Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-08-20
1993-05-25
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514422, 514439, 514551, 514563, 546209, 546226, 546247, 548517, 548527, 548540, 560 1, 560 41, 560121, 560423, 560125, 560126, 560169, 562437, 562432, 562560, 562503, 562505, 562507, 562564, 562508, 549 34, 549449, 549452, A61K 3139, A61K 31445, C07D32710, C07D21126
Patent
active
052140563
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel 1,3,2-dioxathiolane oxide derivative and its intermediate compound. More particularly, the present invention relates to a novel 1,3,2-dioxathiolane oxide derivative having good inhibitory activity against thiol proteases such as calcium-dependent neutral protease (CANP) and cathepsins B, H, and L, and also relates to a 1,3-dioxolane derivative and a 1,2-diol derivative useful to prepare the 1,3,2-dioxathiolane derivative.
BACKGROUND ART
Proteolytic enzymes represented by CANP and including, e.g., cathepsin B, papain, ficin, bromelin, and bromelan are generally called thiol proteases because they have a thiol group at the active center. On the other hand, it is known that substances having CANP inhibition activity not only specifically affect the thiol group of the CANP to inhibit its activity but also have an inhibitory effect on other thiol proteases.
Therefore, substances capable of inhibiting proteases such as CANP and cathepsin B are expected to useful the cure, mitigation, treatment, or prevention of diseases to which these proteases are related, e.g., myotonic dystrophy, inflammation, renal hypertension, cataract, myocardial infarct, viral infectious diseases, malignant tumors, osteoporosis, and allergic diseases.
Conventionally known examples of a compound having thiol protease inhibition activity are E-64, a mold metabolite, a series of epoxy succinic acid derivatives such as E-64-c as derivatives of E-64, and aldehyde derivatives of leupeptin and antipine belonging to a secondary metabolite of an actinomycete.
E-64 is an epoxysuccinic acid derivative obtained from a bran solid culture of an Aspergillus japonicus TPR-64 strain and represented by the following formula (e.g., Published Unexamined Japanese Patent Application No. 52-23021 and Published Examined Japanese Patent Application No. 64-5031): ##STR2##
Both E-64-c and loxistatin as its ethylester are derivatives of the above E-64 and are represented by the following formula (e.g., Published Unexamined Japanese Patent Application No. 55-115878): ##STR3##
The above two compounds, especially loxistatin, have attracted attention due to their effect as proteolytic enzyme inhibitors, and are therefore currently being studied to develop a practical use therefor an agent for treating muscular dystrophy and the like.
DISCLOSURE OF INVENTION
It is an object of the present invention to provide a novel compound effective in the cure, mitigation, treatment, or prevention of diseases as described above. The present inventors have conducted extensive studies to achieve this object, and have found that a novel 1,3,2-dioxathiolane oxide derivative has high specific inhibitory activity against thiol proteases, and established the present invention.
The novel 1,3,2-dioxathiolane oxide derivative according to the present invention is represented by the following formula [I]: ##STR4## wherein X represents --S(O)-- or --S(O).sub.2 --; or a lower alkyl group;
R.sup.2 represents a lower alkyl group which may be substituted with a methylthio group, or a benzyl group; and represent a hydrogen atom, an alkyl group having one to ten carbon atoms, a lower alkyl group substituted with a guanidyl group, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a benzyl group, or a phenethyl group, or together form an alkylene group.
The lower alkyl group represented by R.sup.1 and R.sup.2 represents a straight-chain or branched alkyl group having one to five, and preferably, one to four carbon atoms. Examples of this alkyl group are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, and a tert-butyl group etc.
The alkyl group represented by R.sup.3 and R.sup.4 represents a straight-chain or branched alkyl group having one to ten carbon atoms. Examples of this alkyl group are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl
REFERENCES:
patent: 4333879 (1982-06-01), Tamai et al.
patent: 4382889 (1983-05-01), Tamai et al.
patent: 5023342 (1991-06-01), Sharpless et al.
Chemical Abstracts 101: 7167x, p. 613, abstract of J.P. 59-07,186 [84-07,186] (1984).
T. Seki, Chemical Abstracts 87: 202,125b, p. 784, abstract of 52-23021 (1977).
O. Kawabata, et al. Chemical Abstracts, 106: 176,398g, p. 731, abstract of JP-61-227,578 [86-277,578] (1987).
Hara Shin
Haruta Jun-ichi
Ohta Akira
Tanaka Masahiro
Uchida Itsuo
Japan Tobacco Inc.
Raymond Richard L.
Russell Mark W.
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