HU197301B - Process for producing 15/r+s/-fluor-11,15-dideoxy-prostaglandin e under 1 - Google Patents

Abstract

Field of the Invention The present invention relates to a process for the preparation of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin Nem derivatives of formula (I) having a significant anti-aggregation activity, wherein R 1 is ethyl, methyl, hydrogen, sodium, R2 or R3 is hydrogen or fluoro. The process according to the invention is carried out by treating a solution of the methyl or ethyl esters of the 11-deoxy-prostaglandin E1 in an organic solvent at a temperature below 0 ° C with morpholino-sulphotrifluoride and then extracting the resulting fluorides by extraction with an organic solvent. purification by chromatography, the ester is suitably saponified. FOR MANUFACTURING 197301 -1-

Description

The present invention relates to a process for the preparation of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin.

State of the art

At present, several substances are known to reduce platelet aggregation, such as dipyridemols {M. D. Mashkovsky, Lekarstvenny sredstva, Moscow, Medizin, 1984. B.I. 420-421. side).

However, said composition does not have a significant anti-aggregation effect.

Derivatives of 15-phosphorous prostenoic acid of similar chemical structure are known to reduce platelet aggregation capacity. Examples of such compounds are 15-fluoro-15-deoxy-prostaglandin E1 and 15-fluoro-15-deoxy-prostaglandin J2. (959

No. 785 Soviet Union Copyright Certificate, C 07 C 177/00, A 61 K 31/557, 1982).

However, these compounds, when incubated with thromboxytes-enriched plasma for 30-45 minutes, significantly lose their aggregation effect, which makes them difficult to apply in medical and biological experiments.

These compounds are synthesized in several steps and the final product can only be obtained in extremely low yields. For these reasons, these compounds are not used in practice.

Discussion of the Invention

The 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 derivatives of the present invention are novel and have not yet been reported in the literature.

The present invention relates to the preparation of novel compounds having a significant delayed anti-aggregation activity and which can be obtained by simplified technology.

This problem was solved by the preparation of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 derivatives of formula (I) - wherein in formula (I), R ¹ is methyl, ethyl, hydrogen, sodium, R ² or R ³ is hydrogen or fluoro.

The compounds of the present invention are colorless, viscous liquids, which are generally highly soluble in organic solvents and sparingly soluble in water. An exception is the 15 (R + S) -fluoro-ll, 15-dideoxy-prostaglandin Ei sodium salt (R ¹ is Na), which is sparingly soluble in water.

The compounds of the invention have delayed anti-aggregation activity.

Derivatives of 15- (R + S) -fluoro-1,15-dideoxy-prostaglandin E1 according to the invention were tested in vitro using the Born method.

To 0.9 ml of platelet-enriched plasma was added 0.1 ml of fluorinated prostaglandin derivative prepared by dissolving an aliquot of the prostaglandin standard solution in dimethyl sulfoxide (10 mg / ml) in 0.1 ml of physiological saline - and 5 Mg, in sample 1 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E 1 methyl ester, in sample 3 15-fluoro-15-deoxy-prostaglandin E 1 methyl ester, sample 4 contains 15-fluoro-15-deoxy-prostaglandin J2 methyl ester.

Samples were incubated at room temperature for 10 minutes and adenosine diphosphate at a concentration of 2 g / ml was added. A saline solution containing the same amount of dimethyl sulfoxide was added to the control in place of an aliquot of prostaglandin. A reduction of 80% was observed in sample 1, a decrease of 85% in the third sample and a decrease of 79% in the fourth sample. Platelet aggregation induced by adenosine diphosphate returned to baseline in 60 minutes in the third sample and 120 minutes in the fourth sample. During the same time (6C min), a 30% and greater reduction in platelet aggregation was observed in the first and second samples compared to the control. This effect was observed for E1 methyl ester of 15 (RtS) -fluoro-11,15-dideoxy-prostaglandin over 120 minutes.

Under similar conditions, the maximum reduction in platelet aggregation induced by the known formulations, dipyridomoyl, was 48% relative to control. The results of the tests are listed in Tables 1 and 2.

Accordingly, the derivatives of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 according to the invention exhibit significant anti-aggregation activity against the dipyrimodol formulation and exhibit a delayed effect on anti-aggregation of 15 (luor) Known derivatives of prostaglandin should be about 2.5-fold higher.

L97301

Table 1

Effect of Fluorostaglandins and Dipyridomo 'on Anti-Aggregation of Platelets

Sample row- number The test compound 5 mg / ml Inhibition of platelet aggregation, measured 10 minutes after incubation of the test compound in plasma (%) 1 2 3 First Methyl 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E ¹ (R ¹ is methyl) 80 Second The ethyl ester of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E ¹ (R ¹ is ethyl) 85 Third The 15-fluoro-15-deoxy-prostaglandin E ¹ methyl ester 85 4th 15-Fluoro-15-deoxy-prostaglandin J2 methyl ester 79 5th The 15 (R + S) -fluoro-ll, 15-dideoxy-prostaglandin El ^(R1 = hydrogen) 74 6th Sodium salt of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E ¹ (R ¹ is sodium) 67 7th Dipiridomol 48 Table 2 Fluorostaglandin duration of anti-aggregation effect

Sample prostaglandin Prostaglandin in plasma row- 5 mg / ml pre-incubation number relative to the drift level

change in anti-aggregation effect (minutes)

10 30 60 120 First Second Third 4th 5th 6th First The methyl ester of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin (R ¹ is methyl). 100 75 50 50 Second Ethyl ester of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E ¹ (R ¹ is ethyl) 100 62 35 30 Third The methyl ester of 15-fluoro-15-deoxy-prostaglandin E1 100 23 0 0 4th The methyl ester of 15-fluoro-15-deoxy-prostaglandin Jz 100 63 20 0

The compounds of the invention was prepared by the known 11-deoxy-prostaglandin E ^l methyl or ethyl ester, which is prepared in an organic solvent such esters was treated at a temperature below 0 ° morpholino-5 lino szulfotrifluoriddal. The resulting fluorides were extracted with a suitable organic solvent and then purified by chromatography on silica gel. If necessary, alkaline saponification of the sensory space is then performed.

For a better understanding of the invention, the following examples are provided to prepare the compound of the invention.

Example 1

Ethyl ester of 11-deoxy-prostaglandin E1 (100 mg, 0.27 mmol) was dissolved in 10 mL of dried methylene chloride and the resulting solution was cooled to -78 ° C and treated with 140 µL of morpholinosulfotrifluoride under stirring under argon. ml of methylene chloride. After stirring for 25 hours at -78 ° C, saturated ammonium chloride solution (2.5 ml) was added and the mixture was allowed to warm to room temperature with constant stirring. The reaction mixture was diluted with water (7.5 mL), the aqueous layer was separated and the product was dissolved in methylene chloride. These combined organic phases were washed with saturated sodium carbonate (25 mL), washed with water to neutral pH, then washed with saturated sodium chloride (15 mL) and finally dried over sodium sulfate. The desiccant was filtered off, the filtrate was evaporated and the residue was dissolved in hexane and chromatographed on a column of silica gel (100-160 µm) (10 g) with 40 hexane-ethyl acetate solution.

80.7 mg (81% yield) of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 ethyl ester are obtained which is a colorless viscous oil, Rf = 0.65 (Silufol). , one spot, eluent: benzene-ethyl acetate 7: 1), mass spectrum (m / z): 368 (M, 2), 348 (M-HF, 7), 323 (M-C 2 H 5 O, 3), 322 { M-C 2 H 5 OH, 7), 303 (15), 302 (M-HF-C 2 H 5 OH, 15) 212 (15), 192 (30), 109 50 (100%), F NMR (5, deuterochloroform) ): -170.25 (m, intensity 2.5), -171.47 (m, intensity 1), ratio of 15 (S) and 15 (R) -epimers 2.5.

Example 2 mg (0.059 mmol) of 11-deoxy-prostaglandin E1 was dissolved in 2 ml of diethyl ester and the solution was cooled to 0 ° C, treated with excess gQ and diazomethane ester solution. The reaction mixture is evaporated to dryness over 30 minutes, the residue is dissolved in 2 ml of methylene chloride and fluorinated with 30 µl of morpholinosulfotrifluoride in the same manner as in Example 1. After proper treatment of the reaction mixture, the crude reaction product is dissolved in hexane and chromatographed on a 3 g silica gel column (100-160 µm) with hexane-ester mixture. so

14.5 g (70% yield) of methyl 15 (R + S) -fluoro-11,15-dioxoxy-prostaglandin E1 are obtained as a colorless viscous oil, Rf = 0.37 (Silufol, one spot, hexane). ester, 2:11; mass spectrum (m / z): 354 (M, 4), 355 (MF, 5), 334 (M-HF, 13), 323 (M-CH 3 O, 3), 322 (M-CH 3 OH). , 7), 303 (18), 302 (M-HF-CH 5 OH, 20), 212 (40), 192 (47), 143 (26), 109 (100%), 1 H-NMR (4, deutero) -chloroform): 5.65 (2H, m ;, C (13> H, C (u> H; 4.85 (1H, dm,

J H 8 Hz, C (15) H); 3.61 (3H1, C (i) OCH3); 2.4 (2H m, C (10) H); 2.25 (2H, t, C <e> H, CcniH;

2.1 (2H, d.d, C <2) H <2) 0.89 (3H t, C <19> CH 3).

¹⁹ F NMR (4, deuterochloroform): 170.3 (m, intensity 2.5), -171.5 (m, intensity 1), 15 (S) - and 15 (R). -empimers ratio is 2.5.

Example 3 15 mg (0.16 mmol) of ethyl 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 are dissolved in 3 ml of a 1: 2 mixture of tetrahydrofuran-methanol and 2 ml of 1 N aqueous sodium hydroxide solution. and the resulting mixture was allowed to stand at room temperature for 18 hours. The reaction mixture was adjusted to pH 2-3 with 1 N hydrochloric acid, evaporated to remove the organic solvent, and dissolved in ethyl acetate (3 x 15 mL). The original organic extract was washed with water to neutral, then washed with saturated sodium chloride solution (10 mL) and dried over sodium sulfate. The desiccant was filtered off and the filtrate was evaporated. The residue was purified by chromatography on 6 g of silica gel (100-160 µm) in a gradient solution of chloroform-ethyl acetate. Thus, 47 mg (92% of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1) was prepared as a colorless viscous oil, Rf = 0.75 (Silufol, one spot, benzene dioxane acetic acid). , 40: 10: 1).

The bulk of the methyl ester prepared by treating 1 mg of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 with a diazomethane ester solution was the same as the mass spectrum of Example 2.

Example 4 15 mg (0.014 mmol) of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 was dissolved in 5 ml of ethanol and 0.375 ml of aqueous sodium chloride solution (5 mg / ml) was added. The mixture was allowed to stand at room temperature for 1 hour and evaporated to dryness. 5.2 g of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 are prepared.

: 97301

Industrial applicability

15-Fluoro-dideoxy-prostaglandin E1 is chemically stable, like natural prostaglandin E1, one of the most active anti-aggregation factors in mammals. They are also stable against prostaglandin dehydrogenase, a fermefit that causes the breakdown of prostaglandin in the body. It has also been found that 15-fluorodideoxy-prostaglandin E1 in experimental animals has a moderate effect on dilating blood vessels, in particular coronary arteries. Based on these properties and because of their low toxicity of 25 mg / kg, the compounds of the present invention can be used as inhibitors of platelet aggregation or platelet aggregation in blood preservation and may also be used in surgery when using artificial blood circulation. 15-Fluorodideoxy-prostaglandin E1 has a positive effect on anti-aggregation and is thus useful in the treatment of patients with cardiovascular disorders.

Claims (1)

Patent Claim Point A process for the preparation of 15 (R + S) -fluoro-11,15-dideoxy-prostaglandin E1 derivatives of general formula (I) having a delayed action and a high degree of anti-aggregation activity. R ¹ is ethyl, methyl, hydrogen, sodium, R ² or R ³ is hydrogen or fluorine, characterized in that a solution of the methyl or ethyl esters of 11-deoxy-prostaglandin E 1 in organic solvent is below 0 ° C. After treatment with morpholinosulfotrifluoride at 15 ° C, the resulting fluorides are extracted by extraction with an organic solvent and the crude product is purified by chromatography, preferably the ester is saponified alkaline.