Benzothiophene derivatives, their preparation and use as urokina

Details Benzothiophene derivatives, their preparation and use as urokina Benzothiophene derivatives, their preparation and use as urokina

1999-03-12

2000-07-25

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

5142111, 5142242, 540468, 540552, 544 48, C07D49304, C07D49504, C07D51304, A61K 31381, A61K 31542

Patent

active

060937106

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to novel amidino derivatives and pharmaceutically acceptable salts thereof, which are useful as urokinase inhibitors, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, to a use of the same as a medicament and to a method of the therapeutic treatment of diseases in a human being or an animal.
Accordingly, one object of the present invention is to provide novel amidino derivatives and pharmaceutically acceptable salts thereof, which are useful as urokinase inhibitors.
Another object of the present invention is to provide processes for the preparation of novel amidino derivatives and salts thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said amidino derivatives and pharmaceutically acceptable salts thereof.
Urokinase (urokinase-type Plasminogen Activator, uPA) is a multi-domain serine protease which is able to convert the inactive precursor plasminogen to active plasmine.
Among the family of plasminogen activators, tissue type plasminogen activator (tPA) is present both in normal and in malignant tissue, whereas uPA has been shown to be produced abundantly by several common malignancies such as melanoma and colon, breast and prostate cancers.
Cellular invasiveness initiated by urokinase causes many physiological processes such as angiogenesis, neovascularization, bone restructuring, embryo implantation in the uterus (embryonic development), infiltration of immune cells into inflammatory sites, ovulation, trophoblast implantation, breast, uterine, and prostatic involution, spermatogenesis, tissue remodeling during wound repair (wound healing) and organ differentiation, fibrosis, local invasion of tumors into adjacent areas (tumor invasion), metastatic spread of tumor cells from primary to secondary sites (tumor metastasis), and tissue destruction in arthritis.
Inhibitors of urokinase therefore have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-invasive, anti-metastatic, anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive, and tumoristatic activities.


DISCLOSURE OF INVENTION

The object amidino derivatives are novel and can be represented by the following general formula: ##STR3## in which R.sup.1 is hydrogen, optionally substituted lower alkylcarbamoyl(lower)alkylidene, lower alkylidene, lower alkyl, optionally substituted ar(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, protected carboxy(lower)alkyl, carboxy(lower)alkyl, hydroxy(lower)alkyl, optionally substituted lower alkylcarbamoyl(lower)alkyl, lower alkylthio(lower)alkyl, carboxy(lower)alkanoyl, protected carboxy(lower)alkanoyl, aroyl, lower alkanoyl, or optionally substituted arylcarbamoyl(lower)alkyl, N-(lower)alkyl-N-(lower)alkoxycarbamoyl, ##STR4## Y is lower alkylene, --S-- or --SO.sub.2 --, Z is --S-- or --O--, and the line: ##STR5## is a single bond or double bond, or pharmaceutically acceptable salts thereof.
Suitable salts of the object compound (I) are pharmaceutically acceptable, conventional non-toxic salts and may include; metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.); glutamic acid, etc.); and the like.
The object compound (I) and pharmaceutically acceptable salt thereof may include a solvate [e.g. enclosure compound (e.g., hydrate, etc.)].
It is to be noted that the compound (I) and the other compoun

REFERENCES:
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patent: 5089634 (1992-02-01), Powers et al.
patent: 5093332 (1992-03-01), Shepard et al.
patent: 5240923 (1993-08-01), Dean et al.
patent: 5723458 (1998-03-01), Brieaddy et al.
patent: 5889002 (1999-03-01), Nielsen et al.

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