Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-09-29
1998-12-01
Huang, Evelyn
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549548, 549549, A61K 31335, C07D30348
Patent
active
058439927
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/JP96/00889, filed Apr. 1, 1996, issued as WO 96/30354 on Oct. 3, 1996.
FIELD OF THE INVENTION
This invention relates to a novel epoxysuccinic acid derivative and a pharmaceutical composition for treating bone diseases using the same.
BACKGROUND OF THE INVENTION
In the bone tissue, bone resorption and bone formation are continuously and simultaneously performed by osteoclasts and osteoblasts, respectively. The structure and amount of the bone is kept on their balance. However, excessive bone resorption causes bone diseases such as osteoporosis, malignant hypercalcemia, and Pajet's syndrome.
The process of bone resorption (i.e., decalcification) by osteoclasts can be divided into two steps, namely, dissolution of minerals and degradation of bone substrate. The degradation of bone substrate is considered to occur by the action of lysosomal enzymes. According to recent studies, it is recognized that among the lysosomal enzymes, cathepsin L and its and Katsunuma, Molecular Medicine, 30(10), 1310-1318 (1993), and Tezuka et al., J. Biol. Chem., 269, 1106-1109(1994)!. Further, it has been reported Delaisse et al., Biochem. Biophys., Res. Commun., 125, 441-447(1984)!. Therefore, compounds which inhibit action of cysteine protease such as cathepsin L are considered to be of value for treating bone diseases such as osteoporosis.
For instance, it has been already proposed that certain epoxysuccinic acid Provisional Publications No. 63-284127 and No. H2-218610!. However, there have been no reports on the clinical study of the cysteine protease inhibitors, and the study has been recently started.
Japanese Patent Publication No. 61-55509 discloses epoxysuccinic acid derivatives (epoxysuccinum acid compounds) as protease inhibitors in which a thiol group participates in their action. There are given no disclosures, however, with respect to compounds which has a branched chain on the carbon atom adjacently connected to the nitrogen atom of N-substituted carbamoyl group which is attached to the oxirane ring, for instance, diphenyl-methylcarbamoyl and (3-methyl-1-phenylbutyl)carbamoyl.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a compound and a pharmaceutical composition which are useful for prevention and treatment of bone diseases such as osteoporosis, malignant hypercalcemia and Paget's syndrome.
It is another object of the invention to provide a compound and a pharmaceutical composition which are useful for treating osteoarthritis and rheumatoid arthritis which are accompanied by abnormal enhancement of cathepsin L activity.
It is a further object of the invention to provide a compound which is useful as a medicine for treating diseases in which cathepsin B and L participate, such as muscular dystrophy and muscular atrophy.
The present inventors have earnestly studied to solve the above-mentioned problems and have found that the epoxysuccinic acid derivative or its salt which is represented by the below-mentioned formula (I) and has a characteristic feature in that the substituent of the amide group on the right side are branched has an activity of inhibiting bone resorption superior to the epoxysuccinic acid derivatives described in the aforementioned Japanese Patent Publication No. 61-55509, and that it is useful for prevention and treatment of bone diseases. The present invention has been accomplished based on the above finding. The typical activity of the compound of Japanese Patent Publication No. 61-55509 is shown by the comparative compounds X and Y in the hereinafter given in the comparative experiments. ##STR2## in which R.sup.1 represents a hydrogen atom, an alkyl group having 1 to 30 carbon atoms, an aryl group having 6 to 40 carbon atoms, or an aralkyl group having 7 to 40 carbon atoms; each of R.sup.2 and R.sup.3 independently represents an aryl group having 6 to 40 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an alkyl group having 3 to 10 carbon atoms; X represents --O-- or --NR.sup.4 --; and R.sup.4 r
REFERENCES:
patent: 4387238 (1983-06-01), Goi
Hara Kaoru
Masaki Mitsuo
Nomura Yutaka
Takahashi Toshihiro
Yoshino Yasushi
Huang Evelyn
Nippon Chemiphar Co., Ltd.
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