Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1985-12-27
1987-05-12
Gerstl, Robert
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
562503, C07C17700
Patent
active
046652140
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to chemistry and, more particularly, to novel derivatives of 15(R+S)-fluoro-11,15-dideoxyprostaglandin E.sub.1.
BACKGROUND OF THE INVENTION
Known in the art are various substances lowering aggregation of thrombocytes such as Dipirodomole (cf. M. D. Mashkovsky, Pharmaceutical Chemicals, Moscow, Medicina Publishing House, 1984, vol. 1, p. 420-421).
However, this preparation does not exhibit a high antiaggregation activity.
Known in the art are derivatives of 15-fluoroprostanic acids having a close chemical structure, e.g. 15-fluoro-15-deoxyprostaglandin E.sub.1, 15-fluoro-15-deoxyprostaglandin J.sub.2 which lower the aggregation power of thrombocytes. (Cf. USSR Inventor's Certificate No. 959785 Cl. C 07 C 177/00, A 61 K 31/557, 1982).
However, these compounds under the conditions of incubation with blood plasma rich in thrombocytes lose substantially their antiaggregation activity already within 30-45 minutes which hinders their use in medicobiological experiments.
Furthermore, the synthesis of these compounds is a multistaged one and proceeds with a low yield of the final product. For these reasons the above-specified compounds have not obtained a wide application in medical practice.
DISCLOSURE OF THE INVENTION
The 15(R+S)-fluoro-11,15-dideoxyprostaglandin E.sub.1 derivatives are novel and hitherto unknown in the literature.
The present invention is directed to the provision of novel compounds possessing a high antiaggregation activity of a protracted duration and obtained by a simple procedure.
This object is accomplished by that the novel derivatives of 15(R+S)-fluoro-11,15-dideoxyprostaglandin E.sub.1 according to the present invention have the following general formula: ##STR2## wherein: R' is CH.sub.3, C.sub.2 H.sub.5, H, Na; R.sup.2 and R.sup.3 and each H or fluorine.
The compounds according to the present invention comprise colourless viscous liquids which, as a rule, are well soluble in organic solvents and only sparingly soluble in water. The exception is the sodium salt of 15(R+S)-fluoro-11,15-dideoxyprostaglandin E.sub.1 (R'=Na) which is moderately soluble in water.
The compounds according to the present invention possess a protracted antiaggregation effect.
The antiaggregation effect of the derivatives of 15(R+S)-fluoro-11,15-dideoxyprostanglandin E.sub.1 has been studied in in vitro experiments carried out by the Born Method.
To 0.9 ml of a blood plasma rich in thrombocytes 0.1 ml of a solution of a fluorinated derivative of prostanglandin is added which solution has been prepared by dissolution of an aliquote amount of a standard prostanglandin solution in dimethylsulphoxide (10 mg/ml) in 0.1 ml of a physiological solution and containing 5 .mu.g of the compound, in the first sample--methyl ether of 15(R+S)-fluoro-11,15-dideoxyprostanglandin E.sub.1, in the second sample--ethyl ether of 15(R+S)-fluoro-11,15-dideoxyprostanglandin E.sub.1, in the third sample--methyl ether of 15-fluoro-15deoxyprostaglandin E.sub.1, in the 4-th sample--methyl ether of 15-fluoro-15-deoxyprostanglandin J.sub.2. The samples are subjected to incubation for 10 minutes at room temperature, then added with adenosindiphosphate in the final concentration of 2 .mu.g/ml. In the control instead of the aliquote of prostanglandin the physiological solution is added which contains the same amount of dimethylsulphoxide. In the 1-st sample reduction of aggregation of thrombocytes by 80% is noticed, in the second--by 85%, in the third--by 85% and in the fourth--by 79% as compared to the control. Within 60 minutes in the 3-rd sample and within 120 minutes in the 4-th the aggregation of thrombocytes induced by adenosindiphosphates is returned to the initial level. By the same moment (60 minutes) in the 1-st and 2-nd samples there is observed the reduction of aggregation of thrombocytes by 30% and more as compared to the control. The same effect is also observed for methyl ether of 15(R+S)-fluoro-11,15-dideoxyprostanglandin E.sub.1 for the period of 120 minutes.
Under simila
REFERENCES:
Kogtev, Bioorg Khim, 10 1260 (1984).
Guidebook on Pharmacotherapy for Doctors, part 1, 9th rev. and enl.
Bergelson Lev D.
Bezuglov Vladimir V.
Freimanis Yanis F.
Kovalev Sergei G.
Lakin Kapiton M.
Gerstl Robert
Institut Organicheskogo Sinteza An Latir SSSR
Institute Biorganicheskoi Khimii An SSSR
Moskovsky Meditsinsky Stomatologichesky Institut
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