GB2179651A - S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1-one and a process for producing same - Google Patents

Abstract

S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1-one of formula: <IMAGE> which is produced by subjecting carboxyalkylcyclopentenones of general formula <IMAGE> (where n = 4, 6; R = H, C2H5> to microbiological oxidation with 1 to 4 mass percent of dry baker's yeast Saccharomyces cerevisiae, in an aqueous medium in the presence of a source of phosphorus, nitrite or nitroprusside of an alkali metal at 29 to 33 DEG C and a pH value of 7.5 to 9.9, possesses an antisecretory and antiulcerogenic action, and can find application in medicine.

Description

SPECIFICATION S(-)2-(4-ca rboxy-3-hyd roxybutyl) cyclopent-2-)ene-l -one and a process for producing same The present invention relates generally to chemistry and more particularly to a novel compound, viz.

S (-) 2- (4-carboxy-3- hydroxybutyl) cyclopent-2-ene-1 -one and to a process for producing same. The compound in question possesses an antisecretory and antiulcerogenic action and can therefore find application in medicine.

In addition, the compound of the invention is also applicable as an intermediate in the synthesis of prostaglandins, terpenoids, pyrethrins that find application in medicine and farming practice.

A variety of compounds are now in current use that possess an antisecretory and antiulcerative action, such as the drug Cimetidine (cf. W. E. Hansen, S. Bertl, Arzneimittel Forschung/Drug Research, 1983,33(1), 161-163).

However, said drug features a high effective dose and a number of side effects.

Known in the present of the art are such compounds as 6,9-a-oxido-1 1 a, 1 Scr-dihydroxyprosta-6,1 3-dienoic (Prostacycline) and the analogues thereof, such as Carbocycline which have an antisecretory and antiulcerogenic action. The compounds mentioned above, when administered subcutaneously to rats (the effective dose for Prostacycline being 1 mg/kg), inhibit gastric secretion. An optimum antiulcerogenic effect is produced by Prostacycline and Carbocycline when administered in a dose of 500pg/kg, giving 50-percent and 68-percent inhibition, respectively (cf. A. Robert, A. J. Hanchar, C. Lancaster, J. E. Nezamis. Antisecretory and cytoprotective effects of Prostacycline (PGJ2). Fed. Prac., 37, No. 3, 1978, p. 460; B. J. R. Whittle, G. Steel, N. K.Boughton-Smith. Gastrointestinal actions of Carbocyclin, a stable mimic of Prostacyclin. J. Pharm.

Pharmacol, 32, No. 8, 1980, p. 603-604.

There is also known one more compound, viz, 2-(4-carboxybutyl)3-methyl-cyclopentanone, which is likewise capable of inhibiting the secretion of gastric juice (cf. J. F. Poletto, K. F. Bernady, D. Kupfer, R. Partridge, M. I.

Weiss. Prostaglandins and Congeners. Synthesis of Simplified Prostaglandins. Inhibition of Gastric Acid Secretion by 32-(o-carboxyalkyl) -3-alkyl-cycloalkanones. J. Med. Chem., 1975,18, No. 4, p.359-362).

However, all of the compounds mentioned above are featured by high effective doses and are devoid of a selectively directional action.

Both the compound of the invention and the process for its production are novel and have not so far been described in literature.

The invention has for its object to provide a novel compound capable of producing a prominent antisecretory and antiulcerogenic effect and a process for producing same.

The aforesaid object is accomplished due to the fact, according to the invention, the novel compound disclosed in this invention, viz, S(-)2-(4-carboxy-3-hydroxybutyl) cyclopent-2-ene-1 -one has the following formula

The compound of the invention appears as a white-coloured solid substance, melting at within 113 and 11 5 C (with decomposition), readily soluble in water - 78 mg/ml (20"C), in 0.1 N HCI - 44 mg/ml (20"C), in 0.1 N NaOH - 78 mg/ml (20"C). The compound is optically active, [a]20 = -19 to -20 (C = 1-4, in ethanol.

An absolute configuration of the molecule (S) has been established in a diffraction experiment in terms of anomalous scattering of oxygen atoms.

The compound is thermostable at 50"C for 30 days.

Biological potency of the compound in question has been studied in experiments on test animals.

The action of S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1 -one was studied on the model of a stress ulcer according to the K. Takagi's technique (1968) in order to reveal its cytoprotective effects. Male albino rats 120 to 150 g in mass had been left without food 18 hours before the experiment, the water ration remaining unlimited. The compound under study was administered subcutaneously, and the test animals were exposed to a stress effect by submerging them, enclosed in a metallic cage, in water at 22 + 1"C for 21 hours. Thereupon the test animals were sacrificed painlessly, the stomach was taken out, slit open along the greater curve, rinsed with water and fixed for 5 min in a 0.5% formalin solution. Then the stomach was glued to cardboard and examined microscopically.The affections of the gastric mucosa were assessed according to the following three criteria, i.e., the ulcer index (Ul) which was in fact a total area of the gastric ulcers measured planimetrically according to S.

T. Konturek (1968), an average number of ulcers per stomach, and the state of the gastric mucosa estimated in points according to a system suggested by A. A. M. Abdel-Galil (1968). The effect of the compound under study was judged by the cytoprotection (CP) ratio calculated according to D. A. Brodie (1960): CP = Ulcontr. Ultest.100 U 1test S(-)2- (4-carboxy-3-hydroxybutyl)cyclopent-2-en 1-one was dissolved in physiological saline to obtain a required concentration, whereupon 1 ml of the compound was administered subcutaneously in a dose of 0.01; 0.1; 1;10; 100; 1000/1g/kg,1 ml physiological saline administered subcutaneously being the control.

The results of the experiment and the control have been compared with the aid of the Student t-test, and the data obtained are tabulated in Stable 1 below.

The data contained in Table 1 give evidence that the compound of the invention has a cytoprotective activity in a stress ulcer.

TABLE 1 Experimental findings obtained from the study of the cytoprotective activity of the compound in question on the model of a stress ulcer Number Total Number of Dose, of Ulcer number of ulcers per Nos. Compound /lg/kg animals index CP, % ulcers animal Points 1 2 3 4 5 6 7 8 9 1. Control - 6 4.83+0.27 - 129 21.50+7.11 3.66+0.54 2. Compound 0.01 6 4.20+0.98a) 13.04 90 15.00+3.75a) 3.16+1.03a) being disclosed 3. Same 0.1 6 1.79+0.83b) 62.93 71 11.83+5.07 2.50+0.87 4. Same 1 6 1.04+0.53b, 78.46 59 9.83+5.45 1 66+054b) 5.Same 10 6 2.16+1.47 55.27 53 8.83+6.38 116+042b) 6. Same 100 6 2.87+1.07 40.57 33 550+217b) 1.83l1.03 7. Same 1000 6 3.79+0.60 21.53 86 14.33+3.16 3.16+0.42 a) p > 0.05 b) p p(0.001 In terms of the ulcer index (Ul) units S(-)2-(4-carboxy-3-hydroxybutyl (cyclopent-2-ene-1 -one exhibits most potency in a dose of 1 sseg/kg. The minimum number of gastric ulcerations is observed with a dose of 100 pg/kg; however, the area of each ulcer is relatively large in case of the aforesaid dose.An analysis in terms of points shows the highest activity of the compound at a dose of 10 /lg/kg. An assessment of the citoprotection ratio places the maximum effect upon a dose of 1 Hg/kg its percentage amounting to 78.5.

The cytoprotective action of the compound involved has also been studied on the model of an indomethacin-induced ulcer. The compound was studied on male albino rats 170 to 200 g in mass, on the model of an ulcer according to A. Balint (1981). The test animals had been left without food for a period 24 hours before the experiment, while the water supply remained unlimited. Once the compound involved had been administered subcutaneously, indomethacin was administered intraperitineally in a dose fo 30 mg/kg. In a four-hour period the animals were sacrificed painlessly. The stomachs of the test animals were examined as described above with reference to a stress ulcer. The compound of the invention was dissolved in physiological solution to obtain a required concentration, whereupon the compound was administered subcutaneously in an amount of up to 1 ml per injection, in a dose of 0.1; 1; 10; 100; 1000 Fg/kg,1 ml phisiological solution being administered as the control. Indomethacin triturated into a powder and diluted with physiological saline was doped with a drop of Twin-80. The data obtained were processed statistically in a way described above. The results obtained are represented in Table 2 to demonstrate that the compound of the invention exhibits cytoprotective activity towards an indomethacin-induced model of ulcer.

TABLE 2 Experimental findings obtained from the study of the cytoprotective activity of the compound in question on the model of an indomethacin-induced ulcer Number Ulcer Total Number of Dose, of index number of ulcers per Points Nos. Compound lig/kg animals M + m CP, % ulcers animal M f m M + m 1 2 3 4 5 6 7 8 9 1. Control - 12 4.87+0.25 - 244 20.33+2.22 3.75+0.27 2. Compound 0.1 12 2.04+0.47 58.11 88 7.33 AS 1.45 1.83 0.42 being disclosed 3. Same 1.0 12 1.16+0.47 76.18 57 4.75+1.57 1.25+0.37 4. Same 10 12 0.65+0.34 86.65 29 2.41+1.09 1.16+0.23 5.Same 100 12 2.60+0.23 46.11 117 9.75+1.02 2.33+0.29 6. Same 1000 12 3.10+0.42 36.34 159 13.25+2.93 2.50+0.31 P < 0.001 against the control group The value of the ulcer index (Ul) reaches its minimum at a dose of 101lg/kg, the least number of ulcers being observed with the same dose. The tabulated data enable one to infer that the best effect is attained with a dose of 10,ag/kg (the CP ratio being at 86.6 percent).

The effects of the compound being disclosed upon the secretory function of the stomach were studied in experiments on cats who had previously been operated upon for implantation of gastric fistulas. Gastric secretion was stimulated with optimal doses of pentagastrin (5 or 10 Hg/kg depending on the sensitivity of a given animal). 30 min after pentagastric administration the compound of the invention was injected subcutaneously in a dose of 0.1 to 300 pg/kg, and the gastric juice was gathered for a 30-min period. Then the amount of the gastric juice thus collected was measured in millilitres, while the total acidity of the gastric juice was determined by titration aginst a 0.01 N NaOH solution, with the Tepfer's reagent used as an indicator. The total acidity of the gastric juice secreted was calculated in milliequivalents.According to the experiments discussed above the compound of the invention inhibited the gastric juice secretion and caused a reduction in the gastric juice total acidity when administered in as low doses as 0.3 to 3 Hg/kg, the maximum effect being observed upon premilimary administration of the compound involved in a doses of 30 to 300 pglkg. The experiment results are represented in table 3 below.

TABLE 3 Amount and total acidity of gastric juice before and after administration of the compound being disclosed as obtained in experiments on cats No. of test animal Total Total Total Amount of acidity, Amount of acidity, Amount of acidity, Nos. Test scheme juice, ml mEq juice, ml mEq juice, ml mEq 1 2 3 4 5 6 7 8 1. Pentagastrin 9.2 1.31 - - 11.0 1.50 2. Pentagastrin + the 12.3 1.83 - - 8.0 1.10 compound of the invention (0.1 ,ag/kg) 3. Pentagastrin 9.0 1.26 1.40 1.40 18.0 2.03 4. Pentagastrin + the 7.0 0.60 10.0 1.21 10.0 1.14 compound of the invention (0.3 U9/kg) 5.Pentagastrin 11.2 1.54 15.5 2.19 14.0 1.57 TABLE 3-continued Amount and total acidity of gastric juice before and after administration of the compound being disclosed as obtained in experiments on cats No. of test animal Total Total Total Amount of acidity, Amount of acidity, Amount of acidity, Nos. Test scheme juice, ml mEq juice, ml mEq juice, ml mEq 1 2 3 4 5 6 7 8 6. Pentagastrin + the 4.4 0.63 5.5 0.59 7.4 1.05 compound of the invention (3 zg/kg) 7. Pentagastrin 9.0 1.70 9.8 1.41 11.0 1.26 8. Pentagastrin + the 2.5 0.10 4.0 0.21 6.0 0.51 compound of the invention (30 ijg/kg) 9. Pentagastrin 10.5 0.86 6.0 1.60 9.0 0.80 10.Pentagastrin + the 4.0 0.52 9.5 0.40 1.50 0.20 compound of the invention (300 pg/kg) A similar effect is attained with the oral administration route.

Acute toxicity of the compound has been studied in experiments on male albino mice, 20 g mass, with the compound under test administered intravenously in a variety of doses ranging from 50 to 500 mg/kg. No symptoms of toxic effect of the compound involved were noticed.

Nor is the compound of the invention causative of an adverse effect upon the cardiovascular activity when administered within a broad range of doses. In experiments on narcotized (x-glucochloralose-90 mg/kg, and urethane-1 00 mg/kg) cats 2.8 to 3.6 kg mass, the compound of the invention administered in a dose fo 30 to 60 Ug/kg intravenously brought about some hypotensive effect (by 30 mm Hg) of low duration (up to 90 s). With the dose increased to 100,ug/kg the hypotensive effect did not rise.

The compound of the invention exhibited some concomitant hepato-protective action in experiments both in vitro and in vivo. The mutagenic potency of the compound under consideration has also been the subject of investigation, two techniques for estimation of the chromosome mutations being applied, viz, that of the gene mutations and of the dominant lethal mutations in the gametes of mice. No gene mutations were observed under the effect of the compound in question.

Thus, the compound of the invention possesses a pronounced antisecretory and antiulcerogenic action; is of low toxicity, e.g., when administered to mice in a dose 1666 times the effective dose the compound causes no intoxication symptoms in the test animals; is not causative of gene mutations; and is capable of producing more selective effect compared with the heretofore-known compounds of the same character.

The subject of the invention is also a process for producing the novel compound, viz, S(-)2-(4-carboxy-3 hydroxybutyl)cyclopent-2-ene- 1-one.

According to the invention, the process for producing the compound being disclosed consists in that carboxyalkylcyclopentenones of a general formula:

where n = 4, 6; R = H; C2H5, are subjected to microbiological oxidation with dry baker's yeast Saccharomyces cerevisiae taken in an amount of 1 to 4 mass percent, in an aqueous medium in the presence of a source of phosphorus, nitrite or nitroprusside of an alkali metal at 29 to 33"C and the pH value of 7.5 to 9.9, followed by isolation of the end product.

It is expedient that carboxyalkylcyclopentenones be applied in a concentration not exceeding one gram per litre of the medium. It is also preferential to use phosphates of alkali metals as the source of phosphorus.

The process of the invention is carried into effect-as follows.

Microbiological oxidation is carried out by incubation of dry baker's yeast Saccharomyces cerevisiae in an aqueous nutrient medium, containing, as a source of carbon, carboxyalkylcyclopentenones, which are preferably introduced into the nutrient medium in a maximum concentration of 1 g/l. Used as a source of phosphorus may be phosphates of alkali metals, or a potassium-phosphate buffer. Added to the reaction mixture is also sodium nitrite or nitroprusside as an inhibitor of the process.

The reaction occurs within a temperature range of 29 and 33"C and at the pH values of 7.5 to 9.9. The amount of yeast varies within 1 and 4 mass percent, the reaction time is 24 hours. The yield of the end product is withiN 21 to 38 percent. Apart from the end product the reaction mixture can contain also 2-(6-carboxyhexyl) cyclopent-2-ene-1 -one, 2(4-carboxybutyl)cyclopent-2-ene-1 -one and 2-(2-carboxyethyl)cyclopent-2-ene-1 -one.

Identity of the compound being dislosed to the structure of S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2ene-1 -one has been proved by the spectral techniques (PMR, IR, UV), mass-spectra) and by the X-ray diffraction analysis.

The qualitative analysis of the reaction mixture has been carried by the thin layer chromatography (Silufol, UV254, Kavalier, CzSSR). Two systems of solvents and two development techniques have been applied: 1) Diethyl ether: diisopropyl ether: acetic acid = 70:35:3 (by volume). Development has been performed by immersing a chromatogram in a 1-percent solution of potassium permanganate; once the excessive reagent has been washed off with water, the chromatogram is dried at 100"C. Rf-2-(6-carbethoxyhexyl)cyclopent-2-ene-1 one - 0.89; Rf-2- (4-carboxybutyl)cyclopent-2-ene- 1-one - 0.47; Rf-2- (2-carboxyethyl)cyclopent-2-ene- 1-one - 0.38; Rf-2(4-carboxy-3-hydrobutyl)cyclopent-2-ene-1 -one - 0.18; 2) Diethyl ether: benzene: acetic acid = 40:20:20 (by volume).Developed of a chromatogram has been carried out by spraying with a solution, containing 3 g vanillin and 1 ml concentrated sulphuric acid per 100 ml ethanol.

The plate has been heated for a short time until spots appear. 2-(6-carbethyoxyhexyl)cycíopent-2-ene-1 -one, 2- (6-carboxyhexyl)cycíopent-2-ene-1 -one, 2- (4-carboxybutyl)cyclopent-2-ene-1 -one, 2- (2-carboxy ethyl)cyclopent-2-ene-1 -one give yellow spots, while S(-)2-(4-carboxy-3-hydroxybutyí)cyclopent-2-ene-1 one, a brick-red spot. Rf-2-(6-carbethoxyhexyl)cyclopent-2-ene-1 -one - 0.95; Rf-2- (4-carboxybutyl) cyclopent-2-ene-1 -one - 0.77; Rf-2- (2-carboxyethyl)cyclopent-2-ene-1 -one - 0.66; Rf-S(-)2- (4-carboxy-3- hydroxybutyl)cyclopent-2-ene-1 -one - 0.43;The quantitative analysis of the compound being disclosed has been carried out by the highly efficient liquid chromatography technique (column measuring 250 x 2 mm; silasorb 600; 5 p; eluent - 82 percent of hexane, 16.2 percent of isopropanol, 0.9 percent of water, 0.9 percent of acetic acid). Detection has been performed in terms of UV absorption on 240 nm; the chromatograms have been processed by the method of absolute calibration.

To promote understanding of the present invention given below are the following examples of production of the compound being disclosed.

Example 1 Added to 104 mg (0.44 mM) 2-(6-carbethoxyhexyl)cyclopent-2-ene-1 -one are 100 ml 0.1 M solution of dibasic potassium phosphate which has been brought to the pH value of 9.5 with 1 M solution of KOH, 0.015 g (5.10-5 M) sodium nitroprusside and 2 g dry baker's yeast Saccharomyces cerevisiae. The reaction mixture is incubated for 24 hours at 29"C on a rotary shaker (250 rpm), then centrifugalized (4000 rpm, 15 minutes). The centrifugate is separated, the yeast is washed with a 1 .percent NaCI solution and centrifugalized once more.The total centrifugate is acidulated with concentrated HCI to the pH value of 2.0 and extracted twice with ethylacetate (1:2). The ethylacetate solution is dehydrated with an anhydrous sodium sulphate and evaporation-concentrated till an oil-like consistency. The mixture contains 30.7 mg (0.17 mM) 38.6-percent 2-(4-carboxybutyl)cyclopent-2-ene-1-one (Rf - 0.47); 5.8 mg (0.038 mN) 8.8-percent2-(2-carboxy- ethyl)cyclopent-2-ene-1 -one (Rf - 0.38) and 28.9 mg (0.146 mM) 33.4-percent S(-)2-(4-carboxy-3 hydroxybutyl)cyclopent-2-ene-1 -one (Rf - 0.18). Then the end product, i.e. S(-)2-(4-carboxy-3 hydroxybutyl)cyclopent-2-ene-1 -one is isolated.

0.76 g of the resultant oil, containing 0.22 g 2-(4-carboxybutyl)cyclopent-2-ene-1-one and 0.15 g S(-)2-(4-carboxy-3-hydroxybutyl) cyclopent-2-ene-1 -one, is dissolved in 50 ml chloroform and applied to a silicagel-packed column (the height of the silicagel packing, 3.5 cm, diameter, 3.0 cm). Once 2-(4-carboxybutyl)cyclopent-2-ene-1 -one has been separated by washing with 500 ml chloroform, the system is changed for a more polar (8 percent of isopropanol in chloroform, about 100 ml), whereupon 85.4 mg purified S(-) -2- (4-carboxy-3- hydroxybutyl)cyclopent-2-ene- 1-one is isolated (the yield percent being 20.5).

Identification of the end product Elementary analysis: C10H1404 Found, % C 60.24; H 7.46.

Calculated, %: C 60.61? H 7.07.

PMR spectrum in CDCI3, hexamethyldisiloxane, 90 MHz ppm in the b scale: 1.4 (2H; methylene group), 2,4 (8H; methylene groups at carbonyl group and at the double bond); 3.9 (1 H; methyne proton at hydroxyl group), 5.4 (2H; protons of carboxyl and hydroxyl groups), 7,3 (1 H; olephine proton).

IR spectrum (vaseline oil, cam~'): 3350 vOH 3210 V OH 1730 vC=O 1690 vC=O(COOH) 1630 vC=C UV spectrum (ajax in water): 234 nm.

Mass-spectrum molecular ion of methyl ether of S(-)2- (4-carboxy-3-hydrnxybutyl)cyclopent-2-ene-1 -one is unstable (M-1 8) - 194.

Example 2 Added to 90 mg (0.43 mM) 2-(6-carboxyhexyl)cyclopent-2-ene-1 -one are 100 ml 0.1 M solution of dibasic potassium phosphate treated with a 1 M KOH solution to bring the pH value to 9.5, 40 mg (1.3 10-4 M) sodium nitroprusside and 2 g dry baker's yeast Saccharomyces cerevisiae. The reaction mixture is incubated and treated as described in Example 1 to obtain 29.3 mg (0.16 mM) 37.6-percent 2-(4-carboxybutyl)cyclopent-2-ene-1 one; 11.2 mg (7.27 10-2 mM) 17-percent-2- (2-carboxyethyl)cyclopent-2-ene-1 -one, 17.8 mg (0.09 mM) 21-percent S(-)2-(4-carboxy-3-hydroxybutylcyclopent-2-ene-1 -one. Then the end product is isolated as described in Example 1, the yield percent being 10.

Example 3 Added to 100 mg (0.549 mM) 2-(4-carboxybutyl)cyclopent-2-ene-1-one are 100 ml 0.1 M solution of dibasic potassium phosphate treated with 1 M KOH solution to bring the pH value to 9.5, 40 mg (1.3 1 10-4 M) sodium nitroprusside and 2 g dry baker's yeast Saccharomyces cerevisiae. The reaction mixture is incubated and treated as described in Example 1 to obtain 55.2 mg (0.30 mM) 55.2-percent 2-(4-carboxybutyl) cyclopent-2-ene-1 -one, 22 mg (0.14 mM) 26.1-percent 2-(2-carboxyethyl)cyclopent-2-ene-1 -one, and 8.5 mg (4.3 10-2 mM) 7.8-percent S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1 -one. Then the end product is isolated as described in Example 1, the yield percent being 4.

Example 4 Added to 104 mg (0.44 mM) 2-(6-carbethoxyhexyl)cyclopent-2-ene-1 -one are 100 ml 0.1 M solution of dibasic potassium phosphate treated with a 1 M KOH solution to bring the pH value to 9.5, 0.020 g (2.9 1 10-4 M) sodium nitrite and 2 g dry baker's yeast Saccharomyces cerevisiae. The reaction mixture is incubated and treated as described in Example 1 to obtain 7.8 mg (4.28 g 10-2 mM) 9.8-percent 2-(4-carboxybutyl)cyclopent-2-ene-l 1-one, 31.4 mg (0.2 mM) 46.3-percent 2-(2-carboxyethyl)cyclopent-2- ene-1 -one, 14.4 mg (7.27 10-2 mM) 16.5-percent S (-)2- (4-carboxy-3- hydroxybutyl)cyclopent-2-ene-1 -one.

Then the end product is isolated as described in Example 1, the yield percentage being 8.

Example 5 Added to 104 mg (0.44 mM) 2-(6-carbethoxyhexyl)cyclopent-2-ene-1 -one are 100 ml 0.1 M solution of dibasic potassium phosphate treated with a 1 M KOH solution to bring the pH value to 9.5, 0.040 g (1.3 10-4 M) sodium nitroprusside and 4 g dry baker's yeast Saccharomyces cerevisiae. The reaction mixture is incubated and treated as described in Example 1 to obtain 33.7 mg (0.185 mM) 42.2-percent 2-(4-carboxybutyl) cyclopent-2-ene-1 -one, 2.7 mg (0.017 mM) 4.0-percent 2-(2-carboxyethyl)cyclopent-2-ene-1 -one, 13.7 mg (0.069 mM) 15.7-percent S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1 -one. Then the end product is isolated as described in Example 1, the yield percentage being 7.5.

Example 6 Added to 104 mg (44 mM) 2-(6-carbethoxyhexyl)cyclopent-2-ene-1-one are 100 ml 0.1 M solution of a phosphate buffer (pH = 7.5), 30 mg (9.8 10-5 M) sodium nitroprusside and 2 g dry baker's yeast Saccharomyces cerevisiae. The reaction mixture is incubated and treated as described in Example 1 to obtain 37.1 mg (0.20 mM) 46.4-percent 2-(4-carboxybutyl)cyclopent-2-ene-1 -one, 4.6 mg (0.03 mM) 6.8-percent 2-(2-carboxyethyl)cyclopent-2-ene-1 -one, and 20 mg (0.10 mM) 23.1-percent S(-)2-(4-carboxy-3hydroxybutyl)cyclopent-2-ene-1 -one. The end product is isolated as described in Example 1, the yield percentage being 11.

Example 7 Added to 104 mg (0.44 mM) 2-(6-carbethoxyhexyl)cyclopent-2-ene-1 -one are 100 ml 0.1 M solution of dibasic potassium phosphate treated with a 1 M KOH solution to bring the pH value to 9.5, 15 mg (4.9 1 10-5 M) sodium nitroprusside and 2 g dry baker's yeast Saccharomyces cerevisiae. The reaction mixture is incubated at 33"C and treated as described in Example 1 to obtain 27.8 mg (0.15 mM) 34.9-percent 2-(4-carboxybutyl)cyclopent-2-ene-1 -one, 9.8 mg (0.063 mM) 14.5-percent 2-(2-carboxyethyl)cyclopent-2-ene-1 - one, and 33.3 mg (0.168 mM) 38.4-percent S(-)2(4-carboxy-3-hydrnxybutyl)cyclopent-2-ene-1 -one. The end product is isolated as described in Example 1, the yield percentage being 20.

Example 8 Placed in a 2.5-litre cylindrical vessel provided with a stirrer, thermometer and an air supply tube, is 2 1 of a mixture of 0.1 M K2HPO4 and 1 M KOH solutions, then added thereto are 0.8 g (2.7 mM) sodium nitroprusside, 40 g dry baker's yeast Saccharomyces cerevisiae and 1 ml foam-suppressor, viz, propinol. Then added to said reaction mixture under stirring and aeration (40 to 50 I/h), heated to 30"C, is 2 g (8.4 mM) 2-(6-car bethoxyhexyl)cyclopent-2-ene-1 -one. The incubation process proceeds for 24 hours. Then aeration is stopped, 30 ml concentrated HCI is added, and the reaction mixture is stirred for further 15 to 20 min at the same temperature.Then the reaction mixture is centrifugalized for 20 min at 2500 to 3000 rmp to obtain 1.84 1 supernatan liquid, which is then evaporation-concentrated on a rotary evaporator at a maximum temperature of 60"C to an amount of 0.22 1 and four times extracted with-a double volume of ethylacetate. Next ethylacetate is dehydrated and evaporation) concentrated to obtain 1.52 g oil, containing 151 mg (0.83 mM) 9.9-percent 2-(4-carboxybutyl)cyclopent-2-ene-1 -one, 106 mg (0.69 mM) 8.2-percent 2-(2-carboxyethyl)cyclopent-2ene-1 -one, and 610 mg (3.08 mM) 36.7-percent S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1 -one.

Then the end product is isolated as described in Example 1, the yield percentage being 18.

Example 9 Charged into a 200-litre fermentation vat provided with a stirrer (250 rmp) and an aeration system, is 50 I 0.1 M K2HPO4 solution treated with a 1 M KOH solution to bring the pH value to 9.5 m then added thereto are 20 g (67.1 mM) sodium nitroprusside, 1 kg dry baker's yeast Saccharomyces cerevisiae, 50 g (210 mM) 2-(6-carbethoxyhexyl) cyclopent-2-ene-l -one, and 20 ml of a foam-suppressor propinol. The incubation process is carried out under stirring and aeration (0.4:1) at 29 + 1"C for 24 hours. The end pH value is 7.95.

Then the incubate is cooled down to 20"C, and its pH value is brought to 2.0 with concentrated HCI, (750 ml) whereupon the mixture is stirred for another 25 min. Then the mixture is centrifugalized, 35 ml propinol is added to 47 1 of the supernatant liquid (pH = 2.1) and the mixture is evaporation-concentrated to a volume of 10 I.

The evaporation-concentrated incubate is then four times extracted with a double volume of ethylacetate. Next the total ethylacetate is evaporation-concentrated, 6.62 g S (-) 2- (4-carboxy-3- hydroxybutyl)cyclopent-2-ene- 1-one is filtered out as a crude product, and concentration by evaporation is continued until an oil is obtained.

Weight - 57.14 g.

Then 250 silicagel is suspended in 580 ml chloroform, and the mixture is poured into a one-litre cylindrical dividing funnel. Once a silicagel layer has been formed, 57.14 g oil in 100 ml chloroform is transferred to a column.

Then the column is washed with chloroform, and some isopropanol is added thereto.

The initial 3.311 of the eluent that has passed through the column, contains some admixtures, i.e., 2- (4-carboxybutyl)cyclopent-2-ene- 1-one and 2- (2-carboxyethyl)cyclopent-2-ene-1 -one, and also 2.5-percent of the end product. After passing the following portions of the eluent and its evaporation-concentration, an oil is obtained from which is isolated 2.6 g S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1-one as a crude product). Then the crude product is finally purified by washing with acetone through a silicagel bed to obtain 8.22 g (41.5 mM) 19.8-percent S(-)2- (4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1 -one.

The compound of the invention possesses a pronounced antisecretory and antiulcerogenic action, is of low toxicity, produces no gene mutations, and features more selective action compared to the heretofore-known compound of the same character.

Claims (6)

1. S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1 -one of the following formula

2. A process for producing S(-)2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1 -one as claimed in Claim 1, consisting in that carboxyalkylcyclopentenones of a general formula

where n = 4,6; R = H; C2H5, are subjected to microbiological oxidation with dry baker's yeast Saccharomyces cerevisiae, taken in an amount of 1 to 4 mass percent, in an aqueous medium in the presence of a source of phosphorus, nitrite or nitroprusside of an alkali metal at 29 to 33"C and the pH value of 7.5 to 9.9, followed by isolation of the end product.

3. A process as claimed in Claim 2, wherein carboxyalkylcyclopentenones are taken in a concentration not exceeding one gram per litre of the medium.

4. A process as claimed in Claim 2 or 3, wherein used as a source of phosporus are phosphates of alkali metals.

5. S(-)-2-(4-carboxy-3-hydroxybutyl)cyclopent-2-ene-1 -one as claimed in Claim 1, whenever produced by the process as claimed in Claims 2, 3 or 4.

6. A process as claimed in Claim 2, 3 or 4 substantially as described hereinbefore with reference to and as disclosed in the examples cited.