Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-07-13
1995-03-28
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549458, C07D30793, A61K 3134
Patent
active
054017688
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a prostaglandin I derivative which is excellent in the stability and which exhibits sustained activity in vivo, as well as manufacturing process thereof and its use. Further, this invention relates to a compound which may be used as a starting material or an intermediate for producing the derivative.
BACKGROUND ART
Prostaglandin I.sub.2 (PGI.sub.2, prostacyclin) was found by J. R. Vane et al. in 1976. Prostaglendin I.sub.2 is synthesized from arachidonic acid via endoperoxide (PGH.sub.2 or PGG.sub.2) on vascular wall and is drawing attention as a compound having strong platelet aggregation inhibiting action, gastric acid secretion inhibiting action and vasodilation action of peripheral vessels [see C and EN, Dec. 20, 1976, P17 and S. Moncada, R. Gryglewskl, S. Bunting, J. R. Vane, Nature, 263, 633 (1976)]. ##STR1##
PGI.sub.2 has unstable exoenol structure, so that it is very unstable even in neutral aqueous solution and readly converted to 6-oxo PGF.sub.1.alpha. which has little physiological activity. It is a big drawback that PGI.sub.2 has the unstability as descrived above when used as a medicine. Further, PGI.sub.2 has drawbacks in that it is unstable in vivo and its physiological activity does not last.
A variety of derivatives which have been studied to improve the chamical stability and to promote the durability in vivo are not satisfactory.
Especially, as to the durablity of the drug, it was found to be a big drawback that .beta.-oxidation which is a metabolic pathway of fatty acid is easy to occur.
The present inventors intebsively studied based on this finding to find a very stable structure which inhibits the metabolism by .beta.-oxidation to accomplish this invention.
That is, the object of the present invention is to provide a novel PIG.sub.2 derivative having excellent stability and sustained activity in vivo.
DISCLOSURE OF THE INVENTION This invention relates to
2,5,6,7-tetranor-4,8-inter-m-phenylene PGI.sub.2 derivative represented by the formula: ##STR2## (wherein R.sub.1 represents (i) CH.sub.2 CH.sub.2 COOR.sub.2 or cation or ester residue); R.sub.3 represents hydrogen atom, an acyl group having 1 to 12 carbon atoms or an aroyl group having 6 to 15 carbon atoms; X represents group having 3 to 12 carbon atoms, or alkylene group defined as the formula C.sub.t H.sub.2t (t is an integer of 1 to 5); Ar represents a phenyl group unsubstituted or substituted by 1 to 4 substituents selected from the class consisting of alkyl, methoxy, chloro, bromo, fluoro, iodo, trifluoromethyl, nitro, cyano, phenyl and phenoxy), represents a cycloalkyl group with 3 to 12 ring members which is unsubstituted or substituted by 1 to 4 normal alkyl substituents containing 1 to 4 carbon atoms), or meaning as in (ii); R.sub.6 represents (1) a normal alkyl group having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6 carbon atoms, (2) a cyclopentyl or cyclohexyl group unsubstituted or substituted by 1 to 4 normal alkyl substituents containing 1 to 4 carbon atoms, or (3) Ar (wherein Ar has the same meaning as in (ii)).
The novel compound of the present invention represented by the said formula is characterized in that the drawbacks of PGI.sub.2 are largely improved. That is, since the compound of the present invention which is represented by the formula has an inter-m-phenylene structure in place of an exoenol structure which is characteristic to PGI.sub.2, it is very stable even in aqueous solution. Further, .beta.-oxidation of the compound of the present invention, which is a main metabolic pathway of prostaglandin, is conducted very slowly,so that physiological activity thereof lasts very long. Still further, since the compound of the present invention has various physiological activities of PGI.sub.2 in selected forms, it is excellent in application as medicine.
BEST MODE FOR CARRYING OUT THE INVENTION
The formula will now be described in more detail. When R.sub.2 represents an ester residue, R.sub.2 may be group having 3 to 12 carbon atoms; above-descr
REFERENCES:
patent: 4564620 (1986-01-01), Ohno
patent: 4822804 (1989-04-01), Ohno
Nishio Shintaro
Ohno Kiyotaka
Ohtake Atsushi
Takahashi Toshiya
Wakita Hisanori
Gerstl Robert
Miller Austin R.
Toray Industries Inc.
LandOfFree
2,5,6,7-tetranor-4,8-inter-m-phenylene PGI.sub.2, derivative, ma does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 2,5,6,7-tetranor-4,8-inter-m-phenylene PGI.sub.2, derivative, ma, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2,5,6,7-tetranor-4,8-inter-m-phenylene PGI.sub.2, derivative, ma will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2250913