Epoxysuccinic acid derivatives, their production and use

Details Epoxysuccinic acid derivatives, their production and use Epoxysuccinic acid derivatives, their production and use

1995-09-05

1997-10-21

Dentz, Bernard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549548, 549549, C07D30348, C07D40512, A61K 31335

Patent

active

056797087

DESCRIPTION:

BRIEF SUMMARY
This application is a 35 USC 371 National Stage filing of PCT/JP95/01004 published as WO95/32954 on Dec. 7, 1994.


BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to novel epoxysuccinic acid derivatives, which are useful as prophylactic and therapeutic agents of bone diseases and agents of inhibiting thiol protease.
2. Description of Related Art
In bone tissue, bone resorption and formation occur constantly with a good balance to ensure bone homeostasis; bone diseases such as osteoporosis are caused when the balance shifts to the bone resorption side. In recent years, various epoxy compounds possessing prophylactic and therapeutic activity against bone diseases have been reported (JPA H2(1990)-218610, EPA269311).
And, as an in vivo metabolite of loxistatin, a side chain hydroxide has
Currently, bone resorption suppressors such as estrogens and calcitonin are used for the prophylaxis and therapy of bone diseases such as osteoporosis. However, in the case of administration of these therapeutic agents, subjects to be administered are limited, and their efficacy is uncertain in some instances, and satisfactory effects have not yet been brought about. And, at the present stage, compounds showing satisfactory inhibiting action against thiol protease have not yet been available.


SUMMARY OF THE INVENTION

With the above situation in mind, the present inventors have directed their FEBS Letters, Vol. 321, p. 247 (1993)!, which has recently been shown to play a major role in bone resorption. They have conducted a diligent study and found that novel epoxysuccinic acid derivatives show potent actions of inhibiting cathepsin L and, further, of suppressing bone resorption.
Based on these findings, the present inventors have made a further study to accomplish the present invention.
According to the present invention, there is provided: ##STR2## wherein R.sub.1 stands for an optionally esterified or amidated carboxyl group, X stands for an optionally substituted divalent hydrocarbon residue, R.sub.2 stands for hydrogen or an optionally substituted hydrocarbon residue, R.sub.3 stands for an alkyl group which is substituted with a group bonded through O or S(O).sub.n wherein n is 0, 1 or 2, with a proviso that when the partial structural formula: --NH--X--CO-- is leucine residue, R.sub.3 is not 3-hydroxy-3-methylbutyl group nor 4-hydroxy-3-methylbutyl group or a salt thereof, optionally esterified carboxyl group, structural formula: --NH--X--CO-- is an .alpha.-amino acid residue, acid residue is an aromatic amino acid residue, acid is of L-configuration, hydrocarbon residue having a cyclic group, hydrocarbon residue, C.sub.1-15 alkyl group, group which is substituted with a group bonded through O, through O is C.sub.1-16 hydrocarbon-oxy group, hydrocarbon-oxy group is C.sub.1-6 alkoxy group, group which is substituted with a group bonded through S(O).sub.n wherein n is 0, 1 or 2, through S(O).sub.n is C.sub.1-14 hydrocarbon-S(O).sub.n group, hydrocarbon-S(O).sub.n group is C.sub.1-6 alkylthio group, amino-3-methoxypropane, amino-3-methylthiopropane, compound or a salt thereof as defined in term (1) above, thereof as defined in term (1) above, disease, which comprises a compound or a salt thereof as defined in term (1) above, the bone disease is osteoporosis, the manufacture of a medicament for inhibition of a thiol protease, the manufacture of a medicament for preventing or treating a bone disease, osteoporosis, administering an effective amount of the compound as defined in term (1) above or a pharmaceutically acceptable salt thereof to the mammal, comprises administering an effective amount of the compound as defined in term (1) above or a pharmaceutically acceptable salt thereof to the mammal, and osteoporosis.


DETAILED DESCRIPTION OF THE INVENTION

Abbreviations for amino acids and peptides used in the present specification are based on abbreviations specified by the IUPAC-IUB Commission on Biochemical Nomenclature or abbreviations in common use in relevant fields. When the amino acid m

REFERENCES:
patent: 4333879 (1982-06-01), Tamai et al.
Kakegawa et al., "Participation of cethepsin L on bone resorption", FEBS, vol. 321, pp. 247-250, 1993.

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