SU959785A1 - 15-fluoroprostanic acid derivatives decreasing trombocyte aggregation capability - Google Patents

Description

The invention relates to chemistry and experimental medicine.

Natural prostaglandins (derivatives of proethanoic acids) are known, for example, E ^, 1 ^, which are powerful inhibitors of platelet aggregation. In terms of their specific activity, these substances are superior to all other currently known: antiplatelet agents [1].

However, these compounds are rapidly inactivated in the body due to oxidation by the hydroxyl group in position 15. This circumstance severely limits the possibility of using these agents as inhibitors of platelet aggregation ability. Thus, to reduce the aggregation ability of platelets (especially in vivo), it is necessary to obtain compounds that are resistant to 15 oxyprostaglandin dehydrogenase.

The aim of the invention is to obtain derivatives of 15-fluoroprostanoic acids corresponding to the general formulas

where R. = CH ,, H, monovalent cation;

Rj = OH, O;

R-j = Br, J, H;

X = 0, CH _a , N, and containing one (134) or two (54, 134) double bonds that reduce the aggregation ability of platelets.

The compounds contain 13Δ, or two 5A, 13Δ double bonds. These compounds are resistant to the action of 15-hydroxyprostaglandin dehydrogenase. At the same time, the replacement of 15 hydroxyl with fluorine leads to an increase in the antiaggregation effect characteristic of the corresponding natural prostaglandin, and in some cases to the appearance of antiaggregation properties in prostaglandins without such activity (a comparison of prostaglandin E ^ o / and its 15-fluoroanalogue is given in the table) .

Prostaglandin Inhibiting aggregation genius%

methyl ether

15-fluoro-15-deoxy F? _o / methyl ether

75 '

15-fluoro-15-deoxy E ^ methyl ester

5-iodine-1, methyl ether

15-fluoro-15-deoxy

5-iodine-1

Ί

100

Antiagnecionnoe action can be used in carrying out wild-biological research, in particular to study the mechanism of action of prostaglandins.

The anti-aggregation effect of these compounds is confirmed by the following examples.

Example!. Platelet-rich rabbit blood plasma was incubated with prostaglandins ~ Fq_cL (methyl ether) and 15-fluoro-15-deoxyprostaglandin F ^ ol (methyl ether) at a final concentration of 10 μg / ml. Incubation lasted 10 minutes. Aggregation was studied by the Born method using an FEK-56M photoelectrocolorimeter with graphical recording on a KSP4 self-recording potentiometer. In the control, aggregation was 50%. When prostaglandin E ^ c <was added to the plasma, it was 4.5%, and the fluorinated prostaglandin analogue was 30%. Thus, fluorination of prostaglandin at the Fj- ^ B 15 position has led to the ability of the compound to reduce platelet aggregation.

P. PRI me R 2. Enriched with platelets ’rabbit plasma was incubated with prostaglandin E / f and 15-fluorine

15-deoxyprostaglandin (methyl ether) at a final concentration of 10 μg / ml. Incubation lasted 10 minutes. In the control, platelet aggregation capacity was 50%. Prostaglandin E ^ reduced aggregation to 20%. The fluorinated analogue of prostaglandin E ^ depressed it up to 16%. Thus, the fluorinated analogue of prostaglandin E, insensitive to the action of 15-hydroxyprostaglandin dehydrogenase, exhibits an anti-aggregation effect that is close in strength to the known antiplatelet agent prostaglandin E ^.

Example Z. Platelet-rich rabbit blood plasma was incubated with 5-iodine-prostaglandin C (methyl ether) and 15-fluoro-15-deoxy-5-iodine-prostaglandin 1 ₄ (Me20 'typical' ether) at a final concentration of 10 μg / ml . Incubation lasted 10 minutes. In the control, the platelet aggregation ability was 50% 5-iodine-prostaglandin C (methyl 25 ether) reduced it to 16%, 15-fluoro-deoxy-5-iodine-prostaglandin 1,. · up to 15%.

Example 4. Platelet-rich rabbit blood plasma was incubated with 15-fluoro-11-9-epoxymethano-prostaglandin N _g (methyl 'ether) at a final concentration of 10 μg / ml. At the same time, the pad- was noted. aggregation ability. Trom: bocytes by 70%. At the same time, this compound, when added to platelet-rich plasma and stirred rapidly, caused platelet aggregation. When added to platelet-rich plasma, 11.9-epoxymethanoprostaglandin itself is not able to inhibit platelet aggregation in the presence of ADP, but, on the contrary, induces spontaneous platelet aggregation. Thus, the fluorination of a strong aggregation inducer leads to the appearance of anti-aggregation properties in it under incubation conditions with platelet-rich plasma.

The use of derivatives of 15-fluoroprostanoic acids to reduce the aggregation ability of platelets will find application for studying the physiological effects of natural. prostaglandins.

Claims (1)

1. Me GiH J.C. etae Prostagfiandins Nature 1969, 223, p. 742.