DE1643739B1 - Epi-PGF, bisdehydro-epi-PGF, tetradehydro-epi-PGF, their methyl esters and methyl ester triacetates and processes for their preparation - Google Patents

Description

Water, gelatin, lactose, starch, magnesium stearate, talc, vegetable Oils, benzyl alcohols, rubber, polyalkylene glycols, petrolatum, cholesterol or others known excipients. The dosage forms are tablets, capsules, pills, Wells, suppositories, solutions, suspensions or emulsions in Question that may be sterilized or contain auxiliary materials, such as Preservatives, stabilizers, wetting or emulsifying agents, salts for Regulation of omotic pressure or buffer substances. You can have others too contain therapeutically active substances, e.g. B. antibacterial and diuretic substances.

The conversion into the methyl ester or the methyl ester triacetate can also used to make crude compounds obtained by esterification or acetylation and regeneration of the acid group or the alcoholic hydroxyl groups to clean. The methyl esters can also be used as plasticizers for vinyl resins will.

The following example explains the method according to the invention.

Example A solution of 100 mg PGE (7- [3a-hydroxy-2- (3-hydroxyoctenyl- (1)) -5 - oxo - cyclopentyl] - hexanecarboxylic acid) in 10 ccm of methanol was in a Chilled ice bath. A cooled solution of 300 mg of sodium borohydride in 35 cc of methanol given. After standing at 0 ° C for 20 minutes, the mixture became 1 Left to stand at room temperature for one hour. Then water was added and the largest Part of the methanol removed in vacuo. After acidification with hydrochloric acid, the aqueous phase extracted three times with ether. The combined ether extracts were washed with water and concentrated to dryness at room temperature.

The residue was subjected to reverse phase separation chromatography on hydrophobic kieselguhr (treated with dichlorodimethylsilane). 43% strength aqueous methanol was used as the mobile phase and a mixture of equal parts of isooctanol and chloroform was used as the stationary phase. The dried ether extract was placed on the column with 16 com stationary phase and developed with 1200 ccm mobile phase. The 475 to 650 cc fractions were combined and concentrated to dryness and recrystallized from ethyl acetate-pentane. The yield was 37 mg PGF, melting point 101 "C. The 300 to 425 ccm fractions were treated in the same way and recrystallized from ethyl acetate-pentane. They gave 47 mg of crystalline Epi-PGF (7-C3a, SB-dihydroliy-2 - (3-Hydroxyoctenyl- (l)) - cyclopentyl] -hexanecarboxylic acid) with a melting point of 128 "C. The interplanar distances in Angstrom units determined by X-ray diffraction on the crystalline Epi-PGF obtained according to the invention are listed below: Epi-PGF dna 1 10.79 ssch 9.15 ssch 8.41 sh 7.22 m 5.64 m 4.78 ssch 4.66 ssch 4, 53 p 4.37 s dA l 4.27 sh 4.17 m 3.89 m 3.77 m 3.64 ssch 3.58 ssch 3.51 ssch 3.42 ssch 3.38 ssch 3.34 ssch 3.12 ssch (sd) 3.03 ssch 2.96 ssch 2.92 ssch 2.83 ssch 2.70 ssch (d) 2.60 sch (d) 2.46 ssch (d) 2.40 ssch 2.35 ssch 2.32 ssch 2.25 m 2.08 ssch 2.00 ssch (sd) 1.69 ssch (sd) s = strong m = medium sch = weak ssch = very weak d = diffuse sd = very diffuse In the same way, bisdehydro-PGE and tetradehydro-PGE became essentially pure bisdehydro-PGF and bisdehydro-epi-PGF as well as tetradehydro-PGF and tetradehydro -epi-PGF produced.

The compounds obtained were so pure that they were found by partition chromatography using a solvent system of methylene chloride, heptane, acetic acid, Water (15: 15: 6: 4) gave essentially ideal curves.

The melting point for bisdehydro-epi-PGF is 93 to 94 "C.

The paper chromatographic mobility in relation to PGE for descending paper chromatography with ethylene chloride-heptane (1: 1) as the mobile phase and 70% acetic acid as the stationary phase is listed below: PGF (0.64) PGE (1.00) Epi-PGF (0.44) Bisdehyde PGF (0.60) Bisdehydro-PGE (0.90) Bisdehydro-epi-PGF (0.39) Tetradehydro PGF (0.60) Tetradehydro-PGE (0.76) Tetradehydro epi-PGF (0.37) By reacting 2.8 micromoles of Epi-PGF, bisdehydro-epi-PGF and tetradehydro-epi-PGF with a slight excess of diazomethane, which had been prepared in ether from 4 micromoles of nitrosomethyl urethane, standing for 5 minutes and distilling off the ether and the excess diazomethane The crystalline methyl esters of these compounds were prepared to dryness. If these esters were reacted with acetic anhydride in pyridine solution, the corresponding methyl ester triacetates were obtained. The residence time of these esters in relation to the corresponding esters of PGF and Epi-PGF is shown in the table below: Methyl ester PGF compound methyl ester triacetate PGF 1.11 1.14 Epi-PGF 100 1.00 Bisdehydro PGF 0.91 0.99 Bisdehydro-epi-PGF 0.89 0.85 Tetradehydro-epi-PGF Q86 0.86 Tetradehydro PGF 0.91 0.96 Flash heater conditions: 220 ° C .; Column temperature: 200 ° C .; Column pressure: 1.0 kg / cm2; Column 1, 83 mx 5 mm, filled with 0.5% “QF-1” (Dow Corning Corp.) on “Gas Chrom P” (Applied Science Laboratory Inc.), as described by Vanden Hewel, Haahti and H orn ing (J. Am. Chem. Soc., Vol. 83, p. 1513 [1961]).

Claims (2)

Claims: 1. Epi-PGF (7 - [3a, 5 - dihydroxy - 2 - (3-hydroxyoctenyl- (1)) - cyclopentyl] - hexanecarboxylic acid), bisdehydro-epi-PGF (7 - [3a, 5fl - dihydroxy-2- (3-hydroxyoctenyl- (1)) - cyclopentyl] - 4-hexenecarboxylic acid) and tetradehydro-epi-PGF (7- [3a, 5ß - dihydroxy -2- (3-hydroxyoctadienyl- (1,5)) - cyclopentyl] - 4 - hexenecarboxylic acid), their methyl esters and methyl ester triacetates. 2. Process for the preparation of the compounds according to claim 1, characterized in that PGE compounds of the general formula in which X is the - CH CH - group and -Y and Z are the - CH2 - CH2 - group, or X and Y are the - CH = CH group and Z is the - CH2 - CH2 --or - CH = CH - group, reduced in a manner known per se with sodium borohydride, separates the 3 a, 5a-dihydroxy compounds obtained in a conventional manner by chromatography from the 3a, 5fl-dihydroxy compounds and optionally then the 3a, 5ß-dihydroxy compounds per se known manner converts into their methyl esters or methyl ester triacetates. The invention relates to Epi-PGF (7- [3a, 5ß-dihydroxy-2- (3-hydroxyoctenyl- (1)) - cyclopentyl] -hexanecarboxylic acid), bisdehydro-epi-PGF (7- [3a, 5ß-dihydroxy-2- (3-hydroxyoctenyl- (1)) - cyclopentyl] -4-hexenecarboxylic acid) and tetradehydro-epi- PGF (7- [3 a, 5k - dihydroxy-2 - (3 - hydroxyoctadienyl - (1,5)) - cyclopentyl] -4-hexenecarboxylic acid), their methyl esters and methyl ester triacetates and a process for their preparation of these connections. The process according to the invention consists in that the corresponding PGE compounds of the general formula in which X is the - CH = CH - group and Y and Z are the - CH2-CH2 - group, or X and Y are the - CH = CH - group and Z is the - CH2-CH2 - or - The CH = CH group, reduced in a known manner with sodium borohydride, separates the 3a, 5a-dihydroxy compounds obtained from the 3a, 5p-dihydroxy compounds in a conventional manner by chromatography, and optionally then separates the 3a, 58-dihydroxy compounds in a manner known per se Way converts into their methyl esters or methyl ester triacetates. The used as starting materials for the process according to the invention PGE compounds, namely PG, PGE2 and PGE3, can be made using the British Patent specification 851 827 or patent 1 443 474 from fatty animal tissue to be isolated. The compounds according to the invention with an SB hydroxyl group have antihypertensive effects. This is surprising since the epimeric Sa-hydroxy compounds have an antihypertensive effect (see Nobel Symposium 2, Prostaglandins, Almqvist Wiksell, Stockholm, Interscience Publishers, pp. 168/169). The antihypertensive effect of the compounds according to the invention is less than that of PGE, which is an extremely strong antihypertensive Represents means. In contrast to PGE, however, the compounds according to the invention are in resistant to aqueous solutions for parenteral injection. They also influence not clotting like this. The compounds of the invention are thus In any case, preferable to the PGE if it affects blood coagulation is contraindicated. The methyl esters of the compounds according to the invention are obtained after methods known per se, e.g. B. by reaction with diazomethane, or by reaction the silver salts of free acids with methyl iodide. The methyl ester triacetates are made by reacting the methyl esters obtained with acetic anhydride or an acetic acid halide. The implementation takes place advantageous in the presence of an acid-binding agent such as pyridine or trimethylamine, and in the presence or absence of an inert solvent such as dioxane or Methylene chloride. The reaction temperature is preferably kept low, e.g. B. between about 10 and 40 "C. The compounds according to the invention can be used together with a suitable organic or inorganic carriers can be applied parenterally, orally or topically. Suitable carriers are e.g. B.