Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-28
2001-03-27
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...
C514S256000, C514S257000, C514S272000, C544S242000, C544S222000
Reexamination Certificate
active
06207701
ABSTRACT:
TECHNICAL FIELD
The present invention relates substituted benzothiophene compounds which inhibit the urokinase enzyme, pharmaceutical compositions containing these compounds, and medical methods of treatment using these compounds.
BACKGROUND OF THE INVENTION
Urokinase (urinary-type plasminogen activator or uPA (International Union of Biochemistry classification number: EC3.4.21.31)) is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. Plasminogen activation (cleavage of this bond by the urokinase enzyme) 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 (Blasi, F., Vassalli, J. D., and Dano, K. J. Cell Biol. 104:801-804, (1987); Dano, K., Anderson, P. A., Grondahl-Hansen, J., Kristensen, P., Nielsen, L. S., and Skriver, L. Adv. Cancer Res. 44:139-266, (1985); Littlefield, B. A. Ann. N. Y. Acad. Sci. 622:167-175, (1991); Saksela, O., Biochim. Biophys. Acta 823:35-65, (1985); Testa, J. E. and Quigley, J. P. Cancer Metast. Rev. 9:353-367, (1990)). Such processes include, but are not limited to, angiogenesis (neovascularization), bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodelling 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 (Kellen, J. A., Mirakian, A. Kolin, A. Anticancer Res. 8:1373-1376, (1988)) and angiogenesis/capillary network formation in vitro (Alliegro, M. C. and Glaser, B. M. J. Cell Biol. 115[3 Pt 2]: 402a, (1991)).
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 present invention provides a compound of formula
or a pharmaceutically acceptable salt or prodrug thereof wherein,
R
1
is selected from hydrogen, and —NZ
1
Z
2
wherein Z
1
and Z
2
are independently selected from hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
R
2
is selected from hydrogen, AOCH
2−
, AC(O)N(R
3
)—, AN(R
3
)C(O)—, and
R
3
is selected from hydrogen and alkyl;
A is selected from,
B and D are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, amino, aminocarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, mercapto, and nitro;
R
4
is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, and optionally substituted aryl;
R
5
is selected from hydrogen, alkyl, alkoxycarbonyl, alkylcarbonyl, arylalkyl, arylalkoxycarbonyl, and aminocarbonyl; and
R
6
is selected from hydrogen and hydroxy;
provided that when R
1
is hydrogen, R
2
is other than hydrogen.
The present invention also relates to a method of inhibiting urokinase in a mammal, particularly humans, by administering a therapeutically effective amount of a composition comprising a compound of formula (I).
The present invention also relates to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of formula (1) in combination with a pharmaceutically acceptable carrier.
Compounds falling within the scope of formula (I) include, but are not limited to:
4-(2-pyrimidinylamino)-1-benzothiophene-2-carboximidamide, 4-(1,3-thiazol-2-ylamino)-1-benzothiophene-2-carboximidamide,
2-[amino(imino)methyl]-N-phenyl-1-benzothiophene-6-carboxamide, and
2-[amino(imino)methyl]-N-(3-isopropoxyphenyl)- 1 -benzothiophene-6-carboxamide.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the present invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the present invention, may be made without departing from the spirit and scope thereof.
Definition of Terms
As used throughout this specification and the appended claims, the following terms have the following meanings.
The term “alkenyl,” as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl and the like.
The term “alkoxy,” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
The term “alkoxyalkyl,” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.
The term “alkoxycarbonyl,” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.
The term “alkyl,” as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
The term “alkylcarbonyl,” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.
The term “alkylcarbonyloxy,” as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like.
The term “alkynyl,” as used herein, refers to a straight or branched chain hydrocarbon group c
Abbott Laboratories
Donner B. Gregory
Patel Sudhaker B.
Shah Mukund J.
Steele Gregory W.
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