Epoxysuccinamic acid derivatives

Details Epoxysuccinamic acid derivatives Epoxysuccinamic acid derivatives

1993-03-26

1994-01-25

Brust, Joseph Paul

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D40512

Patent

active

052817172

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to epoxysuccinamic acid derivatives useful as medicines, and more particularly to epoxysuccinamic acid derivatives inhibiting cathepsin B specifically, and the preparation intermediates thereof.


BACKGROUND ART

Calcium-activated neutral protease (CANP), cathepsin B and cathepsin L, each of which belongs to cysteine proteases, are considered to be associated with the decomposition of muscular structure protein in malignant muscular atrophy diseases such as muscular dystrophy and distal myopathy.
Some epoxysuccinic acid derivatives such as N-(L-3-trans-carboxyoxirane-2-carbonyl)-L-leucylagmatine
[Agric. Biol. Chem., vol. 42, pp. 523-528 (1978)], epoxysuccinyl dipeptide derivatives (U.K. Patent No. 2,046,730) and the like have been heretofore known as the compound inhibiting several thiol proteases. However, no epoxysuccinic acid derivatives inhibiting specifically only one of the cysteine proteases have been known.
As a result of the earnest research to compounds having an epoxy ring, the present inventors have found the compounds inhibiting cathepsin B ally unlike the known compounds, and have accomplished the present invention.


DISCLOSURE OF THE INVENTION

The present invention is an epoxysuccinamic acid derivative represented by Formula I: ##STR2## (wherein R.sup.1 is an alkyl group having 1 to 10 carbon atoms, a phenyl group or a benzyl group) and a pharmaceutically acceptable salt thereof.
In addition, the present invention is an epoxysuccinamic acid derivative represented by Formula II: ##STR3## (wherein R.sup.1 is as defined above, R.sup.2 is a protecting group of the carboxyl group), which is a preparation intermediate of the compound of Formula I.
In the present invention, the alkyl group having 1 to 10 carbon atoms refers to a straight chain, branched chain or cyclic alkyl group such as, for example, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopropyl group, an isobutyl group, a t-butyl group and a cyclohexyl group, and preferably an n-propyl group and an n-pentyl group. The protecting group of the carboxyl group refers to those used usually in the field of the peptide synthesis chemistry, for example, a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, a t-butyl group, a benzhydryl group, a trimethylsilyl group, a methyl group and an ethyl group.
The pharmaceutically acceptable salts of the present invention are salts with inorganic bases including sodium, potassium, magnesium, ammonium and the like, salts with organic bases or basic amino acids (e.g. triethylamine, cyclohexylamine, arginine and lysine), salts with mineral acids (e.g. sulfuric acid, hydrochloric acid and phosphoric acid), salts with organic acids and acidic amino acids (e.g. acetic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, glutamic acid and aspartic acid).
The compounds of the present invention can be prepared, for example, by the following processes (in the following formulae, R.sup.1 and R.sup.2 are as defined above, and R.sup.2 and R.sup.3 may be the same or different, and each of which is a protecting group of the carboxyl group). ##STR4##
Process (a): An epoxysuccinic acid derivative of Formula III which can be prepared according to the method described in Chem. Pharm. Bull., vol. 35, pp. 1098-1104 (1987), is reacted with 1.0-2.0 molar equivalents of an amine of Formula IV in a solvent such as chloroform, ethyl acetate and N,N-dimethylformamide to give a compound of Formula V.
Process (b): The protecting group of the carboxyl group of the compound of formula V is removed in a solvent such as methanol, ethanol and N,N-dimethylformamide according to a method and conditions used usually in the field of the peptide synthesis chemistry such as a catalytic reduction using a catalyst such as palladium carbon and palladium black, a catalytic transfer hydrogenation (CTH) or hydrolysis using an acid (e.g. trifluoroacetic acid, methanesulfonic acid, hydrobromic acid and hydrochloric acid) or a base (e.g. sod

REFERENCES:
patent: 4333879 (1982-06-01), Tamai et al.
patent: 4382889 (1983-05-01), Tamai et al.
patent: 5068354 (1991-11-01), Murata et al.
Chemical Abstracts, vol. 115, No. 5, Abstract, No. 44893r; Towatori, et al. (1991).
Chemical Abstracts, vol. 115, No. 3, Abstract, No. 24916x; Murata, et al. (1991).
Agric. Giol. Chem., 42(3), 523-528 (1978), "Isolation and Characterization of E-64, A New Thiol Protease Inhibitor", Kazunori Hanada, et al, pp. 523-528.

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