Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-06-29
1997-07-15
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3133
Patent
active
056483511
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP93/01886 filed Dec. 24, 1993.
TECHNICAL FIELD
This invention relates to a new use of macrolide compounds.
In more detail, this invention relates to a new use of macrolide compounds for preventing or treating cerebral ischemic disease.
Accordingly, this invention provides a new use of the macrolide compounds for preventing or treating cerebral ischemic disease.
BACKGROUND ART
The macrolide compounds used in this invention are known and disclosed, for example, in European Patent Publication No. 0184162 and International Publication No. WO 89/05304.
These known macrolide compounds include the fermentation products, such as FR-900506, FR-900520, FR-900523 and FR-900525 which were isolated from microorganisms belonging to genus Streptomyces, such as Streptomyces tsukubaensis No. 9993 (FERM BP-927) or Streptomyces hygroscopicus subsp. yakushimaensis No. 7238 (FERM BP-928), and their related compounds prepared from these fermentation products.
These macrolide compounds were indicated inter alia for use in the treatment of rejection to transplantation, autoimmune diseases and infectious diseases caused, for example, by Aspergillus, Fusarium, Trichophyton, and the like.
DISCLOSURE INVENTION
The inventors of this invention have surprisingly found that the macrolide compounds mentioned hereinbelow have a neuroprotective activity, and that they are useful for preventing or treating cerebral ischemic disease, particularly cerebral infarction. The macrolide compounds used in this invention can be represented by the following general formula (I). ##STR2## wherein each vicinal pair of substituents [R.sup.1 and R.sup.2 ], [R.sup.3 and R.sup.4 ], [R.sup.5 and R.sup.6 ] independently attached; group; with R.sup.1 it may represent .dbd.O; groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by .dbd.O; R.sup.22 and R.sup.23 independently represent H or alkyl; represent (R.sup.20 a, H) and (R.sup.21 a, H) respectively; R.sup.20 a and R.sup.21 a independently represent OH, O-alkyl or OCH.sub.2 OCH.sub.2 OCH.sub.2 OCH.sub.3 or R.sup.21 a is protected hydroxy; atom in an epoxide ring; together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N--, S-- or O-- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and --CH.sub.2 Se(C.sub.6 H.sub.5).
The specific examples of the definitions of compound (I) and the preferred working modes of the invention are described in detail below.
The term "lower" as used in this specification means, unless otherwise indicated, any number of carbon atoms between 1 and 6, inclusive.
Suitable "alkyl" means straight or branched saturated aliphatic hydrocarbon residue and may include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, and the like.
Suitable "alkenyl" means straight or branched unsaturated aliphatic hydrocarbon residue having one double bond and may include lower alkenyl such as vinyl, propenyl (e.g. allyl), butenyl, methylpropenyl, pentenyl, hexenyl, and the like.
Suitable "aryl" may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like.
Suitable examples of the protective group in the "protected hydroxyl group" may include: (e.g. methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more desirably C.sub.1 -C.sub.4 alkylthiomethyl groups, and most desirably methylthiomethyl; tri-substituted silyl groups such as tri(lower)alkylsilyl groups (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl-dimethylsilyl, tri-tert-butylsilyl, etc.), lower alkyl-diarylsilyl groups (e.g. methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl, etc.), more desirably tri(C.sub.1 -C.sub.4)alkylsilyl and C.sub.1 -C.sub.4 alkyldiphenylsilyl groups and most
REFERENCES:
patent: 5266594 (1993-11-01), Dawson et al.
Brian Research, vol. 595, No. 1, pp. 145-148, (1992), Y. Shiga, et al., "Cyclosporin a Protects Against Ischemia-Reperfusion Injury in the Brain".
Proc. Natl. Acad. Sci., vol. 90, pp. 9808-9812, Nov. (1993), T. Dawson, et al., "Immunosuppresant FK506 Enhances Phosphorylation of Nitric Oxide Synthase and Protects Against Glutamate Neurotoxicity".
The New York Times Science, May 25, (1993), G. Kolata, "Brain Researcher Makes It Look Easy", pp. B6-B7.
Butcher Steven P.
Kelly John S.
Sharkey John
Fujisawa Pharmaceutical Co. Ltd.
Henley III Raymond
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