Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-25
2002-12-17
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S147000
Reexamination Certificate
active
06495562
ABSTRACT:
TECHNICAL FIELD
The instant invention provides naphthamidine compounds which inhibit urokinase, methods for making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
BACKGROUND OF THE INVENTION
Urokinase is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. Plasminogen activation (cleavage of this bond by urokinase) results in formation of plasmin, a potent general protease.
Many cell types use urokinase as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular support structures such as extracellular matrix (ECM) and basement membrane (BM). Cells exist, move, and interact with each other in tissues and organs within the physical framework provided by ECM and BM. Movement of cells within ECM or across BM requires local proteolytic degradation or modification of the structures and allows cells to invade adjacent areas previously unavailable prior to the degradation or modification.
Cellular invasiveness initiated by urokinase is central to a variety of normal and disease-state physiological processes (
J. Cell Biol.
1987, 104, 801-804 and
Adv. Cancer Res.
1985, 44, 139-266). Such processes include angiogenesis, bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodeling during wound repair and organ differentiation, fibrosis, tumor invasion, metastatic spread of tumor cells from primary to secondary sites, and tissue destruction in arthritis. Amiloride, for example, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumor metastasis in vivo (
Anticancer Res.
1988, 8, 1373-1376) and angiogenesis in vitro (
J. Cell Biol.
1991, 115[3 Pt 2], 402a).
Inhibitors of urokinase, therefore, have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive and tumoristatic uses.
SUMMARY OF THE INVENTION
In its principle embodiment, the instant invention provides a compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein
R
1
is hydrogen or hydroxy;
R
2
is selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxyalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl, and —NR
a
R
b
, wherein R
a
and R
b
are independently selected from the group consisting of hydrogen, aryl, and heteroaryl; and
wherein R
4
and R
5
are on adjacent carbon atoms and, taken together with the carbon atoms to which they are attached, are pyridine or a nitrogen-containing heterocycloalkyl,
wherein the groups defining R
3
can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy, hydroxyalkyl, aryl, arylalkyl, alkanoyl, alkoxycarbonyl, alkenyl, alkynyl, halo, haloalkyl, heteroaryl, heteroarylalkyl, and a nitrogen protecting group.
In another embodiment, the instant invention provides a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
In another embodiment, the instant invention provides a method of inhibiting urokinase in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In another embodiment, the instant invention provides a method for the preparation of a compound of formula (I),
the method comprising:
(a) reacting a compound of formula (Ia)
wherein R
f
is cyano or —C(═NR
1
)NH
2
and wherein R
2
and R
3
are as previously defined, with diazomethane or trimethylsilyldiazomethane in the presence of a palladium catalyst;
(b) optionally reacting the product from step (a) with an anionic nitrogen source.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the instant invention comprise 6,8-disubstituted 2-naphthamidines which are useful for the treatment of urokinase-mediated diseases.
When used throughout this specification and the appended claims, the following terms have the meanings indicated:
The term “alkanoyl,” as used herein, represents an alkyl group attached to the parent molecular moiety through a carbonyl group.
The term “alkenyl,” as used herein, represents a monovalent straight or branched chain group of one to six carbon atoms containing at least one carbon-carbon double bond. The alkenyl groups of this invention can be optionally substituted with an alkoxy, amino, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, thioalkoxy, thioaryloxy, or thioheteroaryloxy substituent, wherein the aryl and the heteroaryl substituents can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, amino, halo, and cycloalkyl.
The term “alkoxy,” as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
The term “alkoxyalkyl,” as used herein, represents an alkoxy group attached to the parent molecular moiety through an alkyl group.
The term “alkoxycarbonyl,” as used herein, represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.
The term “alkyl,” as used herein, represents a saturated straight or branched chain monovalent group of one to six carbon atoms derived from a hydrocarbon group. The alkyl groups of this invention can be optionally substituted.
The term “alkynyl,” as used herein, represents a monovalent straight or branched chain group of one to six carbon atoms containing at least one carbon-carbon triple bond. The alkynyl groups of this invention can be optionally substituted with an alkoxy, amino, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, thioalkoxy, thioaryloxy, or thioheteroaryloxy substituent, wherein the aryl and the heteroaryl substituents can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, amino, halo, and cycloalkyl.
The term “amino,” as used herein, represents —NR
10
R
11
wherein R
10 and R
11
are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, and (cycloalkyl)alkyl; or R
10
and R
11
, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, piperidinyl, and pyrrolidinyl.
The term “anionic nitrogen source,” as used herein, represents lithium hexamethyldisilazide, potassium hexamethyldisilazide, or sodium hexamethyldisilazide.
The term “aryl,” as used herein, represents phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, and indenyl. Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring such as dihydronaphthyl, tetrahydronaphthyl, and indanyl can be attached through either the saturated or unsaturated part of the group. The aryl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkyl, alkoxy, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, perfluoroalkyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, alkoxycarbonyl, perfluoroalkoxy, and —NR
c
R
d
, wherein R
c
and R
d
are independently hydrogen or alkyl.
The term “arylalkyl,” as used herein, represents an aryl group attached to the parent molecular moiety through an alkyl group.
The term “aryloxy,” as used herein, represents an aryl group attached to the parent molecular moiety through an oxygen atom.
The term “cycloalkyl,” as used herein, represents a saturated monovalent cyclic hydrocarbon.
The term “(cycloalkyl)alkyl,” as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
The term “halo,”
Bruncko Milan
Dalton Christopher Robin
Giranda Vincent Louis
Gong Jianchun
McClellan Willian J.
Abbott Laboratories
Davis Zinna Northington
Donner B. Gregory
Steele Gregory W.
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