38&ggr; and p38&dgr;). The p38 kinases are responsible for phosphorylating and activating transcription factors as well as other kinases, and are activated by physical and chemical stress, pro-inflammatory cytokines and bacterial lipopolysaccharide.
More importantly, the products of the p38 phosphorylation have been shown to mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2. Each of these cytokines has been implicated in numerous disease states and conditions. For example, TNF-&agr; is a cytokine produced primarily by activated monocytes and macrophages. Its excessive or unregulated production has been implicated as playing a causative role in the pathogenesis of rheumatoid arthritis. More recently, inhibition of TNF production has been shown to have broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1(HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpes virus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
Similarly, IL-1 is produced by activated monocytes and macrophages, and plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
Additionally, the involvement of p38 has been implicated in stroke, Alzheimer's disease, osteoarthritis, lung injury, septic shock, angiogenesis, dermatitis, psoriasis and atopic dermatitis.
J. Exp. Opin. Ther. Patents
, (2000) 10(1).
The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
Certain 6-aryl-pyrido[2,3-d]pyrimidin-7-ones, -7-imines and -7-thiones are disclosed as inhibitors of protein tyrosine kinase mediated cellular proliferation in WO 96/34867, published Nov. 7, 1996 (Warner Lambert). Other 6-aryl-pyrido[2,3-d]pyrimidines and naphthyridines are also disclosed as inhibitors of tyrosine kinase in WO 96/15128, published May 23, 1996 (Warner Lambert). 6-alkyl-pyrido[2,3-d]pyrimidin-7-ones are disclosed as inhibitors of cyclin-dependent kinases in WO 98/33798, published Aug. 6, 1998 (Warner Lambert). Certain 4-amino-pyridopyrimidines are disclosed as inhibitors of dihydrofolate reductase in EP 0 278 686A1, published Aug. 8, 1988 (Wellcome Foundation).
SUMMARY OF THE INVENTION
One aspect of the present invention provides compounds represented by Formula I and II:
or pharmaceutically acceptable salts thereof,
wherein:
Z is N or CH;
W is NR
2
;
X
1
is O, NR
4
(where R
4
is hydrogen or alkyl), S, or CR
5
R
6
(where R
5
and R
6
are independently hydrogen or alkyl) or C═O;
X
2
is O or NR
7
;
Ar
1
is aryl or heteroaryl;
R
2
is hydrogen alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkyloxycarbonyl or —R
21
—R
22
where R
21
is alkylene or —C(═O)— and R
22
is alkyl or alkoxy;
R
1
is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R
12
—SO
2
-heterocycloamino (where R
12
is haloalkyl, aryl, aryalkyl, heteroaryl or heteroaralkyl), —Y
1
—C(O)—Y
2
—R
11
(where Y
1
and Y
2
are independently either absent or an alkylene group and R
11
is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl)(cycloalkyl)alkyl or (heterocyclyl)(heteroaryl)alkyl;
R
3
is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R
31
(where R
31
is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR
32
—Y
3
—R
33
(where Y
3
is —C(O), —C(O)O—, —C(O)NR
34
, S(O)
2
or S(O)
2
NR
35
; R
32
, R
34
and R
35
are independently hydrogen or alkyl; and R
33
is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substituted phenyl)or acyl;
R
7
is hydrogen or alkyl; and
R
8
and R
9
are independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, —C(O)—R
81
(where R
81
is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono- or di-alkylamino, arylamino or aryl(alkyl)amino) or R
8
and R
9
together form ═CR
82
R
83
(where R
82
and R
83
are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl).
Another aspect of the present invention provides a pharmaceutical formulation comprising a Compound of Formula I or II and a pharmaceutically acceptable carrier, diluent, or excipient therefor.
Compounds of Formula I and II and their aforementioned salts are inhibitors of protein kinases, and exhibit effective activity against p38 in vivo. They are also surprisingly selective against p38 kinase relative to cyclin-dependent kinases and tyrosine kinases. Therefore, compounds of the present invention can be used for the treatment of diseases mediated by the pro-inflammatory cytokines such as TNF and IL-1. Thus, another aspect of the present invention provides a method for treating p38 mediated diseases or conditions in which a therapeutically effective amount of a Compound of Formula I or II is administered to a patient in need of such treatment.
Yet another aspect of the present invention provides a method for preparing the compounds described above and intermediates intermediates of Formula I′ and II″useful therefor.
wherein:
Z is N or CH;
W is S, S(O), S(O)
2
or O;
X
1
is O, NR
4
(where R
4
is hydrogen or alkyl), S, or CR
5
R
6
(where R
5
and R
6
are independently hydrogen or alkyl) or C═O;
X
2
is O or NR
7
;
Ar
1
is aryl or heteroaryl;
R
10
is alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl, or R
10
W together form a leaving group or hydroxy;
R
3
is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R
31
(where R
31
is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR
32
—Y
3
—R
33
(where Y
3
is —C(O), —C(O)O—, —C(O)NR
34
, S(O)
2
, or S(O)
2
NR
35
; R
32
, R
34
and R
35
are independently hydrogen or alkyl; and R
33
is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substituted phenyl) or acyl;
R
7
is hydrogen or alkyl; and
R
8
and R
9
are independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, —C(O)—R
81
(where R
81
is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono- and di-alkylamino, arylamino or aryl(alkyl)amino) or R
8
and R
9
together form ═CR
82
R
83
(where R
82
and R
83
are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl).
DEFINITIONS
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
“Acyl” means a radic

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