Aziridine derivatives, their production and use

Details Aziridine derivatives, their production and use Aziridine derivatives, their production and use

1995-09-05

1997-09-16

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

5142355, 514326, 514336, 514371, 514422, 544111, 546208, 5462681, 548195, 548518, 548966, C07D20316, C07D41300, A61K 3133, A61K 31535

Patent

active

056681283

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to novel aziridinedicarboxylic acid derivatives, which are useful as a prophylactic and therapeutic agent of bone diseases and an agent 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, EP-A 269311].
However, aziridinedicarboxylic acid derivatives having prophylactic and therapeutic activity against bone diseases and activity of inhibiting thiol protease have not been reported yet.
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 secreted from lysosome of osteoclasts have not yet been available.


SUMMARY OF THE INVENTION

With the above situation in mind, the present inventors paid attention to thiol protease, especially cathepsin L [H. Kakegawa et al., FEBS Letters, Vol.321,p.247 (1993)], which has recently been shown to play a major role in bone resorption, and they conducted diligent study and found that novel aziridinedicarboxylic acid derivatives show potent actions of inhibiting cathepsin L and further of suppressing bone resorption.
Based on these findings, the present inventors have made further study to accomplish the invention.
According to the present invention, there is provided: ##STR2## wherein R.sub.1 and Q are independently an optionally esterified or amidated carboxyl group; R.sub.2 is hydrogen, an acyl group or an optionally substituted hydrocarbon residue; X is a divalent hydrocarbon residue which may be substituted; or a salt thereof, salt is a pharmaceutically acceptable salt, partial structural formula: --CO-- N(R.sub.3)(R.sub.4) wherein R.sub.3 and R.sub.4 are independently hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group; or R.sub.3 and R.sub.4 are combined with the adjacent nitrogen atom to represent an optionally substituted heterocyclic group, are independently hydrogen or an optionally substituted hydrocarbon residue; or R.sub.3 and R.sub.4 are combined with the adjacent nitrogen atom to represent an optionally substituted heterocyclic group, optionally esterified carboxyl group, or an acyl group, structural formula: --NH--X--CO-- is an .alpha.-amino acid residue, acid residue is of L-configuration, acid residue is an aromatic amino acid residue, R.sub.4 is hydrogen and the other is an optionally substituted hydrocarbon residue, residue is an alkyl group, residue is an aralkyl group, are combined with the adjacent nitrogen atom to represent an optionally substituted heterocyclic group, group is a 6-membered heterocyclic group, N-[N-[(2S,3S)-3-ethoxycarbonylaziridine-2-carbonyl]-L-phenylalanyl]-2-phen ylethylamine, N-[N-[(2S,3S)-3-ethoxycarbonylaziridine-2-carbonyl]-L-phenylalanyl]isopent ylamine, N-[N-[(2S,3S)-3-ethoxycarbonylaziridine-2-carbonyl]-L-phenylalanyl]-3-meth oxypropylamine, N-[N-[(2S,3S)-3-ethoxycarbonylaziridine-2-carbonyl]-L-phenylalanyl]-N-meth yl-2-phenylethylamine, compound or a salt thereof as defined in term (1) above, disease, which comprises a compound or a pharmaceutical acceptable salt thereof as defined in term (2) above, a medicament for inhibition of a thiol protease, a medicament for preventing or treating a bone disease, osteoporosis, administering an effective amount of the compound or a pharmaceutically acceptable salt thereof as defined in

REFERENCES:
patent: 4418075 (1983-11-01), Tamai et al.

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