CS257298B2 - Production method of derivatives of bicyclo (4.2.%) octanes - Google Patents

Description

The present invention relates to a process for the preparation of novel bicyclo [4.2.1] octanes derivatives and their pharmaceutically acceptable salts and esters, their use in the treatment of cardiovascular diseases, the pharmaceutical preparations comprising these compounds.

Bicyclo [4.2.o] oct-2-en-7-one is readily prepared from 1,3-cyclohexadiene (Tetrahedron,

27: 615 (1971). It can be used as an intermediate in the synthesis of prostaglandins (Tetrahedron Lett., 3091, 1973).

Some analogs of prostaglandins are known which contain a bicyclic carbon skeleton. Carbacycline contains a bicyclo [3.3.1] octane skeleton and is described in various publications (J.

Chem. Soc., Chem. Commun., 1067 (1978); Tetrahedron Lett. (1978); Tetrahedron Lett.

433 (1979); Tetrahedron Lett., 2807 (1979); J. Org. Chem. 44: 2,880, 1979) and patents (Belgian Patent No. 874,135; British Patent No. 2,014,143; French Patent 2,424,908; DE-OS

904 655; Japanese Patent K 79,117,450; South African Patent No. 7,900,176). Numerous analogues of carbaprostacyclines are described in the following publications: US Patent No. 4,306,076, DE-OS

146,278, DE-OS 3,204,443; Prost. Leuke. Med., 9: 307 (1982); J. Org. Chem. 48, 5341 (1983); Tetrahedron Lett. 3493,1983; Biochem. Pharmacol. 32: 2,405, 1983; Prost. Leuko. Copper. 11: 391,1983).

Synthetic prostaglandins (homo PGE ₂ and homo PGF _2ff ) can be prepared with hydroxyl groups and lower side chains in a trans position in a six membered ring (Tetrahedron Lett., 3327, 1971).

The invention relates to a process for the preparation of compounds of formulas 1, 2 and 3 wherein

η

R

R

R is 2 or 3, is CH 3 OH, CHO, CO ₂ R or CO ₂ H, is hydrogen or methyl, and represents straight or branched alkyl having 5 to 10 carbon atoms,

- ^(CH 2> a

Θ ^{CH2 'CH2} O or - (CH _{2) m} -phenyl, wherein a has a value of 0, 1 or 2, b is 3-7, m is 0, 1 or 2 and __ 0 0 i' ii H represents the group -O-X-X, wherein X is -NHCCH3 or -NHC-C8H8, and pharmaceutically acceptable non-toxic salts and esters thereof.

Disclosed is the treatment of cardiovascular diseases in animals (mammals) by administering a therapeutically effective amount of the compounds of formulas 1, 2 or 3, or pharmaceutically acceptable salts or esters thereof.

Further disclosed are pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and a compound of Formula 1, 2 or 3, or a pharmaceutically acceptable salt or ester thereof.

The pharmaceutically acceptable, non-toxic salts of the compounds of formulas 1, 2 and 3 are the carboxylic acid salts obtained by reacting the COOH group in Formula 1, 2 or 3 with COOH in Formula 1 or 3 with a suitable amine or inorganic base. Their preparation is given below.

Pharmaceutically acceptable carboxylic acid esters corresponding to the acids of formulas 1, 2 and 3 are prepared by conventional acid methods, for example by reaction with a suitable diazolaalkane or activated derivative, optionally using a condensing agent such as dicyclohexylcarbodiimide, reaction of a salt with a suitable active alkylating agent, or reesterification of an existing ester. Specific preparations are described in the preparations and examples below.

The term alkyl includes saturated straight and branched chain hydrocarbons containing the specified number of carbon atoms. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl.

Cycloalkyl means a saturated monocyclic hydrocarbon radical having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Phenyl includes all possible isoraeric phenyl radicals.

Optionally or optionally means that the circumstances described may or may not occur, and thus the use of this term includes both of these events.

The term treatment as used herein means treating diseases of mammals, particularly humans, and includes:

(i) prevention of disease in subjects who may have at their disposal but not yet diagnosed;

li) inhibiting the disease, i.e., arresting its development; or iii) eliminating the disease, ie, regression of the disease.

The numbering system for the bicyclo [4.2] octane skeleton in the scheme below is used to name the intermediates and products of the invention.

The absolute stereochemistry of the carbons 1,2,3 and 6, and the 3 'side chain attached to carbon atom 2 are specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon is specified by either R S or S. When the compound is a racemic mixture, the stereochemistry of each chiral carbon is specified by either R 3 or S ^K , referring to the individual enantiomer in the racemate. In this way, the relative stereochemistry is unambiguous and the racemic modification is denoted by the asterisk ^n5t · '. The olefin stereochemistry is designated according to the IUPAC EZ system. The classical nomenclature is used to name compounds having a triple bond as alkynyl; two bonds starting from the same atom represent -ylidene. Examples of names are given below in a preferred embodiment.

A preferred subclass of compounds of the invention includes compounds of formulas 1, 2 and 3 wherein n is 2. Other preferred subclasses are compounds of the invention wherein R ₂ is hydrogen. Yet another preferred subclass includes compounds wherein CHO, CO ₃ R or CO ₂ H, preferably CO ₂ R and CO ₃ H, and particularly preferably CO-, Η. Another preferred subclass includes compounds of the invention wherein R ₃ is a linear or branched alkyl having 5 to 10, preferably or 7, particularly preferably 5 carbon atoms, ^- (CH ₂ ) _y - CH 2 J. ^CH 2 * b '- ^Ct 12 ^or ^

- ^CH 2 -O, preferably - (CH ₂ ) _and -CH (CH ₂ > _b , -CH ₂ -, or -CH ₂ <3, and particularly preferably

- < ^CH 2> and - ^C "Wh

Another preferred sub-group consists of compounds of formulas 1, 2 and 3 wherein n is 2 or 3, R 6 is CO 3 H, CO 3 R or CHO; R ₂ represents hydrogen or methyl; and R1 is a linear or branched alkyl of 5 to 10 carbon atoms, - ( ^CH2 ) a

or -CH

In addition to these subgroups, a preferred group of compounds are those of formulas 1, 2 and 3 wherein n is 2 or 3, R 6 is CHO, CO 3 R or CO ₃ H, R ₂ is hydrogen or methyl, and R 1 is linear or branched alkyl of 5 or 7 carbon atoms, - (CH ₂ ) _and -CH (CH ₂ ) _b ,

or

Particularly preferred among these compounds are those compounds of the invention wherein n is 2 or 3, R ₃ is CO 3 R or CO ₂ H, R ₂ is hydrogen or methyl and R 3 is n-pentyl or - (CH ₂ ) -CH (CH) ₂ ) _b . A particularly preferred sub-group consists of compounds of formulas 1, and 3, wherein n is 2, R 1 is CO ₂ H, R ₂ is hydrogen and R ₃ is ^- (CH ₂ ) _and

-CH (CH3) wherein a is 0 or 1 and b is 3 to 7, preferably 4 or 5, particularly preferably 5; and pharmaceutically acceptable non-toxic salts and esters thereof. A particularly preferred subgroup are compounds of formula 1 wherein: R represents a group COjH; R ₂ represents hydrogen,

R ₃ cyclohexyl. The foregoing data on preferred embodiments of the invention include the pharmaceutically acceptable salts and esters as well as the free bases of the compounds mentioned above or below.

At present, the most preferred compounds of the invention are:

(Z) - (3'S, 1S, 2S, 3R, 6S) - [2- (3'-Hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene] pentanoic acid, (Z) - (3'S, IR, 2R, 3S, 6R) -5- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct -7-ylidene] pentanoic acid, (Z) - (3'S ^X , 1S ^X , 2S ^x 3R ^X , 6S ^x ) -5- (2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl)) -3-hydroxybicyclo (4.2.0) oct-7-ylidene] pentanoic acid, (Z) - / 3'S ^X , IR ⁵¹ , 2R ^X , 3S ^X , 6R ^X / -5- [2- / 3'-hydroxy- 3'-Cyclohexylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] pentanoic acid, (E) - (3S, 1S, 2S, 3R, 6S) -4- [2-] 3'-hydroxy-3'-cyclohexylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid, (E) - (3'S ^X , 1S ^X , 2S ^X , 3R ^X , 6S ^x / -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid, (Z) - (3'S), 1S, 2S, 3R, 6S] -4- [2- (3'-Hydroxy-3'-cyclohexylpros-1'-ynyl) -3-hydroxybenzoyl [4.2.0] oct-7-ylidene] butyric acid, / Z / - (3'S, 1S, 2S, 3R, 6S) -4- [2- / 3'-hydroxy-3'-cyclopentylprop-1'- vinyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid, (Z) - / 3'S ^X , 1S ^X , 2S ^X , 3R ^X , 6S ^x / -4- [2- / 3'- hydroxy-3'-cyclohexylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid, (Z) - (3'S ^X , 1S ^X , 2S ^X , 3R ^X , 6S ^x ) -4- [2- / 3'-hydroxy-3'-cyclopentylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid, and their pharmaceutically acceptable, non-toxic salts and their esters.

Methods for preparing starting compounds and intermediates for preparing compounds of formulas 1, 2 and 3 are described in AO No. 257 285.

The pharmaceutically acceptable non-toxic salts of the compounds of formulas 1, 2 and 3 are prepared by treating the free acids with an appropriate amount of a pharmaceutically acceptable base.

Pharmaceutically acceptable bases include, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, iron hydroxide, cupric hydroxide, manganese hydroxide, aluminum hydroxide, iron hydroxide, manganese hydroxide, isopropylamine, trimethylamine, diethylamine, tripropylamine, ethanolamine 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, procaine, choline, betaine, ethylenediamine, glucososamine, methylglucamine, theobromine, purine, piperazine, N-ethylpiperidine, polyamide resins and the like. For example, to prepare a monovalent cationic salt, the free acid (starting material) of Formula 1, 2 or 3 is treated with a molar equivalent of a pharmaceutically acceptable base in a suitable solvent such as water, methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of the compounds of formulas 1 or 3 to the base is selected to provide the desired ratio for a particular salt. For example, to prepare a divalent cation salt such as calcium or magnesium, the free acid is treated with at least one-half molar amount of a pharmaceutically acceptable base to form a neutral salt. Similarly, for a trivalent aluminum cation salt, at least one-third molar equivalent of the aluminum base is used to form the neutral salt.

The novel free carboxylic acids of formulas 1, 2 and 3 of the invention can be liberated from their possible salts by treating these salts with at least a stoichiometric amount of a strong acid, preferably an inorganic acid such as hydrochloric acid, sulfuric acid and the like at temperatures ranging from about 0 to about 50 ° C, preferably at room temperature.

The pharmaceutically acceptable non-toxic esters of the novel acids of formulas 1, 2 and 3 of the invention may be prepared, for example, by esterifying the corresponding free acids with a solution of a suitable diazoalkane in a suitable inert solvent such as diethyl ether. An alternative and general method for preparing the esterified acids of the invention involves reacting a benzene solution of the carboxylic acid with an alkyl halide in the presence of an organic diazabicycloundecane (DEU) base at temperatures from about 20 to about 80 ° C for about 1 to 12 hours. These conditions are preferably used to esterify acids containing labile functional groups in the molecule, such as prostaglandins and their synthetic analogs, as they avoid acid catalysis and essentially do not use drastic agents (N. Ono et al., Bull. Chem. Soc. Japan,

51, 2401-2404 (1978)).

. Typical esters are those derived from methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, 2-butyl alcohol, 2-pentyl alcohol, isopentyl alcohol, 2-hexyl alcohol and the like.

Alternatively, alkyl esters can be prepared by transesterification catalyzed by the corresponding alkoxide according to methods known in the art. In the preparation of esters by transesterification, it is preferable to proceed from the lower esters to the higher esters, for example from the methyl ester to the isoamyl ester. However, using a significant excess of lower alcohol, the higher esters can be trans esterified to lower esters; for example, using a significant excess of ethanol, the hexyl ester is converted to the ethyl ester by transesterification.

Salts of compounds of formulas 1, 2 and 3 may be exchanged by utilizing different solubility of salts, volatiles or acid activities or by treatment with a suitably selected ion exchange resin. For example, the exchange is effected by reacting a salt of a compound of Formula 1, 2 or 3 with a slight stoichiometric excess of acid having a lower kPa than the acid forming the starting salt. The exchange is carried out at a temperature between about 0 ° C and the boiling point of the solvent used as the reaction medium.

The compounds of the invention are useful in the treatment of cardiovascular diseases; in particular, they function as vasodilators and inhibit the accumulation of cholesterol on the vascular walls and in the plasma. They are also potent inhibitors of platelet aggregation and deprive them of procoagulants and pro-atherosclerotic factors. Therefore, these compounds are useful in the treatment and prevention of cardiovascular diseases including atherosclerosis, thrombotic and vasopastic diseases. They can thus be used as antihypertensives and cholesterol lowering agents.

The compounds of the invention exhibit a spectrum of activity similar to prostacyclins. However, unlike prostacyclins whose therapeutic efficacy is reduced by their extreme chemical instability, the compounds of the invention retain high biological activity because they have significantly higher chemical stability and a combination of the above properties is a prerequisite for prophylactic and / or therapeutic use especially in cardiovascular treatment. and dysfunction. Many of these compounds have selective antithrombotic effects and achieve this therapeutic effect without substantially affecting blood pressure.

Administration of the active compounds in the pharmaceutical compositions described above may be accomplished by any of the routes of administration known for agents affecting the cardiovascular system.

Such procedures include oral, parenteral, topical and other systemic administration. According to the intended method, the formulations may be in the form of a solid, semisolid or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions and the like, preferably in unitary dosage form suitable for administration of an accurate dose. The compositions may contain conventional pharmaceutical carriers or excipients and the active compound of formula 1, 2 or 3 and / or a pharmaceutically acceptable salt thereof, and may further comprise other drugs, pharmaceutical agents, carriers, additives, etc.

A method of treating cardiovascular disease in a mammal comprises administering an effective amount of the compounds of Formulas 1, 2 or 3, or pharmaceutically acceptable non-toxic salts or esters thereof, or pharmaceutical compositions containing the compounds as active ingredients.

Formulations suitable for administration include the compounds of Formula 1, 2 or 3, or pharmaceutically acceptable salts thereof, in an acceptable, non-toxic carrier.

The amount of active compound to be administered will of course depend on the subject being treated, the degree of the disease, the mode of administration, and the attending physician's opinion. However, the effective dose is in the range of 0.001 to 15 mg / kg / day, preferably 0.01 to 3 mg / kg / day. For humans with an average weight of 70 kg, this amount is 0.07 to 1000 mg per day, preferably 0.7 to 210 mg per day.

The novel compounds prepared by the process of the invention may be formulated with suitable pharmaceutical excipients known in the art for the production of cardiovascular preparations. In general, the effective amount of the active ingredient is about 0.001% by weight. % to about 10 wt. based on the total weight of the preparation to be prepared. The balance comprises suitable additives in an amount of from about 90% by weight. % to about 99.999 wt.

For solid preparations, conventional non-toxic solid carriers include, for example, pharmaceutically acceptable mannitol, lactose, starch, magnesium stearate, saccharin sodium, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. The active compounds mentioned above may be formulated as suppositories using, for example, polyalkylene glycols, e.g. polypropylene glycol, as carriers. Liquid pharmaceutical preparations may be prepared, for example, by dissolution, dispersion, etc. The active compounds as defined above and selected pharmaceutical ingredients in a carrier, such as water, saline solution, aqueous dextrosis, glycerol, ethynol, and the like, to form a solution or suspension. If desired, the pharmaceutical compositions may also contain small amounts of non-toxic additives such as wetting or emulsifying agents, pH adjusting agents and the like, for example, sodium acetate, sorbitate monolaurate, sodium triethanolamine, triethanolamine oleate, etc. Methods for preparing these dosage forms. are known or will be apparent to those skilled in the art; see, eg, Reemington's Pharmaceutical Sciences, Mack Publishing Company, Easto, Pennsylvania, 15th Edition, 1975. The compositions or compositions to be administered will in each case contain the active compound (s) in an effective amount to alleviate the symptoms of the disease being treated.

Parenteral administration is generally by injection, either subcutaneously, intramuscularly or intravenously. Injectable preparations may be in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solutions or suspensions in liquids suitable for injection, or as emulsions. Suitable additives are, for example, water, saline, dextroza, glycerol, ethanol and the like. If desired, the pharmaceutical compositions to be administered may contain a small amount of nontoxic suitable additives such as wetting or emulsifying agents, pH adjusting agents and the like such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.

More recent is parenteral administration, which involves the implantation of a sustained release slow release system so as to maintain a constant dose level. See, eg, US Patent No. 3,710,795.

For administration, the suppositories include conventional binders and carriers such as polyalkylene glycols or triglycerides. Suppositories may be prepared from mixtures containing the active ingredient in the range of 0.5 to 10%, preferably 1 to 2%.

The compounds of the above formulas 1, 2 or 3 are prepared by the process of the invention by removing the protecting groups in the compounds of the general formulas 4, 5 or 6

(4) (5) (6) to form compounds of formulas 1, 2 or 3, and optionally obtain the compounds

(a) convert from compounds wherein R 1 is CO 2, H to the corresponding compounds wherein R 1 is CH 2 OH, or

(b) compounds of formulas 1, 2 or 3 wherein R ₃ is CO ₂ H are converted to the corresponding compounds where CHO; or

c) converting compounds of formula 1, 2 or 3 wherein R 1 is COOH to the corresponding compounds wherein R 1 is COOR and optionally

d) converting compounds of formulas 1, 2 or 3 into their pharmaceutically acceptable, non-toxic salts; and

(e) the pharmaceutically acceptable, non-toxic salts of the compounds of formulas 1, 2 or 3 are converted into the corresponding acids or esters; and

f) acids of formulas 1, 2 or 3 are converted into pharmaceutically acceptable, non-toxic esters,

(g) converting pharmaceutically acceptable, non-toxic esters of the compounds of formulas 1, 2 or 3 into the corresponding acids or salts; and

h) converting pharmaceutically acceptable, non-toxic esters of the compounds of formulas 1, 2 or 3 into other pharmaceutically acceptable non-toxic esters; and

i) converting pharmaceutically acceptable non-toxic salts of the compounds of formulas 1, 2 or 3 into other pharmaceutically acceptable non-toxic salts.

The cleavage of the protecting groups can be carried out at the 3- and 3'-positions with dilute aqueous acid, preferably a mineral acid such as sulfuric acid in acetonitrile or hydrogen fluoride or tetrabutylammonium chloride in tetrahydrofuran at 0 to 40 ° C as described in J. Amer. Chem. Soc., 94, 6190 (1972) to give compounds of formula 1, 2 or 3.

The following examples serve to illustrate the invention and its closer illumination. The invention is not limited to the scope of the invention.

He did

Compounds in which R 1 represents CH ₂ OH

A. Preparation of methyl- (Z) - (3'S, 1S> 2S, 3R, 6S) -4- [2- (3'-tert-butyldimethylsilyloxy-3'-cyclohexylprop-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclo [4.2.0] oct-7-ylidene] butyrate and related compounds.

A mixture of 0.52 methyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2. O-oct-7-ylidene-butyrate, 0.55 g of t-butyldimethylsilyl chloride, 0.18 g of 4-dimethylaminopyridine, 2 ml of triethylamine and 10 ml of dichloromethane were stirred at 23 ° C for 24 hours. After dilution with 20 ml of dichloromethane, the mixture is washed with 10 ml of water, three times with 20 ml of 1N hydrochloric acid and with 10 ml of saturated sodium bicarbonate solution. Drying over sodium sulfate afforded 0.78 g of the title compound.

In the same way, but using other suitable esters, the following compounds are obtained:

methyl- (Z) - (3'S, 1S, 2s, 3R, 6S) -5- [2- (3'-tert-butyldimethylsilyloxy-3'-cyclohexylprop-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclof4,2.0] oct- 7-ylidene pentanoate, methyl- (Z) - (3S ^X , 1S *, 2S ¹ , 3R *, 6S ⁾ -4- [2- (3'-tert-butyl) dimethylsilyloxybicyclo [4.2.0] oct-7-ylidene] butyrate, methyl- (E) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-tert-butyldimethylsilyloxy-3'-cyclohexylprop-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclof4. 2-ioct-7-ylidene-butyrate, methyl- (E) - / 3'S ^st , 1S ^lt , 2S ^K , 3R ¹ , 6S ^x / -4- (2-) -3'- tert -butyldimethylsilyloxy-3'-yklohexylprop- ¹ ' 4-O-oct-7-ylidene-butyrate, methyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-tert-butyldimethylsilyloxy-3 ') -inyl] -3-tert-butyldimethylsilyloxybicyclo [4.2] -cyclopentylprop-1'-ynyl-3-tert-butyldimethylsilyloxybicyclo [4.2.1] oct-7-ylidene] butyrate and methyl- (Z) - (3'S ^x , 1S *, 2S ^X , 3R ^X , 6S *) - 4 - [2-] - (3'-tert-Butyldimethylsilyloxy-3'-cyclopentylprop-1'-yl) -3- tert-butyldimethylsilyloxybicyclof4.2.Octo-7-ylidene-butyrate.

B. Preparation of (Z) - 3'S, 1S, 2S, 3R, 6S / 4- [2- (3'-tert-Butyldimethylsilyloxy) -3'-cyclohexylprop-1-ynyl] -3-tert. butyldimethylsilyloxybicyclo [4.2.0] oct-7-ylidene] -1-butanol and related compounds.

To a stirred mixture of 0.1 g lithium aluminum hydride in 15 ml diethyl ether was added dropwise a solution of 0.78 g methyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-tert-butyldimethylsilyloxy)]. 3'-Cyclohexylprop-1'-ynyl] -3-tert-butyldimethylsilyloxybicyclo [4.2.1] oct-7-ylidene] butyrate in 5 ml diethyl ether. The mixture was heated to reflux for 2 hours. After cooling the reaction mixture, 0.1 ml of water, 0.1 ml of 15% sodium hydroxide and 0.3 ml of water are gradually added dropwise. The resulting precipitate was filtered off. Evaporation of the filtrate gave 0.7 g of the title compound.

In the same manner, but using other suitable starting compounds prepared according to the procedure described in paragraph A above, the following compounds were prepared:

/Z/-/3'S, 1S,2S,3R,6S/-5-f2-/3'- tert -butyldimethylsilyloxy-3'-cyclohexylprop- 1'-inyl/-3- tert -butyldimethylsilyloxybicyclof4.2.0]okt-7 -ylidene-1-pentanol, (Z) - (3S ^X , 1S ^X , 2S ^X , 3R ^X , 6S *) - 4-2- (3'-tert-Butyldimethylsilyloxy-3'-cyclopropyl-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclo [4.2.0] oct-7-ylidene] -1-butanol, [E] - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-tert-butyldimethylsilyloxy-3'- cyclohexylprop-1'-lny1 / -3-terc.butyldimethylsilyloxybicyklof 4.2.a] oct-7-ylidene -1-butanol, /E/.-/3's', ^x lS, 2S ^{and <*,} 3R * ^l *, 6S * 1- [4- [2- (3'- ^tert- Butyldimethylsilyloxy) -3'-cyclohexylprop-1'-ynyl] -3- ^tert -butyldimethylsilyloxybicyclof4.2. oj Oct-7-ylidene-1-butanol, (Z) - / 3'S, 1S, 2S, 3R, 6S(-4-, 2-, 3'-tert-butyldimethylsilyloxy-3'-cyclopentyprop-1-ynyl) - 3-terc.butyldimethylsilyloxybicyklof4.2.o] oct-7-ylidenf-1-butanol and / Z / - / ^K 3'S *, 1S *, 2S ^{K, 3R> t,} 6S ^K / -4-2- / 3 'tert-butyldimethylsilyloxy-3'-yclopentylprop-1'-vinyl] -3-tert-butyldimethylsilyloxybicyclo [4.2.0] oct-7-ylidene-1-butanol.

C. Preparation of /Z/-/3'S,1S,2S,3R,6S/-4-f2-/3'- hydroxy-3'- cyclohexylprop- 1'-inyl/-3-hydroxybicyclo[4.2.0jokt-7- 1-butanol, and related compounds of formulas 1, 2 and 3, wherein R 1 is CH ₂ OH.

To a solution of 0.15 g (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3-tert-butyldimethylsilyloxy-3'-cyclohexylprop-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclo ( 4.2.0-J-7-ylidene-1-butanol in 3 ml of tetrahydrofuran, 5 ml of 1M tetrabutylammonium fluoride in tetrahydrofuran are added, after 12 hours at 23 ° C the solution is diluted with 20 ml of water and extracted into diethyl ether. flash chromatography on silica gel using ethyl acetate / hexane (1: 1) afforded 0.8 g of the title compound.

In the same manner, but using the other compounds described in paragraph B of this example, the following compounds of formulas 1, 2 and 3 are prepared in which R 1 is CH 3 OH:

/Z/-/3'S,lS,2S,3R,6S/-5-f2-/3'- hydroxy-3'-cyclohexylprop- 1'-inyl/-3-hydroxybicyclof4.2.Ojoct-7-ylidene -1 -pentanol, (Z) - (3'S *, 1s ' ^e , 2s' ^c , 3R ^M , 6S ^K ) -4- (2- / 3'-hydroxy-3'-cycloprop-1'-ynyl) -3- hydroxybicyclo [4.2.0] oct-7-ylidene-1-butanol, [E] - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl)] /-3-hydroxybicyklof4.2.Oj EKT-7-ylidene -1-butanol / E / - / 3'S *, lS ^{divided, 2S, t, 3H, t, 6S, T} / 4-f 2- / 3 'hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo-4.2.0 oct-7-ylideh] -1-butanol, (Z) - (3'S, 1S, 2S, 3R, 6S) -4 2- (3'-hydroxy-3'-cyclopentylprop-1'-ynyl) -3-hydroxybicyclo [4.2.1] oct-7-ylidene] -1-butanol and (Z) - (3 ') ^K , 15 ^K 2S ^K , 3R ^K , 6S ^K [-4- [2- / 3'-Hydroxy-3'-cyclopentylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] -1- butanol.

Example 2

Preparation of (Z) - (3'S, 1S, 2S, 3R, 6S / 4- (2- (3'-hydroxy-3'-cyclohexylprop-1'-vinyl) - 3-hydroxybicyclo [4.2.1] oct-7-ylidene) -1-butanal and related compounds of formulas 1, 2 and 3, wherein R 1 is CHO.

A. To a stirred mixture of 0.25 g of pyridinium chlorochromate in 7 ml of dichloromethane is added a solution of 0.2 g of (Z / - / - 3'S, 1S, 2S, 3R, 6S/-4-[2-/3'- tert-butyldimethylsilyloxy). 3'-Cyclohexylprop-1'-ynyl] -3-tert-butyldimethylsilyloxybicyclo [4.2.0] oct-7-ylidene] -1-butanol, prepared according to Example 1A in 3 ml of dichloromethane. After 4 hours at 23 ° C, the solution is decanted from the precipitate and filtered through 10 g of florisil with dichloromethane. The filtrate was concentrated to a residue which was dissolved in 3 mL of tetrahydrofuran. To this solution was added 2 mL of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 16 hours at 23 ° C, this solution is diluted with 20 ml of water and the product is extracted into diethyl ether. Evaporation of the solvent followed by flash chromatography using ethyl acetate and hexane (30:70) afforded 0.1 g of the title compound.

B. In the same manner, but using other suitable compounds prepared by the procedure of Example 1, the following compounds of Formulas 1, 2 and 3 are prepared in which CHO is:

/Z/-/3'SKlSj2St3R,6S/-5-[2-/3'-hydroxy-3'-cyclohexylprop-l*-inyl/-3-hydroxybicyclof4.2.0jekt-7-yliden]-1-pentanal, (Z) - / 3'S ⁵ⁱ , 1s ' ^t , 2S ^5t , 3R ^{, <} , 6s'^</ -4- f2-/3'-hydroxy-3'-cycloprop- 1-vinyl/-3- hydroxybicyclof4.2.0joct 7-ylidene-1-butanal, [E] - (3'S, 1S, 2S, 3R, 6B) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3- hydroxybicyclo £ 4.2.Ojokt-7-ylidene] -1-butanal, / E / - / 3 ¹ *, 1S *, ^{2S! Í K} 3R, 6S ^li / -4-2- / 3'-hydroxy-3 * -cyclohexyl-prop-1'-ynyl) -3-hydroxybicyclo [4.2.1] oct-7-ylidene] -1-butanal, [Z] - (3'S, 1S, 2S, 3R, 6S) -5-f2- / 3 '-hydroxy-3'-cyclopentylprop-1'-ynyl / -3-hydroxybioylclo [4.2.0] oct-7-ylidene] -1-butanal and (Z) - / 3'S ^X , 1S ^X , 2S ^X , 3R ^K , 6S ^{K /} -4-f2-/3'- Hydroxy-3'- cyclopentylprop-l'-inyl/-3-hydroxybicyclo[4.2.0]okt-7-yliden]-1-butanal.

Example 3

Preparation of methyl- (Z) - (3S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct -7-ylidene / butyrate and related compounds and other pharmaceutically acceptable esters.

A. To a solution of 0.5 g (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo- 4.2.0] oct-7-ylidene] butyric acid in 10 ml of diethyl ether is added an excess of ethereal diazomethane until the solution turns yellow. Evaporation of the solvent gave 0.52 g of the title compound, [.alpha.] _D = + 134 DEG (MeOH); Elemental analysis: calculated C 73.37% H 8.95%, found C 73.03%, H 9.15%.

B. In the same manner, but using other suitable starting compounds of formulas 1, 2 and 3, the following esters are obtained: methyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- / 3'- hydroxy-3'-cyclohexylprop-1'-ynyl-3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate;

methyl- (Z) - (3'S ^K , 1S ^K , 2S ^X , 3R ^K , 6S ^K ) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo] 4.2.0 .] oct-7-ylidene] butyrate, MS m / z 378 (M + NH4 +; MH ⁺ 361, elemental analysis: calculated C 73.30%, H 8.95%, found 73.54%, H 8 82%;

methyl- (E) - (3'S, 1S, 2S, 3R, 6S) -4- {2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene ] butyrate;

methyl / E / - / ⁱ 3'S *, 1 S ^{H, K} 2 S, 3 R ^{K K} 6S /-4-f2-/3'-hydroxy-3'-cyklohexylprop-l'-inyl/-3-hydroxybicyklo[4.2 10] oct-7-ylidene] butyrate;

methyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclopentylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7 -ylidene / butyrate;

methyl- (Z) - (3'S ^X , 1S ^K , 2S ^K , 3R ^K , 6S ^K ) -4- [2- (3'-hydroxy-3'-cyclopentylprop-1'-ynyl) -3-hydroxybicyclo [4.2] .Ojokt-7-ylidene] butyrate and methyl / Z / - / ^H 3'S, lR ^{M, 5R} 2R, ^{3S, t,} 6R ^K / -4- [2- / 3'-hydroxy-3'-cyclohexylprop-l 1-vinyl [-3-hydroxybicyclo [2.2.0] oct-7-ylidene] butyrate, MS m / z 378 (M + NH4 +; MH ⁺ 361; elemental analysis: calculated C 73.30%, H 8.95% Found C 73.47%, H 8.81%.

Example 4

Preparation of p-benzamidophenyl- (Z) - (3 * S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'11)

3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate and related compounds of formulas 1, 2 and 3, where CO is R.

A. Solution /Z/-/3'S,1S,2S,3R,6S/-4-f2-/3'-hydroxy-3'-cyclohexylprop-l'-inyl/-3~hydroxybicyclo[4.2.0]okt- 7-ylidene] butyric acid (35 mg, 0.101 mmol) in acetone (2.7 mL) was treated with triethylamine (28.2, µL, 0.202 mmol). The solution was cooled to -5 ° C under nitrogen and isobutyl chlorocarbonate (27.3 µL, 0.202 mmol) was added. After 5 min at -5 ° C, a solution of p-benzamidophenol (109.2 mg, 0.51 mmol) in dry pyridine (1.1 mL) was added. After 3 hours at room temperature, the solvent was removed under reduced pressure (vacuum). The residue was extracted with dichloromethane and the solid (excess p-benzamidophenol) was filtered off. After evaporation of the solvent, the residue was purified by column chromatography using 30% acetone in hexane to give the title compound (12 mg). Mass spectrum: m / z 541 (M < + &gt;). Elemental analysis for C ^ ^H ^ gOON: Calculated: C 75.39%, H 7.26%, N 2.59%. Found: C 75.28%, 7.23%, N 2.48%. Mp 154-155 ° C; (? Z) _D = 86.9 ° (CHCl 3).

B. In the same manner, but using other suitable compounds of formulas 1, 2 or 3, wherein R 1 is CC 1 H, replacing p-benzamidophenol with other suitable substituted phenols, the following compounds are prepared in which R ₂ is CO ₂ : p- acetylphenyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -5- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7- ylidenepentanoate; p-acetylaminophenyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0.] oct-7-ylidene butyrate, elemental analysis: calculated

C 72.62%, H 7.78%, N 2.92%, found C 72.25%, H 7.86%, N 2.56%;

p-benzoylphenyl- (Z) - (3S ^K , 1S ^X , 2S ^K , 3R ^X , 6S ^x ) -4- [2- (3'-hydroxy-3'-cycloprop-1'-ynyl) -3-hydroxy bicyclo (4.2.0) oct-7-ylidene] butyrate, pN ', N'-dimethyllureidophenyl- (E) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'- cyclohexylprop-1'-vinyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate;

p-benzamidophenyl- (E) -3'S ^x , 1S ^X , 2S ^X , 3R ^X , 6S ^X / -4- [2- (3'-hydroxy-3'-hydroxy-cyclohexylprop-1'-ynyl) -3- hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate;

p-benzoylphenyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4-] 2- (3-hydroxy-3'-cyclopentylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate and p-methylureidophenyl- (Z) - / 3'S ^X , 1S ^X , 2S ^X , 3R ^X , 6S ^x / -4- [2- (3'-hydroxy-3'-cyclopentylprop-1)] 4'-vinyl] -3-hydroxybicyclo [4.2]. O] oct-7-ylidene] butyrate.

Example 5

Preparation /Z/-/3'S,1S,2S,3R,6S/-4-[2-/3'-hydroxy-3'-cyclohexylprop-1'-inyl/-3-hydroxybicyclo[4.2.0]okt-7 sodium butyl butyrate

58.3 mg of sodium 2-ethylhexanoate is dissolved in 0.2 ml of a 9: 1 mixture of diethyl ether and tetrahydrofuran. Tetrahydrofuran was added dropwise until a clear solution was obtained. 70 mg of (Z) - (3'S, 1S, 2S, 3R, 6S) -4-] 2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7 -ylidene] butane was dissolved in 3 ml of acetone and treated with a solution of sodium 2-ethylhexanoate. The mixture was stirred for 30 minutes and then evaporated to dryness. 6 ml of a 9: 1 mixture of diethyl ether and tetrahydrofuran was added to the dry mass and the mixture was refluxed for 30 minutes. The solid was collected by filtration, washed with 2 mL of a mixture of diethyl ether and tetrahydrofuran (9: 1) and dried in vacuo to give 56.0 mg of the title compound.

Example 6

Preparation of / Z/- / 3'S, 1S, 2S, 3R, 6S / 4- (2-) - 3'-hydroxy-3'-cyclohexylprop-1'-ynyl-3-hydroxybenzoylof4.2.0joct-7-ylidene-butyrate sodium.

mg /Z/-/3'S,lS,2S,3R,6S/-4-[2-/3'-hydroxy-3'-cyclohexylprop-l*-inyl/-3-hydroxybicyclof4,2.0jokt-7-ylideneButyric Acids Dissolve in 1 ml of methanol and add 18,5 mg of sodium bicarbonate dissolved in 1 ml of water. The mixture was stirred at room temperature for one hour, azeotroped twice with benzene and dried under high vacuum for 3 hours. The solid was recrystallized from methanol and diethyl ether and dried in vacuo at room temperature overnight to give 75 mg of the title compound, fx) _Q - 112.4 °, mp 73-83 ° C.

In the same way there is obtained / Z / - 3'S, 1S, 2S, 3S, 6,6R, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S; Potassium-7-ylidene] butyrate, [α] _{D =} 110.3 ° (MeOH); mp 73-83 ° C.

Example 7

Preparation of /Z/-/3*S, 1S, 2S, 3R, 6S/-4- 1,2-/3*- hydroxy-3'-cyclohexylprop- 1'-vinyl/-3- hydroxybenzoylof4.2.0Joc-7-ylidene-butyrate calcium.

mg /Z/-/3'S,1S,2S,3R,6S/-4-12-/3'- hydroxy-3'- cyclohexylprop- 1'-inyl/-3-hydroxybicyclo4.2.0jokt-7-yliden]butyric acid and 7.01 ml of calcium oxide are mixed in 1.5 ml of water and

1.2 ml tetrahydrofuran. The mixture was heated at 50 ° C for 30 minutes and filtered. The residue was dissolved in 1.2 mL of tetrahydrofuran and then 15 mL of ether was added. The residue was dissolved in 1.2 mL of tetrahydrofuran and then 15 mL of ether was added. The precipitate was stirred at room temperature and then filtered. The solid was washed with anhydrous ether and dried under high vacuum at room temperature overnight to give 66 mg of the title compound, [α] _{D =} 114.0 °, mp 138-143 ° C.

In the same way are prepared / Z / - / - 3'S, 1S, 2S, 3R, 6S / 4- [2- (3'-hydroxy) -3'-cyclohexylprop- (1'-vinyl) -3-3-hydroxybicyclo[4.2.0]okt- 7-ylidene] magnesium butyrate, [ _.alpha. ] _D = 122.2 DEG (MeOH);

Mp 131-135 ° C.

Example 8

Preparation of ethylenediamine salt of (Z) - / 3'S, 1S, 2S, 3R, 6s / 4- / '2- / 3'-hydroxy-3'-oxy-hexylprop- 1*-inyl/-3- hydroxybicyclo[4.2.0 , Joc-7-ylidene] butyric acid

95.3 mg of (Z) - (3) 3S, 1S, 2S, 3S, 6S, 4S, 4S-4'-hydroxy-3'-hydroxy-3'-cyclohexyl-prop-1'-ynyl-3-hydroxybicyclo-4.2. O-oct-7-ylidene-butyric acid was dissolved in 5 ml of ether and 7.5 mg of ethylenediamine dissolved in 4 ml of ether was added. A precipitate formed immediately. The suspension was stirred at 30 ° C for 30 minutes. The precipitate was filtered off, washed with ether and dried under high vacuum at room temperature overnight to give 60 mg of the title compound.

The dicyclohexylamine acid salt of (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo] is prepared in the same manner. 4.2.Ojokt-7-ylideneButyric acid.

Example 9

Preparation of the tromethamine acid salt of (Z) - 3'S, 1S, 2S, 3R, 6S / 4-, 2'-3'-hydroxy-3'-cyclohexylprop-1'-vinyl / 3-hydroxybicyclo [4.2]. Oj oct-7-ylidene butyric acid [Z] - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo] -butyric acid 4.2.0] Butyric oct-7-ylidene is dissolved in 1 ml of methanol and 26.7 mg of tromethanolamine are added. The reaction mixture was heated at 50 ° C for 10 minutes, cooled to room temperature, and ethyl acetate was added dropwise to the clear solution until the solution became cloudy. The mixture was stirred at room temperature for 4 hours and filtered, washed with ethyl acetate and dried under high vacuum at room temperature overnight to give 90 mg of the title compound, m.p. Mp 48-51 ° C; (dt) β 83.8 ° (MeOH); MS m / z 364 (M + NH 4); elementary analysis; calculated C 61.83 H, H 8.93%, ´ N 2.88%, found C 62.12%, H 8.90%, N 2.93%.

In the same way, the diethanolamine salt of (Z) - / - 3'S, 1S, 2S, 3R, 6S / 4- (2'-hydroxy-3'-cyclohexyl-prop-1'-vinyl) -3-hydroxybicyclo-4.2 is prepared. Butyl-7-ylidene. Example 10

Preparation of the N-methyl-D-glucamine salt of (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3-cyclohexylprop-1'-ynyl) -3-hydroxybicyclof4] .2.0Jokt-7-ylidenebutyric acid [Z] - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo] [4.2.0] oct-7-ylidene] is dissolved in 2 ml of methanol and 10 ml of ethyl acetate are added. The mixture was stirred at room temperature for 2 hours. The formed crystals were filtered, washed with ether and dried under high vacuum at room temperature overnight to give 90 mg of the title compound, mp 52-55 ° C, [α] _{D =} 62.8 °; MS m / z 364 (M + NH ^4); Elemental analysis: calculated C 62.09%, H 8.75%, N 2.59%, found C 60.34%, H 9.15%,

N, 2.47%.

Example 11

A mixture of 448'mg of triethylamine salt with (Z) - (3 * S, 1R, 2R, 3S, 6R) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4] 2.0] oct-7-ylidene] butyric acid in 7 ml of water and 6 ml of tetrahydrofuran was treated with calcium oxide (28 mg) and the mixture was heated at 50 ° C for one hour. The tetrahydrofuran is then evaporated under reduced pressure and the water is removed under vacuum to give (Z) - (3'S, 1R, 2R, 3S, 6R) -4- [2-] / 3'-hydroxy-3'-cyclohexylprop-1'- calcium 3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate, which is further purified as described in Example 7.

Example 12

A solution of methyl- (Z) - (3'S, IR, 2R, 3S, 6R) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo (4.2.0) oct- 7-ylidene] butyrate (200 mg) in 5 ml of isopropanol was contacted with a catalytically effective amount of sodium isopropoxide (10 mg) and heated to reflux for 3 hours until about 2 ml of solvent was distilled off the flask. It is evaporated to dryness, treated with 5 ml of pH 7 phosphate buffer, and the isopropyl ester formed is extracted with ethyl acetate, and purified by flash chromatography on silica gel eluting with a 40% ethyl acetate / hexane mixture to give the pure ester.

Example 13

Mixture /Z/-/3'S,1R,2R,3S,6R/-4-[2-/3'-hydroxy-3'-cyclohexylprop-1'-inyl/-3-hydroxybicyclo[4.2.0]okt-7 -ylidene] butyric acid (448 mg), 152 mg of diazabicycloundecane and 156 mg of iodoethane in 5 ml of dry benzene were heated at reflux for 6 hours. The solvent was then removed under reduced pressure and the residue was treated with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were washed well with water, dried: MgSO4 and evaporated to give ethyl (Z) - (3'S, 1R> 2R, 3S, 6R) -4-T2- (3'-hydroxy-3'-cyclohexylprop- 1'-Inyl / -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate.

Example 14

To a mixture of 0.2 ml of a 0.5N aqueous lithium hydroxide solution in 0.5 ml of methanol was added 35 mg of ethyl- (Z) - / 3'S, IR, 2R, 3S, 6R / -4-C2- / 3'-hydroxy 3'-Cyclohexylprop-1-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate, and the mixture was stirred under nitrogen for 24 hours. The solvent was then removed in vacuo and the residue triturated with ether to give (Z) - (3'S, 1R, 2R, 3S, 6R) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl)] Lithium butyrate -3-hydroxybicyclo [4.2.0] oct-7-ylidene.

Example 15 /Z/-/3'S,IR,2R,3S,6R/-4-[2-/3'-hydroxy-3'-cyclohexylprop-l'-inyl/-3-hydroxybicyclof4.2.0] oct-7- The calcium ylidene butyrate (1.52 g) was partitioned between dichloromethane (100 mL) and 0.5% aqueous acetic acid (100 mL) and shaken well. The aqueous phase was separated and extracted four times

100 ml of dichloromethane. The combined extracts were dried (anhydrous sodium sulfate) and evaporated to dryness to give 1.38 g (Z) - / 3'S, IR, 2R, 3S, 6R / -4- / 2- / 3'-hydroxy-3'-cyclohexylprop 1- (1'-ynyl) -3-hydroxybicyclo [phi] oct-7-ylidene] butyric acid.

Example 16

Inhibition of platelet clotting

Human venous blood from non-drug volunteers was collected into 15 ml vacuum vials and naticoagulated with 0.5 ml 11.4% sodium citrate. Blood was centrifuged at room temperature for 15 minutes at 150 g in a Sorvall GLC-28 centrifuge and the supernatant containing platelet-rich plasma (PRP) was aspirated. Platelet-poor plasma (PPR) was prepared by centrifugation of blood from which PRP was removed by centrifugation at 12,800 g for 3 minutes in an Eppendorf centrifuge at room temperature. Platelet coagulation was performed according to the method of Born (J. Physiology, 168, 178 (1983) in a Payton aggregometer. Platelet coagulation was induced by the addition of ADP (2-5 nmol) to 1 ml PRP containing 10 _of µl of different concentrations of test compounds or vehicle incubated. aggregometrické in a cuvette at 37 ° C for 5 minutes at a speed of 500 min ^-1. Then, for each of the test compounds were applied on semilogarithmic paper dependency% inhibition relative to the concentration and the concentration corresponding to 50% inhibition was expressed as ICGG the compound. All tested Compounds (1-2 mg) were prepared as 0.01 mol stock in 10% ethanol and 59 mM sodium carbonate.

Subsequent dilutions were made with water. The following table summarizes the test results:

Compound

PGE _X 0,02-0,08 /Z/-/3'S,IR,2R,3S,6R/-4-[2-/3'-hydroxy-3'-cyclohexylprop-1'/-3-hydroxybicyclof4.2.0 Oct-7-ylidene-butyric acid 0.0034 (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3] -hydroxybicyclo [4. 2. Oocok-7-ylidene] butyric acid 0.004

4-acetylaminophenyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclof4,2.0] oct-7- Butylene 0,0042 tromethamine acid salt / Z / - / - 3'S, 1S, 2S / 3R, 6S / 4- [2-, 3'-hydroxy-3'-cyclohexylprop-1'-vinyl] -3-hydroxybicyclo-4.2 0.01 Joct-7-ylidene] butyric 0.011

N-methyl-D-glucamine salt of (Z) - (3'S, 1S, -)

2S, 3R, 6S / -4- [2- / 3'-Hydroxy-3'-cyclohexylprop-1

(vinyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid 0.012 dicyclohexylamine salt of (Z) - (3'S, 1S, 2S, 3R, 6S) -4- (2'-hydroxy) 3'-Cyclohexylprop-1'-ynyl] -3-hydroxybicyclo [4.2.1] oct-7-ylidene butyric acid 0.014 diethanolamine salt of (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [ 2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene butyric acid 0,011 ethyleneamine salt of (Z) - / 3 * S, 1S, 2S, 3R, 6S / _t

-4- [2- / 3'-hydroxy-3'-cyclohexylprop-l'-ynyl / -3-hydroxybicyklof4.2.0] oct-7-ylidenJmáselná 0.0084 / Z / - / ^5T 3'S, lS ^{K, K} 2 S 3R ^IT 6S /-4-f2-/3'-hydroxy-3'-cyklohexylprop-1'-inyl(-3-hydroxybicyklo[4.2.oJokt-7-ylidenJmáselná acid 0.012 ^K / Z / - / 3'S, lS 2S, 3R, 6S / -5- [2- (3'-Hydroxy-3'-cycloprop-1'-ynyl) -3-hydroxybicyclo [1,2-a] oct-7-ylidene] pentanoic acid

0.01

Compound / Z / - 3'S, 1S, 2S, 3R, 6S / 4'-2'-3'-hydroxy-3'-cyclohexylprop-1'-ynyl-3-hydroxybicyclo* 4.2. Calcium butyrate 0.015 (Z) - / 3'S *, IR *, 2R *, 3S *, 6R * (-4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl)) (3-Hydroxybicyclof4.2.o]oct-7-ylidene) butyric acid 0.014 (Z) - (3S, 1R, 2R, 3S, 6R) -5- [2- (3'-hydroxy-3'-cyclohexylprop-)] 1'-ynyl / hydroxybicyklof 4.2.0Jokt -3-7-ylidenJpentanová acid 0.017 / Z / - / 3'S *, lS I2S ^5R *, 3R * ^'i, 6S ^5t / -5- [2- / 3'-hydroxy -3'-cyclohexylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] pentanoic acid 0.022 (Z) - (3'S ^K , 1R ^K , 2R ^K , 3S ^J , 6R ^K ) -5-12-] 3'-hydroxy-3'-cyclohexylprop-1'-ynyl-3-hydroxybicyclo [4.2.0] oct-7-ylidene] pentanoic acid 0.027 (E) - / 3'S, 1S, 2S, 3R, 6S / -4- ( 2- / 3'-hydroxy-3'-cyclohexylprop-1'-ynyl / -3-hydroxy 4/1 2.Ojokt-7-ylidene-methyl-butyric acid 0.045 / Z / - / ⁱ 3'S, lR ^t 2R ^K , 3S *, 6R * [4- (2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyrate 0.11 (E) - / 3'S *, 1S *, 2S *, 3R *, 6S ^{M /} -4- f2- / 3'-hydroxy-3'-cyclohexylprop-1'-iny1/-3-hydroxybicyclo[4.2.0] oct-7 - Butylidenbuttering acid to 0,1 /E/-/3'S,1S,3R,6S/-5-[2-/3'-hydroxy-3'-cyclohexylprop-1'-inyl/-3-hydroxybicyclof4.2.0]ekt-7- pentanic acid 0,17 methyl- (Z) - (3'S *, 1S *, 3R *, 6S ^H ) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclophosphate] .2.0jokt-7-ylidene-butyrate 0.35 / Z / - 3'S, 1S, 2S, 3R, 6S/-4-f2-/3'-hydroxyoct-l'-inyl/-3-hydroxybicyclo[4.2.0jokt- 7-ylidene-butyric acid Pentyl-7-ylidene-pentanoic acid. 0,19 methyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- (2 '- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo] Butyrate 0.35 (Z) - / 3'S, 1R, 2R, 3S, 6R / 4- [2- (3'-hydroxy) oct-1'-vinyl] -3-hydroxybicyclof4.2. oj oct-7-ylidenJmáselná 0.45 acid / Z / - / 3's' ^i, 1 ^R! 2R ^M , 3S ^} ', 6R ^, 4' - (4 ') - 2- (3'-hydroxy-3'-cyclohexylbut-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene-butyric acid 0.32 /E/-/3*S,lS,2S,3R,6S/-4-f2-/3'-hydroxyoct- 1'-inyl/-3-hydroxybicyclof4.2.Octok-7-ylidene butyric acid 0,85

4-Benzamidophenyl- [E] - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-Hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.0] oct -7-ylidene butyrate 0.02 2

Compound

(Z) - (3'S, 2S, 3R, 6S) -4- [2- (3'-Hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo (4.2.0) oct-7-ylidene] butyrate (Z) - / 3'S, 1S, 2S, 3R, 6S / 4- (2-) - 3'-hydroxy-3'-yoyl-hexylprop-1'-ynyl (3-hydroxybicyclo [4.2.0] oct-7-ylidene) potassium butyrate /Z/-/3'S,1S,2S,3R,6S/-4-Í2-/3'-hydroxy-3'-cyclohexylprop-l'-inyl/-3-hydroxybicyclo[4.2.0]okt-7-yliden ] Magnesium butyrate (Z) - (3'R ^M , 1S *> 2s, 3R *, 6S *) - 4- [2- / 3'-hydroxy-4'-endobicyclof3.1.0] hex-6-ylbut-1 '-inylJ-3-hydroxybicyclo [4.2.0) oct-7-ylidene] butyric acid / Z / - / 3'S *, ^{lS> t,} 2S *, 3R ^ie, 6S * / - 4-2- / 3'-hydroxy -3 * -cyclopentylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene-butyric acid (E) - / 3'S *, 1S *, 2S ^X , 3R *, 6S ^K / -4- 12- (3'-hydroxy-3)

-cyclopentylprop-1'-ynyl / -3-hydroxybicyclo [4.2.1] oct-7-ylidenebutyric acid

0,0042

0.0066

0.016

0.1

0.62

0.14

Example 17

Antihypertensive activity

The antihypertensive effects of prostaglandin-like compounds were evaluated in spontaneously hypertensive rats (SHR / NCrlBR). Under ether anesthesia, cannulas were inserted into the femoral arteries and veins and rats were fixed in the dorsal position. Lidocaine was administered after anesthesia. Blood pressures were obtained using a femoral artery cannula and recorded on a Beckeman R611 polygraph. Groups of 4 rats were studied for each compound. The vehicle was administered at the beginning of the experiment and the compounds were then administered intravenously at 30 minute intervals at increasing doses of 1, 3, 10, 30 and 100 µg / kg. The baseline mean arterial blood pressure was the blood pressure immediately before the first dose of the compound. ED ₂ ^b q yls calculated by linear regression procentálního net reduction in mean blood pressure after administration of each dose of the compound. The duration of action was determined as a return to 90% of the control blood pressure when administered intravenously at 100 _of µg / kg.

Results

Compound /Z/-/3'S,1R,2R,3S,6R/-4-£2-/3*-hydroxy-3'-cyclohexylprop-l'-inyl/-3-hydroxybicyclo[4.2.0]okt-7 -ylidene] butyric acid (Z) - (3 'S, 1S, 2S, 3R, 6S) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2] .0] oct-7-ylidene-butyric acid [Z] - (3'S *, 1S *, 2S *, 3R *, 6S *) - 4- [2- / 3'-hydroxy-3'-cyclohexylprop-1'- vinyl) -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid [Z] - (3'S, 1S, 2S, 3R, 6S) -5- [2- (3'-hydroxy-3'-cyclohexylprop-1 *)] -inyl / -3-hydroxybioyklo [4.2.0] n-7-ylidene-pentanoic acid (Z) - / 3'S ^K , IR *, 2R *, 3S *, 6R *, [4- (2-3) -hydroxy] _2Q // ig / kg

-3'-Cyclohexylprop-1'-ynyl] -3-hydroxybicyclo [4.2.-oct-7-ylidene] butyric acid (Z) - '3'',1s', 2S ^SI , 3R ^, ', 6S ^{, <} / -5 -? - / 3'-hydroxy19

3 ' -cyclohexylprop-1 ' -yl] -3-hydroxybicyclo [4.2.1] oct-7-ylidene] pentanoic acid methyl- [Z] - (3'S *), 1S *, 2S *, 3R *, 6S * / -4- [ 2- / 3'- 68

(hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo [4.2.1] oct-7-ylidene] butyrate (Z) - (3'S, 1S, 2S, 3R, 6S) -4-η 2 - / 3 ' -hydroxyoct-1'- 35

-inyl / -3-hydroxybicyclo [4.2.0] oct-1-ylidene-butyric acid / Z / -3'S, IR, 2R, 3S, 6R / -4- [2- (3'-hydroxyoct-1'-100)]

-inyl / -3-hydroxybicyclo [i. 2. Oct-7-ylidene butyric acid

Example 19

The antihypertensive effects of prostaglandin-like compounds have been evaluated in male and female non-blooded cats under pentobarbital anesthesia with cannulas inserted into the femoral arteries and veins and thoracotomies to insert the Walton-Brodie needle into the right ventricle. After surgery, animals were evaluated for cardiovascular and autonomic tests, which included administration of various autocoids, before and after intravenous administration of each of the 7 doses of the test compound. Mean blood pressure, myocardial strength and heart rate derived from blood pressure were monitored. The test compound was administered intravenously at doses of 1, 3, 10 and 30 µm / kg. Autocoids were not administered after a dose of 30 µg / kg. Baseline arterial blood pressure was blood pressure immediately prior to each administration of the test compound. The Εϋ ₂ θ values were calculated by linear regression of the percent reduction in mean blood pressure of several cats after each dose of compound.

Results

Compound ED ₂₀ (µg / kg) (Z) - (3'S, IR, 2R, 3S, 6R) -4- [2- (3'-hydroxy)]

3'-Cyclohexylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid (Z) - (3'S, 1S, 2S, 3R, 6S) -4- (2 '- 3') -hydroxy- 5

-3 * -cyclohexylprop-1'-ynyl] -3-hydroxybicyclo [4.2.0] oct-7-ylidene] butyric acid (Z) - (3 * S, 1S, 2S, 3R, 6S) -5-f2- (3'-Hydroxy-3'-13)

-cyclohexylprop-1'-ynyl / -3-hydroxybicyclo [4.2.0] oct-7-ylidene] pentanoic acid

Claims (2)

SUBJECT OF THE INVENTION Process for the preparation of bicyclo derivatives f4.2. Ojes of octanes of formula 1, 2 or 3 (3) wherein -ch ₂ , -CH ₂ -Qy or - (CH ₂ ) _m -phenyl, where 2 or 3 is CH 2 OH, CHO, CO 3 R or CO 3 H, represents hydrogen or methyl, and represents a linear or branched alkyl having from 5 to 5 carbon atoms; 10 carbon atoms, group - (CH ₂ ) -CH 2 -7cH ₂ / _b , a represents 0, 1 or b represents 3 to 7, m represents 0, 1 or 2, And a pharmaceutically acceptable, nontoxic salts and esters thereof, characterized in that the protecting groups in the compounds of formulas 4, 5 or 6 are deprotected. (4) (6) wherein both substituents R 1, R ₂ and R 1 are and the compounds obtained are optionally as defined above and Pt is a protecting group. (a) convert from compounds where R 1 is CO ₂ H to the corresponding compounds where R 1 is CH 3 OH, or (b) compounds of formulas 1, 2 or 3 wherein R 1 is CO 3 H are converted to the corresponding compounds wherein R 1 is CHO; or c) converting compounds of formula 1, 2 or 3, wherein R 1 is COOH to the corresponding C 1 H 3; a compound wherein R 1 is COOR and optionally is d) converting compounds of formulas 1, 2 or 3 into their pharmaceutically acceptable, non-toxic salts; and e) the pharmaceutically acceptable, non-toxic salts of the compounds of formulas 1, 2 or 3 are converted to the corresponding acids or esters; and f) acids of formulas 1, 2 or 3 are converted into pharmaceutically acceptable, non-toxic esters, g) converting pharmaceutically acceptable, non-toxic esters of the compounds of formulas 1, 2 or 3 into the corresponding compounds; acids or salts; and h) converting pharmaceutically acceptable, non-toxic esters of the compounds of formulas 1, 2 or 3 into other pharmaceutically acceptable non-toxic esters; and i) converting the pharmaceutically acceptable non-toxic salts of the compounds of formulas 1, 2 or 3 into other pharmaceutically acceptable non-toxic salts.