Pyrrolidine derivatives

Details Pyrrolidine derivatives Pyrrolidine derivatives

1993-11-15

1994-10-25

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548413, A61K 3140, C07F 902

Patent

active

053589610

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/KR 92.00066 filed Nov. 24, 1992.


TECHNICAL FIELD

This invention relates to new pyrrolidine derivatives represented by general formula(I) as below and their pharmacologically acceptable salts which are useful as antihypertensive ##STR2## wherein,
R.sup.1 is saturated or unsaturated alkyl of 2 to 20 carbon atoms, or aryl group;
R.sup.2 is saturated or unsaturated alkyl of 1 to 17 carbon atoms, or aryl group;
R.sup.3 is hydrogen atom, saturated or unsaturated alkyl of 1 to 20 carbon atoms, or aryl group or its derivatives; and
X is oxygen or sulfur atom.


BACKGROUND OF THE INVENTION

Platelet activating factor(PAF) was first identified in 1979 to be 1-O-alkyl-2-O-acetyl-sn-glycerol-3-phosphocholine by Benveniste et al. [C. R. Acad. Sci., Paris(D), 289, 1037-1040(1979)].
It was also reported that this PAF produces a variety of physiological responses such as platelet activation and antihypertension. The conjugates of nucleosides with PAF derivatives or with their analogues have been reported to exhibit diverse pharmacological activities such as anticancer, antiinflammation and antivirus activity in literatures [Journal of Medicinal Chemistry, 25, 1322(1982), Biochemical and Biophysical Research Communication, 85, 715(1978), Biochemica et Biophysica Acta, 69, 604(1980), J. Med. Chem., 28(2), 171-7(1985), Ibid., 31(9), 1793-8(1988), Ibid., 33(5), 1380-6(1990)].
Most of the antihypertensive agents, so far used in medicine have to be taken orally or by intravenous administration and the dosage has to be repeatedly administered to maintain proper plasma concentration of a drug.
However to achieve and maintain a plasma concentration of drug within the therapeutical range is not easy. If the plasma concentration of drug remains high it leads to related side effects and development of tolerance to the drug. The problem of economy of long term oral therapy also cannot be disregarded.
Development of transdermal therapeutic mode of delivery of antihypertensive agent with favorable pharmacokinetic parameters maintained for a long duration time, with improved convenience and patient compliance, and with minimal side effects has been for long considered necessary.


SUMMARY OF THE INVENTION

The objective of this invention is to provide new pyrrolidine derivative antihypertensive compounds with convenient dosage regime compared to convenient therapy, and superior therapeutic effect.


DETAILED DESCRIPTION OF THE INVENTION

This invention relates to new pyrrolidine derivatives shown by above formula (I) and especially new compounds having excellent physiological activities as antihypertensive agent.
In the above formula(I), R.sup.1 is octadecyl, cetyl, methyl, ethyl, dodecyloxy, methylphenyl or sulfonyloctyl group; R.sup.2 is methyl, ethyl, propyl, butyl, heptadecyl, pentadecyl, oleyl or cetyl group; R .sup.3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclohexyl, benzoyl, benzyl, p-nitrobenzyl, p-toluenesulfonyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl or phthalimidomethyl group.
The phospholipid part of above formula(I) consists either D, L or DL type of optical isomers and the part linked to phosphoric acid am angiotensin converting enzyme(ACE) inhibitors and their derivatives commonly used as antihypertensive agent.
Present invention also includes the compositions of above reffered structure(1) antihypertensive agents in pharmaceutical dosage forms including transdermal therapeutic dosage form.
New pyrrolidine derivatives of this invention represented by formula(I) are new conjugates introducing ACE inhibitor into basic structure of glycerol. Specifically, conjugates of 1-S- or 1-O-alkyl-2-O-acyl phospholipids are linked with ACE inhibitors or their derivatives by phosphate ester bond and resulting compounds are new synthetic compounds with favorable antihypertensive activity.
The methods for preparing new compounds of this invention are as follows;
New pyrrolidine derivatives and their salts of above formula(I) can be prepared by condensation of compound(II) with com

REFERENCES:
patent: 4468519 (1984-08-01), Krapcho

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