Alkylamino-substituted bicyclic nitrogen heterocycles

Details Alkylamino-substituted bicyclic nitrogen heterocycles Alkylamino-substituted bicyclic nitrogen heterocycles

2000-10-20

2003-11-04

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S256000

Reexamination Certificate

active

06642241

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to bicyclic nitrogen heterocycles. More particularly, the invention is concerned with alkylamino-substituted dihydropyrimido-[4,5-d]pyrimidinone derivatives, a process for their manufacture and pharmaceutical preparations containing them.
BACKGROUND OF THE INVENTION
Mitogen-activated protein kinases (MAP) are 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; and p38&ggr;). The p38 kinases are responsible for phosphorylating and activating transcription factors as well as other kinases, and are themselves 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 herpesvirus-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.
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
In one aspect, the present invention provides compounds represented by the formula:
in which:
the subscript n represents an integer of from 0 to 3, preferably 1 or 2;
R
1
represents hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl or aralkyl;
each R
2
, when present, independently represents alkyl, halo, heteroalkyl, or vinyl;
R
3
represents heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylcarbonyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkylalkyl, heterosubstituted cycloalkylalkenyl, heterosubstituted cycloalkylalkynyl, heteroalkylsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, arylheteroalkyl, heteroarylheteroalkyl, -(alkylene)-C(O)R
31
or -(heteroalkylene)-C(O)R
31
;
wherein R
31
represents alkyl, haloalkyl, hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
and their pharmaceutically acceptable salts.
In another aspect, the present invention provides compositions comprising a pharmaceutically acceptable excipient and a compound of formula I, above.
In yet another aspect, the present invention provides methods of preparing the compounds described above. Briefly, the methods involve either:
(a) treating a compound of formula II
 wherein n, R
2
and R
3
have the meanings provided in claim 1, with the proviso that any interfering reactive group present is optionally in protected form, and L is a leaving group,
with an amine of formula III
R
1
—NH
2
  (III)
wherein R
1
has the meaning provided with reference to formula I above, with the proviso that any interfering reactive group present is optionally in protected form, and where required, deprotecting any protected reactive groups. or
(b) treating a compound of formula IV
 wherein R
1
, n, and R
2
have the meanings provided for formula I, with the proviso that any interfering reactive group present is optionally in protected form,
with an alkylating agent of formula V
R
3
—X  (V)
wherein R
3
has the meaning provided with reference to formula I, and X is a leaving group or a hydroxy group that is activated during the reaction, with the proviso that any interfering reactive group present is optionally in protected form, and where required, deprotecting any protected reactive groups.
The compounds of formula I and their aforementioned salts are inhibitors of protein kinases, and exhibit surprisingly effective activity against p38 in vivo. Interestingly, the compounds of formula I do not exhibit activity against the T-cell tyrosine kinase p56
lck
at levels below about 10 &mgr;M. The compounds can be used for the treatment of diseases mediated by the pro-inflammatory cytokines such as TNF and IL-1.
Accordingly, 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 subject in need of such treatment.
In still another aspect, the present invention provides methods of preparing medicaments useful for the treatment of the p38 mediated diseases and conditions.
DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
As used herein:
“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, n-propyl, 2-propyl, 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, propylene, 2-methylpropylene, pentylene, and the like.
“Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
“Alkynyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
“Cycloalkyl” refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons. The cycloalkyl may be optionally substituted independently with one, two, or three substituents selected from alkyl, optionally substituted phenyl, or —C(O)R (where R is hydrogen, alkyl, haloalkyl, amino, monsubstituted amino, disubstituted amino, hydroxy, alkoxy, or optionally substituted phenyl). More specifically, the term cycloalkyl includes, for example, cyclopropyl, cyclohexyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2-carboxamidocyclohexyl, 2-dimethylaminocarbonyl-cyclohexyl, and the like.
“Cycloalkenyl” means an unsaturated non-aromatic monovalent cyclic hydrocarbon radical of three to seven ring carbons. Representative examples include cyclohexenyl and cyclopentenyl.
“Cycloalkylalkyl” means a radical —R
a
R
b
where R
a
is an alkylene group and R
b
is a cycloalkyl group as defined herein, e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.
“Acyl” means the group —C(O)R′, where R′ is alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
“Alkoxy”, “aryloxy”, “aralkyloxy”, or “heteroaralkyloxy” means a radical —OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, pyridin-2-ylmethyloxy, benzyloxy, and the like.
“Halo” or “Halogen,” means fluoro, chloro, bromo, or iodo,

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