7-oxo-pyridopyrimidines (II)

Details 7-oxo-pyridopyrimidines (II) 7-oxo-pyridopyrimidines (II)

2001-08-30

2003-02-11

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S279000

Reexamination Certificate

active

06518276

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to 7-oxo-pyridopyrimidines. 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 which 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).
Certain pyrido[2,3-d]pyrimidines are disclosed as inhibitors of protein tyrosine kinase mediated cellular proliferation in WO 96/34867, published Nov. 7, 1996 (Warner Lambert).
The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
SUMMARY OF THE INVENTION
One aspect of the present invention provides compounds represented by the Formula:
a prodrug or a pharmaceutically acceptable salt thereof, in which:
R
1
is hydrogen or alkyl;
R
2
is —CR′R″—R
a
(where R′ and R″ are hydrogen, hydroxyalkyl or alkyl with at least one being alkyl or hydroxyalkyl and R
a
is hydroxyalkyl), R
x
—S—R
y
—(where R
x
is alkyl and R
y
is alkylene), alkoxy-substituted alkyl, heterocyclylalkyl or C
4
-C
5
cycloalkyl, wherein each of the hydroxy group present in R
2
can be independently in the form of an ester, a carbamate, a carbonate, or a sulfonate derivative; or
R
1
and R
2
together with the nitrogen atom to which they are attached form aheterocyclyl group;
R
3
is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, amino, monoalkylamino, dialkylamino, alkylene-C(O)—R (where R is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl; and
Ar
1
is aryl.
The compounds of Formula I and their aforementioned salts are inhibitors of protein kinases, and exhibit effective activity against p38 in vivo. Therefore, the compounds 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 methods for the treatment of p38 mediated diseases or conditions in which a therapeutically effective amount of a compound of Formula I is administered to a patient in need of such treatment.
Yet another aspect of the present invention provides methods for preparing the compounds described above.
Still yet another aspect of the present invention provides methods for preparing medicaments useful for the treatment of the p38 mediated diseases and conditions.
DEFINITIONS
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
“Acyl” means a radical —C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein. Representative examples include, but are not limited to formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.
“Acylamino” means a radical —NR′C(O)R, where R′ is hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein. Representative examples include, but are not limited to formylamino, acetylamino, cylcohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, and the like.
“Alkoxy” means a radical —OR where R is an alkyl as defined herein e.g., methoxy, ethoxy, propoxy, butoxy and the like.
“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like. “Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
“Alkylthio” means a radical —SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.
“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical which is optionally substituted independently with one or more substituents, preferably one, two or three, substituents preferably selected from the group consisting of alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro, cyano, amino, monoalkylamino, dialkylamino, methylenedioxy, ethylenedioxy and acyl. More specifically the term aryl includes, but is not limited to, phenyl, chlorophenyl, fluorophenyl, methoxyphenyl, 1-naphthyl, 2-naphthyl, and the derivatives thereof.
“Cycloalkyl” refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl, and the like.
“Cycloalkylalkyl” means a radical —R
a
R
b
where R
a
is an alkylene group and R
b
is cycloalkyl group as defined herein, e.g., cyclohexylmethyl, and the like.
“Dialkylamino” means a radical —NRR′ where R and R′ independently represent an alkyl, hydroxyalkyl, cycloalkyl, or cycloalkylalkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methylethylamino, di(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino, (cyclohexylmethyl)(ethyl)amino, and the like.
The term “each of the hydroxy group present in R
2
can be independently in the form of an ester, a carbamate, a carbonate or a sulfonate derivative” means that hydroxy group(s) (—OH) which are present in the R
2
group can be independently derivatized as R
a
—C(═O)—O—, R
a
R
b
N—C(═O)—O—, R
a
—O—C(═O)—O— or R
a
—SO
2
—O—, respectively, where R
a
and R
b
is independently hydrogen, alkyl, aryl or aralkyl as define

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