HU190901B - Process for preparing new carbacycline derivatives and pharmaceutical preparations comprising these compounds - Google Patents

Abstract

The present invention provides a process for the preparation of carbacycline derivatives of formula (I) and the hydrogen atom of R2, for the preparation of their pharmaceutically acceptable salts and isomers, as defined herein. R '' is a xor2 group of the general formula: wherein R, hydrogen, C1-C4 alkyl or phenacyl, or R11 is O11 is -C-NHR wherein R3 is C1-C4 alkanoyl or 1 C4 -C4 alkanesulfonyl, dihydroxy (C1-C5) alkyl or hydrogen, X is methylene or oxygen, A is trans-CH = CH- or -C = C, W is hydroxymethylene, wherein the hydroxyl group is - or in / J configuration, n is 1 or 2, XI ^ 2 II) -1-

Description

D is a C 1-4 straight chain alkylene,

E is -CsC- or a group -CH = CR ₇ wherein R ₇ is hydrogen, C 1-4 alkyl, or halogen,

R ₄ is C 1-7 alkyl,

R ₅ is hydroxy.

The compounds of the present invention are useful as an active ingredient in anti-platelet aggregation-lowering anti-hypertensive coronary artery disease drugs.

The present invention relates to novel prostacyclin derivatives and to pharmaceutical compositions containing them.

A DE-OS 2845 770, 29 00 352, 29 02 442,. German Patent Laid-Open Nos. 29 04 655, 29 09 088 and 29 12 409 disclose certain (5E) - and (5Z) -6a-carba-prostaglandin L analogs. The nomenclature used for the compounds of the invention is based on the suggestion of Morton and Brokaw (J. Org. Chem. 44, 2880 (1979f)). In the synthesis of the compounds in question, two types of isomers are always formed with respect to the double bond, which can be characterized by the addition of (5E) or (5Z). The structure of these isomers is illustrated in the attached drawings by formulas (A) ((5E) -6a-carba-prostaglandin-1, 1) and (B) ((5Z) -6a-carba-prostaglandin-1, 1).

The state of the art with respect to prostacyclines and their analogs is very rich and widely known. Thus, it is well known that, by virtue of its biological and pharmacological properties, this family of compounds is useful in the treatment of mammals (including humans). However, their use as a medicament is often difficult, since the therapeutic effect time of these compounds is too short from a therapeutic point of view. The aim of all structural changes to date has been to increase both the duration of action and its selectivity.

It has been found that introducing a cycloalkyl group at the 16-position of the carbacycline molecule results in a longer duration of action, greater selectivity and improved efficacy.

The compounds of the invention have antihypertensive and bronchodilatory effects, in addition, they inhibit platelet aggregation and gastric secretion, and ultimately have a vasodilating effect.

FIELD OF THE INVENTION The present invention relates to carbacycline derivatives of formula (I) and, where R is hydrogen in formula (I), to their physiologically acceptable salts with bases.

In the general formula (I)

R ^X is -C formula OR _2, where

R _{2 is} hydrogen, C 1-4 alkyl or phenacyl, or R 1 is one

SHE

II-C-NHR ₃ wherein

R 1 is C 1 -C 4 alkanoyl or C 1 -C 4 alkanesulfonyl, dihydroxy (C 1 -C 5) alkyl or hydrogen,

X is methylene or oxygen,

The trans-CH = CH or CsC group,

W is a hydroxymethylene group in which the hydroxy group may be in the α or β configuration, n is 1 or 2,

D is a C 1-4 straight chain alkylene,

E is -CsC- or one

CH = CR ₇ - wherein R ₇ is hydrogen, C 1-4 alkyl or halo,

R ₄ is C 1-7 alkyl,

R ₅ is hydroxy.

The compounds of formula (I) exist in both (5E) and (5Z) isomeric forms.

R 1 as alkyl is a linear or branched C 1 -C 4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.

R ₂ can be a substitute phenacyl groups.

R, represents a residue of a physiologically tolerable acid, namely C 1 -C 4 alkanoyl groups and C 1 -C 4 alkanesulfonyl groups derived from: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid and methanesulfonic acid, , butanesulfonic acid.

The hydroxyl group in W may be in the a- or / (-) configuration.

Exemplary acyl groups include those already listed for R, and include, for example, acetyl, propionyl, and butyryl.

The substituent R _{4 is} a straight or branched C 1 -C 7 alkyl group. By way of example, the following groups are listed: methyl, ethyl, propyl, butyl, isobutyl-tert-butyl, pentyl, hexyl, heptyl.

The alkylene group D may be a linear group having from 1 to 4 carbon atoms, such as methylene, ethylene, propylene, tetramethylene.

For the formation of salts with the free acids (R ₂ = H), all inorganic and organic bases which are known to those skilled in the physiological field may be used.

190,901 are considered to be suitable for the formation of tolerable salts. For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia and amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine and the like.

The carbacycline derivatives of formula (I) are prepared by:

a) a compound of formula II wherein R ₄ , W, n, D, E, and R ₄ are as defined above, while the B is a trans bond or a -CH = CBr- group, the free hydroxyl groups present optionally after reaction with a Wittig reagent of formula (III);

b) preparation of (I) compounds wherein X is O, (IV) a compound of formula wherein R _4, R _s, A, W, D, E and n are as defined above, in the present after protecting free hydroxy groups with optionally a haloacetic acid derivative of formula (V): - in which Hal denotes chlorine, bromine or iodine atom, a trialkylsilyl group or an alkali metal such as sodium with _R an alkyl group or alkyl groups R etherified in the presence of a base of potassium or lithium, then the product of process (a) or (b) is optionally separated into cis-trans isomers as desired and / or the protected hydroxyl group (s) in the product is liberated, or converting the carboxyl group into an amide or from a carboxyl-containing compound in a physiological from this point a salt is formed with an acceptable base.

The compounds (III) with a Wittig reagent of the formula 0 ° C to to 100 ° C temperature range, preferably between 20 ^C-60 C, and an aprotic solvent or a mixture thereof, preferably of formula (II) in dimethylsulfoxide, dimethylformamide or tetrahydrofuran. The Wittig reagents of formula (III) are prepared from the corresponding phosphonium salts with methanesulfinylmethyl sodium or methanesulfinyl potassium or potassium tert-butylate in dimethylsulfoxide or dimethylsulfoxide-tetrahydrofuran. Separation of the resulting Z and E-configurated olefins (5,6-position) is carried out in a conventional manner, for example by column chromatography or thin layer chromatography. When B represents a group -CH-t-CBr-, the Wittig- During olefinization, hydrogen bromide is simultaneously cleaved and a 13,14-acetylene bond is formed.

The compounds of formula (IV) and the haloacetic acid derivatives of formula (V) are reacted with one another in a temperature range of 0 ° C to 100 ° C, preferably 10 ° C to 80 ° C, and in an aprotic solvent such as dimethylsulfoxide, dimethylformamide, tetrahydrofuran, etc. or in a mixture of such solvents. Suitable bases for the etherification reactions are those customary to those skilled in the art. Examples of such bases are sodium hydride, potassium tert-butylate, butyllithium, and the like.

When R 1 represents a -COOR group in which R 1 is a C 1 -C 4 alkyl group, this ester group may be formed by methods known to those skilled in the art. For example, the carboxy compound is reacted with a diazocarbon hydrogen in a manner known per se. For esterification with diazocarbons, for example, the diazocarbon is in an inert solvent, preferably diethyl ether ^; and the solution is mixed with a solution of the carboxy compound in the same solvent or another inert solvent such as dichloromethane. The reaction is complete for 1-30 minutes, then the solvent (s) is removed and the resulting ester is purified in the usual manner. The diazoalkanes required for the reaction are partly known and may be prepared by known methods (see Org. Reactions Bd. 8, 389-394 (1954)).

The ester group of the formula RCO -COOR is formed by reacting the carboxylate anion with the corresponding alkyl halide or a Hal-CH, II

With a halogen ketone of formula C-Ar; in the latter Ar is phenyl.

The carbacyclin derivative of formula (I) wherein R ₂ = H can be neutralized with the appropriate amount of the appropriate inorganic bases and converted into salts. For example, by dissolving the appropriate acid in water containing a stoichiometric amount of base and then evaporating the water or adding a water miscible solvent such as alcohol or acetone to the solution, a solid, inorganic salt of said acid derivative is obtained.

Salts formed with amines are prepared in conventional manner. For example, the carbacyclic acid is dissolved in a suitable solvent such as ethanol, acetone, diethyl ether or benzene, and the required amine is added at least stoichiometrically to the former solution. The salt is then usually precipitated in solid form or can be recovered in the usual way by evaporation of the solvent.

Among the protecting groups, the acyl group is introduced by reacting a compound of formula (I) per se with a carboxylic acid derivative such as an acid chloride or an anhydride, or the like.

The release of the functionally modified hydroxyl group (s) leading to the compounds of formula (I) is carried out in a known manner. For example, the ethereal protecting groups are cleaved in aqueous solution, with an organic acid such as acetic acid, propionic acid, or in an aqueous solution with an inorganic acid such as hydrochloric acid. In order to increase the solubility, a water-miscible inert organic solvent is suitably added to the reaction mixture; an organic solvent suitable for this purpose is, for example, an alcohol such as methanol or ethanol, and an ether such as dimethoxyethane, dioxane or tetrahydrofuran. The use of tetrahydrofuran is preferred. The ether slope3

The reaction is preferably carried out at a temperature between 20 ° C and 80 ° C.

The silyl ether protecting groups are cleaved, for example, with tetrabutylammonium fluoride. Examples of the solvent include tetrahydrofuran, diethyl ether, dioxane, dichloromethane and the like. suitable. The cleavage is preferably carried out at a temperature between 0 ° C and 80 ° C.

The saponification of acyl groups is carried out, for example, with an alkali metal or an alkaline earth metal carbonate or hydroxide, in an alcohol or in an aqueous alcohol solution. Alcohols include aliphatic alcohols such as methanol, ethanol, butanol and the like. but methanol is preferred. Among the alkali metal carbonates and hydroxides, potassium and sodium compounds are particularly preferred, of which potassium compounds are particularly preferred. For example, among the alkaline earth metal carbonates and hydroxides, the use of calcium carbonate, calcium hydroxide and barium carbonate is preferred. The reaction is carried out at a temperature of -10 ° C to 70 ° C, preferably 25 ° C.

SHE

II

The amide group of the formula R 1 -C NHR ₃ may be formed by methods known to those skilled in the art. The carboxylic acids of formula I (R 1 = H) are first converted to the mixed anhydride in the presence of a tertiary amine such as triethylamine with chloroformate. The mixed anhydride is then reacted with an alkali metal salt of the corresponding amide or with ammonia (R 1 - H). This reaction is carried out in an inert solvent such as tetrahydrofuran. dimethoxyethane, dimethylformamide. hexamethylphosphoric triamide, or a mixture of such inert solvents, and is carried out in a temperature range of -30 ° C to 1-60 ° C, preferably 0 ° C to 30 ° C.

A further possibility of forming an amide group of the formula RC is -CONHR is that the 1-carboxylic acid of the formula I (R 1 = H) is optionally protected with a compound of the formula VI after the optional temporary protection of the free hydroxyl groups. wherein R 1 is as defined above.

The reaction of compounds of formula (I) containing a carboxyl group with isocyanates of formula (VI) is optionally carried out with the addition of a tertiary amine such as triethylamine or pyridine. This reaction is carried out in the absence of a solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, dichloromethane, diethyl ether or toluene and from -80 ° C to -100 ° C. in the temperature range, preferably 0 ° C to 30 ° C.

If the parent compound contains a hydroxyl group (s) in the prostane, it (s) will also react. If a final product is desired that contains the partially free hydroxyl group (s) in the prostane, then it is convenient to start with compounds in which the said group (s) is preferably protected with an ethereal or acyl group which is readily cleaved.

For example, the starting compounds of formulas II and IV can be prepared by reacting an aldehyde of formula VII (see DE-OS 28 45 770) with a compound of general formula VIII in a manner known per se. with a phosphonate of the formula wherein D, E and R ₄ are as defined above. This reaction is carried out in the presence of a deprotonating agent such as sodium hydride or potassium tert-butylate to give a ketone of formula IX wherein X is hydrogen. If the reaction is carried out in the presence of a further brominating agent, such as N-bromosuccinimide, the ketone of formula IX, wherein X represents a bromine atom, is obtained.

After reduction of the keto group with zinc borohydride or sodium borohydride or reaction with alkyl magnesium bromide or alkyl lithium, the epimers are separated to give compounds of formula (X).

The ester group is then saponified with potassium carbonate in methanol, for example, and optionally hydrogenated on the double bond or optionally etherified with dihydropyran, and optionally, for example, with potassium tert-butylate in dimethylsulfoxide, optionally, the free hydroxyl groups are functionally modified, for example by an etherification reaction with dihydropyran. In this way, the ketones of formula XI are prepared.

An olefinic reaction is then carried out with triethyl phosphonoacetic acid or trimethyl ester of phosphonoacetic acid followed by reduction with lithium aluminum hydride. In this way, the double bond yields the isomeric compounds of formula IV and optionally separates the isomers.

The keto group of the compounds of formula (IX) is reduced with sodium borohydride and the epimers are optionally separated. For example, the ester group is saponified with potassium carbonate in methanol and ketal cleaved with aqueous acetic acid, and the epimers are optionally separated. In this way, the ketones of formula (XII) are obtained and finally the parent compounds of formula (II) are obtained by etherification of the hydroxyl groups with, for example, dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid.

The phosphonates of formula VIII are prepared in a manner known per se. An ester of formula XIII, wherein n, D, E, and R ₄ are as defined above, while R _{x is} a C 1 -C 5 alkyl group, is reacted with an anion of methyl phosphonic acid dimethyl ester.

The esters of formula (XIII) are also prepared in a manner known per se by reacting a dianion (XIV) with a halogen compound (XV). In the formula mentioned (XIV) and (XV) wherein n, D, E and _R4 are as defined above, and Hal is chlorine, bromine or iodine, represents.

190 901

The compounds of the present invention have antihypertensive and bronchodilatory properties and are also useful for inhibiting platelet aggregation. Therefore, the novel carbacycline derivatives of formula (I) exhibit pharmacologically valuable active ingredients, namely, greater specificity and, in particular, a substantially longer duration of action and, moreover, greater stability with respect to PGE than the corresponding prostaglandins. The high tissue specificity of the new prostaglandins has been demonstrated by tests on organs with smooth muscles, such as guinea pig hips or isolated trachea in rabbits, where significantly less stimulation can be observed than with natural E, A or F natural prostaglandins.

The novel carbacycline analogs have the same properties as prostacyclines. These include, for example, reducing peripheral artery and coronary resistance, inhibiting platelet aggregation, dissolving platelet thrombi, protecting myocardial cells and thereby reducing systemic blood pressure without concomitantly decreasing heart rate or heart rate. The novel compounds are therefore for the treatment of stroke, apoplexy, for the prevention and treatment of certain coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral arterial disease, atherosclerosis and thrombosis, and for the treatment and prevention of They inhibit gastric and intestinal mucosal cells, as well as liver cells and pancreatic cells. These new compounds also have anti-allergy properties and reduce pulmonary resistance and pulmonary blood pressure. The kidneys increase blood flow and can be used in place of heparin or as an adjuvant in dialysis treatment (eg haemofiltration). They can be used for the preservation of preserved plasma preparations, in particular platelet preparations. They prevent birth pains (ie uterine contractions), are useful in treating pregnancy toxicities, improve blood flow to the brain, etc. The novel carbacycline derivatives even possess antiproliferative and anti-diarrhoegene properties. The novel carbacyclines of the present invention may be used even in combination with, for example, β-blockers or diuretics.

Pharmacological studies prepared by the method of the present invention and comparative to PGE1 were performed. Compounds inhibited platelet aggregation. The results are shown in the table below.

The test compound Platelet aggregation Example number inhibitory effect Example 1 8.75 Example 2 6.13 Example 5 12.22 PGE 1.00

Our studies demonstrate that the compounds of the present invention (compounds of Examples 1, 2 and 5) inhibit platelet aggregation 6 to 12 times more potent than PGE.

The compounds are administered to humans at a dose of 1-1500 µg / kg / day. In the case of a pharmaceutically acceptable carrier, this amount may be in the range of 0.01 to 100 mg per dosage unit.

The compounds of the present invention, when administered intravenously at doses of 5, 20 and 100 µg / kg body weight to waking hypertensive rats, exhibit a greater and prolonged antihypertensive effect than PGE or PGA, and do not cause diarrhea as caused by PGE or cardiac arrhythmia. that the PGA does.

The compounds of the present invention, when administered intravenously to narcotic rabbits, cause greater and significantly longer blood pressure reductions than PGE1 and PGA without affecting the other smooth muscle organs or the function of these organs.

For parenteral administration, sterile injectable, aqueous or oily solutions may be employed. For oral administration, for example, tablets, dragees or capsules are suitable.

Therefore, it is also within the scope of the present invention to provide pharmaceutical compositions comprising the compounds of formula (I) and the usual excipients or carriers.

The active compounds of the present invention, in combination with conventional and known excipients for Galenic pharmaceutical formulations, are useful, for example, in the preparation of medicaments having antihypertensive activity.

Example 1 (5E) -18,18,19,19-Tetradehydro-16,16-trimethylene-α-carba-prostaglandin-1,

To a solution of 9.36 g of 4-carboxybutyl-triphenylphosphonium bromide in 20 ml of dimethylsulfoxide and 8 ml of tetrahydrofuran is added 4.74 g of potassium tert-butylate at 5 ° C and the mixture is stirred for 45 minutes. Stir at 5 ° C. 1.65 g of (R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - ([E) (3R) -3- (tetrahydropyran-2-) are added to the red ilene solution. yloxy) -4,4-trimethylene-oct'-en-6-ynyl] -bicyclo [3.3.0] octan-3-one dissolved in 2 ml of tetrahydrofuran and stirred for 3 hours at 35 ° C. . It is then poured onto ice water, acidified to pH 4 with citric acid solution and extracted with dichloromethane. The organic layer was extracted with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography. Hexane-ethyl acetate (1: 1), first, 280 mg of Z-configuration olefin, followed by 700 mg of (5E) 8,18,19,19-tetradehydro-16,16-trimethylene-6a-carbapro-prostaglandin-1, - 11.15-bis (tetrahydropyranyl) ether was obtained as a colorless oily substance.

IR (CHCl 3): 3520, 2940, 2860, 1710, 1073, 1019, 972 / cm -1.

To remove the protecting groups, 650 mg of the product obtained by the above olefinization reaction are stirred for 24 hours at 25 ° C with 20 ml of acetic acid-water-tetrahydrofuran (65:35:10). The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel. Elution with ethyl acetate / ethyl acetate (99.9: 0.1) gave 320 mg of title 5

190.901 is obtained in the form of a colorless oily substance.

IR: 3600, 3520, 3410 (broad), 2937, 2860, 1710, 972 cm @ -1.

The starting material for the preparation of the title compound is prepared as follows:

la) 2-Oxo-3,3-trimethylene-hept-5-yno-isophonic acid dimethyl ester

To a solution of diisopropylamine (44.52 g) in tetrahydrofuran (200 ml) was added a solution of butyl lithium in hexane (1.66 mol, 265 ml) followed by cyclobutanecarboxylic acid (20.02 g). The mixture was stirred for an additional 30 minutes at -10 ° C and 31.92 g of 1-bromo-2-butine was added dropwise and stirring was continued at 25 ° C for 16 hours. The reaction mixture was poured into ice-water (600 mL), acidified to pH 4 with 2N hydrochloric acid and extracted with ether. The extract was washed with brine, dried over magnesium sulfate, and the ether was evaporated in vacuo. The residue was purified by distillation. This gives 18 g of 2,2-trimethylenehex-4-acetic acid, 140-

143 ° C.

IR: 3520, 2985, 2961, 1700, 1425, 1408, 1100, 1035,

920, 880 / cm.

For esterification, 14 g of the acid thus obtained are heated to reflux for 6 hours in 200 ml of methanol in the presence of 2 ml of concentrated sulfuric acid. The mixture was cooled, poured onto ice (150 mL) and extracted with ether. The extract was washed first with sodium carbonate solution and then with sodium chloride solution, then dried over magnesium sulfate and the ether was evaporated in vacuo.

Vacuum distillation gave 13 g of 2,2-trimethylene-hex-4-acetic acid methyl ester, b.p. 92-94 ° C / 1999.83 Pa.

IR: 2985, 2951, 2921, 2858, 1725, 1431, 1330, 1099, 978.875 / cm.

To a solution of 21.35 g of methane phosphonic acid dimethyl ester in 300 ml of tetrahydrofuran is added dropwise at -70 ° C 200 ml of a 1.7M solution of butyllithium in hexane. After 20 minutes, to the solution was added dropwise 13 g of the ester prepared above in 50 ml of tetrahydrofuran, and the mixture was stirred for an additional 5 hours at -70 ° C. 12 ml of acetic acid are then added and the mixture is evaporated under reduced pressure. The resulting residue was dissolved in water (50 mL) and extracted several times with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was distilled in vacuo to give 15.1 g of the title compound as a colorless liquid, b.p. 133-139 ° C / 66.66 Pa.

IR: 3420 (broad), 2988, 2952, 2850, 1702, 1251, 1030 / cm.

1b) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) -3-oxo-4,4-trimethylene-oct-1-en-6-ynyl] ]) - bicyclo [3.3.0] octane

To a suspension of 980 g of sodium hydride in 200 ml of dimethoxyethane was added dropwise a solution of 11.62 g of the phosphonate obtained in 1a) in 120 ml of dimethoxyethane at 0 ° C and the mixture was stirred for 1 hour at 0 ° C. stirred. Subsequently, 11.40 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3.0] octane dissolved in 120 ml of dimethoxyethane are added dropwise. and kept at 0 ° C for 2 hours. The reaction mixture was poured into 800 mL of saturated ammonium chloride solution and extracted with 5 ether. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel with hexane-ether (1: 1) to give 9.10 g of the title compound as 10 colorless oily substances.

IR: 2940, 2859, 1712, 1686, 1621, 1600, 1584, 1270, 980, 942 cm @ -1.

le) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) - (3R) -3-hydroxy-4,4-trimethylene-oct-1-ene -615 inyl] -bicyclo [3.3.0] octane

8.10 g of the ketone prepared in 1b) are dissolved in 200 ml of methanol and 3.60 g of sodium borohydride are added to the solution at -40 '' Con. The reaction mixture was stirred at -40 ° C for 30 minutes, then diluted with ether (2 L) and extracted several times with 50 ml of brine. The organic phase is then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel using ether-hexane (7: 3) as eluent. This gave 4.9 g of the title compound as a colorless oily substance.

IR: 3600, 3520, 2938, 2888, 1713, 1601, 1586, 1275, 970, 943 cm.

In addition to the above product, 3.55 g of 15/3-hydroxy compound (PG numbering) is obtained as a more polar component.

Id) (IR, SS, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) ~

6 - [(E) - (3R) -3-Tetrahydropyran-2-yloxy] -4,4-trimethylene-35-oct-1-en-6-yl] -bicyclo [3.3.0] octan-3-one

The compound (4.9 g) obtained in Example 1 (c) was stirred in methanol (150 ml) with anhydrous potassium carbonate (2.25 g) overnight. The mixture was then concentrated in vacuo, the residue taken up in 40 liters of ether, extracted with water and dried over magnesium sulfate. Evaporation of the ether gave 4.75 g of crude nuts, which were stirred with 170 ml of acetic acid-water-tetrahydrofuran (65:35:10) at room temperature for 20 hours. This re45 mixture was then concentrated in vacuo and the residue was purified by silica gel chromatography eluting with hexane-ethyl acetate (3: 7). 2.95 g of keto-diol are obtained, which is dissolved in 100 ml of dichloromethane and then 50 g of the solution are added at 0 ° C with 4 g of dihydropyran and 30 mg of p-toluenesulfonic acid. After stirring for 30 minutes at 0 ° C, the mixture was poured into 50 ml of sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue thus obtained was chromatographed on silica gel with hexane-ethyl acetate (7: 3). This gave 3.92 g of the title compound as a colorless oily substance.

IR: 2941.2868, 1738, 972 / cm.

Example 2 (5E) -13,14-Didehydro-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

9.40 g of 4-carboxybutyltriphenylphosphonium bromide

-611

To a solution of 190.901 ml of dimethylsulfoxide and 8 ml of tetrahydrofuran is added 4.75 g of potassium tert-butylate at 5 ° C over 45 minutes and the mixture is stirred for another 45 minutes at 5 ° C. 1.95 g of (R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -2-bromo-3-tetrahydropyran-2-yl are added to the red ilene solution. oxy) -4,4-trimethylene-oct-1-ene-6-ynyl] -bicyclo [3.3.0] octan-3-one dissolved in 4 ml of tetrahydrofuran and stirred for 4 hours at 40 ° C. The reaction mixture was poured into ice-water, acidified to pH 4 with citric acid and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel. Hexane-ethyl acetate (3: 2) was mixed with 200 mg of the 5Z-configuration olefin first, followed by 730 mg of (5E) -13,14-didehydro-18,18,19,19-tetradehydro-16,16-trimethylene-6a- as the polar component. carbaprostaglandin _I2 -l 1,15-bis- (tetrahydropyranyl ether) as a colorless oil.

IR: 3520, 2941, 2860, 1710, 1020 / cm.

To remove the protecting groups, the above product (700 mg) was stirred overnight at 25 ° C in 25 ml of acetic acid-water-tetrahydrofuran (65:35:10). The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel. Elution with ethyl acetate-acetic acid (99.9: 0.1) gave 350 mg of the title compound as a colorless oily substance.

IR: 3600, 3405 (broad), 2930, 2221, 1711, 1603, 1012 / cm.

The starting material for the title compound is prepared as follows:

2a) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6- (2-bromo-3-oxo-4,4-trimethylene-oct-1-en-6-ynyl) ) bicyclo [3.3. octane

A suspension of 1.81 g of sodium hydride (55% in mineral oil) in 180 ml of dimethoxyethane was added dropwise at 0 ° C to 11.8 g of 2-oxo-3,3-trimethylene-hept-5-infosphonic acid in 75 ml of dimethoxyethane. dimethyl ester and then stirred at 0 ° C for one hour. 7.40 g of finely powdered N-bromosuccinimide are then added. The resulting mixture was stirred at 0 ° C for 30 min and 11.40 g of (R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3.0] was added. octane dissolved in 90 ml of dimethoxyethane and the mixture was stirred for 2 hours at 0 ° C. The reaction mixture was then poured into saturated ammonium chloride solution and extracted with ether. The organic extract was washed neutral with brine, then dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-ether (1: 1) to give 8.92 g of the title compound as a colorless oily substance.

IR: 2935, 2878, 1712, 1690, 1602, 1588, 1450, 1275, 944 cm.

2b) (1R, 5S, 6R, 7R) -7-Hydroxy-6 - [(3S) -2-bromo-3-hydroxy-4,4-trimethylene-oct-1-en-6-ynyl] -bicyclo [3.3. 0] octane-3-one

8.50 g of the ketone prepared in Example 2a are dissolved in 175 ml of methanol and 3.60 g of sodium borohydride are added portionwise at -40 ° C and the reaction mixture is stirred for 30 minutes at -40 ° C. The mixture was diluted with ether, washed neutral with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product (mixture of 15-epimers) was dissolved in methanol (250 mL), then potassium carbonate (3.60 g) was added and the mixture was stirred overnight at 25 ° C. The mixture was then concentrated in vacuo, then diluted with ether and washed neutral with dichloromethane. It was then dried over magnesium sulfate and concentrated in vacuo. The residue was stirred for 16 hours at 25 ° C with 300 ml of acetic acid-water-tetrahydrofuran (65:35:10) and concentrated in vacuo. Chromatography on silica gel with ether-methylene dichloride: d, first, 2.10 g of 15 N-hydroxy compound (PG numbering) and then 2.90 g of the title compound (according to PG nomenclature 15- hydroxy) in the form of a colorless oily substance.

IR: 3600, 3420 (broad), 2957, 2931, 1738, 1600, 1405 / cm -1.

c) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) 6 - [(3S) -2-bromo-3- (tetrahydropyran-2-yloxy) -4,4- trimethylene-oct-l-en-6-ynyl] bicyclo [3.3.0] octan-3-one

2 g of the α-alcohol prepared according to Example 2 (b), 20 mg of p-toluenesulfonic acid and 2 g of dihydropyran are dissolved in 50 ml of dichloromethane and the solution is stirred for 30 minutes at 0 ° C. The solution was then diluted with dichloromethane and extracted with sodium bicarbonate solution, followed by brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with hexane-ether (6: 4) gave 2.60 g of the title compound as a colorless oily substance.

IR: 2938, 2865, 1735, 1452, 1121 / cm -1.

Example 3 (5E) -20-Methyl-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

1.50 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) -4,4 starting from trimethylene-non-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one and proceeding in a manner analogous to that described in Example 1. Thus 630 mg of (5E) -20-methyl-16,16-18,18,19,19tetradehidro trimethylene-6a-carba-prostaglandin I ₂ -ll, 15-bis (tetrahydropyranyl ether) as a colorless oily substance .

IR: 3520, 2940, 2862, 1712, 1070, 1020, 974 / cm.

The deprotection was carried out as described in Example 1 to give 310 mg of the title compound as a colorless oily substance.

IR: 3600, 3520, 3405 (broad), 2938, 2862, 1710, 972 cm @ -1.

The starting material for the title compound is prepared as follows:

3a) 2-Oxo-3,3-trimethylene-oct-5-in-phosphonic acid dimethyl ester

In a procedure analogous to Example 1 (a), 2,2-trimethylene hept-4-acetic acid, starting from cyclobutanecarboxylic acid and 1-bromo-2-pentine, is boiled and converted to the methyl ester. (boiling point: 111-112 ° C / 1999.83 Pa). This ester was also prepared according to Example 1 (a) in Example 7

-713

190.901 of lithium derivative of diphosphonic acid dimethyl ester to give the title compound, b.p. 145-147 ° C / 39.99 Pa.

IR: 3420 (broad), 2982, 2948, 2851, 1702, 1250, 1028 cm @ -1.

3b) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) -3-oxo-4,4-trimethylene-non-1-en-6-ynyl] ]) - bicyclo [3.3.0] octane

In an analogous manner to that of Example 1 (b), 11.40 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3. O] octane is reacted with 2-oxo-3,3-trimethylene-oct-5-in-phosphonic acid dimethyl ester. 10.02 g of the title compound are obtained in the form of a colorless oily substance.

IR: 2942, 2861, 1712, 1688, 1620, 1600, 1585, 1270, 981.944 / cm.

3c) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) - (3R) -3-hydroxy-4,4-trimethylene-non-1- I-6inil] bicyclo [3.3.0] octane

Start from 10 g of the compound of Example 3 (b) and proceed analogously to Example 1 (c). 5.95 g of the title compound are obtained in the form of a colorless oily substance.

IR: 3600, 3520, 2937, 2880, 1712, 1601, 1585, 1270, 972, 948 cm @ -1.

3d) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) 6 [(E) - (3R) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylene -non-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one

Starting from 5.50 g of the compound prepared in Example 3 (c) and carrying out the ester cleavage and the ketal cleavage in analogy to Example 1 d), the hydroxy groups are protected as bis (tetrahydropyranyl) ether. 4.25 g of the title compound are obtained in the form of an oily, colorless substance.

IR: 2940, 2865, 1738, 976 cm @ -1.

Example 4 (5E) -20-Ethyl-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostagtandin- ₁₂

700 mg of (R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylene Starting from -dec-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one and proceeding in a manner analogous to that described in Example 1. to give 270 mg of (5E) -20-ethyl-16,16-18,18,19,19tetradehidro trimethylene-6a-carba-prostaglandin I ₂ -ll, 15-bis (tetrahydropyranyl ether) as a colorless oily substance .

IR: 3520, 2945, 2870, 1711, 1072, 1020, 976 cm-1.

The deprotection was carried out as described in Example 1 to give 140 mg of the title compound as a colorless oily substance.

IR: 3600, 3505, 3410 (broad), 2940, 1711, 976 cm @ -1.

The starting material for the preparation of the title compound of this example is prepared as follows:

4a) 2-Oxo-3,3, -trimethylene-non-5-in-phosphonic acid dimethyl ester

In analogy to Example 1 (a), starting from cyclobutanoic acid and l-bromo-2-hexine, 2,2-trimethylene oct-4-acetic acid (boiling point: 178-180 ° C / 14 torr) was prepared and converted to the methyl ester. (boiling point: 128-130 ° C / 15 torr). The ester is also

Example 1 (a) is reacted with a lithium derivative of dimethyl methane phosphonic acid ester to give the title compound. It boils at 150-152 ° C (13.33 Pa).

IR: 3420 (broad), 2986, 2951, 2850, 1704, 1250, 51031 cm -1.

4b) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) -3-oxo-4,4-trimethylene-dec-1-en-6-ynyl] ]) - bicyclo [3.3.0] octane

Example analogous to Example 1 (b)

10.0 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3. Ooctane is reacted with 2-oxo-3,3-trimethylene-non-5-in-phosphonic acid dimethyl ester to give a colorless oily substance

8.50 g of the title compound are obtained.

IRISH; 2945, 2860, 1712, 1687, 1601, 1585, 1269, 978, 948 cm @ -1.

4c) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) - (3R) -3-hydroxy-4,4-trimethylene-dec-1-ene -6inil] bicyclo [3.3.0] octane

Starting from 8.00 g of the compound prepared in Example 4 (b) and proceeding in analogy to Example 1 (c). 4.85 g of the title compound are obtained in the form of an oily consistency.

IR: 3600,3510,2940,2881,1712,1600,1585,1272, 974, 946 / cm.

4d) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) -6 [(E) - (3R) -3- (tetrahydropyran-2-yloxy) -4,4- trimethylenedec-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one

Starting from 4.00 g of the compound prepared in Example 4 (c), analogously to Example 1 (d), ester cleavage and ketal cleavage are carried out, followed by protection of the hydroxyl groups as bis (tetrahydropyranyl) ether. 3.10 g of the title compound are obtained in the form of an oily, colorless substance.

IR: 2940, 2860, 1738, 974 / cm @ -1.

Example 5 (5E) -13,14-Didehydro-20-methyl-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

To a solution of 4-carboxybutyl-triphenylphosphonium bromide (4.71 g) in dimethylsulfoxide (10 mL) and tetrahydrofuran (5 mL) was added potassium tert-butylate (2.38 g) at 5 ° C and 45 min. stirring was continued for 5 minutes at 5 ° C. 1.00 g of (R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -2-bromo-3- (tetrahydropyran-2-) are added dropwise to the red ethylene solution. yloxy) -4,450 trimethylene-non-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one dissolved in ml of tetrahydrofuran and stirred for 4 hours at 40 ° C. The reaction mixture was poured into ice water, acidified to pH 4 with citric acid and quenched with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate liver and concentrated in vacuo. The residue was purified by chromatography on silica gel. Hexane-ethyl acetate (1: 1) was first treated with 170 mg (5Z-13,14-didehydro-20-methyl-18,18,19,19-tetradehydro-16,16-trimethylene-6-carba-prostaglandin- _12). -1,15-bis (tetrahydropyranyl) ether, followed by 430 mg of the corresponding 5E compound as the more polar component, is dissolved in 15 ml of acetic acid-tetrahydrofuran at 25 ° C for 16 hours to remove the protecting groups.

-815

190.901 (65:35:10). The reaction mixture is concentrated and the residue is purified by chromatography on silica gel with ethyl acetate. 190 mg of the title compound are obtained in the form of a colorless oily substance.

IR: 3600.3410 (broad), 2935.1712.1602.1015 / cm.

The starting material for the preparation of the title compound is prepared as follows:

5a) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6- (2-bromo-3-oxo-4,4-trimethylene-non-1-en-6-ynyl) ) bicyclo [3.3.0] octane

6.49 g of 2-oxo-3,3-trimethylene-oct-5-inphosphonic acid dimethyl ester with 3.70 g of N-bromosuccinimide and 5.70 g of (R, 5S, 6R, 7R) -3,3-ethylenedioxy -7-Benzoyloxy-6-formyl-bicyclo [3.3.0] octane was reacted in analogy to Example 2 (a). 5.10 g of the title compound are obtained in the form of an oil.

IR: 2942, 2877, 1712, 1688, 1600, 1585, 1451, 1270, 948 cm @ -1.

5b) (IR, 5S, 6R, 7R) -7-Hydroxy-6 - [(3S) -2-bromo-3-hydroxy-4,4-trimethylene-non-1-en-6-ynyl] -bicyclo [3.3. 0Joktán-3-one

Starting from 5 g of the compound prepared in Example 5 (a), it is reduced with sodium borohydride in analogy to Example 2 (b), and the benzoate is cleaved with potassium carbonate in methanol and subjected to ketal cleavage. 1.75 g of the title compound are obtained in the form of a colorless oily substance.

IR: 3600, 3410 (broad), 2955, 2930, 1738, 1600, 1407 / cm.

5c) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) 6 - [(3S) -2-bromo-3- (tetrahydropyran-2-yloxy) -4,4- trimethylene-non-l-en-6-ynyl] bicyclo [3.3.0] octan-3-one

Starting with 1.50 g of the walnut prepared in Example 5 (b), it is reacted with dihydropyran and p-toluenesulfonic acid according to the procedure described in Example 2 (c). This gave 1.95 g of the title compound as a colorless oily substance.

IR: 2940, 2861, 1738, 1450, 1120 / cm -1.

Example 6 (5Z) -13,14-Didehydro-20-methyl-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

160 mg obtained in Example 5 (5Z) -13,14didehidro-20-methyl-18,18,19, 19-tetra adehidro-16,16-trimethylene-6a-carba-prostaglandin I ₂ -ll, 15-bis (tetrahydropyranyl) ether was stirred in 25 ml of acetic acid-water-tetrahydrofuran (65:35:10) for 16 hours at 25 ° C and the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate as the eluent. 75 mg of the title compound are obtained as a colorless oily substance.

IR: 3600, 3410 (broad), 2938, 2221, 1712, 1600, 1015 / cm.

Example 7 (5E) -20-Ethyl-13,14-didehydro-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

1.50 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -2-bromo-3- (tetrahydropyran-2-yloxy) -4,4-trimethylene-dec. -1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one was started and analogous to Example 2. 270 mg of the title compound are obtained in the form of a colorless oily substance.

IR: 3600, 3410 (wide), 2932, 2226, 1712, 1601, U15 / cm.

The starting material for the preparation of the title compound of this example is prepared as follows: 7i) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloci-6- (2-bromo-3-oxo-4), 4-trimethylene-dec-l-en-6-ynyl) b> cyclo [3.3.0] octane

In a manner analogous to that described in Example 2 (a), 12.9 g of dimethyl ester of 2-oxo-3,3-trimethylene-non-5-phosphonic acid are 7.40 g of N-bromosuccinimide and 11.40 g. (1R, 5S, 6R, 7R) -3,3-ethylene-n-dioxy-7-benzoyloxy-6-formyl-bicyclo [3.3. Starting with Ooctane 51, 11.25 g of the title compound is obtained, which is an oily consistency.

IR: 2941, 2875, 1690, 1602, 1586, 1451, 1275, 948 cm @ -1.

7b) (1R, 5S, 6R, 7R) -7-Hydroxy-6 - ([3S] -2-bromo-3h, hydroxy-4,4-trimethylene-dec-1-en-6-yl) -bicyclo [ 3.3.0] octan-3-one

Starting from 10 g of ketone prepared in Example 7 (a) and proceeding in analogy to Example 2 (b). This gave 2.52 g of the title compound as a colorless oily substance.

IR: 3600, 3420 (broad), 2955, 2930, 1738, 1600, 1402 / cm -1.

7i) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) -6 - ((3S) -2-bromo-3- (tetrahydropyran-2-yloxy) -4,4- trimethyl i-dec-l-en-6-ynyl] bicyclo [3.3.0] octan-3-one

From the 2 g of nuts prepared according to Example 7 (b), a

In a manner analogous to that described in Example 2 (c), 2.45 g of the title compound is obtained. The product is an oily, colorless substance.

IR: 2942, 2826, 1737, 1453, 1120 / cm.

Example 8 (5E) -20-Methyl-19,19,20,20-tetradehydro-16,16-trim, 'ethylene-6a-carba-prostaglandin- ₁₂

In a manner analogous to that described in Example 1, 1.50 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3S) -3- (tetrahydropyran) are obtained. -2-I-oxy) -4,4-trimethylen-non-1-en-7-ynyl] -bicyclo [3.3.0] octan-3-one to obtain 300 mg of the title compound as a colorless, oily substance .

IR: 3600, 3405 (broad), 2938, 2855, 1711, 976 cm @ -1.

\ To prepare the title compound of this example, the starting material required is prepared as follows:

8a) 2-Oxo-3,3-trimethylene-oct-6-in-phosphonic acid dimethyl ester

First, cyclobutanecarboxylic acid and 1-bromopentine were reacted analogously to Example 1 (a). 2,2-Trimethylene-hept-5-acetic acid is obtained, m.p. 155-158 ° C / 14 torr. This acid is esterified with methanol in the presence of sulfuric acid. The thus-obtained 2,2-trimethylene-hept-5-acetic acid methyl ester is boiled at 108-110 [deg.] C. under a pressure of.

JR: 2965,2950,2921,2849,1728,1430,1330,1097, 970,870 / cm.

From this, also by the procedure of Example 1 (a), the title compound is obtained which is a colorless liquid boiling at 148 DEG-150 DEG C. under 39. Pa.

-917

190 901

IR: 3420 (broad), 2990, 2954, 2848, 1702, 1250, 1030 / cm.

8b) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) -3-oxo-4,4-trimethylene-non-1-en-7-ynyl] ]) - bicyclo [3.3.0] octane

In a procedure analogous to that of Example 1 (a), 10 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3.0] octane and Example 8 From the phosphonate obtained in (a), 11.30 g of the title compound is obtained in the form of a colorless oily substance.

IR: 2942, 2860, 1710, 1688, 1620, 1600, 1585, 1275, 980, 948 cm @ -1.

8c) (IR, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) - (3R) -3-hydroxy-4,4-trimethylene-non-1-ene -7inyl] bicyclo [3.3.0] octane.

Starting from 11.0 g of ketone prepared in Example 8 (b), proceed analogously to Example 1 (c). This gives 7.51 g of the title compound (15a-hydroxy) as a colorless oily substance.

IR: 3600, 3510, 2940, 28881, 1712, 1600, 1585, 1275, 974, 947 / cm.

8d) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) 6 - [(E) - (3R) - (tetrahydropyran-2-yloxy) -4,4-trimethylenone] l-en-7-ynyl] bicyclo [3.3.0] octan-3-one.

Starting with 5 g of 15a-alcohol prepared according to Example 8 (c) and proceeding in analogy to Example 1 (d). This gave 4.05 g of the title compound as a colorless oily substance.

IR: 2940, 2826, 1738, 974 cm.

Example 9 (5E) -13,14-Didehydro-20-methyl-19,19,20,20-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

In a manner analogous to that described in Example 2, 500 mg of (R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -2-bromo-3- (tetrahydropyran-2) (Yloxy) -4,4-trimethylene-non-1-en-7-ynyl] -bicyclo [3.3.0] octan-3-one, 105 mg of the title compound are obtained. The product obtained is a colorless oily substance.

IR: 3600, 3410 (broad), 2938, 2228, 1710, 1601, 1010 / cm.

The starting material for the preparation of the title compound of this example is prepared as follows:

9a) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6- (2-bromo-3-oxo-4,4-trimethylene-non-1-en-7-yl) ) bicyclo [3.3.0] octane

In analogy to Example 2 (a), 5 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3.0] octane 2-oxo-3 With 3-trimethylene oct-6-inphosphonic acid dimethyl ester and N-bromosuccinimide. 4.75 g of the title compound are obtained in the form of a colorless oily substance.

IR: 2938, 2876, 1712, 1688, 1602, 1588, 1451, 1270, 948 cm @ -1.

9b) (1R, 5S, 6R, 7R) -7-Hydroxy-6 - [(3S) 2-bromo-3-hydroxy-4,4-trimethylen-non-1-en-7-ynyl] -bicyclo [3.3. .0] octan-3-one

Starting with 3.10 g of ketone prepared according to Example 9 (a) and proceeding in a manner analogous to Example 2 (b). 700 mg of the title compound (15a-hydroxy) are obtained in the form of a colorless oily substance.

IR: 3600.3410 (broad), 2955, 2930, 1738, 1600 / cm. 9c) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) 6 - [(3S) -2-bromo-3- (tetrahydropyran-2-yloxy) -4,4- trimethylene-non-l-en-7-ynyl] bicyclo [3.3.0] octan-3-oti

Starting with 600 mg of nuts prepared according to Example 9 (b) and proceeding analogously to Example 2 (c). 730 mg of the title compound are obtained in the form of a colorless oily substance.

IR: 2940, 2868, 1740, 1451, 1120 cm -1.

Example 10 (5E) -18,18,19,19-Tetradehydro-16,16-tetramethylene-6α-carba-prostaglandin- ₁₂

In an analogous manner to Example 1, 500 mg of (R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2) Starting with 105 mg of the title compound as a colorless oily product, starting from the oxy) -4,4-tetramethylene-oct-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one.

IR: 3600, 3525, 3410 (broad), 2938, 2860, 1710, 976 cm @ -1.

The starting materials required for the preparation of the title compound of this example are prepared as follows:

10a) 2-Oxo-3,3-tetramethylene hept-5-inphosphonic acid dimethyl ester

To a solution of 44.52 g of diisopropylamine in 200 ml of tetrahydrofuran is added 265 ml of a 1.66 M solution of butyllithium in hexane at -30 ° C. Subsequently, 22.83 g of cyclopentanecarboxylic acid was added dropwise and the reaction mixture was stirred for 30 minutes at -10 ° C. Subsequently, 31.92 g of 1-bromo-2-butine was added dropwise and the mixture was stirred for 16 hours at 25 ° C, then poured into 600 ml of ice-water and acidified with hydrochloric acid. After extraction with ether, the extract was washed with brine and concentrated in vacuo. The residue was distilled to give 21.30 g of 2,2-tetramethylene-hex-4-acid, boiling at 155-157 ° C / 13 torr.

IR: 3520 (broad), 2982, 2960, 1702, 1425, 1100, 1035 / cm.

For esterification, 20 g of the above acid are refluxed in 250 ml of methanol containing 2.5 ml of concentrated sulfuric acid for 6 hours. This gives 18.10 g of 2,2-tetramethylene-hex-4-acetic acid methyl ester, m.p. 110-111 ° C / 1866.51 Pa.

IR: 2951, 2860, 1728, 1430, 1331, 1098 / cm.

The above ester was prepared as described in Example 1 (a)

Convert to 2-oxo-3,3-tetramethylene-hept-5-inphosphonic acid dimethyl ester. The title compound was boiled at 120-122 ° C / 21.33 Pa.

IR: 3425 (broad), 2980, 2951, 2853, 1705, 1250, 1033 cm @ -1.

10b) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) -3-oxo-4,4-tetramethylene-oct-1-en-6-ynyl] ] bicyclo [3.3. OJoctane g (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3.0] octane 2-oxo-3,3-tetramethylene-hept-5-one reaction with dimethyl ester of phosphonic acid, analogous to that described in Example 1 (b).

190,901 don. 5.35 g of the title compound are obtained in the form of a colorless oily substance.

IR: 2940, 2865, 1711, 1684, 1622, 1600, 1585, 1275, 978, 947 / cm.

10c) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) - (3R) -3-hydroxy-4,4-tetramethylene-oct-1-ene6 ynyl] bicyclo [3.3. octane

Starting from 5.20 g of ketone prepared according to Example 10 (b), and starting from Example 1 (c). of this manual. 1.95 g of the title compound are obtained in the form of a colorless oily substance.

IR: 3600,3515,2945,2878,1712,1601,1585,1274, 976,947 / cm.

10d) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) 6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) -4,4- tetramethylene-oct-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one

Starting from 2.75 g of the compound prepared in Example 10 (c) and proceeding in a manner analogous to Example 1 (d). This gave 2.05 g of the title compound as a colorless oily substance.

IR: 2943.2870, 1740,976 / cm.

Example 11 (5E) -18,19-Didehydro-19-methyl-16,16-trimethylene-6? -Carba-prostaglandin- ₁₂

500 mg of (R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -7-methyl-3- (tetrahydropyran-2-yloxy) -4,4 starting from trimethylene octa-1,6-dienyl] -bicyclo [3.3.0] octan-3-one and proceeding in a manner analogous to that described in Example 1. 112 mg of the title compound are obtained in the form of a colorless oily substance.

IR: 3600, 3520, 3410 (br), 2935, 1711, 1601, 9761cm.

The starting compounds for the preparation of the title compound of this example are prepared as follows:

11a) 6-Methyl-2-oxo-3,3-trimethylene-hept-5-ene phosphonic acid dimethyl ester

To a solution of diisopropylamine (53.10 g) in tetrahydrofuran (250 ml) was added a solution of butyl lithium (1.18 mol, 1.66 mol) in hexane at -30 ° C followed by cyclobutanic acid (24.02 g). The mixture was stirred for an additional 30 minutes at -10 ° C and 42.91 g of 1-bromo-3-methyl-2-butene was added dropwise, followed by stirring at 25 ° C for 18 hours. The reaction mixture was poured into 1 liter of ice water, acidified to pH 4 with 2N hydrochloric acid and extracted with ether. The extract was washed with brine, dried over magnesium sulfate, and the ether was evaporated in vacuo. The residue was purified by distillation. This gives 26.30 g of 5-methyl-2,2-trimethylene-hex-4-enoic acid (b.p. 158-159 ° C / 14 torr), which in analogy to Example 1 (a) is 23.5 g. To 5-methyl-2,2-trimethylene-hex-4-enoic acid methyl ester (boiling point):

108-110 ° C (1866,51 Pa).

IR: 2980, 2948, 2857, 1728, 1430, 1080, 932 cm -1.

20 g of the methyl ester prepared above are reacted with dimethyl methane phosphonic acid ester as described in Example 1 (a). This gave 23.30 g of the title compound as a colorless liquid, boiling at 138-140 ° C / 19.99 Pa.

IR: 3420 (broad), 2988, 2950, 2855, 1704, 1250, 1035 / cm.

11b) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) -7-methyl-3-oxo-4,4-trimethylene octa-1,6] -dietdl] bicyclo [3.3. OJ octane was prepared from (R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3.0] octane and the phosphonate prepared according to Example 11 (a), and 5.95 g of the title compound are obtained in a manner analogous to that described in Example 1 (b). The product is a colorless, oily substance.

IR: 2948, 2860, 1712, 1620, 1600, 1585, 1272, 977, 948 cm @ -1.

11c) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyl-6 - [(E) - (3R) -3-hydroxy-7-methyl-4,4-trimethylene octa-1 , 6-dienyl] bicyclo [3.3.OJoktán

Starting with 5.00 g of ketone prepared according to Example 11 (b) and proceeding analogously to Example 1 (c). This gave 2.88 g of the title compound (15a-hydroxy) as a colorless oil.

IR: 3600, 3510, 2940, 2868, 1712, 1600, 1584, 1272, 9 cm, 948 / cm.

ljd) (1H, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) 6 - [(E) - (3R) -7-methyl-3- (tetrahydropyran-2-yloxy) - 4,4tnmetilén-octa-l, 6-dienyl] bicyclo [3.3.0] octan-3-one

All. Starting from 2.50 g of the compound prepared according to example 1c), a procedure analogous to that described in example 1d) is carried out. 1.90 g of the title compound are obtained in the form of a colorless oily substance.

IR: 2940, 2871, 1738, 976 cm @ -1.

Example 72 (5E) -18,18,19,19-Tetradehydro-16,16-trimethylene-N-methanesulfonyl-6a-carba-prostaglandin-1,1-carbotamide

190 mg of (5E) -18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin-I (prepared in Example 1) in 4 ml of dimethylformamide are added at 0 ° C. 80 mg of butyl chloroformate and 60 mg of triethylamine. After 30 minutes, 240 mg of methylsulfonamide sodium salt (prepared from methylsulfonamide and sodium methylate) and 1 ml of hexamethylphosphoric triamide are added and the reaction mixture is stirred for 3 hours at 25 ° C. The reaction mixture was then poured into citrate buffer pH 5 and extracted several times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane containing 1-5% isopropanol. This gave 135 mg of the title compound as an oily substance.

IR: 3600, 3410 (broad), 2960, 2855, 1728, 976 cm @ -1. Example 13 (5E-13,14-Didehydro-18,18,19,19-tetradehydro-1,6,6-trimethylene-6a-carba-prostaglandin-1,1-carboxamide

200 mg of (5E) -13,14-didehydro-18,18,19,19-tetradehydto-16,16-trimethylene-6a-carba-prostaglandin- ₁₂ (see Example 2) are dissolved in 5 ml of tetrahydrofuran. solution was added 90 mg of triethylamine and ^f 0 ° C ^| 8 mg of isobutyl ester of chloroformate. One hour

-1 121

After 190,901, ammonia gas was introduced at 0 ° C for 10 minutes and then allowed to stand at 25 ° C for 1 hour. For work-up, the mixture was diluted with water, extracted with dichloromethane, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel with 1-5% isopropanol in chloroform gives 160 mg of the title compound as a colorless oily substance.

IR: 3600, 3450, 3405, 2955, 2868, 2220, 1670, 1588 / cm -1.

Example 14 (5E) -18,19-Didehydro-19-chloro-16,16-trimethylene-6-carba-prostaglandin- ₁₂ g (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) ) -6 - [(E) - (3R) -7-chloro-3- (tetrahydro-pyran-2-yl) -4,4trimetilén-octa-l, 6-dienyl] bicyclo [3.3.0] octan-3 from the Wittig reaction of Example 1 (6 hours at room temperature) followed by deprotection to give the title compound (130 mg) as a colorless oily substance.

IR: (film): 3500 (wide), 2930, 2850, 1710, 1660, 975 / cm @ -1.

The starting materials for the preparation of the title compound of this example are prepared as follows:

14a) To a solution of 6-chloro-2-oxo-3,3-trimethylene-hept-5-ene-phosphonic acid dimethyl ester in diisopropylamine in 200 ml of tetrahydrofuran - 267 ml of 1.66 M in hexane at 30 ° C butyl lithium solution and then 20.2 g of cyclobutanecarboxylic acid are added. The mixture was then stirred for an additional 30 minutes at -10 ° C and 30 g of 1,3-dichlorobutene (2) was added dropwise. After stirring for an additional 16 hours at room temperature, the reaction mixture was poured into 1 liter of ice water, acidified to pH 4 with 2N hydrochloric acid and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by distillation. 22.3 g of 5-chloro-2,2-trimethylene-hex-4-enoic acid are obtained, m.p. 146-150 ° C / 4 torr. This was esterified according to the procedure described in Example 1 (a) to give 21 g of 5-chloro-2,2-trimethylene-hex-4-enoic acid methyl ester, b.p. 107-110 ° C / 433.288 Pa.

IR: (film): 2970, 2950, 2890, 1735, 1665, 1195, 1170 / cm.

This 21 g of methyl ester was also reacted with dimethyl phosphonic acid dimethyl ester of Example 1 (a) to give 20.5 g of the title compound as a colorless liquid.

IR: (film): 3400, 2980, 2945, 2850, 1710, 1666, 1260, 1030 cm -1.

14b) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) -7-chloro-3-oxo-4,4-trimethylene octa-1,6] -dienyl] bicyclo [3.3.0] octane

In the same manner as in Example 1 (b), 6 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo [3.3.0] octane and Starting from the phosphonate obtained in (a), 6.2 g of the title compound are obtained in the form of a colorless oily substance.

IR: (film): 2950, 2855, 1720, 1670, 1630, 1600, 1583, 1270, 715 / cm

14c) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6 - [(E) - (3R) -7-chloro-3-hydroxy-4,4-trimethylene octa1 , 6-dienyl) bicyclo [3.3. octane

6.2 g of the α, β-unsaturated ketone prepared according to Example 14 (b) are obtained in a manner analogous to that described in Example 1 (c). 3.2 g of the title compound (15a-alcohol) are obtained in the form of a colorless oily substance.

IR: (film): 3500 (wide), 2950, 2860, 1720, 1665, 1600, 1580, 1270, 715 / cm.

14d) (1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) 6 - [(E) - (3R) -7-chloro-3- (tetrahydropyran-2-doxy) - 4,4trimetilén-octa-1,6-dienyl] bicyclo [3.3.0] octan-3-one

Starting from 3.1 g of the compound prepared in Example 14 (c) and proceeding in analogy to Example 1 (d). 2.3 g of the title compound are obtained in the form of a colorless oily substance.

IR: (film): 2940, 2870, 1735, 1665, 1180, 1125, 1080, 1020 cm -1.

Example 15 (5E) -3-Oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

510 mg of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) ) To a solution of 4,4-trimethylene-oct-1-en-6-ynyl] -bicyclo [3.3.0] octane-3-ylidene} -ethan-1-ol in tetrahydrofuran (15 mL) was added sodium hydride (55 mg, 55% in mineral oil). slurry and reflux for 1 hour. Then, 166 mg of bromoacetic acid dissolved in 5 ml of tetrahydrofuran are added, the mixture is refluxed for 18 hours, then diluted with ether and extracted four times with 25 ml of 4% sodium hydroxide solution each time. This extract was acidified with 10% sulfuric acid at 0 ° C to pH 3 and extracted with dichloromethane. The organic extract was extracted with brine, dried over magnesium sulfate and evaporated in vacuo. In this way 440 mg of (5E) -3-oxa-18,18,19,19tetradehídro-16,16-trimethylene-6a-carba-prostaglandin I ₂ -l 1,15-bis- (tetrahydropyranyl ether) which was the 30 ml of acetic acid-water-tetrahydrofuran was stirred at 25 ° C for 18 hours to remove the protecting groups. Toluene was added and the residue was chromatographed on silica gel, eluting with ethyl acetate containing 0.1% to 1% acetic acid. This gives 283 mg of the title compound as a colorless oily substance.

IR (CHCl ₃ ): 3680, 3400 (broad), 2930, 1730, 1600, 1425, 970 / cm -1.

The starting material for the preparation of the title compound of this example is prepared as follows:

15a) 2 - {(E) - (1S, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) ) -4,4trimetilén-oct-l-en-6-ynyl] bicyclo [3.3.0] octan-3-ylidene} ethan-l-ol

To a solution of 3.32 g of phosphonoacetic acid triethyl ester in 75 ml of tetrahydrofuran at 0 ° C is added 1.42 g of potassium tert-butylate, followed by

-1 223

The mixture was stirred for 10 minutes and 4 g of (R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran) dissolved in 40 mL of toluene were added. 2-Yloxy) -4,4-trimethylene-oct-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one. After stirring for 18 hours at 24 ° C, the reaction mixture was diluted with ether (400 mL), extracted once with water, once with 20% sodium hydroxide, then washed with water to neutral, dried over magnesium sulfate and concentrated in vacuo. The residue was filtered through silica gel with hexane-ether (1: 1). This gave 4 g of the unsaturated ester as a colorless oily substance.

IR: 2940, 2870, 1700, 1652, 972 cm @ -1.

To a solution of the above 4 g ester in 130 ml of ether was added portionwise 1.1 g of lithium aluminum hydride with stirring at 0 ° C, and the mixture was further stirred for 30 minutes at 0 ° C. The excess reagent was then quenched by dropwise addition of ethyl acetate and water (6 mL) was added, stirred for 20 hours at 20 ° C, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with ether-hexane (3: 2). 1.1 g of 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3] are thus obtained as less polar compounds. - (tetrahydropyran-2-yloxy) -4,4-trimethylene-oct-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-ylidene} -ethan-1-ol, followed by 2, 1 g of the title compound is obtained in the form of a colorless oily substance.

IR: 3600, 3450, 2940, 2865, 1600, 974 / cm @ -1.

Example 16 (5Z) -3-Oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

490 mg of 2 - {(Z) - (1S, 5S, 6R, 7R) -7 - [(tetrahydropyran-2-yloxy) -4,4-trimethylene-oct-1-en-6-ynyl] -bicyclic [3.3.0] Octane-3-ylidene) -ethan-1-ol was prepared and followed in analogy to Example 15. This gave 220 mg of the title compound as a colorless oily substance.

IR: 3600.3400 (broad), 2930, 1732, 1600, 972 cm @ -1.

Example 17 (5E) -13,14-Didehydro-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

260 mg of 2 - {(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -3- (tetrahydropyran-2-yloxy) - To a solution of 4,4-trimethylene-octa-1,6-dinyl] -bicyclo [3.3.0] octan-3-ylidene-ethan-1-ol in 7 ml of tetrahydrofuran is added 60 mg of a 55% suspension of sodium hydride in mineral oil, and the reaction mixture is refluxed for 1 hour. Thereafter, 82 mg of bromoacetic acid dissolved in 2.5 ml of tetrahydrofuran are added and the mixture is refluxed for 18 hours, then diluted with ether and extracted four times with 15 ml of 4% sodium hydroxide solution each time. This extract was acidified with 10% sulfuric acid at 0 ° C to pH 3 and extracted with dichloromethane. The organic extract was extracted with brine, dried over magnesium sulfate and concentrated in vacuo. In this way 250 mg of (5E) -13,14-didehydro-3-oxa-18,18,19,19-te trade hydro-16,16-trimethylene-6a-carba-prostaglandin I ₂ -l 1,15-bis- (tetrahydropyranyl) ether was added which was stirred with 25 ml of acetic acid-water-tetrahydrofuran for 12 hours at 25 ° C to remove the protecting groups. Toluene was added and the residue was chromatographed on silica gel, eluting with ethyl acetate containing 0.1% to 1% acetic acid. 130 mg of the title compound are obtained in the form of a colorless oily substance.

IR: 3680.3400 (broad), 2930, 2225, 1730, 1602 cm-1. The starting material for the preparation of the title compound of this example is prepared as follows:

L ⁷⁾ (IR, 5S, 6S, 7R) -3,3-ethylenedioxy-7- (tetrahidrnpirán-pyran-2-yl) -6 - [(3S) -2-bromo-3- (yl tetrahydropyran2 oxy) -4,4-trimethylene-oct-1-en-6-ynyl] -bicyclo [3.3.0] octane g (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7 To a solution of benzoyloxy-6- (2-bromo-3-oxo-4,4-trimethylene-oct-1-en-6-ynyl) -bicyclo [3.3.0] octane in 70 ml of methanol was added portionwise at -40 ° C. 2 g of sodium borohydride and the mixture was stirred at -40 ° C for 45 minutes. The mixture was then diluted with ether, washed neutral with water, dried over magnesium sulfate and concentrated in vacuo.

The crude product (mixture of 15-epimers) was dissolved in methanol (100 mL), potassium carbonate (1.2 g) was added and the mixture was stirred at 23 ° C for 20 hours under argon. The reaction mixture was concentrated in vacuo, diluted with ether and washed neutral with brine. The solution was then dried over magnesium sulfate and concentrated in vacuo. Chromatography on a silica gel column, eluting with ether-hexane (3: 2), gave 0.8 g of the 15 J configuration alcohol, followed by 0.9 g of the 15a configuration (PG nomenclature) as the polar component. in the form of an oily substance.

Dissolve 0.8 g of the above alcohol, 8 mg p-toluenesulfonic acid and 0.7 g dihydropyran in dichloromethane and stir at 0 ° C for 45 minutes. Subsequently, the reaction mixture is diluted with ether, extracted with dilute sodium bicarbonate solution, washed with water, neutralized, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-ether (7: 3) to give 1.1 g of the title compound as a colorless oily substance.

IR: 2940, 2875, 1450, 948 cm @ -1.

17b) (1R, 5S, 6S, 7R) -7- (Tetrahydropyran-2-yloxy) (N - [(3 S) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylene) -l, 6-diynyl] bicyclo [3.3.0] octan-3-one

1.1 g of the compound prepared according to Example 17 a) is dissolved in a mixture of 12 ml of dimethyl sulfoxide and 5 ml of theta-hydrofuran and 325 mg of potassium tert-butylate is added and the mixture is stirred for 2 hours at 22 ° C. The solution was then diluted with 50 mL of water and extracted three times with 50 mL of ether-hexane (3: 2). The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was stirred for 20 hours with 30 ml of acetic acid-hydrogen tetrahydrofuran (65:35:10), then concentrated in vacuo and purified by silica gel chromatography. 0.6 g of an oily substance is eluted with ether, 20 ml of me13

-1 325

190.901 in dichloromethane was reacted with 0.45 dihydropyran and 5 mg p-toluenesulfonic acid at 0 ° C. After 30 minutes, the mixture was diluted with ether, extracted with sodium bicarbonate solution and water, then dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel, eluting with hexane-ether (1: 1), afforded 0.8 g of the title compound as a colorless oily substance.

IR: 2945, 2880, 2210, 1736 / cm.

17c) 2 - {(E) - (1S, 5S, 6S, 7R) -7- (Tetrahydropyran-2-yloxy) -6 - [(3S) -3- (tetrahydropyran-2-yloxy) -4]; 4-trimethylene-octa-l, 6-diynyl] bicyclo [3.3.0] octan-3-ylidene} ethan-l-ol

To a solution of 0.66 g of the triethyl phosphonic acetic acid in 15 ml of tetrahydrofuran was added 280 mg of potassium tert-butylate at 0 ° C. The solution is stirred for 10 minutes, then 0.8 g of the ketone prepared in Example 17 (b) is dissolved in 8 ml of toluene and the whole is stirred for 18 hours at 24 ° C. The reaction mixture was diluted with ether (100 ml), extracted once with water and once with 20% sodium hydroxide solution, then washed with water until neutral, dried over magnesium sulfate and concentrated in vacuo. The residue was filtered through silica gel with hexane-ether (1: 1). 0.81 g of the unsaturated ester is thus obtained in the form of a colorless oily substance.

IR: 2942, 2873, 2210, 1700, 1650 / cm -1.

To a solution of the above 0.8 g ester in 25 ml ether was added 220 mg of lithium aluminum hydride in portions with stirring at 0 ° C, and the mixture was further stirred for 30 minutes at 0 ° C. The excess reagent was quenched by dropwise addition of ethyl acetate and water (1 mL) was added, stirred at 20 ° C for 2 hours, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with ether-hexane (3: 2). As a less polar compound, 230 mg of 2 - {(Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -3- (tetrahydropyran-2-) yloxy) -4,4-trimethylene-octa-1,6-dinyl] -bicyclo [3.3.0] octan-3-ylidene} -ethan-1-ol, followed by 240 mg of the title compound of a colorless oily consistency. material.

IR: 3600, 3450, 2940, 2215 / cm.

Example 18 (5E) -3-Oxa-20-methyl-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

In analogy to Example 15, 300 mg of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) 6 - [(E) - (3R) -3 - (Tetrahydropyran-2-yloxy) -4,4-trimethylene-non-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-ylidene} -ethan-1-ol compound. The product is an oily, colorless substance.

IR: 3600, 3410 (broad), 2932, 1732, 1600, 972 cm @ -1.

The starting material for the preparation of the title compound of this example is prepared as follows:

18a) 2 - {(E) - (1S, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) ) -4,4-Trimethylene-non-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-ylidene} -ethan-1-ol

2.1 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) -4,4 starting from trimethylene-non-1-en-6-ynyl] -bicyclo [3.3.0] octan-3-one and following the procedure of Example 15 (a). When separating the isomers by chromatography, 0.6 g of 2 - {(Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylenethiophene-non-l-en-6-ynyl] bicyclo [3.3.0] octan-3-ylidene} ethan-l-ol, 0.65 g of the title compound is obtained in the form of a colorless oily substance.

IR: 3600, 3420, 2942, 2865, 1600, 972 cm @ -1.

Example 19 (5E) -13,14-Didehydro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

In a manner analogous to that described in Example 15, 200 mg of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S)) - 3- (tetrahydropyran-2-yloxy) -4,4-trimethylene-nona-1,6-dinyl] -bicyclo [3.3.0] octan-3-ylidene} -ethan-1-ol, 89 mg of the title compound are obtained. The product is an oily, colorless substance.

IR: 3600, 3406 (br), 2930, 2862, 2221, 1730, 1600 / cm.

The starting material for the preparation of the above title compound is prepared as follows:

19a) 2 - {(E) - (1S, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) -6 - [(3S) -3- (tetrahydropyran-2-yloxy) -4, 4-trimethylene-nona-l, 6-diynyl] bicyclo [3.3.0] octan-3-ylidene} ethan-l-ol

1.5 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylenone] -1,6-Dinyl] -bicyclo [3.3.0] octan-3-one is prepared and analogously to Example 15 (a). Thus, as less polar compound, 420 mg of 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -3- (tetrahydropyran-2-) yloxy) -4,4-trimethylene-nona, 1,6-dinyl] -bicyclo [3.3.0] octan-3-ylidene} -ethan-1-ol, followed by 820 mg of the title compound as a more polar compound as a colorless oily substance. form.

IR: 3600, 3420, 2948, 2862, 2225, 1600 / cm.

Example 20 (5E) -18,19-Didehydro-9-methyl-3-oxa-16,16-trimethylene-6a-carba-prostaglandin- ₁₂

250 mg of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3R) -3- (tetrahydropyran-2-yloxy) ) Starting from -7-methyl-4,4-trimethylene-octa-1,6-dienyl] -bicyclo [3.3.0] octan-3-ylidene] -ethan-1-ol and analogous to that described in Example 15). we act. 110 mg of the title compound are obtained in the form of a colorless oily substance.

IR: 3600, 3415 (broad), 2942, 2860, 1734, 1601, 976 / cm.

The starting material for the preparation of the title compound is prepared as follows:

20a) 2 - {(E) - (1S, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) -6 - [(E) - (3E) -3- (tetrahydropyran-2-yloxy) ) -7-Methyl-4,4-trimethylene-octa-1,6-dienyl] -bicyclo [3.3.0] octan-3-ylidene} -ethan-1-ol g (1R, 5S, 6R, 7R) - 7- (tetrahydro-pyran-2-yl) -1427

190 901

6 - [(E) - (3R) -7-methyl-3- (tetrahydro-pyran-2-yl) -4,4trimetiIén-octa-l, 6-dienyl] bicyclo [3.3.0] octan-3- and proceeding in a manner analogous to that described in Example 15 (a). This gave 1.60 g of the title compound as a colorless oily substance as a more polar product.

IR: 3600, 3410, 2938, 2858, 1160, 1015, 974 / cm @ -1.

Example 27 (5E) -l 3,14-didehydro-20-methyl-3-oxa18,18,19,19, -Tetradehydro-16,16-trimethylene-6a-carbaprostaglandin-I _2, methyl ester

100 mg of (5E) -13,14-didehydro-20-methyl-3-oxa18,18,19,19-tetradehydro-16,16-trimethylene-6a-carbapro-prostaglandin- ₁₂ (product prepared according to Example 5). A solution of diazomethane in ether was added dropwise at 0 ° C to a solution of dichloromethane in dichloromethane and 5 ml of dimethoxyethane until the yellow color of the reaction solution persisted. The solution was then concentrated in vacuo and the residue was purified by silica gel chromatography. Elution was carried out with methylene chloride containing 2% isopropyl alcohol. This gave 80 mg of the title compound as a colorless oily substance.

IR: 3600, 2942, 2860, 2228, 1742, 1135 cm @ -1.

Example 22 (5E) -3-Oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- _12- acetylamide

255 mg of (5E) -3-oxa-18,18,19,19-tetradehidro16.16- trimethylene-6a-carba-prostaglandin I ₂ -ll, 15-bis (tetrahydropyranyl) ether (see Example 15) in 5 ml To this solution of acetonitrile was added triethylamine (63 mg), followed by the addition of acetyl isocyanate (48 mg) in acetonitrile (2 ml) at 0 ° C. The mixture was then heated at 20 ° C for 2 hours and then concentrated in vacuo. The residue was diluted with 100 ml of citrate buffer pH 5, extracted with dichloromethane, washed successively with sodium bicarbonate solution and brine, then dried over magnesium sulfate and concentrated in vacuo. To remove the protecting groups, the residue was stirred in acetic acid-water-tetrahydrofuran (65:35:10) for 18 hours and concentrated in vacuo. The residue thus obtained is chromatographed on silica gel, eluting with methylene chloride (3% isopropyl alcohol). 105 mg of the title compound are obtained in the form of a colorless oily substance.

IR: 3600, 3500, 3410, 2950, 2862, 1725, 1138, 976 cm @ -1.

Example 23 (5E) -3-Oxa-20-methyl-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- _12- carboxamide

To a solution of (5E) -3-oxa-20-methyl-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin- ₁₂ (196 mg) in dimethylformamide (5 ml) was added at 0 ° C. 65 mg of triethylamine and 90 mg of isobutyl ester of chloroformate. After one hour, dry ammonia gas was added to the solution for 15 minutes and the mixture allowed to stand at 0 ° C for 2 hours. For work-up, the mixture is diluted with citrate buffer pH 5, extracted with ethyl acetate, the extract is washed first with sodium bicarbonate solution and then with sodium chloride solution and evaporated under vacuum over magnesium sulfate. The residue was chromatographed on silica gel with 2% isopropanol in dichloromethane. This gave 150 mg of the title compound as a colorless oily substance.

IR: 3600, 3495, 3410, 2955, 2868, 1662, 1135, 976 cm @ -1.

Example 24 (5E) -13,14-didehydro-20-methyl-3-oxa-18,18,19,19t'tradehidro-16,16-trimethylene-6a-carba-prostaglandin-I ₂ - (2,3 dihydroxy-propyl) -amide

192 mg of (5E) -13,14-didehydro-20-methyl-3-oxa18.18.19.19- solution of tetradehydro-16,16-trimethylene-6akarba prostaglandin I ₂ 4 ml of acetone was added at 0 ° C 59 mg triethylamine and 80 mg isobutyl ester of chloroformate. After 30 minutes, 240 mg of 1-amino-2,3-dihydroxypropane dissolved in 3 ml of acetone and 5 ml of acetonitrile were added. After 2 hours at 20 ° C, the mixture was concentrated in vacuo. The residue was then diluted with dichloromethane (100 mL), extracted with brine, dried over magnesium sulfate and concentrated in vacuo. The residue thus obtained is chromatographed on silica gel, eluting with 20% isopropyl alcohol in methylene chloride. 150 mg of the title compound are obtained in the form of a colorless oily substance.

IR: 3600, 3420 (broad), 2952, 2865, 2221, 1653, 1135, 1030 / cm.

Example 25 (5R) -3,14-Didehydro-20-methyl-3-oxa-18,18,19,19t'tradehydro-16,16-trimethylene-6a-carba-prostaglandin- _12- phenacyl ester

200 mg of (5E) -13,14-didehydro-20-methyl-3-oxa18.18.19.19- tetradehydro-16,16-trimethylene-6a-carbaprostaglandin-I ₂ was dissolved in 8 mL of acetone was added a solution of t z 150 mg of ω-bromoacetophenone and 2 ml of triethylamine are added and the mixture is then stirred overnight at room temperature. Ether (200 ml) was added and the mixture was partitioned between water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with methylene chloride (2% acetone) to give the title compound (190 mg).

IR: 3600, 2950, 2866, 2225, 1748, 1708, 1138, 1028 / cm.

Example 26 (5E) -13,14-Didehydro-20-meth-3-oxa-18,18,19,19t-tradehydro-16,16-trimethylene-6a-carba-prostaglandin- _1,2- tris (hydroxymethyl) ) -aminomethane salt

A solution of (5E) -13,14-didehydro-20-methyl-3-oxa18,18,19,19-tetradehydro-16,16-trimethylene-6a-carbapro-prostaglandin- ₂ (168 mg) in acetonitrile (34 mL) was added at 70 ° C. Tris (hydroxymethyl) aminomethane (60 mg), dissolved in water (0.2 ml). The mixture was allowed to cool with stirring, and after 16 hours, the solvent was decanted and

-1 529

190.901 residues are dried under vacuum. 145 mg of the title compound are obtained in the form of a waxy mass.

IR: 3500 (br), 2930, 1695 (br) / cm (KBr).

Claims (4)

Claims A process for the preparation of the pharmaceutically acceptable salts and isomers of the carbacyclin derivatives of formula I and R _{2 in the} form of their bases, wherein Q X R 1 is a group of the general formula wherein R _{2 is} hydrogen, C 1-4 alkyl or phenacyl, or R 1 is one SHE II -C-NHR _{3 in} which R 1 is C 1 -C 4 alkanoyl or C 1 -C 4 alkanesulfonyl, dihydroxy (C 1 -C 5) alkyl or hydrogen, X is methylene or oxygen, The trans is -CH = CH- or -CH = C-, W is a hydroxymethylene group in which the hydroxy group may be in the α or β configuration, n is 1 or 2, D is a C 1-4 straight chain alkylene, E is -C = C or one -CH = CR ₇ - wherein R ₇ is hydrogen, C 1-4 alkyl or halo; R ₄ is C 1-7 alkyl, Wherein R ₅ is hidroxilcsoportazzal that a) (II) compound wherein R _and W, n, D, E and _R4 are as defined above and B is trans double bond or a -CH group = CBr-formula represents the presence of free hydroxyl groups optionally after reaction with a Wittig reagent of formula (III), and b) preparation of (I) compounds wherein X is O, (IV) a compound of formula wherein R _4, R _s, A, W, D, E and n are as stated above, the present with a haloacetic acid derivative of formula (V), optionally Hal means chlorine, bromine or iodine, R _g is etherified with a trialkylsilyl group containing 1 to 4 carbon atoms, or an alkali metal such as sodium, potassium or lithium, and then deprotected in the product of (a) or (b). and then separating the resulting product 16 into cis-trans isomers, optionally and in any order, esterifying the free carboxyl group of the product, or converting the carboxyl group into an amide, or forming a physiologically acceptable salt with a base containing the carboxyl group. (Priority: February 18, 1983) 2. A process according to claim 1 for the preparation of a pharmaceutically acceptable salt or isomer thereof of a carbacycline derivative of formula (I) and a hydrogen atom of R ₂ , wherein SHE // R, is -C ^x _OR2 group of general formula wherein R ₂ is hydrogen or C 1-4 alkyl, or -C-NHR ₃ where R ₃ is hydrogen, C 1-4 alkanoyl, or C 1-4 alkanesulfonyl, X is methylene, A is trans -CH = CH- or -C = C, W is a hydroxymethylene group in which the hydroxy group may be in the α or β configuration, n is 1 or 2, D is a C 1-4 straight chain alkylene, E is -C = C- or one -CH = CR ₇ - wherein R _{7 is} hydrogen, C 1-4 alkyl or halo, R ₄ is C 1-7 alkyl, R 1 is a hydroxy group, wherein a compound of formula II wherein R 1, W, n, D, E and R ₄ are as defined above and B is a trans double bond or -CH-CBr-, optionally protecting the free hydroxy groups present by reacting with a Wittig reagent of formula (III) and cleaving the protecting group, if present, in the resulting product, optionally and in any order, separating the cis-trans isomers, or converting the carboxyl group into an amide or forming a physiologically acceptable salt from the carboxyl-containing compound with a base. (Priority: March 12, 1982) 3. A process for the preparation of a medicament for lowering blood pressure as well as bronchodilators, vasodilators, inhibitors of platelet aggregation and reducing gastric acid secretion, characterized in that one or more compounds of the general formula I according to claim 1 or R _{z are} hydrogen atoms. is a salt of these compounds with physiologically acceptable bases - in the formula (I): R 1, R ₂ , R ₃ , n, A, W, D, E, R ₄ , R 1 and R ₇ are as defined in claim 1; in the case of one of their isomers a -1 631 190.901 mixed with excipients commonly used in pharmaceutical technology to form a pharmaceutical composition. (Priority: February 18, 1983) 4. A process for the preparation of a medicament for lowering blood pressure, bronchodilator, vasodilator, inhibiting platelet aggregation and reducing gastric acid secretion, characterized in that one or more of the compounds of the general formula I according to claim ₂ or R _{2 are} hydrogen atoms. salts of these compounds with physiologically acceptable bases - wherein R 1, R ₂ , R ₃ , n, A, W, D, E, R ₄ and R _{5 in} formula (I) are as defined in claim 2, optionally in the form of one of their isomers, when mixed with auxiliary agents commonly used in pharmaceutical technology to form a pharmaceutical composition. Published by the National Office of Inventions Responsible for publishing: Zoltán Himer Head of Department Published by Technical Publisher Made in Borsodi Printing House