Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-20
2002-09-17
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S006000, C544S256000, C544S230000
Reexamination Certificate
active
06451804
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to bicyclic nitrogen heterocycles. More particularly, the invention is concerned with certain heteroalkylamino-substituted dihydropyrimido[4,5-d]pyrimidinone derivatives, pharmaceutical preparations containing them, methods for their use as therapeutic agents, and methods for their manufacture.
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;, p38&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:
wherein
the subscript n is an integer of from 0 to 3;
R
1
is acyl, heteroalkyl, arylheteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylcarbonyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkylalkyl, heterosubstituted cycloalkylalkenyl, heterosubstituted cycloalkylalkynyl, heteroalkylsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclyl spiro cycloalkyl, -(alkylene)—C(O)—R
11
or -(heteroalkylene)—C(O)—R
1
;
wherein:
R
11
is alkyl, haloalkyl, amino, monosubstituted amino, disubstituted amino, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, or alkoxy;
R
2
is each independently in each occurrence alkyl, halo, heteroalkyl or vinyl;
R
3
is hydrogen, alkyl, heteroalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, cyanoalkyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, -(alkylene)—C(O)R
31
, or -(heteroalkylene)—C(O)R
31
; and
R
4
is hydrogen, alkyl, or -(alkylene)—C(O)R
31
;
wherein:
R
31
is alkyl haloalkyl, hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and their individual isomers, racemic or nonracemic mixture of isomers, and their pharmaceutically acceptable salts thereof.
In another aspect, the present invention provides methods of preparing the compounds described above.
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 p
56
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-methyl-propylene, pentylene, and the like.
“Alkenylene” means a linear or branched divalent hydrocarbon radical containing from two to ten carbon atoms and also containing at least one carbon-carbon double bond, e.g., —CH═CH—, —CH
2
CH═CH—, —C(CH
3
)═CH—, CH
2
CH═CHCH
2
—, 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, but is not limited to, for example, cyclopropyl, cyclohexyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2-carboxamidocyclohexyl, 2-dimethylaminocarbonylcyclohexyl, and the like.
“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 hydrogen, 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, preferably fluoro or chloro.
“Haloalkyl” means alkyl substituted with one or more same or different halo atoms, e.g., —CH
2
Cl, —CF
3
, —CH
2
CF
3
, —CH
2
CCl
3
, and the like, and further includes those alkyl groups such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
“Hydroxyalkyl” means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methyl-propyl, 2-hydroxybutyl, 3-hyd
Dunn James Patrick
Fisher Lawrence Emerson
Goldstein David Michael
Harris William
Hill Christopher Huw
Peries Rohan
Shah Mukund J.
Syntex (U.S.A.) LLC
Truong Tamthom N.
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