CS253326B1 - Prostaglandin F2oc Analogs - Google Patents

Abstract

Analogues of prostaglandin F2 oC of the general formula I, where X represents an oxygen or sulfur atom and the COOR substituent is in position 2 or 3, R represents hydrogen, methyl or ethyl, R^ represents n-butyl, 3-chlorophenoxy- or 3-trifluoromethylphenoxy group, R2 represents hydrogen or tetrahydropyran-2-yl, A represents a hydroxyl group or OR2 and B represents hydrogen or A+B together together represent the OCH2CH2O group, have potential use in veterinary and human medicine. Their production method, for example, consists in adding a solution of lactol of general formula II in the above-mentioned solvent to a 2 to 4 molar excess of the in situ prepared ylide of general formula III, where X and R have the meanings given above, in a tetrahydrofuran or 1,2-dimethoxymethane environment at a temperature of 20-10 °C, after which, after the olefination reaction, an aqueous solution of sodium chloride and sodium hydrogen sulfate is gradually added to the reaction mixture, after which the product of general formula I is isolated directly from the organic phase, or only after the action of acidic reagents.

Description

The invention relates to a prostaglandin analogue of the general formula I, where X represents an oxygen or sulfur atom and the COOR substituent is in position 2 or 3, R represents hydrogen, methyl or ethyl, R ¹ represents n-butyl, 3-chlorophenoxy or 3-trifluoromethylphenoxy group, A represents a hydroxyl group or

2 OR , B represents hydrogen or A + B together represent an OCH 2 CH 2 O group, R represents hydrogen or tetrahydropyran-2-yl.

The compounds of the general formula I represent a new group of prostaglandin F ₂ analogues. From the known state of the art (Chem. Eng. News 1982, No 33, p. 30; Kontakte (Merck Darmstadt) 1093 (2), p. 27 and 1984 (2), p. 50; Angew. Chem. 95, 782 (1983); Angew. Chem. 95, 854 (1984) it is possible to assume increased stability and therapeutic efficacy for the compounds of the general formula I.

The subject of the invention is also a method for preparing compounds of general formula I. The essence of the method according to the invention consists in adding lactol of general formula II, where R, R, A, B have the meanings given above, to the in situ prepared ylide of general formula III, where R and X have the meanings given above, in an environment of anhydrous tetrahydrofuran or 1,2-dimethoxyethane in an inert nitrogen or argon atmosphere at a temperature of 20-10 °C, wherein R, R, A, B have the meanings given above, whereby the molar ratio of compounds of general formula III:II is 4 to 2:1.

The ylide of general formula III is prepared from the corresponding triphenylphosphonium halide by the action of a base, preferably potassium tert-butylate. The course of the olefination reaction can be monitored by thin layer chromatography. After the reaction is complete, usually after 2 to 24 hours, the reaction mixture is decomposed successively with aqueous sodium chloride and sodium hydrogen sulfate. The organic phase is separated and the aqueous layer is extracted with the above-mentioned solvent. The distillation residue obtained from the combined organic fractions after drying with an inorganic drying agent such as anhydrous sodium or magnesium sulfate and evaporation of the solvent is chromatographed on a silica gel column, preferably in the benzene-ethyl acetate system.

In the case where a lactol of general formula II was used in the olefination reaction, where R + H and

A+B together represent OCH-CH-O, the desired product of the general formula I is obtained. In other cases, ^zz 2 when R represents tetrahydropyran-2-yl and A represents an OR group, the protecting group is removed by the action of acidic reacting agents. Preferably, this deprotection is carried out using an acidic ion exchanger in the H cycle such as Dowex 50 in an acetone-methanol-water environment at a temperature of 15 to 35 °C. After separation of the ion exchanger, extraction of the product with an organic solvent is carried out by a known procedure, combined with subsequent chromatographic purification, and the product of the general formula I, where R=H and A represents a hydroxyl group, is obtained in high yield.

The method according to the invention does not require expensive equipment, uses readily available reagents and can be carried out in larger quantities without any problems. From the point of view of occupational safety and environmental protection, especially waste water, it is fully satisfactory, so that the costs of waste disposal are minimal.

The invention is demonstrated by several specific examples, which are illustrative only and do not limit the scope of the invention in any way.

Example

To a suspension of 1.34 g of (2-methoxycarbonyl-5-furyl-methyl)triphenylphosphonium chloride (mp 219-221 °C) in 9 ml of anhydrous tetrahydrofuran (nitrogen atmosphere) at a temperature of 10-15 °C was added dropwise 2.1 ml of a 1.477 M solution of potassium tert-butoxide in tetrahydrofuran. After a few minutes, 411 mg of lactol of general formula II (where R ⁴ = 3-chloro2 2 phenoxy, B = H, A = OR , R = tetrahydropyran-2-yl) in 5 ml of tetrahydrofuran was added to the resulting ylide. After 5 hours of stirring at 20 to 25 °C (the reaction was monitored by thin-layer chromatography on silica gel), 0.85 ml of water, 2.6 ml of saturated sodium chloride solution and finally 0.45 ml of 4 M sodium hydrogen sulfate solution were gradually added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with 3x 10 ml of the above-mentioned solvent. The combined extracts were dried over magnesium sulfate, the solvents were evaporated and the distillation residue (2.01 g) was chromatographed on a column of ' 253326 silica gel (eluent benzeneethyl acetate, 4:1). 466 mg (91.2%) of oily, yellowish product I was obtained, where R , R , A, B have the above-mentioned meaning, X denotes oxygen and R denotes CH ₃ group.

Mass spectrum (m/z, % rel. int.): 85 (100), 71 (98), 57 (95), 41 (8.0), 155 (30),

229 (17), 139 (15), 267 (10), 267 (10), 295 (5), 384 (6). The infrared spectrum contains the bands (CHClj) (cm ^-1 ): 3,600, 3,500, 2,950, 1,720, 1,595, 1,505.

Example 2

Mix 209.3 mg of the compound of general formula I, from Example 1, 6 ml of acetone, 3 ml of methanol,

2.5 ml of water and 500 mg of Dowex 50 in H ⁺ cycle were stirred at room temperature for 24 hours. The reaction progress was monitored by thin layer chromatography on silica gel. The aspirated ion exchanger was washed with 2x 3 ml of acetone-water mixture (7:3), the organic solvents from the combined fractions were; evaporated under reduced pressure, the distillation residue (aqueous phase) extracted with 5x 5 ml of ethyl acetate, the combined organic fractions dried over magnesium sulfate, the solvents evaporated and from the distillation residue (154 mg) 128 mg (86%) of the product of general formula I was obtained by column chromatography on silica gel (eluent benzene-acetic acid-methanol in a volume ratio of 16:1:1), where R denotes methyl, R ¹ denotes 3-chlorophenoxy, B denotes hydrogen, A denotes a hydroxyl group and X denotes oxygen.

Mass spectrum (m/z, % rel. int.): 43 (100), 165 (88), 105 (58), 139 /(54), 321 (20); ΜΪ' = 462 (12.5), MΙ - H ₂ 0 =444 (1.5), MΙ - 2 HjO = 426 (1), MΙ - 3 H ₂ O = 408 (0.5).

The infrared spectrum contains bands (CHCl-j): 3,600, 3,429, 3,010, 2,940, 1,720, 1,600,

505/cm ¹ ).

Example 3

To a solution (argon atmosphere) of the ylide of general formula III, where R denotes methyl, X denotes oxygen, prepared from 1.11.g of (3-methoxycarbonyl-5-furylmethyl)triphenylphosphonium chloride, m.p. 162-172 °C, in 8 ml of tetrahydrofuran and 1.7 ml of a 1.477 M solution of potassium tert-butoxide (339 mg of lactol of general formula II, where R denotes 3-chlorophenoxy, R denotes 2-tetrahydropyran-2-yl, B=H, A=OR), dissolved in 4 ml of tetrahydrofuran, was added with stirring at room temperature. After 24 hours, the reaction mixture was worked up as in Example 1 and 214 mg was obtained. 12 of the product of general formula I, where R, R, R, Β, A, X have the above meaning, the mass spectrum of which contains the ionic species (m/z,·% rel. int): 85 (100), 71 (36), 4.1 (15), 177 (4), 265 (4), 163 (3), 304 (3), 251 (2), 407 (1), 226 (1).

The infrared spectrum contains bands (CHCl^) at (cm ¹ ): 3,600, .3,480, 3,020, 2,960, 1,720, 1,600, 1,480.

Example 4

From a mixture of 327 mg of the compound of general formula I from example 3, 8.5 ml of acetone, 3. ml of methanol, 3.5 ml of water and 800 mg of Dowex 50 in the H ⁺ cycle, after 24 hours of stirring at room temperature, the ion exchanger was again suctioned off, washed with 2x 3 ml of an acetone-water mixture (7:3) and the organic solvent was suctioned off from the combined portions under reduced pressure. After analogous treatment of the reaction mixture as in example 2, 167 mg (69.9%) of the product of general formula I was obtained, where R denotes methyl,

2

R denotes 3-chlorophenoxy, R =B=H, A=OH, in the form of a yellowish oil, the mass spectrum of which contains the ionic species (m/z, % rel. int.): 137 (100), 79 (80), 91 (71), 111 (68), 181 (24),

163 (29), 322 (8), 278 (6), 304 (3), 250 (3), 209 (3).

Infrared spectrum (CHCip contains bands (cm ^-1 ): 3,600, 3,410, 3,010, 2,940, 1,720,

600, 1,480.

and

Example 5

To a solution of the ylide of general formula III, prepared in situ from 1.56 g of (3-ethoxycarbonyl-5-thienylmethyl)triphenylphosphonium chloride, mp 212-218 °C, in 10 ml of anhydrous tetrahydrofuran and 2.25 ml of a 1.477 M solution of potassium tert-butoxide, was added 385 mg of lactol of general formula II (where R = η-C^Hg-, B = H, A = OR , R = tetrahydropyran-2-yl) with stirring at room temperature. After 24 hours of stirring at 22 to 25 °C, the reaction mixture was worked up as in Example 1. 286 mg (55%) of a light yellowish oil of the compound of general formula I was obtained, where R, B, A, R have the above meanings and R represents C ₂ H ₅ , X represents a sulfur atom.

The infrared spectrum (CHClj) contains bands (cm L: 3,600, 3,380, 3,010, 2,940, 1,710,

550, 1,515.

Example 6 κ To a solution of the ylide of general formula III prepared from 1.1 g of (2-carboxy-5-thienylmethyl)triphenylphosphonium chloride in 10 ml of 1,2-dimethoxyethane and 3.5 ml of a 1.477 M solution of potassium tert-butoxide, 289 mg of lactol of general formula II, where R -n-C^Hg-, B=H, A=OR , R = tetrahydropyran-2-yl, was added at room temperature (nitrogen atmosphere). After 8 hours of stirring at the above temperature, the reaction mixture was worked up as in Example 5. 268 mg of the product of general formula I was obtained, where R denotes Η, X denotes a sulfur atom and R , R , A, B have the meanings given above. In the infrared spectrum (CHClg), the following bands were found (cm^): 3,600, 3,450, 3,010, 2,940, 1,680, 1,530.

Example 7

To a solution of 2.1 millimoles of the ylide of general formula III, where R denotes methyl, X denotes an oxygen atom, prepared from (2-methoxycarbonyl-5-phenylmethyl)triphenylphosphonium chloride in a nitrogen atmosphere, was added at 10 °C with stirring 210 mg of lactol of general formula II, where R^ = 3-chloro2 phenoxy, A+B denotes the OCH^C^O group and R denotes hydrogen. After 6 hours of stirring at the above temperature, the reaction mixture was worked up as in Example 1 and 243 mg of the product of general formula I, where R, R, R, A+B and X have the above meanings, were obtained as a pale yellowish oil.

The following ionic species were found in the mass spectrum (m/z, % rel. int.): 363 (100), 345 (22),

223 (42), 277 (24), 319 (3), 473 (10.2), ΜΪ = 504 (0.6).

The infrared spectrum (CHCl^) contains bands (cm ¹ ): 3,620, 3,460, 3,020, 2,960, 1,720,

595, 1,505, 1,480.

Furthermore, compounds of general formula I were prepared according to the above procedures, the spectral characteristics of which are in agreement with the proposed structure and where:

R R ¹ R ² A B X 8 ^and CH ₃ 3-chlorophenoxy THP OTHP H with 9* CH ₃ 3-chlorophenoxy H OH H · ' with 10° C,H _R 3-chlorophenoxy THP OTHP H With ^llbc 2 ^H 5 3-chlorophenoxy H OH H ^: with 12 ^and CH ₃ n-butyl THP OTHP H 0 13 ^and CH n-butyl . H OH H 0 14° CH ₃ n-butyl THP OTHP H 0 15 ^b CH ₃ n-butyl ; H OH H 0 16 ^and CH ₃ n-butyl THP OTHP H with 17 ^and CH ₃ n-butyl H OH H with l« ^{b C} 2 ^H 5 n-butyl H OH H with 19 ^and H n-butyl H OH H with 20 ^points H n-butyl THP OTHP H with

r; R ¹ R ² A B X 21 ^b H n-butyl H OH H with 22 ^b CH ₃ 3-chlorophenoxy H oh ₂ ch ₂ o 0 23 ^and CH, 3-chlorophenoxy H oh ₂ ch ₂ o with 24 C,H,. 3-chlorophenoxy H _{OCH2CH2O ​} with 25 CHj 3-CF _o C _ï H.O3 6 4 H _{OCH2CH2O ​} 0

^{and a} substituent at the 2-position of the heteroaromatic nucleus.

a substituent in the 3-position of the heteroaromatic nucleus,

THP stands for tetrahydropyran-2-yl group.

SUBJECT OF THE INVENTION

Claims (4)

SUBJECT OF THE INVENTION 1. An analog of prostaglandin F ot the general formula I wherein X denotes oxygen or sulfur and R ¹ COOR is in position 2 or 3, R denotes hydrogen, methyl or ethyl, R is n-butyl, 3-chlorophenoxy, or 3-trifluoromethylphenoxy, R is hydrogen or tetrahydropyran-22 -yl, A denotes a hydroxyl group or OR and B denotes hydrogen or A + B together denotes an OCi-C ^R ^O group. 2. A process for the preparation of compounds of the formula (I) in which A, B, R, R have the above-mentioned meaning according to claim 1, characterized in that, are as defined above, in tetrahydrofuran or 1,2-dimethoxyethane is added at 20 ± 10 ° C to a solution of the lactol of formula (II) in the above solvent, after which an aqueous solution of sodium chloride and sodium hydrogen sulphate is added successively to the reaction mixture after the olefination reaction. of formula I or after treatment with acidic reagents. 3. A process according to claim 1, wherein the base is potassium tert-butylate. * 4. A process according to claim 1 or 2, wherein the acid reagent is used 4. ion exchange in H cycle.