HU182726B - Process for producing the 9-desoxy-9a-methylene-isosteres of pgi2/prostacyclin/ - Google Patents

Abstract

A wide range of 9-methylene carbaprostacyclin analogs and homologs, and intermediates for them (~250), were prepd. from appropriate bicyclic precursors; racemic and optically active compds. were prepd. Thus, 1.1g Na- borohydride was treated with 11.6g bicyclo [3,3,0 octane-3,7-dione in 100mL ethanol and 100mL CH2CL2 to give 9.1g 7-hydroxy-bicyclo[3.3.0 octane-3-one, 0.065 mol. of which were treated with 12.8g dimethyl-tertiary-butylcyllyl chloride and 8.85g imidazole to give 2.85g 7-oxo-hydroxy-bicyclo[3.3.0 -octane-3-one-dimethyl tertiary-butylcyllyl ether and 11.8g 7-endo-hydroxy-bicyclo-[3.3.0 -octane-3-one-7-dimethyl-tertiary-butylcyllyl ether. The latter compd. in Me2CO3 was treated with Na-hydride to give I.

Description

The present invention relates to a process of formula I wherein:

B is a carboxyl group that is free or is esterified with a C 1 -C 4 alkyl group, or a group -C / OB 1, where R 'may be the same or different and is a C 1 -C 4 alkyl group,

D is methylene, hydroxymethylene, carbonyl or oxygen,

One of R 1 and Bp is a hydrogen atom and the other is a hydroxyl group, or both are hydrogen, or R 1 and Bp together form an oxo group,

B and one of B 1 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and the other is hydroxy or C 1-4 alkoxy, or B is. collectively represents an oxo group,

On and Rg are each independently hydrogen, alkyl of 1-4 carbon atoms, or ³ halogen,

Y is a 1,2-ethylene group of the formula -C = C 1-4. a group cis or trans -OH-CS-, -NH-CO- or -NH-CHp-,

I is - CHp / _m wherein m ^ is zero or 1 or O, m ^ and Bip are each independently 0, 1 or 2, n ^ and np are independently 0, 1, 2 or 3, p and q are each independently 0,1 or 2, with the proviso that the sum of p and q may be an integer from 1 to 4 and is hydrogen, C 1-4 alkyl, C 5-7 monocycloalkyl, unsubstituted or phenyl substituted with halo (1-4C) alkyl or 3-7 membered. a saturated heterocyclic ring in which the heteroatom can be oxygen or sulfur, 9-deoxy-9a-methylene-PGIp isosteres. lactones derived therefrom, and their veterinary acceptable salts. .

In the formulas of the present specification, the dotted line with / indicates the substituents that are attached to a ring in the configuration, i.e., below the plane of the ring, and those with a / biocyclic group consisting of A and B fused rings. + q + l / .3-0 "-alkane ring system are attached in endo configuration and those attached to a carbon chain such that the carbon atom bearing this substituent has the configuration S. However, the wedge valence line / - l / denotes alternate carbons, that are attached to a ring in the configuration, i.e., above the plane of the ring, and those that are in the bio-cyclo / p + q + 1 /. Attached to a 3.0J-alkane ring order in exo-configuration and those attached to a carbon chain

-2182.726 that the carbon atom of this substituent has the configuration B.

The wavy valence line / / denotes substituents of unspecified stereochemistry, such that they may be in the ring position>> or <, in the endo or exo configuration of the bicycloalkane ring system substituents, and in the carbon chain configuration of the substituent B or S.

The condensed rings A and B present in the compounds of formula I and derivatives thereof described herein are bonded to one another in a cis-position; both of the hydrogen atoms attached to the attachment points of the bicyclic system are outside the dihedral angle of the naturally occurring rings.

The side chain (jv chain) attached to the cyclopentane ring A is trans-spaced relative to the B ring and exo-configured with respect to the bicyclic system.

The compounds of the invention may have two geometric isomers depending on the configuration of the double bond exocyclic relative to ring B, i.e. depending on whether the carbon chain (s) attached to this double bond is on the same side as cyclopentane A ring-linked carbon chain / w-chain - in this case the configuration of the exocyclic double bond is considered cis, or on the opposite side - in this case it is referred to as the trans configuration. In the general formula I and in the following formulas, the wavy bond which represents the bonding of these carbon chains means that both geometric isomers, individually and in the form of their mixtures, are included within the scope of the invention.

The above notations refer to natural compounds. In the enanthomers of the invention, however, the configuration of all asymmetry centers is exactly the opposite of that found in natural compounds. so the enantiomers are a reflection of natural substances. The d, l-mixtures are equimolar mixtures of compounds of natural configuration and the corresponding enantiomers.

The alkyl, alkenyl, alkynyl and alkoxy groups present in the compounds of the invention may have straight or branched carbon chains.

B is a carboxyl group in free or esterified form or a carboxyl group in salt form.

C 1-4 alkyl is preferably methyl, ethyl or propyl.

The C 2 -C 4 alkylene group is preferably ethylene or propylene.

C 1-4 alkoxy is preferably methoxy, ethoxy or propoxy.

C 2-4 alkynyl is preferably ethynyl.

E and _R6 are each independently hydrogen,

C 1-4 alkyl or fluoro.

When B 1 is alkyl having 1 to 4 carbon atoms, it is preferably methyl.

When R ₇ is monocycloalkyl, it is preferably cyclopentyl, cyclohexyl, cycloheptyl.

-3182.726

When R is a carboxyl group in the esterified form, it is preferably a group of the formula -COORg where Rg is a C 1-4 alkyl group, and in particular methyl, ethyl or propyl.

The compounds of the formula I can be formulated with both organic and inorganic acids and bases to form pharmaceutically acceptable salts for human and veterinary use.

Examples of pharmaceutically acceptable inorganic acids for human and veterinary use are hydrochloric acid, bromohydric acid and sulfuric acid. Examples of such organic acids are citric acid, fumaric acid, tartaric acid, maleic acid, methanesulfonic acid and ethanesulfonic acid. Acceptable inorganic bases include, for example, hydroxides of alkali metals, alkaline earths, zinc and aluminum. Acceptable organic bases include amines such as methylamine, diethylamine, trimethylamine, ethylamine, d-butylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine. , allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine. phenylethylamine, phenylethylamine * ethylenediamine, diethylenetriamine, or other similar aliphatic, aromatic or heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine, and substituted derivatives thereof such as 1 -methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine,

1,4-dimethylpiperazine, 2-methylpiperidine, and hydrophilic amines such as mono-, di-triethanolamine, 2-amino-2-butanol, 2-amino-1-butanol, 2-amino-2 ethyl-l, 3-propanediol. 2-amino-2-methyl-1-propanol, tris- (hydroxymethyl) -aminomethane, N-phenylethanolamine, N- (p-tertiary-amyl-phenyl) -diethanolamine, ephedrine, procaine and the like. - amino acids such as lysine and arginine.

Preferred salts of the compounds of the invention are those compounds of formula I wherein R is -COCR. group wherein R _d represents a y FEUTRE ^Q-mentioned human or veterinary acceptable base derived cation.

In this patent, the compounds of the present invention are bicyclo / p+q+ l/.5-0. as alkane derivatives. or preferably a compound containing 20 carbon atoms, referred to as Prepacyclic Acid II. The position of the oxygen atom in the prostatic clanic acid bane is numbered 9a.

Thus, a compound of formula I wherein p = q = 1 is an octyl derivative of bicyclo 5 · 5 · θ, or preferably 9a-deoxy-9a-methylene-prostacyclic acid, because the 9a-position of the oxygen atom of prostacyclic acid is methylene group. A compound of general formula I wherein ps 2 and q = 1 is a nonyl derivative of bicyclo 4.5.0, or preferably 9a-deoxy-9a, 9b-dimethylene-prostacyclic acid, since two methylene groups are substituted for the 9a-heteroatom of prostacyclanic acid. is in the molecule.

An analog I Compounds of formula I in which is called a q = 2, 7a-homo ~ derivatives, of a compound of the formula is wherein p or q is zero, ^"9 nor-metllén-" or "7 - nor -methylene- ^w derivatives.

The same designations (homo, dihomo, nor, dinor, etc.) are also used to indicate that the compounds of the present invention have more or less carbon atoms in the chain or carbon chain of the compounds according to the invention.

-4182.726

Δ according to the above nomenclature the name of the compound of formula la:

HidLroxi 7- endo-6-exo / ^{3'S-hydroxy-trans-octen-l-yl} / -blciklo'3 «3.0 octyl 3/5 * / - * tranaz pent-5-m or énaavi 15S-Dihydroxy-9a-deoxy-9a-methylene-prostacyclo-5-trans, 13-trans-dienoic acid, and the compound of formula Ib is:

8- endo-hydroxy-7-exo / ^{3, B-hydroxy-4'S-methyl-non-l-yl} / -bicik10'4.3-0 nonyl 3/6 »/ - hex-6'cisz-enoic acid; obsession

11,15B-Dihydroxy-16S, 20-dimethyl-9a-dExoxy-9a-methyl 1 -ene-7a, 2a-dihomoprostacyclic-5-cephenic acid.

Preferred compounds of the present invention are those compounds of formula I wherein B is a carboxyl group in free or salt form, R7 is a straight or branched alkyl group containing from 1 to 4 carbon atoms or an optionally substituted phenyl group as defined above, a saturated monoheterocyclic group. (preferably tetrahydrofuryl or tetrahydrothienyl) or a 5-7 carbon monocycloalkyl group and the other substituents have the meanings given above.

For the preparation of the compounds of the present invention, the present invention provides; in our minds we do it

1 / a compound of formula III wherein p, q,

Y, n 1, n ₂ , I, R 5, Bg, and By are as defined above, and one of the groups R and R 2 is hydrogen and the other is hydroxy, or a bonding moiety attached to the bicyclic system via an ether linkage. , or both are hydrogen, or Β'χ and B ' ₂ together are an oxo protecting group, one of R * 3 and B' 2 being hydrogen,

C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, and the other is hydroxy, C 1 -C 4 alkoxy, or a protecting group attached to the chain via an ether linkage, or R 4 and R 4 together are an oxo protecting group, alkylating with a compound of formula IV wherein D, mj and m ₂ are as defined above,

Or formula B / R _e is / CgHc / zP- _0/2 p - group is / 0 / CR, wherein alkyl or phenyl, and _these groups having the same or different and each is C1-6 alkyl in R

B "* is a free, esterified with C1-4 alkyl or in salt form, carboxy, -C / OR * /, a group of formula in which B 'is as defined above, and ^P is removed, if desired, optionally present in the molecule optionally present protecting groups, obsession

2 / a compound of formula V wherein B "', m ₂ , Ρ» q, R' - ^ and R " ₂ are as defined above and

D 'is methylene, oxygen, b, wherein

Σ * represents a sulfur atom and B ' _a and B' ^ taken together

-5182.726

Form a C 2 -C 4 alkylene chain or a group of formula CH OCOR * wherein R * has the meaning given above or D ', R "* and" together represent a group of formula c where m ₂ is as defined in any one of alkylation with a compound of the formula. wherein E, n ^, R5, Rg X, and R? Z is hydrogen or halogen to give a compound of formula VII wherein R * ', D *, m ^, p, q, R', R * 2 »

Z, n _x , R ₅ , R ₆ , X, n ₂ and Ro are as defined above and, if desired, deprotecting the optional compounds of formula VII to provide a compound of formula I wherein X is -CH =. A group of the formula wherein Z is as defined above and R 1 and R 4 together are oxo and / or, if desired, one of the following steps is carried out;

a) reducing a compound of formula I wherein R1 and R4 together are oxo and deprotecting to give a compound of formula I wherein R? one of R4 and R4 is hydrogen and the other is hydroxy;

b / starting from a compound of formula I wherein R1 and R4 together are oxo, nucleophilic addition of a free carbonyl group on the side chain, followed by deprotection to produce a compound of formula I wherein one of R1 and R4 is a is hydroxy and the other is C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl;

c) etherifying a compound of formula I wherein one of R 1 and R 4 is a hydroxy group and any hydroxyl groups that may be present in the molecule, and then removing any protecting groups that may be present to form a compound of formula I wherein one of each of §3 and R4 is C1 -C4 alkoxy;

d / dehydrohalogenating a compound of formula I wherein X is -CH = CZ-, wherein Z is halogen and all hydroxy, oxo and carboxyl groups optionally present in the molecule are dehydrohalogenated and removing any protecting groups that may be present to form a compound of formula I wherein Y is -C5C-;

e / a compound of formula I wherein one of R 3 and R 4 is hydrogen and the other is hydroxy and / or one of R 1 and R ₂ is hydrogen and the other is hydroxy and the optional additional hydroxyl group in the molecule is protected by oxidation and deprotection. such a compound of the general formula is obtained, wherein R 4, R 5 and EA / or R ^ and _R2 are oxo;

-6182.726 f / a compound of formula I wherein D is carbonyl; and the other carbonyl group which is not intended to be converted is protected to form a compound of formula I wherein D is CHOH;

g / a compound of formula I wherein D is CHOH and the other hydroxy group which is not intended to be protected is converted to a tosyl or mesylate, the tosylate or mesylate is reduced and the protecting group present is removed. Thus, a compound of general formula I is obtained in which D represents a methylene group;

h) esterifying a compound of formula I wherein R represents a carboxyl group to form a compound of formula I wherein R is a carboxyl esterified with C 1-4 alkyl;

1 / saponifying a compound of formula I wherein R is an esterified carboxyl group to give a compound of formula I wherein R is a carboxyl group;

j / transesterification of an orthoester of formula I wherein R is -C / OR &gt; / z to give a compound of general formula wherein R is -COOCH3; means;

k) converting a compound of formula I into a lactone or salt;

1 / a compound of formula I in the form of a salt. converting a compound of general formula I in free form;

m / a compound of formula I containing a protecting group is converted to the free compound and n / a mixture of isomeric compounds of formula I is separated into the individual isomers.

The protecting groups for the hydroxyl groups are the ether or zerol groups which can be cleaved under mild conditions, for example by acid hydrolysis. Preferred such groups are silyl ethers, such as trialkylsilyl ethers such as trimethyl, dimethylterteryl butyl, dimethylisopropyl, or dimethylethyl azylyl ethers; Also preferred are acetal ethers and enol ethers, such as tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, oxatlanyl ethers, and d, e, and f where Alk is C 1-6 alkyl. ethers.

Preferably, ketone or thio-ketal opportunites are used to protect the oxo groups, such as those of formula b wherein X ', R _a ' and R fc * are as defined above.

In a preferred embodiment of the process of the invention, the compounds of formula III are alkylated with the compounds of formula IV in the same manner as the compounds of formula V with the compounds of formula VI, except that the alkylating compounds IV or VI applied to 1.1 molar equivalents of the compounds of formula III and V / '. The reaction is carried out in an inert solvent such as an open-chain or cyclic ether such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; an aliphatic or aromatic hydrocarbon such as n-hexane, n-heptane, benzene or toluene; a halogenated hydrocarbon such as dichloromethane or carbon tetrachloride; or in a mixture of these solvents. In the specific case where Ξ is a compound of formula IV or VI, dimethyl sulfoxide, hexamethylphosphonic triamide and other proton-free solvents are particularly preferred. Dimethylsulfoxide is reacted with an alkali metal hydride to form dimethylsulfinylcarbanion, which can form carbanions of formulas IV and VI from the corresponding phosphoranes and phosphonates; therefore, this solvent is particularly advantageous as it enables the formation of carbanions of formulas IV and VI in situ (in the reaction mixture). The alkylation reactions described above may be carried out at a temperature of 0 to 100 ° C, but particularly preferably at room temperature.

A mixture of reactive geometric isomers between the compounds of formula III and the compounds of formula IV in which the new exocyclic double bond formed in the reaction and the corresponding substituents thereof are in either cis or trans position relative to one another. When a compound of formula V is reacted with a compound of formula VI, either the cis or trans isomer is formed, or only one, depending on whether the parent compound of formula V is a pure cis or trans isomer , desire is a mixture of these two isomers. If desired, the pure geometric isomers may be separated from each other by recrystallization from a suitable solvent or by chromatography on a thin layer, column, or by low-, medium-, or high-pressure liquid-liquid chromatography. Suitable carriers are silica gel or magnesium ion silicate, and the mobile phase is, for example, cyclohexane, n-hexane, benzene, dichloromethane, diethyl ether, diisopropyl ether, ethyl acetate or methyl acetate.

If necessary, ethereal protecting groups may be removed from the hydroxyl moieties by mild acidic hydrolysis, for example with a monovalent or polyvalent carboxylic acid such as acetic acid, formic acid, citric acid, tartaric acid or oxalic acid, in a solvent such as water, 2-dimethoxyethane or a small molecular weight alcohol; or a low molecular weight sulfonic acid such as p-toluene azulfonic acid in an alcohol such as anhydrous ethanol or methanol; or a polystyrene sulfonic acid ion exchange resin. It can be used, for example, a 0.1-0.25 normal solution of a polyhydric acid such as oxalic acid or citric acid in a suitable low boiling water miscible solvent which can be easily distilled off under reduced pressure after the reaction.

The silyl groups in the silyl ethers are selectively deprotected by fluoride ions in the presence of other protecting groups such as tetrahydrofuran or dimethylformamide as a solvent.

The ester-like protecting groups may be removed by conventional hydrolysis methods.

-8182.726

The ketal thioketal ca- torate used to protect the oxo groups is generally cleaved in the same way as the acetal and thioacetal groups by slight acid hydrolysis as described above.

The thioketal and thioacetal groups may be selectively deprotected in the presence of other protecting groups, for example, with mercuric chloride in aqueous acetone or acetonitrile, or a mixture thereof as a solvent, in the presence of an alkaline earth metal such as calcium or magnesium carbonate.

In a further preferred embodiment of the process of the present invention, when a compound of formula 1 wherein R 1 and R 2 'are taken together is an oxo group, it is desired to reduce to a compound of formula I wherein one of R 1 and E 4 is hydrogen and another hydroxyl group, this reaction is preferably carried out in liquid ammonia as a solvent, a cosolvent / co-solvent such as tertiary-butanol, an alkyl substituted 2-propanol containing 1 to 4 carbon atoms, or a cyclic ether such as in the presence or absence of tetrahydrofuran or dioxane, with an excess of an alkaline metal or alkaline earth metal such as lithium, sodium, potassium or calcium. After the reaction, a weak acid such as ammonium chloride or ammonium sulfate is used as proton source, or an aliphatic alcohol such as ethanol or propanol. The reaction may be carried out at a temperature between -70 ° C and the boiling point of the solvent.

In another preferred embodiment of the process of the present invention is a compound of formula I wherein R 1 and R 2 are. together represents an oxo group, the free Kaibonyl group in its side chain is to be subjected to a nucleophilic addition reaction to form a secondary or tertiary alcohol derivative, depending on the nucleophile.

If the secondary alcohol is to be produced in the above reaction, the borohydride or zinc borohydride of an alkali metal or alkaline earth metal such as sodium, lithium, calcium or magnesium is preferably used as the nucleophilic agent to afford the compound of formula I after removal of any protecting groups. , where Rx and Bz, one of which is hydrogen and the other of which is hydroxy. 0.5 to 6 moles of reducing agent, based on the starting carbonyl derivative of formula I, are used in an aqueous or anhydrous solvent, such as a linear or cyclic ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or dioxane. ; an aliphatic or aromatic hydrocarbon such as n-heptane or benzene; a halogenated hydrocarbon such as dichloromethane; or in a solvent containing a hydroxyl group, such as methanol, ethanol or isopropanol, in a mixture thereof. The reaction is carried out at -40 ° C to the reflux temperature of the solvent, but preferably at -25 ° C to + 25 ° C. * '...........'

If a tertiary alcohol is to be produced in the above reaction, an organometallic compound (organometallic compound) is used as the reaction partner and, where appropriate,

Removal of protecting groups present at -9182.726 gives the compound of formula I wherein one of R3 and R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and the other is hydroxy . As the organometallic compound, for example, a magnesium derivative such as RioMgHal can be used, wherein R 1g is C 1 -C 4 alkyl, C 2 -C 4 alkenylsulfate and Hal is halogen, and preferably chlorine or bromine; a lithium cuprate such as BiqCuII. where · Bio significant of the above; an organic lithium derivative, such as a compound of Formula RioII, wherein Bio is represented by the above; or an acetylide of an alkali metal or alkaline earth metal having the general formula Bii-C = ^c , wherein n is 1 or 2, Bu is hydrogen, straight or branched alkyl having from 1 to 4 carbon atoms, and M is an alkali metal or alkaline earth metal atom. Preferably 1.05 molar or more of the organometallic compound is used per carbonyl compound and the reaction is carried out in an anhydrous solvent such as a proton-free solvent such as dimethylsulfoxide or hexamethylphosphoric triamide, a linear or cyclic ether. such as diethyl ether, tetrahydrofuran, anisole, dioxane or 1,2-dimethoxyethane; or aliphatic or aromatic hydrocarbons such as n-heptane, n-hexane, benzene or toluene. The reaction is carried out at a temperature from about -70 ° C to the reflux temperature of the solvent, and preferably from -60 ° C to 20 ° C.

Whether secondary or tertiary alcohol is prepared in the above reaction, a mixture of epimeric and B-alcohols is obtained as the nucleophilic addition product. If desired, the pure S and B alcohols which are characterized by the azimetric triacentrate of the formula g and h, wherein B ₂ is hydrogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, phenyl, or C 1-6 -alkyl substituted with a substituent group may be separated by the above-mentioned fractional crystallization or chromatography methods.

In a further preferred embodiment of the process of the present invention, if these secondary or tertiary alcohols obtained as described above are to be etherified and after removal of the optional protecting group, it is desired to produce compounds of formula I wherein . one of which is C 1 -C 4 alkoxy and the other is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, the starting alcohols being a catalyst such as fluoroboric acid or boron. in the presence of trifluoride in an organic solvent such as dichloromethane with a diazoalkane.

Alternatively, the hydroxyl group may be reacted, either in free form or in the form of a salt, with an alkyl halide, represented by a base such as silver oxide.

-10182.726 in the presence of a solvent such as dimethylsulfoxide or dimethylformamide. According to a further preferred embodiment of the process of the present invention, a compound of formula I wherein Y is -CH = CZ-, wherein Z is dehydrohalogenation of a halogen atom to produce a compound of formula I wherein Y is -C = In the case of the group C, the dehydrohalogenating ring is preferably methyl azulfoxonium methyllide (GHx-SO-CH2 '), diazabicyclohedecene, diazabicyclononene or an amide or alcohol of an alkali metal. The dehydrohalogenating agent is used in an amount of 1 to 5 moles, preferably 1.51.8 moles, based on the starting compound of formula I, and the reaction is preferably carried out under an oxygen-free atmosphere in an inert solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide. or in the above-mentioned linear or cyclic ether, or aliphatic or aromatic hydrocarbon, liquid ammonia or a mixture thereof at a temperature of -60 ° C to + 100 ° C. If we don't work in ammonia; the reaction is preferably carried out at room temperature.

Dehydrohalogenation of compounds of formula I wherein Y is -OH = 0Z-, wherein Y is hydrogen and Z is in a trans-spaced position, where Z is halogen, to the corresponding derivatives containing -C = C nucleophilic addition of a carbonyl group, and also before the etherification of the alcohol formed.

The reactions listed below are carried out by conventional methods: if desired, converting a compound of formula I into another. also the compound of formula I, its lactone derivative or its salt, liberates the free compound from one of its salts and separates the pure isomers from the mixture of isomers.

In an analogous manner, a compound of formula I wherein both Βχ and B2 are hydrogen can be prepared from a compound of formula I wherein one of R1 and R8 is hydrogen and the other is hydroxy and one as D a compound of formula I containing a methylene group may be prepared from another compound of formula I containing a D-CE-OH group.

A compound of formula I wherein Bz and R4 together are oxo may be prepared by reacting a compound of formula I wherein one of Rz and B4 is hydrogen and the other is hydroxy with a neutral, preferably chlorinated, compound. excess oxidation of manganese dioxide in a solvent such as dichloromethane or chloroform, or by another method, the same compound in an inert solvent such as dioxane, benzene, or a mixture thereof at a temperature of from about 40 ° C to about 1.1 ° C. Oxidation is carried out with 2 molar equivalents of dichlorodicylbenzocnone.

In an analogous manner, a compound of formula I can be prepared wherein B 1 and B ₂ together are oxo,

-11182726 by oxidizing a compound of formula I wherein one of R @ 1 and R @ ₂ is hydrogen and the other represents a hydroxyl group. by oxidation of a compound of formula I containing a D-carbonyl group.

If several secondary alcoholic groups are present in the molecule and only one is to be oxidized, the other secondary alcoholic groups must be protected as described above and then deprotected after the reaction.

For the preparation of compounds of formula I wherein B is an esterified carboxylic acid, such as an alkoxycarbonyl group containing from 1 to 12 carbon atoms, compounds of formula I containing R as the free carboxyl group are esterified by one of the conventional methods, e.g. , for example in the presence of p-toluenesulfonic acid, by treatment with a suitable alcohol, such as an aliphatic alcohol having from 1 to 12 carbon atoms, or alternatively by treatment with a diazoalkane.

If desired, are compounds of formula I wherein R is an esterified carboxyl group such as an (1-4C) alkoxy / carbonyl group, a conventional method of hydrolysis? r can be converted to the corresponding free carboxylic compound as R,

For example, in water or aqueous alcohol, the esters are treated with the hydroxide of an alkali metal or alkaline earth metal and the mixture is acidified.

Compounds of formula I wherein R is -C / OR'A, wherein R 'is as described above, can be prepared from the corresponding compounds containing the free or esterified carboxyl group as R by following conventional procedures. The resulting imino ester is reacted, for example, with a suitable alcohol by the method described in J. Am. Chem. Soc., 64, 1827 (1942).

The compounds of formula I can be converted into their lactone derivatives or their salts by conventional methods, and the free compounds can be liberated from their salts by conventional methods.

The pure isomers can also be isolated from the mixture of isomeric signals of the compounds of formula I by conventional means such as fractional crystallization or chromatography.

Compounds of formula IV wherein E is a group of the general formula (R @ O / 2P - yo) wherein R _e is as defined above are prepared by reacting a compound of formula VIII wherein

R _e , mp D, m ₂ and R '' are as defined above, with at least one molar equivalent of a base such as an hydride of an alkali metal or alkaline earth metal such as sodium, potassium, lithium or calcium, an alcohol of an alkali metal or alkaline earth metal such as for example, sodium or potassium tert-butylate, an alkali metal or alkaline earth metal amide, such as sodium amide, or an alkali metal or alkaline earth metal salt of a carboxamide, such as the sodium salt of acetamide or narrowquinimide.

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Those compounds of formula IV. wherein E is / ΟθΗς / χΡ-, is prepared by reacting a compound of formula IX wherein m · “D, m ₂ and B” are as defined above and Hal is a halogen in an organic solvent such as benzene, acetonitrile or in diethyl ether, 1.1 molar equivalents to 1.3 molar equivalents of triphenylphosphine, and the phosphonium acid thus obtained is treated with an equivalent of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate .

The compounds of formula VI is prepared analogously as described above for the preparation of compounds of formula IV of the method, namely the X wherein Βθ, Z, m, R, X, n is ₂ and R7 is as defined above; or a compound of formula XI wherein Hal, Z, mi, Re, R g, X, n ₂ and R _? is as defined above for compounds. '

Compounds of formula VIII and X are prepared by methods known in the art, e.g., Corey et al.

J. Amer. Chem. Soc., 90, 3247 (1968); and 88, 5654 (1966). Compounds of formulas IX and XI are also prepared by methods known per se.

Compounds of formula III and V have not yet been described in the literature.

Compounds of formula III wherein X is 1,2-ethylene, -Ca C-, or -GH = CZ-, in which the hydrogen atom and Z are in a transient position relative to one another, wherein Z is above, is prepared by the following formula: wherein a Ρ »Q, ® ^a is as defined above

G is a protected carbonyl group or a group of formula CH CG ' _? wherein OG * is a silyl ether group or an acetalea ether group, reacting the compound with a compound of formula VI to give a compound of formula XIII wherein G, p, q, Β _χ , Z, R _{2 2} , η _χ , Rc, Rg, X, n ₂ and R _? is converted to a compound of formula XIII obtained above and then optionally b / optionally obtained in (a) to a compound of formula XIV wherein

G, Ρ »4» R * i »R * 2» ® * 3 »B'zp ⁿ i» ^r 5> Eg »X» b ₂ and R? has the meaning given above and; _. '·

Ϊ 'is 1,2-ethylene. a group of formula -C6C or a -CH = CZ group having a hydrogen atom and Z in a trans-position relative to one another, wherein Z is a protecting group for the compound of formula XV by removal of the above and then c / aa G where p, q, S'q »R ' ₂ ,

Ϊ ', R'jj, B * 4, ni, R 5, R 6' X 'H 2 and R 7 are as defined above and g is CH OH or carbonyl; and, if desired, d / oxidizing a compound of formula XV wherein G 'is -CH-OH and all other hydroxyl groups present in the molecule in the present invention are in the protected form described above.

-13182726

It is of formula III. wherein Y is -NH-CHp- is prepared by reacting a compound of formula XVI wherein G, p and q are as defined above and R * _x and R ' ₂ are as defined above, with the proviso that can only hidroxilcsoporttóí different compound with a reducing agent in the presence of a compound of formula wherein R'z, R _{'4> η} χ, R ^, Rg, X, n is ₂ and R XVII is as described above, is reacted with an aldehyde, and the other protecting groups present in G and present in the present case are removed.

Compounds of formula III wherein Y is -NH-CO- are prepared by reacting a compound of formula XVI in the presence of a base with a compound of formula XVIII wherein Hal is halogen, preferably chlorine and R'x, R * ₄ , n 1, R e, R 8, X, n ₂ and R n are as defined above, followed by removal of other protecting groups in G and optionally present.

Compounds of formula XII are reacted with compounds of formula VI under the same conditions as compounds of general formula V with regions of formula VI.

If desired, a compound of Formula XIII is converted in an analogous manner to a compound of Formula XIV as described above for the conversion of a compound of Formula I to another compound of Formula I; for example a nucleophilic addition reaction. the side chain carbonyl group, the alcoholic hydroxyl group, is etherified, dehydrohalogenated or hydrogenated.

As mentioned above, when G is a pCH OG 'group, the OG' group may be an azyloxy group such as a tralkylsilyloxy group such as trimethyl, dimethyl tert-butyl, dimethyl isopropyl or dimethylethylsilyloxy, and preferably dimethyl-tert-butylsilyloxy, or an acetal ether group, such as tetrahydropyranyloxy, tetrahydrofuranyloxy, dioxanyloxy, oxathanyloxy, and preferably tetrahydropyranyloxy. group.

In the compounds of Formula XIV, the protecting group in G 'can be removed as described above, that is, the Silyl sweep can be selectively removed by fluoride ions and the acetal ethers can be cleaved by acid hydrolysis. If a protecting group G 'is to be cleaved in the presence of other, easily cleavable ether groups, then, if OG * is a silyloxy group, these easy cleavage groups must be acetal ether groups, and if OG * is an acetal ether group, these groups must be silyloxy groups.

When G is a protected carbonyl group, the protecting groups are preferably acetal or thioacetal groups such as dimethoxyacetal, dletoxyacetal, dimethylthioacetal or diethylthloacetal, and preferably dimethoxyacetal or ketal or thiocetal group. ethylenedioxy-ketal of formula (i), propylene-dithioketal of formula (j), propylene-dioxy-ketal of formula (k) or ethylene-dithioketal of formula (1) and preferably ethylenedioxy-ketal-14182726.

The deprotection of the compounds of formula XIV and, if desired, the conversion of the hydroxy groups of the compounds of formula XV into, for example, acetal ether groups or silyloxy groups, is carried out as described previously.

If desired, the oxidation of compounds of Formula XV wherein G 'is a group of formula A may be carried out by methods known per se for oxidation of secondary alcohols; for example, the alcohol is treated with a solution of chromic anhydride sulfuric acid in an organic solvent such as acetone.

Reductive amination between the compounds of formula XVI and the aldehydes of general formula XVII is carried out under the usual conditions for such reactions, preferably with a mixed hydride such as sodium borohydride or lithium aluminum hydride as the reducing agent.

The reaction between the compound of formula XVI and the compound of formula XVIII is carried out under standard conditions for acylation of amines.

Compounds of formula V are prepared by reacting a compound of formula XIX wherein p, q, R * x, and R'g are as defined above and

T is a group of the formula wherein X ', R * _is aa

R 11 is as defined above.

reacting with a compound of formula IV to yield a compound of formula XX, wherein R »» »m _2s ^D» l * ^m Ρ ^»B '* l ^b> 2 θ ³ are as defined above; and b / optionally converting a compound of formula XX into a compound of formula XXI wherein R '', m ₂ , D *, πΐχ, p, q, R ', R' ₂ and T are as defined above; and finally removing / deprotecting the aldehyde protecting group in T.

The reaction between the compound of formula XIX and the compound of formula IV is carried out under analogous conditions to those described for the reaction of the compound of formula III with the compound of formula IV, thereby obtaining a mixture of two isomeric olefins which the exocyclic double-bond configuration resulting from this reaction is / cis or trans / different. The pure isomeric signal of the compounds of general formula XX can be separated as described above by fractional chelation or by chromatography.

If desired, a compound of Formula XX may be converted to a compound of Formula XXI as described above for analogous reactions with Formula I Compounds. For example, a compound of formula XXI wherein D is &gt; CH &lt; OC &gt; OCOR * wherein Β &quot; is as defined above may be prepared by preparing a compound of formula XX wherein D is &quot; CH-OH &quot; etherification by one of the conventional methods known per se. Further, a compound of formula XXI wherein

-15182,726

D 'represents a group of formula b wherein X', R ' _a and R * u are as defined above, by preparing a compound of formula XX wherein D represents a carbonyl group by one of the conventional acetalization or thioacetation methods known per se. .

The aldehyde protecting group in the compounds of Formula XXI is removed as described above, so if the aldehyde protecting group is an acetal moiety, it is preferably by acid hydrolysis _? or, if thioacetal moiety, after treatment with mercury (II) chloride. If the aldehyde protecting group is to be selectively cleaved in the presence of another protected carbonyl group, when the aldehyde is protected as thioacetal, the other protected carbonyl groups must be acetal and when the aldehyde is acetal protected, they must be thioaethal.

Compounds of Formula XII are prepared by synthesizing a compound of Formula XXIIA or XXIIB wherein p and q are as defined above, and

G · * is converted to a carbonyl protected compound as described above into a compound of formula XXIII wherein p, q and G are as defined above; and then b) a compound of formula XXIII thus obtained having the formula 0 = C / 0Rj_x / ₂ , wherein

C 1-6 -alkyl or C 1-6 -alkyl substituted with aryl, to react a compound of formula XXIV wherein p, q, G and R 1 -x are as defined above; c) reducing the compound of formula XXIV thus obtained to a compound of formula XXV wherein G, p, q and R 1 are as defined above; then d / optionally separating the pure optical antipodes of the compound of formula XXV; and then optionally converting a compound of Formula XXV to a compound of Formula XXVI wherein G, P, q 'and R 1' are as defined above; and finally converting f / XXV or XXVI in a compound of formula to a compound of formula XXVIII, where θ »P, Q, B *] _ ^whether B _'2 are as defined above.

Compounds of Formula XXIII wherein G is -CH OG * wherein G 'is as described above may be prepared by methods known per se from the compounds of Formula XXIIA, for example, by starting with an azylaryl in the presence of a base. a halide, a silazane, or a silyl trifluoroacetamide derivative, or a compound of formula m wherein X 'is oxygen or sulfur, or - CH2 / r- where r is zero or 1.

Compounds of formula XXIII, wherein G is a protected carbonyl group, can be prepared by reacting compounds of formula XXIIB in pyridine as a solvent with an excess of pyridine-chromic anhydride, or in a mixture of benzene and dimethylsulfoxide as a solvent, pyridine trifluoride. dicyclohexylcarbodiimide in the presence of acetate

-16182,726

Oxidation according to Moffatt.

The reaction between the compounds of the formula XXIII and the compounds of the formula Q1C / OBpy2, where Β-, χ is as defined above, and preferably a methyl group, is carried out on a base such as sodium methylate, sodium ethylate, sodium hydride, potassium hydride, or potassium tert-butylate in an amount of from 2 to 4 moles, with from 6 to 12 moles of carbonic acid diester, in a solvent or in an inert solvent in an oxygen-free medium. The reaction is carried out at a temperature of about 0 ° C to about 80 ° C, and the reaction takes about 10 minutes to 1 hour. The reaction yield varies between 5% and 90%, depending on the temperature, reaction time and concentration of the reagents.

The reduction of the compounds of formula XXIV may be carried out with an boron hydride of an alkali metal or alkaline earth metal, in aqueous solution, preferably at a pH of 5 to 3 or 7.2, or in a mixture of methylene chloride and ethanol as solvent with ethanolic sodium borohydride. temperature. The reduction usually takes place within half an hour, and then the excess reagent is decomposed by the addition of an easily reducing compound such as acetone and a proton donor (proton transfer agent) such as acetic acid.

The pure optical antipodes of the compounds of Formula XXV wherein G is as described above are resolved by the customary hydrolysis of the ester group with an optically active base, such as quinine, zinconin, ephedrine, of the acid thus obtained. -phenyl-1-aminoethane, dihydroabiethylamine, amphetamine or arginine is used to form a salt and the diastereomeric salts thus obtained are separated, for example, by fractional crystallization. The optically active acid is then recovered by converting the above salt to the sodium salt and then acidifying the aqueous solution to a pH where the protecting group in G is not yet degraded.

If desired, the protecting groups may be deprotected prior to resolution. and after separation, we can rebuild them.

The optically active free acid can then be converted to the corresponding optically active ester of formula XXV in a manner known per se, for example by treatment of the acid with a suitable diazoalkane.

If desired, the same method can be used to separate optical antipodes of compounds of formula XXVI.

Alternatively, optical antipodes of compounds of Formulas XXV and XXVI wherein G is a protected carbonyl group may be separated by deprotecting the G group and the liberated carbonyl group with an optically active primary amine such as arginine. reacting with lysine, alanine, 1-phenyl-1-ethylamine, 1-phenyl-1-propylamine or the like to form the corresponding optically active alkyl ester Schiff bases; the latter can be separated by methods known per se, such as fractional crystallization or high performance liquid chromatography, followed by hydrolysis of the imino group in a manner known per se. pure optical antipodes of compounds XXV'and XXVI can be prepared by conventional chalation or acetalization.

-17182,726

If desired, a compound of Formula XXV can be converted to a compound of Formula XXVI, either as a racemic mixture or as pure optical antipodes separated as described above. This reaction changes the configuration of the hydroxyl group attached to the cyclopentane ring. In this step, the hydroxyl group is esterified, for example, with 2-4 molar equivalents of triphenylphosphine and 2-4 molar equivalents of carboxylic, acetic, benzoic or p-phenyl-benzoic acid, or in an inert solvent such as an optionally halogenated aromatic hydrocarbon such as benzene or chlorobenzene or a cyclic ether such as tetrahydrofuran with 2 to 4 molar equivalents of the diethyl ester of azodicarboxylic acid and then selectively saponification, for example, by transesterification in the presence of an alkali metal carbonate, e.g.

Compounds of formula XXVII may be prepared by methods known per se from the compounds of formula XXV or XXVI. For example, a free hydroxyl group in a compound of Formula XXV or XXVI can be converted to a C 1-6 alkoxy or a readily cleaved ether such as a silyloxy or acetal ether group by the same etherification method as analogous to the compounds of general formula 1 reactions described above.

The free hydroxyl group in a compound of Formula XXV or XXVI can be converted to an ortho group and the ketone thus obtained can be converted to a ketal or thioketal using the same methods described above for the conversion of compounds of Formula I into tertiary alcohols.

The free hydroxyl group in a compound of Formula XXV or XXVI can be converted to a hydrogen atom by treatment with a sulfonic acid chloride such as p-toluenesulfonyl chloride, methanesulfonic acid chloride or benzenesulfonic acid chloride, followed by the sulfonic acid ester thus obtained is reduced by one of the conventional methods, for example lithium aluminum hydride. In this reaction, the ester group of the formula -COOR3 is also reduced to the -CHgOH group which can then be oxidized with the Moffatt reagent to the aldehyde group.

One of the formulas XXVIII wherein one of R @ 1 and R @ ₂ is hydrogen, C1 -C4 alkyl, C2 -C4 alkenyl, the other is hydroxy, C1 -C6 alkoxy or an easily cleavable group. ether group, or R ", and E'h is a jointly protected carbonyl group," ^x can be reduced in a manner known per se, for example with diisobutylaluminum hydride or lithium diisobutylaluminum hydride to the corresponding compound of formula XXVII.

When compound (XXVIII) is reduced with lithium aluminum hydride in a manner known per se,

-18182726 gives the corresponding primary alcohol which can also be obtained by reducing the free acid in tetrahydrofuran with borane. The free acid, on the other hand, is prepared by hydrolysis of the ester. The primary alcohol thus obtained can then, as mentioned above, be oxidized, for example, with Moffat reagent to the corresponding aldehyde.

Compounds of formula XVI may be prepared by methods known per se, for example starting from compounds of formula XXVIII, wherein _? when OG 'is a silyloxy group, all secondary alcoholic hydroxy groups present in the molecule are protected as an acetal ether group, while if OG' is an acetal ether group, these secondary hydroxy groups are protected as silyloxy groups. For example, a compound of formula XVI can be prepared from a compound of formula XXVIII by the following reaction sequence:

selectively removing, if desired, the gamma group in G;

b) oxidation of the free hydroxy group, if necessary, from a group of the formula CH - OG * to an oxo group, e.g.

c) hydrolyzing the ester group to a carboxyl group;

d) converting the carboxyl group into a mixed anhydride, for example, by reaction with an acid chloride such as an alkyl or benzyl ester of chloroformic acid or plvaloyl chlorocarbonate in an inert, anhydrous solvent such as acetone, tetrahydrofuran or dichloromethane;

e / converting the mixed anhydride, for example, by treatment with an acetone solution of an alkali metal azld to the azide;

f) preparing amine from the azide by Curtius rearrangement;

g / and finally, if desired, converting the amine of formula XVI thus obtained into another amine of formula XVI *

The compounds of formulas XVII and XVIII are known and may be prepared by known methods.

. Compounds of formula XIX are prepared from compounds of general formula XII wherein, when G is ~ CH

OG ', preferably G' is a silyloxy group, and when one of R ' ₁ and R' ₂ is hydrogen and the other is hydroxy, the latter is preferably protected as an ether or ester, as follows: sequence:

acetal or R ' _u is as defined above, and the aldehyde group is a thioacetal group, wherein X "R""' _{b is} preferably converted to a thloaethal group, optionally G is selectively removed by fluorine ions;

c / optionally oxidizing the free hydroxyl group with an Jones reagent to an oxo group;

d / If desired, the protecting groups R '' or R ' _{2 are} selectively removed from the secondary hydroxyl groups.

-19182,726

The compounds of formulas XXIIA and XXIIB are prepared by methods known per se. For example, a compound of Formula XXIIA wherein p = q = 1 is prepared by bicyclo ^. 3 x 3'O-Octane-3,7-dione J. Am. Chem. Soc. 82, 6347 (1960), or the bicyclo 3.3.0 octane-3,7-dione monoacetate, J. Org. Chem. 39, 2377 (1974), and then the acetal group is converted to the oxo group. In both cases, the resulting hydroxy ketone of Formula XXII, where p = q = 1, is a mixture of the endo-hydroxy derivative and the exo-hydroxy derivative containing about 80% of the endo-isomer. These two isomers are also easily separated. by separating the corresponding racemic silyloxy derivative by fractional crystallization, as mentioned above several times.

A compound of Formula XXII wherein p = 1 and q = 2 can be prepared from bicyclo 4.3.0 non-7-en-3-one of Formula XXIX wherein the two rings are bonded to one another in a cyano-position by converting the ketone group into acetal or thioacetal as described above, hydroboronating the double bond in the usual manner, and then deprotecting the ketone group as described above.

For example, the compound of formula XXIX is described in J.P. Vidal's method can be used to prepare the Sterochimie et Selecitivité Reactionelle en Serie Bicyclo ç-3 · c-alcanique, Université de Sciences et Techniques for Languages, Academie de Montpellier, n ° d'ordre O.N. R.S.A.O. 11257 (1975). '·

For example, a compound of formula XXIIA prepared as described above wherein p = 1 and q = 2 can be converted to another compound of formula XXII by acetalization, thioacetation, oxidation or Bayer-Williger reaction in analogy to those described above. ·

A compound of formula XXIIB wherein p = 0 and q = 1, or p = 1 and q = 0 can be prepared by methods known per se from 5-exo-bromo-6-endo-hydroxybicyclo 3 * 2.0 heptane-2 on from J. Chem.Soc. Parkin, 1, 1767 (1965): for example, thioacetalization of said bromohydrin by acetalation followed by dehalogenation to a compound of formula XXIIB by a conventional method in organic chemistry. Dehalogenation may be accomplished, for example, by reduction with chromium II salts, palladium on calcium carbonate or palladium on charcoal and catalytic hydrogenation in the presence of a hydrocarbon-binding agent, or by reduction with tributyl on anhydride.

A compound of Formula XXIIB wherein p = 2 and q = 1, or q = 2 and p = 1 can be prepared, for example, starting from compound XXIX by the following reaction sequence: carbonyl group, for example, with lithium aluminum hydride in diethyl ether, The alcohol is protected, for example, as tetrahydropyranyl ether or silyl ether, and the double bond is hydroboronated by conventional means. the resulting product is oxidized, the hydroxyl group is deprotected and the product is acetalized.

A compound of formula XXIIB. where p = q = 2, methods known per se can be prepared, for example, from 2-hydroxy-perhydro-azulen-2-one, the latter of which is described by D.K. According to the method of Banerjee and K. Sankara Ram, Ind. J. Chem.

-20182,726

The compound of Formula XXIX can also be used to prepare a compound of Formula XII wherein G is

CH * OG group of the formula wherein G * is azililcaoport, and when R '] _ and _R'? one of which is hydrogen and the other is hydroxy, this hydroxy group is preferably protected as an acetal ether or ester according to Scheme A.

Accordingly, the compound of formula XXIX can be converted into the keto-ester of formula XXX, which is known per se, for example as described above, which is then reduced to the> -hydroxy ester of formula XXI and the hydroxyl group protected as an acetal ether. The compound XXXII thus obtained is hydroboronated in the usual manner and the reaction leads to a mixture of alcohols XXXIIIa and XXXIVa, the components of the mixture are separated by chromatography or fractional crystallization, followed by separation of the alcohols XXXIIIb and XXXIVb is converted into ethers and then reduced to diisobutylaluminum hydride in toluene to give compounds of formula XII in a manner known per se.

The biological activity of the compounds of the formula I is the same as that of the natural prostacyclin (PGI ₂ ), but the compounds according to the invention have a particular advantage over the latter in that they are more stable at pH values from 0 to 11 and especially at physiological pH. they work longer and more evenly. This greater stability results from the fact that the chemical structure of these compounds is different from that of the natural prostacyclin. Because the 2-oxabicyclo / 3.3.0-octane system contains a heteroatom, an oxygen atom, the natural prostacyclin is an exocyclic enol ether and is therefore highly acid sensitive. The product of the acid reaction, 6-keto-PGP ·, has hardly any biological effect that is characteristic of natural prostacyclin. On the other hand, the bicyclic system of the compounds of the present invention does not contain oxygen and thus is not enol ethers. Because they are not as sensitive as natural analogues, they can be administered orally.

In addition, the compounds of Formula I, TSI * · -oldalláncúban monographs, there is a triple bond in 13-14-position or the 15-position hydroxyl group / R Z or R ₄ hydroxy groups present tess / near a bulky group such as 1 An alkyl group containing 6 carbon atoms, or an electron withdrawing group such as fluorine, is more resistant to metabolic degradation in the body, for example by 15-PG dehydrogenase, than natural prostacyclin.

The biological effects of natural prostacyclin are known, for example, when administered to patients with asthma by inhalation / warm-up / post-administration of pro-pacacycline, it inhibits bronchoconstriction induced by non-specific modes such as water spray or exercise / 5. Bianco et al.,

J. Sl. Medical Science, 6, 256 / 19-8 / 7 · Prostacycline, when administered to humans as an infusion, has antihypertensive, vasodilatory, antiplatelet, and anti-aggregating effects. Székely et al., Pharm. Gap. Comm., 10, 5 ^ 5/1978/7; stimulates / stimulates the uterine muscle in monkeys and humans? In addition, prostacyclin has luteo21 in animal studies

It also has a lithic effect and also protects the gastric mucosa in animal studies, such as in rats, against ulcers caused by non-steroidal anti-inflammatory drugs such as acetylsalicylic acid or Indomethacin.

In addition to its effects mentioned above, the natural prostacyclic is highly chemically degradable and therefore not useful in medicine. As mentioned above, the compounds of formula I exhibit the same biological activity as the natural prostacyclin, but the stability of the compounds of the invention is not as low as that of the prostacyclin.

The following table shows the in vitro inhibitory effect of the two compounds of the invention and prosttaicycline on platelet aggregation-induced plasma rich in 10 micromoles of ADP as well as the antihypertensive effect on anesthetized rats.

Compound In Vitro Aggregation Relative Effect Inhibiting Antihypertensive Effect

ΙΟ ^ θ ng / ml / 1/100/2/25 1,15 / 3/20 0,25 / 1 / Prostacyclin / 2/11>, 15S-Dlhydroxy-9a-deoxy-9a-methylene-pro-pacacyclo-5-trans , 13-trans-dienoic acid / 3 / ILa, 15S-Dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prosatacyclo-5-trans, 13-trans-dienoic acid

IC 50 Concentration inhibiting 50% of platelet aggregation.

Prostalcoin and dl-11 ', 15S-dihydroxy-9a-deoxy-7-normethylene-pro-acylcla-5,131R-anhydrous and the syndrome show that these two of the same dose of compound, which inhibits gastric ulcer 10 times more potently than prosatacycline.

The dose of dl-11β, 5S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18,19,20-trinor-prostacyclic -5 at a dose which produced the same degree of inhibition of aggregation as prostacyclin The in vitro luteolytic activity of 13-trans-dienoic acid and 11x, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17,18,19,20-tetrahoro-prostacyclo-5cis, 13-trans-denoic acid is 5-fold ,. and eight times more potent than pros2tacycline.

In cases where the use of natural prostaglandins or prostacyclin in medicine is warranted, the compounds of the present invention having prostacyclic and prostaglandin-like effects may be used. For example, ^T may be used in the treatment of asthma, these compounds, as specifically bronchodilation. There are a variety of ways to administer the cause for this purpose: orally / orally / in the form of tablets, capsules, pills, or liquids such as drops or syrups; rectally / rectally / in the form of suppositories; intravenously / intravenously / intramuscularly / intramuscularly or subcutaneously / subcutaneously; inhaled »

-22182.726 in the form of aerosols or nebulized solutions; or by inhalation of dust. These compounds may be administered at a dose of about 0.01 mg / kg to about 4 mg / kg / day, but the dosage will depend on the age, weight and condition of the patient and the route of administration.

When used in the treatment of asthma, the compounds of the present invention may be combined with other anti-asthma agents such as sympathomimetics / sympathetic nervous system (s) such as isoproterenol, ephedrine and the like; xanthine sarmase wedges such as theophylline or aminophylline; and corticosteroids such as prednisolone or ACTE (adrenocorticotropic hormone).

In addition, the compounds of the present invention have an astringent effect on the uterus and can thus be used in obstetrics in either human or animal use to induce labor or to expel a dead fetus. For this purpose, these compounds are administered intravenously at a dose of about 0.01 g / kg / per day until delivery or are administered orally.

The compounds of the present invention also have luteolytic activity and can thus be used for contraception. Their advantage in this regard is that they have little effect on smooth muscle contraction and thus have no side effects such as natural prostaglandins such as vomiting and diarrhea.

Furthermore, these compounds also have a gastric ulcer inhibitory activity, and thus their use can reduce and control excessive gastric acid secretion in mammals. These compounds minimize or completely eliminate the formation of ulcers in the gastrointestinal tract and accelerate the healing of existing ulcers. For therapeutic purposes, the compounds are administered by intravenous infusion or intravenous, subcutaneous or intramuscular injection; administered by intravenous infusion at a dose of 0.1 microgram / kg to 500 microgram / kg per minute. For both the injection and infusion modes, the total daily dose will be between 0.1 mg / kg and 20 mg / kg, depending on the age, body weight and condition of the patient or treated animal and the route of administration.

However, as with natural prostacyclins, the most important biological activity of the compounds of the invention is their antiplatelet effect, i.e., their ability to inhibit platelet aggregation, reduce their adhesion to one another, prevent the formation of blood clots, and prevent the formation of blood clots. .

This antiplatelet effect is coupled with a relaxing / relaxing effect on the coronary artery. Therefore, these compounds can be used for the prevention and treatment of myocardial infarction, as well as for the treatment and prophylaxis of thrombosis, atherosclerosis, tonsillectomy and other similar conditions, and more generally for the treatment and prevention of dihiperlipidemia.

For this purpose, these compounds may be administered by conventional administration methods, i.e., intravenously, subcutaneously, intramuscularly, or the like. In urgent cases, they are preferably administered intravenously at a dose of 0.005 mg / kg / day to 20 mg / kg / day, depending on the age, weight and condition of the patient and the route of administration.

-23,182.726

As mentioned, the compounds of the invention can be used in both human and veterinary medicine and can be administered in various ways. Orally in the form of tablets, capsules, drops or syrups; rectally in the form of suppositories; parenterally subcutaneously or intramuscularly in the form of solutions or suspensions; preferably in an emergency, intravenously; after inhalation aerosols or in the form of porous solutions; in the form of long acting sterile subcutaneous implant preparations; or endovaginally (in the vagina), for example in the form of suppositories for vaglalia.

The compounds of the present invention can be formulated for human and veterinary use by conventional techniques, using conventional carriers and / or diluents. For example, for intravenous injection and infusion solutions, sterile and isotonic / aqueous osmosis / water solutions are preferably used. Both for subcutaneous and intramuscular injection, sterile aqueous solutions or suspensions containing water or a non-aqueous solvent are prepared. Implantation purposes can be used containing the active ingredient impregnated implanted sterile tablet or silicone rubber, the active ingredient will get through v ^1.

Common carriers and diluents include water, gelatin, lactose, dextrose, sucrose, mannt, sorbitol, cellulose, talc, stearic acid, calcium and magnesium stearate, glycols, starch, acacia, gum dagrant, alginic acid, alglutates, vegetable oils and the like.

Aqueous suspensions or solutions of these compounds, and preferably their salts, such as their sodium salts, are used in powdered medicated sprays. Alternatively, the compounds may be dissolved in a conventional propellant such as dichlorodifluoromethane or dichlorotetrafluoroethane and placed in a pressurized small container. If the propellant is insoluble in the propellant, an additional solvent must be added, such as ethanol, dipropylene glycol and / or a high vapor pressure substance.

The invention is further illustrated by the following non-limiting examples.

Example I

To a solution of II (6 g / 0.084 mol / bicyclo) -3,7,7-octane-3,7-dione in 100 ml dichloromethane and 100 ml ethanol is added 1.1 g / 0.029 mol sodium borohydride. After 45 minutes the excess reagent was quenched by slow addition of acetone (20 mL), neutralized and the solvent evaporated under reduced pressure. The residue was dissolved in water and dichloromethane, the solvent was distilled off from the organic solvent side, and the residue was filtered through a pad of silica gel using hexane / diethyl ether (7 x 10 3). In this way, 9.1 g of 7? -Hydroxy-biocyclo / 3 x 3 * 0? octane-3 is obtained. IR spectrum (film): 3400, 1740 cm ^-1 . To a solution of 7h-hydroxybicyclo [3.3.2] octane-3-one (0.065 mol) in 27 ml of anhydrous dimethylformamide was added 12.8 g of dimethyl tert-butylsilyl chloride and

8.85 6 imidazole. The reaction mixture was heated at 60 ° C for 5 hours and then cooled to volume.

-24182.726 was diluted with twice water and extracted three times with 40 ml and twice with 20 ml of diethyl ether. The combined organic solvent solutions were washed with 5% aqueous sodium bicarbonate solution, then water, and the solvent was distilled off. 15.8 g (95%) of crude product are obtained. This crude product was chromatographed on silica gel with 2.85 g of 7-exo- (dimethyl-tert-butylloxy) -bicyclo [3.3.0] octan-3-one (b.p. 40-42 ° C) and 11.8 g of 7-endo- dimethyl tertiary-15-butylsilyloxy / bicyclo [3.3.3] octane-5-one, m.p. 51-52 ° C.

11.8 g (0.0463 mol) of a solution of 7-endo- (dimethylterio-tert-butylsilyloxy) -bicyclo [3.3.0] octan-3-one as described above in 295 ml of carbonic acid dimethyl ether are obtained in anhydrous form. With stirring, 6.95 S of 80% sodium hydride is carefully added under a neutral atmosphere. After the evolution of hydrogen ceases, the reaction mixture is stirred at 75-80 ° C for 40 minutes. After cooling, the mixture is diluted with 2 volumes of diethyl ether, and 13 g of acetic acid is carefully added. The organic layer was separated after the addition of a pH 5.2 to 5.5 buffer solution and the aqueous solution was extracted with diethyl ether. The combined organic solvent solutions were quenched with sodium sulfate and the solvent was distilled off. There were thus obtained 12.82 g of methyl dl-7-endo- (dl-methyl-tert-butylsilyloxy) -bicyclo [3.2.0] octan-3-one-2-carboxylic acid methyl ester (14.49 g). 85% of theory. Chromatography on silica gel (45 x product) using 97 x 3 gold hexane / diethyl ether as eluent gives 10.81 g of pure product, _χ = 254 myu, _r = 7000.

In all of the above steps, but starting from the exo-isomer, dl-7-exo- / dimethyl-tertiary-bublo-slyloxy / bicyclo-3-methyl-3-octane -3-on-2-carboxylic acid methyl ester is obtained. % ~ nyu _! _- ^- = 6500.

Example 2.

7.5 g of dl -? - endo / t-butyl-dimethyl-silyloxy / bicyclo * lo / 3.3 · 0 / octan-3-one-2-one and lever b av oxohexandioate 75 ml _{t n} di chloro methanol and 75 ml of ethanol are added with stirring at -20 ° C, and 0.9 g of sodium borohydride is added. After stirring for a quarter hour, the excess reagent was quenched by addition of 12 ml of acetone. The mixture was allowed to warm to 0 ° C, 20% potassium dihydrogen phosphate solution (20 ml) was added and the solvent was distilled off under reduced pressure and the residue was extracted several times with diethyl ether. The combined organic solvent was washed with water (5 mL) and the solvent was distilled off. The residue was crystallized from n-hexane to give 4.8 g of dl-3-endo-hydroxy-7-endo- / dimethyl-tert-butyl-azyloxy / -bicyclo-3- 3,7-octane-2-oxo-carboxylic acid methyl. ester is obtained, m.p .: 68-70 ^o g 'of the material in the mother liquor was 25 g of silica bound * flax, and n-heptane and diethyl ether -. 90: 10 eluting mixture. In this way, an additional 2 g of product are obtained which is sufficiently pure for further reaction.

To a mixture of dl-3-endo-hydroxy-7-endo / dimethyl-tert-butylsilyloxy / bicyclo [3.3.07] octane-2-exo-carboxylic acid methyl ester in 80 mL of methanol and 20 mL of water was added g of potassium hydroxide and reflux for half an hour. The methanol was then distilled off, the remaining aqueous mixture was acidified to pH 5.1 and extracted with ethyl acetate. The organic solvent25

Evaporate the solvent from a slurry of -25182726 to give 5.1 g of dl-3-endo-hydroxy-7-endo- (dimethyl-tert-butylsilyloxy) -bicyclo [3.3.07] octane-2-carboxylic acid. This product was dissolved in 150 ml of acetonitrile and 2.81 g of d - / + / - ephedrine was added. After standing for 4 hours at room temperature, the crystallizing salt was filtered off and recrystallized twice from acetonitrile. In this way, 1.85 g of (+) - 3-endo ₌ hydroxy-7-endo- (dimethyl-cis-cis-butylsilyloxy) -bicyclo [3.3.0] octane-2-exo-carbonic acid d - [+] - ephedrine salt is obtained / = + 52 DEG C. All the mother liquors are combined and the solvent is distilled off, the residue is dissolved in water and a 0.68 g solution of sodium hydroxide is added to the aqueous solution. The d - / + / - ethylene is isolated by extraction with benzene and the sodium salt solution is acidified to pH 5 and then extracted with ethyl acetate. The ethyl acetate was distilled off and the residue

2.2 g of 1-ephedrine were treated. The resulting salt was recrystallized several times, yielding 2.3 g of tert-butyl-3-endo-hydroxy-7-endo- / dimethyl-tert-butylsilyloxy / -bicyclo-3,3,7-octane-2-exo-carboxylic acid 1 ephedrine salt nyerünk.f _<D = -49 °.

Example 3

To a solution of 6.28 g of dl-3-endo-hydroxy-7-endo- / dimethyl-tert-butyl-3-oxyloxy / -bicyclo [3.3?] Octane-2-exo-carboxylic acid methyl ether in 30 ml of anhydrous dichloromethane 2.19 g of 2,3-dihydropyran and 39 mg of p-toluenesulfonic acid are added. The mixture was allowed to stand at room temperature for 3 hours and then twice.

wash with 5 ml of a 5% aqueous sodium bicarbonate solution. The dichloromethane was evaporated, yielding 8 g of dl-3-endo / tetra ^{»hydro-pyran-2-yloxy} / endo -7 / dimethyl-t-butylsilyloxy / -bicyclo / 3.3.07oktán The methyl ester of -2-exo-carboxylic acid was obtained, which was dried by dissolving twice in Ϊ5 ml of anhydrous benzene and distilling off the solvent.

The residue is dissolved in 30 ml of anhydrous diethyl ether and this dropwise solution is added dropwise over a quarter hour to a stirred suspension of 0.6 g of lithium aluminum hydride in 40 ml of anhydrous diethyl ether. After stirring for a further half hour, the excess reagent was quenched by careful addition of 5 mL of acetone followed by water-saturated diethyl ether. Anhydrous sodium sulfate (10 g) was added, the solids were filtered off and the solvent was evaporated. 7.2 g of dl-3-endo- / tetrahydropyran-2 * -} 1-oxy-7-eno-dimethyl-tert-butylsilyloxy / -2-exo-hydroxymethyl- bicyclo / 3.3 «p7octane cye * us. M ⁺ 370 m / e.

In all of the above steps and using optically active starting materials, the following compounds are obtained:

nat-3-endo- (tetrahydropyran-2-yloxy) -7-endo- / dimethyl-tert-butyl-11,11-oxy / -2-exo-hydroxymethyl- b i 0 i ki0 / 3.3.07 octane-3-endo / tetrahydro-pyran-2'-yl · oxy / -7-endo / dimethylterieri-b uti-1 1-1 oxl / -2-exo-hi dr oxymethyl 1-bicyclo [3.3.

When 1,4-diox-2-ene is used in place of 2,3-dihydropyran, the corresponding 3- (1,4-dioxo-2-yloxy) derivatives are obtained.

Example 4

3.8 g dl-3-endo-hydroxy-7-endo- / dimethyl-tert-butyl-26182.726

To a solution of methyl silyloxy / bicyclo [3.2.0] octane-2-exo-carboxylic acid methyl ester in 40 ml benzene was added 3.66 g benzoic acid and 7.9 g triphenylphosphine, and 5.30 was added with stirring. gazodicarboxylic acid diethyl ester in 15 ml of benzene and the whole is stirred for 40 minutes. The solution is then washed twice with 20 ml of 2N sulfuric acid solution, three times with 15 ml of sodium carbonate solution and finally washed with water until neutral. The solvent was distilled off to give the dl-3-exo-benzoyloxy-7-endo- (dimethyl-tert-butylsilyloxy) -blelloxy-3,3,7-octane-2-exo-carboxylic acid methyl ester NMR spectrum:

endo / fi 5.8 m / 2 endo / H 3.32, d, d /, -CO ₂ CH, / 3H, 3.64, j / endo / H 4.4. <m / and to a mixture of dl-7-endo- (dimethyl-tert-butyl-silyloxy) -bicyclo [3.3.0] oct-3-ene-2-exo-carbons bv av-me t-1 and z-space Al 2 96 / jjutuhE.

This crude product was dissolved in anhydrous methanol, stirred for 3 hours, and then 0.5 g of anhydrous potassium carbonate was added. The solvent was distilled off, the residue was dissolved in ethyl acetate and saturated aqueous potassium dihydrogenphosphate solution, the organic solvent solution was washed to neutral and the solvent was distilled off. The residue was chromatographed on silica gel eluting with hexane followed by a mixture of hexane and diethyl ether. In this way, the following products are obtained:

α-1,01 g of di-7-eno-dimethyl-tert-butylsilyloxy / bicyclo [3.2.0] oct-3-ene-2-carboxylic acid methyl ester, dissolved in methanol and 0, Hydrogenation is carried out in the presence of 3 g of 5% palladium on carbonate precipitated with calcium carbonate at room temperature and pressure. There was thus obtained methyl d1-7-endo- (dimethyl-tert-butyl-azyloxy) -bicyclo [3.3.0] octane-2-carboxylic acid: M296;

b / 2.01 g of methyl dl-3-exo-hydroxy-7-endo- (dimethyl-tert-butylsilyloxy) -bicyclo [3.3.0] octane-2-carboxylic acid as described in Example 2. Dl-3-exo-hydroxy-7-endo / dimethyl-tert-butylsilyloxy / -bicyclo [3.3.0] octane-2-exo-carboxylic acid is hydrolyzed with 5% potassium carbonate in methanol / water (80:20). Li 300. This acid is separated into pure optical antipodes using / + / - Es / - / - amphetamine.

Treatment of the +/- 3 -3-oxo-hydroxy-7-endo- / dlmethyl- tert-butylsilyloxy / -bicyclo-3 · 03.07-octane-2-exo-carboxylic acid with diethyl ether diazo * -methane solution -We win. This is converted to 2,3-dihydro-plránnal and litlum-aluminiüjSt hydride reduction of diethyl ether / + / - 3-exo / ^{PI-tetrahydro-pyran-2-yloxy} / -7 - endo (dimethyl-tert-butylsilyloxy) -2-exo-hydroxymethyl-bicyclo [3.3.0] octane is obtained. 370 ·

The racemic mixtures and the / - / - enantiomers are prepared analogously.

Example 5 ........ _____________________________________________________________ ______-_________________ g dl-7-endo- / dimethyl-tert-butylsilyloxy / -bicyclo [3.3.0] octane-3-exo-carboxylic acid methyl ester 100 ml aqueous methanol solution was boiled with 2 g of potassium hydroxide and saponified. The methanol is then distilled off under reduced pressure, the aqueous potassium salt solution is shaken to remove neutral impurities, acidified and extracted with diethyl ether. The diethyl ether solutions were combined and the solvent was distilled off to give 4.5 g of racemic acid which was +/-.

-27182.726 / - / - ephedrine is separated into optical antipodes. Dissolve 1.32 g of 7 - [(7-benzo [d] -methyl-tert-butylsilyloxy) -bicyclo [3.3.0] octane-2-exo-carboxylic acid in 20 ml of tetrahydrofuran and add 10 ml of 1M tetrahydrofuran. furan borane solution. The mixture was stirred at room temperature for 4 hours and then the excess reagent with 20 ml of 1.5 N sodium hydroxide-ol _r dat quenched by careful addition. The tetrahydrofuran is then distilled off under reduced pressure, and the remaining aqueous solution is extracted with diethyl ether. The combined organic solvent solutions were washed to neutral and the solvent was distilled off to give 1.02 g of N- (7-endo / dimethyl-tert-butylsiloxy) -2-exo-hydroxy-methyl-biocyclo / 3 '. 3 «07 octons are obtained. M ⁺ 270.

The / + / - isomer and racemic mixture were prepared analogously.

Example 6

To a solution of 2.7 gdl-7-endo- (dimethyl-tert-butylsilyloxy) -2-exo-hydroxymethylbicyclo / 5.3.07 octane in 20 ml dichloromethane 0.95 § 2,3-dihydropyran and 20 mg of g-toluenesulfonic acid are added and the mixture is stirred for 3 hours at room temperature. The mixture was then washed with 7% aqueous sodium bicarbonate solution, then with water, and the organic solvent was distilled off. This gives crude dl-7-endo- (dimethyl-tert-butylsilyloxy) -2-exo- (tetrahydropyran-2'-yloxy) -methyl-bicyclo [3.3.0] octane / ω 354 / . This crude product is dissolved in ± 5 ml of tetrahydrofuran *, 4 * 5 g of tetrabutylammonium fluoride are added and the mixture is stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel using a mixture of benzene and diethyl ether as eluent. 2.1 g of dl-7-endo-hydroxy-2-exo- (1-tetrahydro-pyran-2'-yloxy) -methyl-hyclo [3.2.0] g are obtained. IR / film /, 3400, 1280 ^cm-1: 250. This was dissolved in 20 ml of acetone and with stirring was added 4.2 ml of 8% Jones reagent under fifteen ^delta temperature between -8 and -20 ° C aqueous solution of chromium trioxide in sulfuric acid. / Add enough reagent * to permanently light pink color. / Stir for a further 14-20 minutes, add 1.5 ml isopropanol dropwise and dilute the green solution with 6 volumes of benzene. The solution was washed neutral with 20% aqueous ammonium sulfate solution and the combined aqueous solutions were shaken with benzene. The combined benzene solutions were dried and the solvent was distilled off. There was thus obtained 1.82 g of ali-2-exo- / tetrahydropyran-2 ^, 3-yloxy / methyl-bicyclo. /3 starts3.07 octane-7- one wins. IR spectrum (film): 1740, 1228 cm ^-1 ; M + 235.Nat and enant isomers are prepared analogously ·

Example 7

--6 - - 76 g / -butyl 4-carboxy / triphenylphosphonium bfomid EA 2.38 vk, l-2-e3co- / ^{tetrahydro-pyran-2-yl-oxy} / methyl-bicyclo / A solution of 6.57 g of potassium tert-butylate in 65 ml of dimethylsulfoxide is added dropwise to a solution of 3-O-7-octane-7-one in 40 ml of dimethylsulfoxide under external cooling and stirring at 20-22 ° C. The mixture was then diluted to twice its original volume with water, acidified to pH = 5 * θ, and extracted with diethyl ether. The combined organic solvent solutions were shaken several times with 0.5 N sodium hydroxide,

The extracts were acidified to pH 5 and extracted with diethyl ether: pentane (1: 1). The latter organic solvent solutions are concentrated to a small volume and a solution of diazomethane in diethyl ether is added until the color of the mixture is permanently yellow. The solvent was distilled off, the residue was dissolved in 50 ml of acetone, 20 ml of 2N aqueous oxalic acid solution * were added and the mixture was kept at 40-45 ° C for 8 hours. The acetone is then distilled off under reduced pressure, the remaining aqueous solution is partitioned between ethyl acetate and the combined organic solvent solutions are distilled off. The residue is chromatographed on silica gel, eluting with diethyl ether, to give 5-cis and 5-trans z-dl-5- / 2'-exohydroxymethyl-cyclohexyl-3. 3 · 07 oct-7'-enyl / pentenoic acid methyl ester (1 * 75 g / ·) The pure isomers, i.e. 5-tranaz-dl and 5-cis-dl, are obtained by high pressure liquid. separation by liquid chromatography; the latter product is called, - (2R) -12-octanor-12-hydroxymethyl-9a-deoxy-9a-methylene-prostacyclo-6-cis-enoic acid methyl ether. Nuclear Magnetic Resonance Spectrum 54/14, 5.15 - m /, -COCCH, / 3H,

3.67 s / g H * 252. ^{2 5}

If, in the above step, instead of 4-carboxybutyl / triphenylphosphonium bromide as Wittig's reagent, but 3-carboxypropyl / triphenylphosphonium bromide, 5-carboxypentyl / triphenylphosphonium bromide or (4-Carboxy-2-oxa-butyl) -triphenylphosphonium bromide, the methyl ether of the following acids can be obtained:

di- 1 - [(2R) -12-octanor-2-nor-12-hydroxypexymethyl-9a-deoxy-9a-methylene-prostacyclic-5-cis-acetic acid; M 238;

dl -, - (? 12?, 12? -octanor-2a-homo-12-hydroxymethyl-9? -deoxy-9? -methylene-prostacifc-5-cis-acetic acid; M ⁺ 266;

c11-9 - (2Q-12) -octanor-3-oxa-12,-hydroxyurethyl-9a-desoxy-9a-methylene-prostacycl-5-cis-enoic acid; M ⁺ 254;

And further to their 5-trans isomeric signal and its pure nat and enant antipodes.

Example 8

7.16 g of methyl (? 20-? 2-octanor-12-hydroxymethyl-9α-deoxy-9α-methylenepostacyclo-5-cis-enoic acid methyl ester) were prepared in 60 ml of benzene and 20 ml of dimethylsulfoxide. of dicyclohexylcarbodiimide (8.9 g) and pyridinium trifluoroacetate solution (14.2 ml) prepared by adding 1 ml of trifluoroacetic acid and 2 ml of pyridine to 25 ml of a 75:25 mixture of benzene: dimethylsulfoxide / . The mixture was stirred for 1 hour, then diluted with benzene (100 mL) and a solution of 3 g of oxalic acid in water was added dropwise. The precipitated dicyclohexylurea was filtered off, the organic solvent was separated and washed with water (5 x 6 mL). Concentration of the solution yields a benzene solution of the 12-formyl derivative which is added simultaneously to a solution of the sodium salt of 2-oxo-heptyl-dimethylphosphonate. The latter reagent was prepared by adding dropwise 7 to 58 g of 2-oxo-heptyl / dimethylphosphonate in 40 ml of anhydrous solution to a suspension of 1.02 g of sodium hydride / 80% mineral oil dispersion / benzene suspension under stirring under a neutral atmosphere. benzene, and the mixture was stirred until hydrogen evolution ceased. After the formyl derivatives were added to this phosphonate sodium salt solution, the mixture was stirred for an additional 20 min.

After stirring at -29182.726 cent, it was neutralized with saturated aqueous monosodium phosphate solution. The organic solvent solution was separated, concentrated to a volume of 1.5 ml, and chromatographed on silica gel using cyclohexane / diethyl ether as eluent. 6.4 g of 9a-deoxy-9a-methylene-15-oxo-prostacyclo-5-ol, 13-trans-dienoic acid methyl ester are obtained. M ⁺ 346.

Starting from the analogous 12? -Hydroxymethyl derivatives mentioned in Example 7 and following the above procedure, the methyl ether of the acids listed below is obtained:

9α-deoxy-9α-methylene-15-oxo-2-n-prodecylacetyl-5-cyano, 13-tranenec-denoic acid; M 332;

9a-deoxy-9a-methylene-15-oxo-2a-homo-propazole-5-cis, 13-trans-dienoic acid; M 360 »

9a-deoxyl-9a-methylene-15-oxo-3-oxa-prac tacla-5-c is z, 13-tr ans z-dienoic acid; M * 348;

and 5-t-cans isomeric signals thereof, in their nat and enant antipodes and in their dl forms.

9 «Example

To a solution of 1,35,6-2-exo-hydroxymethyl-7-endo- / dimethyl-tert-butyl-silyloxy / -bicyclo [3.3.0] octane in 5 ml of pyridine was added with cooling and stirring at 5-8 ° C. 82 g of benzoyl chloride. After stirring for 8 hours at room temperature, 2N sulfuric acid solution was added and the mixture was extracted with diethyl ether. There was thus obtained 2-exo-benzoyloxymethyl-7-endo- (dimethyl-tert-butylsilyloxy) -bicyclo [3.3.07] octane. To remove the silyl protecting group, this product is boiled in 20 mL of acetone with 8 mL of 2N oxalic acid. The acetone is then distilled off under reduced pressure and the residue is extracted with diethyl ether. Purification by chromatography on silica gel gave 1.11 g of 2-exo-benzoyloxymethyl-7-endo-hydroxybicyclo [2.2.0] ol. IR spectrum / film / 3420 cm ^-1 . This product is dissolved in pyridine and added to a solution of 1 g of chromium trioxide in 10 ml of pyridine. After 6 hours at room temperature, the mixture was diluted with 20 ml of benzene and the insolubles were filtered off. The filtrate was distilled off under reduced pressure and the residue was dissolved in 2N sulfuric acid and benzene.

The benzene solution was washed with 2N sulfuric acid, then water, and the benzene was distilled off. 0.98 g of exo-benzoyloxymethylbicyclo [3.3.07] octane-7-one (IR) (film): 1745, 1705 cm <^-1> , M 258 / m.p. This compound is dissolved in 5 ml of anhydrous tetrahydrofuran and the solution is added to a solution of the sodium salt of 2-oxo-5,5,5-trimethoxypentyl / dimethylphosphohate / this reagent is prepared by

To a solution of 2.12 g of (2-oxo-5,5,5-trimethoxypentyl) -dimethylphosphonate in 6 ml of anhydrous tetrahydrofuran is added a suspension of 0.23 g of 80% sodium hydride in tetrahydrofuran /. After stirring for 10 minutes, the mixture is neutralized with 15% potassium dihydrogen phosphate solution, the tetrahydrofuran is distilled off under reduced pressure and the residue is extracted with diethyl ether. The solvent was distilled off from the diethyl ether solution and the residue was chromatographed on silica gel, eluting with a mixture of hexane and diethyl ether, to give 1.1 g / 2'-benzoyloxymethylbicyclo / hexane / 5'-trans-olefin. 3.5.0 /

-30182726 oct-7'-enyl-1,1,1,1-trimethoxypent-5-en-4-one, also known as 123-benzoyloxymethyl 11-2- (20-) -? The orthomethyl ester of 4-oxo-9a-deoxy-9a-methylene-pracstacycl-5-enoic acid (M ⁺ 416) is obtained, the pure 5-cis and G-trans isomers of which are then subjected to high performance liquid chromatography. separate ·

The products thus obtained are treated with aqueous methanol and sulfuric acid to give the corresponding methyl esters. 0.3 g of the methyl ester thus obtained in dichloromethane as a solvent in the presence of a catalytic amount of boron trifluoride etherate at 0 ° C for 4 hours are reacted with 0.25 ml of 1,2-ethanedithiol to give 12,'-benzoyloxy. methyl methyl- (20/12) -bocor-4,4-ethylene-dithio-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester is obtained. M + 446.

Example 10

0.8 g of methyl 12 H -benzoyloxymethyl- (2R, 12D-octanor-4-oxo-9a-deoxy-9a-methylene-prostacyclo-5-enoic acid) is selectively debenzoylated in 10 mL of methanol. stirring 0.15 g of anhydrous potassium carbonate. After completion of the reaction, the solvent is distilled off, the residue is dissolved in 15% aqueous potassium dihydrogen phosphate and dichloromethane and the solvent is distilled off from the organic solvent. In this way, 12i-hydroxymethyl-.alpha., 12'-octanor-4-oxo-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester is obtained. M ⁺ 266. This product was dissolved in a mixture of dichloromethane (10 mL) and ethanol (10 mL), and sodium borohydride (90 mg) was added at -20 ° C. and the mixture was stirred for 2 hours. The excess reagent was then quenched with 15% aqueous acetic acid, the solvent was distilled off and the residue was chromatographed on silica gel using diethyl ether as eluent. There were thus obtained 0.21 g of 12-hydroxymethyl-7- (20,12) -afeanor-4S-hydroxy-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester (1 - 268). 13 g of 4R-hydroxy isomer (M ⁺ 268) are obtained.

The esters obtained above were hydrolyzed separately in 20% aqueous methanol with 19% potassium carbonate solution and then acidified and extracted with ethyl acetate (0.18 g of 125-hydroxymethyl) - / (octanor-4S-hydroxy-9a-deoxy-9a-methylene-pristacycl-5-enoic acid 1,4,4-lactol (M 236) and 0.11 g of 4R-isomers (M 236) are obtained. The latter products are oxidized as described in Example 8 to give the corresponding 12-formyl derivatives.

Example 11

0.28 g of 4,4-ethylenedithithio-12} -benzoyloxymethyl) -20 [beta] -O-octanor-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ether in anhydrous methanol was added to the mixture. is selectively debenzoylated with carbonate to give the corresponding 12 (5-hydroxymethyl) derivative. This product is oxidized as described in Example 8 to give the 12 '} - formyl derivative.

0.12 g of the 12-formyl derivative thus obtained in benzene from 20% of 0.177 g of (2-oxo-3,3-dimethylheptyl) -dimethylphosphazonate with 80% of sodium 16,16-Dimethyl-4,4-ethylene-dithio-15-oxo-9a-deoxy-9a-methylene-prostacyclo-5,13-

-31182.726 (4-Cyclohexyl-2-oxobutyl) -dimethylphosphonate is obtained as the aldehyde from 4S-lactone obtained in Example 10, analogously to 4S-hydroxy-15-oxo-9a-deoxy. -9a-methylene-17-cyano-hexyl-18,19,20-one-or-1-yl-5,13-trans-dienoic acid 1,4-lactone. Starting from M ⁺ 370 · N-3-phenoxy-2-oxopropyl-dimethylphosphonate, 4S-hydroxy-15-oxo-9a-deoxy-9a-methylene-16-phenoxy-17,18,19 20-tetrachloroporacyclo-5,15-trans-dienoic acid 1,4-lactone is obtained. M 366.

Example 12

As the phosphonate, (2-oxo-3S-methylheptyl) -dimethylphosphonate and / or (2-oxo-3S-fluoroheptyl) -dimethylphosphonate, as the aldehyde, pedi-12-formyl - / 20 - 12-octane Using 4R-hydroxy-9a-deoxy-9a-methylene-prostacyclic-5-enoic acid 1,4-lactone and following the procedure described in Examples 8 and 11, 4R-hydroxy-15-oxo-9a is obtained. deoxy-9a-methylene-16S-methyl-prostacyclo-5,13-trans-dienoic acid 1,4-lactone M 344 and 4R-hydroxy-15-oxo-9a-deoxy-9a-methylene-16S-fluoro- prostacyclo-5,13-tranazadiene-1,4-lactone. Sat 348.

Example 13

0.7 g of 15-oxo-9-deoxy-9-methylene-prosta-5-cis, 13-trans-dienoic acid me't-yl ester and 7 ml of dichloromethane was added 7 ml of ethanol at -20 ^° C 38 mg of sodium borohydride are added at room temperature. After stirring for 20 minutes, the reaction was quenched by the addition of 2 mL of acetone and 2.5 mL of 20% aqueous sodium dihydrogen phosphorate solution. The mixture was then concentrated under reduced pressure and the residue was partitioned between dichloromethane. The combined organic solvent solutions were evaporated and the residue was chromatographed on silica gel using diethyl ether as eluent. Thus, 0.32 g of 15 S-hydroxy-9a-deoxy-9a-mephcylene-prostacyclo-5-cis, 13-trans-denenoic acid methyl ester, M 348, 5 cis: p = + 26 °, 5 trans: -> + 86 ° (in methanol); NMR / CDC1 _Z / ppm: 0.90 / 3H, t /, 3.74 / H m / 4 _to 1 / H, m /, 5.29 / IH, br t /? 5.51 / 2H, m /; IR: = 1710 ^cm, and 0.26 g of 15R-isomer, M 348, oia.s; _D = .220, _{5 te10} :, _D = .54 in _{methanol / -}

Starting from the 15-oxo derivatives obtained as described in Examples 8, 11 and 12, and reducing them in each of the above manner, the following methyl esters are obtained:

9a-deoxy-9-methylene-15S-hydroxy-2-nor-prosta-5-ciaz, 13-trans-diénaav; M, 344 m / e;

9a-deoxy-9a * methylene-15S-hydroxy-2a-homo-propylacta-5-cis, 13-trans-dienoic acid; M ⁺ 362 m / e;

9a-deoxy-9-methylene-15S-hydroxy-3-oxa-prosta-cis-5-trans-13 _T-dienoic acid; M 350 m / e;

9a-deoxy-9a-methylene-4,4-ethylenediothio-15S-hydroxy-prostacyclo-5-cis, 13-trans-dienoic acid; M, 438 m / e; and 1,4-lactones of the acids listed below: 9a-deoxy-9a-methylene-4S, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prostacyclo-5-cis, 13-tranazadiene; -H ₉ 0: 354 m / e; 9a-deoxy-9a methylene 4S,

15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-pro-aza-5-ciaz, 13-trans-dienoic acid; M-HpO: 350 m / e;

9a-desoxy-9a-methylene-4R, 153-dihydroxy-165-aetyl-prostacyclo-5-ol, 13-trans-dienoic acid: M- ₂ θ: 32S m / y;

-32182,726

9a-deoxy-9a-methylene-4R, 15S-dihydroxy-16S-fluoro-prostacyclo-5-cis, 13-transz-diene-av; M -H _? 0; 332 m / e; as well as their 5-trans-geometric flavor isomers, all in the form of their native enant antipodes and in d1.

Example 14

To a solution of 0.35 g of 15-oxo-9a-deoxyl-9a-methylene-proazacac-5-ciazole, 13-trans-dienoic acid methyl ether in 10 ml of 2: 1 diethyl ether: toluene at -30 ° C. 5 ml of a 5% solution of methyl magnesium iodide in diethyl ether are added with stirring and the mixture is stirred for 4 hours. The mixture was then allowed to warm to 0 ° C and a 20% aqueous solution of ammonium chloride was added. The organic solvent solution was washed with water, followed by sodium bicarbonate solution, and finally with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. This gives a mixture of 15S and 15R alcohol. This mixture was chromatographed on silica gel, eluting with 80 g of a mixture of diethyl ether and diisopropyl ether, to give 0.1 g of 15S-hydroxy-9α-deoxy-9α-methylene-15β-ethyl-prostacyclo-5-cis, 13-trans. methylenedioxylate / M.

We gave 344 m / e / 15 and 0.1 g of R-isomer: H ₂ 0th

15 · example

Using the same starting material as in Example 14 and reacting it in anhydrous tetrahydrofuran as a solvent with 8 ml of a 0.3 molar solution of ethinylmagnesium bromide in tetrahydrofuran, after chromatography on silica gel, 15 oxy-9a-deoxy-oxy-9a-methylene-propyl acyl-5-cis, 13-trans-dienoic acid methyl ester = + 26 ° in methanol and its 15R isomer is obtained. .

Using a 0.3 molar solution of vinyl magnesium bromide, 15-vinyl-15S-hydroxy-9a-deoxy-9a-methylene-proline taci-cl-5-c, 13- the trans-dienoic acid methyl ester is obtained at? 19 = + 19 ° / its 15R isomer.

Example 16

0.26 g of 9a-deoxy-9a-methylene-4R, 15S-dihydroxy-16S-methyl-propyl-5-cis, 13-transz-diene av-1,4-2- Add the solution of la kt on dichloromethane with stirring at -10 to -8 ° C

A solution of boron trifluoride etherate (0.3 mL) in dichloromethane (0.00012 mol) was added, followed by diazomethane (5%) in dichloromethane to give a permanently yellow color.

The solution was washed first with 5% aqueous sodium bicarbonate solution and then with water, then the solvent was distilled off and purified by chromatography on 3 g of silica gel to give 0.21 g of 9a-deoxy-9a-methylene-4R-hydroxy 15S-Methoxy-16S-methyl-prostacylcla-5cis, 13-trans-dienoic acid 1,4-J-lactone is obtained. M 360 m / e.

Example 17

0.74 g of dl-2-exo-hydroxymethyl-3H-oxo-tetrahydro-pyran-2'-yloxy-7-endo / dimethyl-tert-butylsilyloxy / bicyclo / 3.3 * 0 / octane in 15 ml of anhydrous dichloromethane, a solution of 3 »Collins reagent ^ made 7CcHcN _2/2 .Cr0 ₅ 7 40 ml of anhydrous dichloromethane 1 g, 0-5 C chilled ^ homürsékletre a stirred solution of. The mixture was stirred for a quarter hour and then.

Add -33182.726 diatomaceous earth and filter. This gives a clear solution of the corresponding dl-2-exo-formyl derivative. The solvent was distilled off under reduced pressure. the residue is dissolved in anhydrous benzene and the solution is added to the sodium salt of 2-oxooctyl / dimethyl phosphonate. The latter reagent was prepared by dropwise addition of a solution of 0.07 g of 80% sodium hydride in 20 ml of benzene in a solution of 0.59 g of 2-oxooctyl / dimethylphosphonate in 10 ml of benzene. stirring until the evolution of hydrogen ceases, i.e. about 1 hour. / The mixture is stirred for 20 minutes, then. neutralized with excess 25% aqueous sodium dihydrogen phosphate solution, the organic solvent solution was separated and dried. The solvent was distilled off and the residue was chromatographed on silica gel eluting with a mixture of cyclohexane and diethyl ether. In this way, 0.81 g of dl-2-ethoxy-3'-oxo-non-1,1 ^, trace-en-1'-yl / -3-exo / tetrahydropyran-2'-yloxy / -7 yield endo-dimethyl-tert-butylsilyloxy / bicyclo / 3.3.07 octane. Oil, 228 m / u / in methanol /, - = 8940. “ ^max

Example 18 .............._

1.05 g of dl-2-exo-hydroxymethyl-3-endo- (tetrahydro-pyran-2 * -yloxy) -7-endo- (dimethyl-tert-butylsilyloxy) -bicyclo / 3,33. To a stirred solution of benzene: dimethylsulfoxide (75 ml) was added dropwise a solution of dicyclohexylcarbodiimide (0.89 g) followed by pyridinium trifluoroacetate (1.42 ml). After stirring for 3 hours, benzene (20 ml) was added and the excess dicyclohexylcarbodiimide was quenched by addition of a solution of oxalic acid (0.13 g) in water (3.8 ml). The benzoloa solution was separated, washed to neutral and the solvent was distilled off under reduced pressure. There is thus obtained a solution of 2-exophormyl-3-endo- (tetrahydropyran-2'-yloxy) -7-endo- (dimethyl-tert-butylsilyloxy) -bicyclo [3.3.0] octane. / The product is not prepared

The dl, nat and enantiomeric formyl derivatives are prepared in the above manner. Similarly, starting from 7-exo- (dimethyl-tert-butylsilyloxy) -bicyclo [3.1.0] octan-3-one and

In the same manner as in Examples 1, 2 or 3, 2-exoformyl-3-endo / tetrahydropyran-2'-yloxy / -7-exo / dimethylterer-butylsilyloxy / -bio-cyclo / 3 → 3 → 07-octane.

19 · example

To a suspension of 43.5% of 80% sodium hydride in 10 ml of benzene was added a solution of 322 mg of (2-oxo-heptyl) -dimethylphosphonate in 5 ml of benzene, and the mixture was stirred until hydrogen evolution ceased. The mixture is then protected from light, 25 g of finely powdered N-bromosuccinimide are added and the mixture is stirred for a further 5 minutes. Then, 0.37 g of 2-exo-formyl-3-endo- (tetrahydropyran-2'-yloxy) -7-endo- (dimethyl-tert-butylsilyloxy) -bicyclo [3.3. benzene, and the mixture may be stirred for an additional quarter hour. The mixture was partitioned between benzene and 15% sodium dihydrogen phosphate solution, the organic solvent was separated, dried and the solvent was distilled off. The residue was chromatographed on silica gel, eluting with 80:20 cyclohexane / diethyl ether to give 0.42 g of 2-exo / 2 ^, -bromo-3 ^, -oxooct-1'-enyl / -3-endo- / tetra34

-34182726 hydropyran-2'-yloxy-7-endo- (dimethyl-tert-butylsilyloxy) -bicyclo [0.8] octane, _max = 251 m / u = 9250.

When 2-oxo-3R-fluoroheptyl / dimethylphosphonate is used as the phosphonate, the corresponding 2-exo / 2 ^, -bromo-3 ^, -oxo-4 '

R-fluorooct-1'-trans-enyl derivative is obtained. '___, = 252 m / u / in methanol /, - = 8940. ^max '

Example 20

To a suspension of 3θ mg of 80% sodium hydride in 5 ml of benzene was added dropwise a solution of 0.3 g of 3-oxo-4- (2'-tetrahydrofuryl) -butyl-7-dimethylphosphonate in hydrogen stirring until development is complete. Then, 0.37 g of 2-exo-formyl-3-endo- (tetrahydropyran-2 * -yloxy) -7-exo- / dimethyl-tert-butylsilyloxy / bicyclo [3 · 3 · 7] octane are added. and stir the mixture for an additional 20 minutes. The mixture was then partitioned between benzene and 20% aqueous sodium dihydrogen phosphate solution. The organic solvent solution is separated, the solvent is distilled off and the residue is chromatographed on silica gel, eluting with a mixture of benzene and diethyl ether. Yield: 0.35 g of 2-exo / 3'-oxo-5 * - / 2 '' - furyl teurahidro / ^{pent-l, l-trans-ene,} endo -il7-3 / tetrahydro- pyran-2 * -yloxy-7-exo- (dimethyl-tert-butylsilyloxy) * -bicyclo [3.3.0] octane = 229 m / u = 8800.

Example 21

2-Exo-formyl-7-exo-bicycloalkane 2-exo-formyl-3-endo- (tetrahydropyran-2'-yloxy) -7-endo / dimethyl-tert-butylsilyloxy starting from bio-cyclo / 3.3 «07 octane and used with the phosphonates listed below:

/ 2-oxoheptyl / -dimeti1 phosphonate;

/ 2-oxo-octyl / dimethyl phosphonate;

/ 2-oxo-3S-methylheptyl / dimethyl phosphonate;

/ 2-oxo-4-cyclohexylbutyl / -dimeti1 phosphonate;

/ 2-oxo-4-phenyl-butyl / dimethyl phosphonate;

(2-oxo-3- [m-trifluoromethyl-phenoxy-propyl] -7-cimethyl-phenyl) -fone; / 2-oxo-3-methyl-3-tert-butyl / dimethyl phosphonate; and in the same manner as in Example 20, the following compounds were obtained:

^{7tetrahidropiran-3-endo-2'-yl-oxy} / -7-exo / tert-butyl-dimethyl-silyloxy / -2-exo / ^{3-oxo-oct-l-trans-l'-en-} il-bicyclo ^ 3.3.07 octane; _max = 228 m / u, - = 8700;

3-endo-oxy-2'-yl tetrahydropyran / / 7-exo / dimethyl tercia £ * -szililoxl butyl / -2-exo / 3 ^{-oxo-non-l-en-l} -trans * -il / -biclklo / 3 «3« 07 octane; Λ _max - 228 m / u »- = 8950;

3 endo / ^{tetrahydro-pyran-2-yloxy} / -7-exo / dimethyl tert.butyl azililoxi / -2-exo / 3 -oxo ^ S-methyl-oct-l'- trans-en-l "yl / -bicyclo / 3.3.07oktáá; > _{m & x} = 228 m / u, á, = 8400;

3-endo- (tetrachydro-pyran-2 ^, -yloxy) -7-exo / dimethyl-tert-butylsilyloxy / -2-exo-3'-oxo-5'-cyclohexylpento- 1'-1r ans-en * -l * -yl / -bicyclo / 3 / 3.0 / octane; λ max * ^{223 c} '^9100;

3-endo-1-tetrahydro-pyran-2'-yloxy-7-exo- / dimethyl-tert-butyl-silyloxy / -2-exo-3'-oxo-5-enyl -pent-1'-tr ans z-en-1 * -yl / bicyclo23 * 3.07octane; _max = 227 m / u, £ = 14,250.

-35182,726

Example 22 0.3 g of dl-2-exo / 2'-bromo-3 * -oxo-4 ^, R-fluorooct-1 * is added dropwise to a solution of zinc borohydride in 0.1 M diethyl ether over a quarter hour. ^{trans-en-l-yl} / -3-endo / ^{tetrahydro-pyran-2-yl-oxy} / endo -7 / dimethyl-tert.butyl-silyloxy / bicyclo ° Z ^ .3 A solution of octane in 10 ml of anhydrous diethyl ether was added and the mixture was stirred for 2 hours. The reaction was then quenched by the addition of a saturated aqueous sodium chloride solution and 2N sulfuric acid. The organic solvent solution was separated, washed with water, followed by 5% sodium bicarbonate solution and then again with water, and the solvent was distilled off.

This gives a mixture of 3'S and 3'B-hydroxy derivatives, which are separated by liquid-liquid chromatography using diisopropyl ether as eluent. Thus, 0.11 g of dl-2-exo / ^{2, bromo-3, S-hydroxy-4-R-fluoro oct-l, trans-en-l-yl} / -3-endo / tetrahydro-pyran-2'-yl / 7-semen / dimethyl-t-butylsilyloxy / bicyclo £ 3-3 »07oktánt / M ⁺ -H ₂ 0 r _{Ή_} 0ΙΙ / Ο, -Η, θΟρ /:

442, 444 m / e / and 0.1 g of 3 ^, R-epimer were obtained.

23 · example

0.3 g of 2-exo- (3'-D-x-5 * - (2-tetrahydro-furyl) -pent-1'-trans-en-1,1'-yl ⁾ -3-3-endo- / tetrahydropyran- To a solution of 2 * -yloxy / -7-exo-dimethyl-tert-butylsilyloxy / bicyclo [3.3.0] octane in 3 ml of dichloromethane and 3 ml of ethanol is added 25 mg of sodium at -10 to -15 ° C. -bórhidridet. After stirring for half an hour, 1 x 5 ml of acetone and 3 ml of saturated aqueous sodium dihydrogen phosphate solution are added. The organic solvents were distilled off under reduced pressure and the residual aqueous solution was extracted with dichloromethane. The dichloromethane solution was dried over sodium sulfate and the solvent was distilled off. The residue was chromatographed on silica gel eluting with hexane / diethyl ether. Thus 0.1 g of 2-exo / ^5, S-hydroxy-5 '- / 2 ^* -tetrahldro-furyl / ^{pent-l, trans-l} -yl / endo -3 / tetrahidio- ^{pyran-2-yloxy} / -7-exo / dimethyl tertiary-'Uutil elm · yl -oxy / bicyclo- / 3 · 3 · 07pktánt and 0.11 g of 3-R-isomer, both for “M ⁺ -Η-Ο-λΑ -OH:

374 m / e. ^ά \ _J

Example 24

Starting from the compounds obtained in Examples 19, 20 and 21 and following the procedure of Examples 22 and 23, the following compounds were prepared:

3-endo- (tetrahydropyran-2 ^, 11-yloxy) -7-endo- (dimethyl-tert-butylsilyloxy) -2-exo-2'-bromo-3'S-hydroxy-oct-1 'trans-en-l-llZ-bicyclo ^^' O / octane; -H ₂ 0-102: 424.426 m / e;

3-endo- / tetrahydropyran-2'-yloxy-7-endo- / dimethyl-tert-butyl-sonyloxy / -2-β-O-3 * S -hydroxy-oct-1 '-tran a-z-en-1 * -ylbicyclo [beta] -5,7-octane; M ⁺ H ₂ O - 102: 346 m / e;

3 endo / ^{tetrahydro-pyran-2} -yl-oxy / endo -7 / dimethyl-t-butylsilyloxy / -2-exo / 3 * hldrpxi ^S-4, S-methyl-oct- panel &apos; -en-l "yl / bicyclo / 3.3.0 / octane; M-H ₂₀ O-102: 360 m / e;

3 endo / ^{tetrahydro-pyran-2-yloxy} / -7-eudo- / dimethyl-t-butylsilyloxy / -2-exo / ^{3, S-hydroxy-non-l-en} -trans * -l-yl / r-bicyclo ^ 3 »3» 07oktán; M-H ₂ 0-H ₂ 0 to 102: 360 m / e;

-36182,726

3-endo- (tetrahydropyran-2'-yloxy) -7-endo- / dimethyl-tert-butylsilyloxy / -2-exo / 3'S-hydroxy-5 * -cyclohexylpent -1? -trans-en-1? -11? -bicyclo? 3? 3? 07 -octane; M-H ₂ 0-102: 386 m / e;

3 endo / tetrahydropyran-2? -Yloxy / endo -7 / t-butyl-dimethyl-silyloxy / -2-exo / 3-S-hydroxy-5-phenyl-pent-l * * * -trans-en-l-yl / -bicyclo / 3.3 • O / octane; M -1 ^ 0-102: 380 m / e;

3-endo- (tetrahydro-pyran-2 * -yloxy) -7-endo- (dimethyl-tert-butylsilyloxy) -2-exo- (3 * S-hydroxy-4 * -) - m-trifluoride methyl-phenoxy-but-1 * -trans-en-1 * -yl-7-bicyclo [3.3.07] octane; M-HpO -102.250 m / e; ".

3-endo-oxy-tetrahydropyran-2'-yl / / 7-eKdo- / dimethyl-t-butylsilyloxy / exo -2 / 3-S-hydroxy-4'-butoxy-pent metllT4 * -l'-trans-en-l-yl * / bicyclo- / 3 * 3 * 07oktán; M ⁺ H = -102: 396 m / e; "/

3 endo / tetrahydropyran-2 '-yloxy / endo -7 / dimethyl-t-butylsilyloxy / -2-exo / 2 * ~ bromo-3-B-hydroxy-oct-l * -trans-en-l-yl * / ^ -bioiklo 3.3.07oktán; M ⁺ -H 2 O -102; 424, 426 m / e;

3-endo- (tetrahydro-pyran-2'-11-oxy) -7-endo- (dimethyl-tert-butylsilyloxy) -2-exOT / 3'B-hydroxy-oct-1 * -trans- en-l-yl / bicyclo ^ 3-3 »07oktán; Μ ~ Η ₂ θ −102: 346 m / e;

3-endo- (tetrahydropyran-2'-yloxy) -7-endo- / dimethyl-tert-butylsulfoxyl-2-exo-3'-B-hydroxy-4'S-methyl -oct-1 * -1r ans z-en-1'-yl / -blcyclo [3? 3 * 07] octane; M ⁺ -¾ ⁰ -102: 360 m / e ;.

3 endo / tetrahydropyran-2'-yloxy / endo -7 / dimethyl-t-butylsilyloxy / -2-exo / 3 * B ~ hidEoxi ^non-l-en -trans -l'-yl / bicyclo- / 3 «3.07oktán; Μ-H ₂ 0 - 102: 360 m / e;

3-endo-oxy tetrahydro-pyran-2'-yl / / endo -7 / dimethyl-t-butylsilyloxy / -2-exo / 3 * E-bLÍdroxi-5'-cyclohexyl-pent-l * * -trans-en-l-yl / bicyclo £ 3 * 5 »07oktán; M -HgO -102 s 386 'rn / e;

3-endo- (tetrahydropyran-2 * -yloxy) -7-endo- (dimethyl-tert-butylsilyloxy) -2-exo-3'R-hic-1'-oxy-5'-phenyl- pent-l-trans-en-l-yl / $ £ ~ bicyclo .3.0 / octane; 1Γ-H-O - 102: 380 m / e;

3-endo- (tetrahydropyran-2'-yloxy) -7-endo- (dimethyl-tert-butyl) -ethylsilyloxy / -2-exo- / 3 * R -hydroxy-4 * - / m trifluoro-methylphenoxy / but-l-en-l * -trans * -il7-bicyclo / 3 "3"07oktán; M ⁺ -H ₂ 0 - 102 t 450 m / e; ". ^d

3 ehdo- / tetrahydropyran-2 '-yloxy / endo -7 / dimethyl tertiary-butiΙ azililoxi / -2-exo / 3-R-hydroxy-4-methyl-4 * * - butoxycarbonylamino-pent-1'-tranaz-en-l-yl / -bioiklo / 3 "3" 07oktán. M -102: 396 m / e.

Example 25

1.17 g of 2-exo- (3'S-hydroxy-oct-1'-tranazen-1 * -yl) -3-endo-tert -hydro-pyran-2'-yl-oxy] To a solution of -7-endo-dimethyl-tert-butylsilyl-oxy-bicyclo [3.3.0] octane in 12 mL of anhydrous dichloromethane was added 120 mg of 2,3-dihydropyran and 5 mg of p-toluene azulfohaav. After 4 hours at room temperature, the mixture was washed with 5% aqueous sodium bicarbonate solution and water. The solvent was distilled off to give 1.45 g of crude 2-exo-3 * 5S- (tetrahydropyran- ^2M -yl-oxy) -oct-1 * -trans-en-1 * -yl7-3-endo. / tetrahydro-pyran-2-yl-oxy / 7-endo- / dimethyl-3-butyl-silyloxy / -bicyclo / 3-octane is obtained. This product is dissolved in 12 ml of tetrahydrofuran and 2 µg of tetrabutylammonium fluoride are added. The mixture was stirred at room temperature for 12 hours, then the solvent was distilled off and

The residue was chromatographed on silica gel eluting with diethyl ether. Thus 920 mg of 2-exo- / 3 * S / tetrahydro-pyran-2-yloxy / ^{oct-l-en-1'-trans-endo} il7-3 / ^{tetrahydro-pyran-2,} -yloxy-7-endo-hydroxybicyclo _[ 3.3.3] octane is obtained. IR / film / 3400 cm ^first

Example 26

Starting from the compounds obtained in Examples 22, 23 · and 24 and following the procedure of Example 25 ·, the following compounds were prepared:

2-exo / ^{2, bromo-3,} S / tetrahydropyran-2 "-yloxy / * -4-fluoro-oct-l-en-trans ~ * l * -il7-3 endo / tetrahydropyran-oxy-2'-yl / 7-endo-hydroxy-bicyclo OLO / 3-3 «07oktán; IR / film /: 3400 ^cm;

2-exo- (2'-bromo-3'R "/ tetrahydropyran-2" -yl) oxy-4 ^, R-fluorooct-1'-trans-en-1 * -yl7-3 endo-oxy tetrahydropyran-2'-yl / / 7-endo-hydroxy-bicyclo / 3.3.07oktán; IR spectrum (film): 3400 cm ^-1 ;

2-exo / 3'S- / tetrahydropyran-2 "-yloxy / -. 5 * - / 2-tetrahydrofuryl / trans-pent-l-en-l-il7-3 endo (tetrahydro-pyran-2'-yloxy) -7-exo-hydroxybicyclo [3.2.0] octane; IR / film / 3400 cm ^- · · *; "

2-exo / 3'R- / tetrahydrofuran · ^'p-pyran-2', ~ yloxy / ^-5, - / 2-tetrahydrofuryl / -pentanoic ^ -l ^ -trans-en-1'- η 7 -3-endo- (tetrahydropyran-2'-yloxy) -7-exo-hydroxybicyclo [3.3.0] octane; IR spectrum / film / 3400, 1250 cm ^-1 ;

2-exo- (2 * -bromo-3 ^, 5S-tetrahydropyran-2'-yloxy) -oct-1'-trans-en-1'-yl] -3-endo- / tetrahydropyran- ² -yloxy / -7-endo-hiöroxi biciklo73.3.07oktán; IR / film /: 3400, .1250 cm - ¹ ·;

2-exo / ^{2, bromo-3,} R / tetrahydro-pyran-2 '' - yloxy / ^{oct-l-en -trans-I} endo- -il7-3 / tetrahydropyran -2'-yloxy / -7-endo-hydroxy-biciklo73.3 «0 / octane; IR spectrum (film): 3400, 1250 cm ^-1 ;

2-exo / 3'S- / tetrahydropyran-2 ^'-yloxy / ^{oct-l-en-l-trans-endo} il7-3 / tetrahydro-pyran-2'-yl [Beta] -7-endo-hydroxybicyclo [3.3.3] octane; IR / film /: 3400, 1250 cm ^{- 1} · ·;

2-exo / 3 * E / tetrahydropyran-2 "-yloxy / ^{oct-l, l-trans-ene,} endo -il7-3 / tetrahydropyran-2'-yl- oxy- (7-end) -hydroxybicyclo [3.3.3] octane; IR spectrum (film): 3400, 1250 cm ^-1 ;

2-exo- (3'S- (tetrahydro-pyran-2'-yloxy) -4'S-methyl-oct-1 * -transen-1'-yl] -3-endo- (1'-tetrahydro-pyr) an-2'-yloxy-7-endo-hydroxy-1-bicyclo [2,3.3] octane; IR / film /: 3400, 1250 cm ⁴ ·;

2-exo / 3'R- / tetrahydropyran-2 "-yloxy / ^{-4'S-inetií-oct-l-trans-en-I-yl} / -3-endo / tetrahydropyran-2 ^, -yloxy-7-endo-hydroxybicyclo73.3.07 octane; IR spectrum (film): 3400, 1250 cm ^-1 ;

2-exo-Z3's - (tetrahydro-pyran-2-yloxy) -non-1'-trans-en-1 * -177-endo-tert-tetrahydro-pyran-2 * -yl oxy-7-endo-hydroxy-bicyclo [beta] -3,7-octane; IR spectrum (film): 3400, 1250 cm -1;

2-exo-Z3'R- / tetrahydro-pyran-2-yloxy / ^{-non-l-en-l-trans-endo} il7-3 / ^{tetrahydro-pyran-2-yloxy} / -7-endo-hydroxy-bicikloZ3.3.07oktán; IR spectrum (film): 3400, 1250 cm ^-1 ;

2-exo- (3'S- (tetrahydro-pyran-2'-yloxy) -5'-cyclohexyl-pent-1'-trans-en-1'-yl) -3-endo- / tetrahydropyran-2 -yl-oxy-7-endo-hydroxy-biciklöZ3 "3"07oktán?; IR spectrum (film): 3400, 1250 cm ^-1 ; "

-38182,726

2-exo / ^3, S / ^{tetrahydropyran-2} '-yloxy / ^{-5 -phenyl-pent-l-en-l -TRANS,} -il7-3' endo / tetr? Hydr o-pyran-2 * -yloxy-7-endo-hydroxy-bicyclo [3.3.0] octane; IR spectrum / film: 3400.1250 cm -1;

2-exo / ^3, R / tetrahydro-pyran-2-yloxy ^,, / * -5 ^{-phenyl-pent-l-en-I -trana2,} -il7-3 endo / tetr? Hydr o -pyran-2 * -yloxy-7-endo-hi (oxy-bicyclo [3.3.0] octane; IB spectrum (film): 3400, 1250 cm <-1 ^> );

2-exo- (3 * S - / tetrahydro-pyran-2-yl-oxy) -4- (m-trifluoromethyl-phenoxy) -but-1'-trans-en-1 * - il7-3 endo ~ © / tetrahydro-pyran-2-yloxy * / endjp -7-hydroxy-bicyclo / 3.3-07oktán; IB spectrum / film / 3400, 125 cm ^-1 ; ............

2-exo / 3'B- / tetrahydropyran-2 '-yl-oxy / -4 ¹ - / m-trifluoromethyl-phenoxy / but-l-trans-en-1 * -il7-3 -endo- (tetrahydropyran-2'-yloxy) -7-endo-bi-dicarbobicyclo [3.3.0] octane; IB spectra / film /: 3400, 1250 cm ^-1 ;

2-exo- (3'S- (tetrahydro-pyran-2-yloxy) -4'-methyl-4'-butoxy-pent-1'-trans-en-1'-yl) -3-3-endo- / tetrahydro pyran-2'-yloxy / -7-endo-hydroxy-bioiElo / 3.3 »07oktán; IR spectrum / film / 3400,

I25O om 'f ;. ~

Example 27

A solution of 0.4 g of chromic anhydride is added in portions to 4 ml of plridine with stirring. After preparation of the complex, 0.36 g of 2-exo- (3'S- / tetrahydro-pyra-B-2-yloxy) -5 '- / 2''-tetrahydrofuran-pent-1'- is added to the mixture. trans-en-1'-yl-7 '- (3'-endo-1'-tetrahydro-pyran-2'-yloxy) -7-exo-hydroxy-bicyclo [3.3.0] octane 4 ml pyridine solution. The reaction mixture was kept at room temperature overnight, then diluted with three volumes of benzene and the insolubles were filtered off. The filtrate was distilled off and the residue was partitioned between benzene and 2N sulfuric acid. The aqueous solution was extracted with benzene and the organic solvent solutions were washed with water, followed by sodium bicarbonate solution and then again with water. The solvent was evaporated, yielding 0.31 g of 2-exo / 3 * S / tetrahydro-pyran-2-yloxy / ^-5, - / 2-tetrahydrofuryl / pent-l-trans En-1'-yl-3- (3-endo-tetrahydropyran-2 * -yloxy) -bicyclo [3.2.0] octan-7-ol is obtained. IR / film /: 1740, 1220 cm ^- *. ~

Example 28

0.8 g of 2-exo / 3 * S / tetrahydro-pyran-2-yloxy / ~ ^{oct-l-en-l-üransz,} -il7-3-eudo- / tetrahydropyran-2 * To a solution of -yloxy / -7-endo-hydroxybicycle / 3 x 3.07 octane in 20 ml of acetone was added 1.6 ml of Jones reagent with stirring at -6 to -10 ° C over a quarter hour. After stirring for a further quarter hour, benzene (80 ml) was added. The organic solvent solution was separated, washed neutral with 15% aqueous ammonium sulfate solution, sealed and the solvent was distilled off. Thus, 0.71 g of 2-exo / 3'S- / pif on-tetrahydro-2-oxy -il' ^M / oct-l-en-l -tranaz * * -il7-3 endo / tetrahydropyran -2'-Yloxy-, -bicyclo [3.2.0] 07-octan-7-one is obtained. IB spectrum (film): 1741 cm <-1>.

Example 29

Starting from the compounds obtained in Example 26 and oxidizing them as described in Examples 27 or 28, the substituents listed below in position 2 are prepared.

Containing the 3-endo- (tetrahydropyran-2 * -yloxy) -bicyclo [3- (3-ol) -7-octane-7-one containing -39182.726: "

2-exo / * ^S-bromo-3, S / ^{tetrahydropyran-2} '-yl-oxy / ^-4, R-fluoro-oct-1-en-1 -trans * * -il7-;

2-exo / 5'-bromo-3'R- / tetrahydropyran-2 "-yloxy / -4'R-fluoropyrrolidin-oct-l-trans-en-l * -il7-;

^Oxo-2/3, S / tetrahydropyran-2 "-yloxy / -5 ^- / ² '-tetrahldro-furiV-pent-1-en * -trans-1'-il7->

2-exo / ^3, R / ^,, tetrahydro-pyran-2-yloxy / -5 * - / 2 ^u tetrahydro * '£ ttrlÍ / tranaz-pent-l-en-l-yl / -;

2-exo- (2 ^, -bromo-3 ^, 5-tetraEidro-pyran-2 ”-yloxy) -oct-1 ^, -transazen-1'-yl-7»

2-exo / ^2-bromo-3'R- / tetrahydropyran-2 "-yloxy / ^{oct-l-en-l-trans} il7->

2-exo / ^3, S / tetrahydro-pyran-2-yloxy ^,, / ~ ^{oct-l-trans-l ep,} -il7í ^exo-2/3, R / tetrahydro-pyran 2 "-yloxy / ^oct-l, trans-en-1 * -11 / 2-exo J ^ 5 * ^s - ^ betrah.idr p-pyran-2-yl-oxy / -4 * s methyl-oct-l-exo- -trans42 * / 3 * R / tetrahydro-pyran-2 '' - yloxy / ^{-4'S-methyl-oct-l-en--tranS2t} I'-yl / - ?

2-exo- / 3 * S- / tert-butyl-2-yl-oxy / non-1 * -tr ans z-en-1 * -117-; 2-exo- (5'R- / tetrahydro-pyran-2 * '-yloxy-non-1 * -trans-en-1 * -yl) -1'-exo-23'S- / tetrahydro-pyran- ? -yloxy / -5'-cyclohexyl-pent-l-en-l-tranaz il7-;

2-exo-Z3 '- (tetrahydropyran-2 ⁿ -yloxy) -5'-cyclohexylpent-1 * -tyano z-en-1 * -yl7-j-_____-__-______;

2-exo / 3'S- / tetrahydro-pyran-2-yloxy / * -5 -phenyl-pent-l-en-TRAN-I'-yl / -?

2-exo / ^3, R / ^{tetrahydro-pyran-2-yloxy} * / ^-5 -phenyl-pent-l-ene-I * -tranai »-il7-» '

2-exo ^ ^3, S / tetrahydropyran-2 '-yl-oxy / -4' - / m-trifluoromethyl-phenoxy / but-l-en-l * -trans-il7-d

2-exo- (3'R- / tetrahydro-pyran-2'-yloxy) -4 * - [m-trifluoromethyl-phenoxy] -but-1 * -tranazen-1'-yl-7;

2-exo / ^5, S / ^H, tetrahydropyran-2-yl-oxy / -4 * -methyl ^ ^{4-butoxy-pent-l-en-1} -trans * * -il7- »

2-exo- (3 * R - / tetrahydropyran- ^2M -yloxy) -4 * -methyl-4 * -butoxypent-1 * -tranazen-1 * -yl7-n

IR of the listed compounds / film / 1740 cm '.

Example 30

2.1 g of dl-2-exo - [3'-oxo-non-1 * -transazen-1 * -yl] -3-oxo- / tetrahydro-planran, prepared as described in Example 17 2 * -yl-*-oxy-7-endo-dimethyl-11-tert-butyl-S4TlTloxi-bi-clo-3; Starting from 3,7,7-octane and 0.17 g of sodium borohydride in dichloromethane and ethanol as solvent at -15 ° C.

As described in Example 23. Reduction of 2.01 g of dl-2-exo - ^ * / S, R / hI | ^{hydroxy-non-l, trans-en-l-oxo} -il7-3 / tetrahydropyran -2'-Yloxy-? -7-endo- (dimethyl-tertiary-eutylsilyloxy) -bicyclo- 3.3-07-octaphate is obtained. Without separating the 3 * S and 3 * R alcohols, 0.4 g of 2,3-di

-40182726 with hydropyran in the presence of 25 mg of p-toluenesulfonic acid to give the corresponding dl-2-exo- (3 *, S, R) -tetrahydropyran-2-yl-oxy-η-one. 1 * -tr ans z-en-1'-i17-3-exo / tertiary tricopyran-2 * - * -yloxy / -7-endo- / dimethyl-tert-butylsilyloxy Octanol is obtained. This product was treated with 2.5 molar equivalents of tetrabutylammonium fluoride in tetrahydrofuran solution to purify the silyl group without purification.

1.660 g of product are thus obtained, dl-2-exo- (3 ', S, R) -tetrahydropyran-2' -yloxy-non-1 ^, -tranazen-1 ^, 1-yl. Oxidation of -3-exo- (tetrahydro-pyran-2 * -yloxy) -7-endo-hydroxy-cyclohexyl-3.07-octane with pyridine chromic anhydride 1.25 g of dl-2-exo-3 '/ S, R (-) - Tetrahydropyran-2-yloxy-non-1'-trans-en-1 * -yl] -3-3-exo- (1E) trihi dr op and an-2 * -yloxy - bic iclo / 3.3.07o ctane-7 is obtained. IR spectrum (film): 1740 cm ^-1 .

Example 31 To a suspension of 80% sodium hydride (80 mg) in anhydrous tetrahydrofuran (10 ml) was added dropwise a solution of (2-oxo-5,5,5,5-trimethoxypentyl) -dimethylphosphonate in 10 ml tetrahydrofuran with stirring. stir until hydrogen evolution ceases. Then 0.67 g of dl-2-exo- (3 * / θ, R) - / tetrahedron-o-pyran-2 '-yloxy-non-1 * -tr ans z-en-1 * is added. -7- 7-exo- (tetrahydroxopyran-2 ^, 3-yloxy) -bicyclo _[ 3.3.0] octan-7-one 'in 5 ml of tetrahydrofuran and stirring at 40-45 ° C for 6 hours. stirring. To the reaction mixture was added 20 ml of 20% sodium dihydrogen phosphate solution and the tetrahydrofuran was distilled off under reduced pressure. The remaining aqueous solution was extracted with diethyl ether, the combined diethyl ether solutions dried over sodium sulfate and the solvent was distilled off. The residue was chromatographed on silica gel using a mixture of cyclohexane and diethyl ether as the eluent to give 0.76 g of dl-4-oxo-11 ·, 15 / S, R /-bis / tetrahydropyran-2′-yloxy -20. Methyl-9a-deoxy-oxa-9a-methylene-pro-acyl-5-trans, 13-trans z-dlenic acid trimethyl orthoester is obtained.

The product obtained above was dissolved in methanol (15 ml) and p-toluenesulfonic acid (6 mg) was added and the mixture was kept at room temperature for 5 hours. Then pyridine (0.1 ml) was added, the solvent was distilled off and the residue was chromatographed on silica gel using a mixture of diisopropyl ether and diethyl ether as eluent. There were thus obtained 0.20 g of dl-4-oxo-11,15S-dihydroxy-20-methyl-9a-deoxy-9a-methylene-propyl-5-tr anz, 13-tr an z- di en av-tr imet il- ^; - orthoester (IR spectrum / film): 1700, 1690 cm ^@ -1; M -H ₂ 0 420, m / e / and 0.21 g of 15R-epimer was obtained. ²

Example 32

The trimethyl orthoesters of the acids listed below are prepared starting from the biocyclo [3.3.3] octan-7-one derivatives as described in Examples 27, 28, and 29; ......

4-oxo-11,15S-dhydroxy-9a-deoxy-9a-methylene-proaza-cyclo-5,13 * trans-dienoic acid; M '- H ₂ O 406;

4-oxo-11x, 15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacyclo-5,13-trans-dienoic acid; M - H ₂ 0 420;

4-oxo-11β, 15S-dihydroxy-9α-deoxy-9α-methylene-17α / 2′-tetrahydro-6β-fur η 1 -18,19,20-1r in orphan tac i 5,13-trans z-di ens av;

-41182.726 lí ⁺ - Η ₂ 0 434;

4-oxo-lla, 15S-dihydroxy-9-deoxy-9-methylene-16- / m-trifluoromethyl «methylphenoxy / -17,18,19,20-tetranor-prosta-5,13-trans di · ^ acetic acid; 1Γ to H-O 510;

and a 15R epimer signal.

From each of the orthoesters obtained as described in Examples 31 and 32, the corresponding methyl esters were prepared by boiling 2 ml of 0.2N oxalic acid solution in 15 volumes of methanol as solvent and distilling off the methanol. The resulting ester is isolated by extraction with diethyl ether. The methyl esters are hydrolyzed in 2% potassium bicarbonate in 80% aqueous methanol to give the free acids.

33 · example

0.45 g of 4-oxo-ll7,15S-dihydroxy-9-deoxy-9-methylene-prosta-5,13-trans-dienoic acid trimethyl orthoester / 7 ^ _{& χ}

- 244 m / U. c) 9850/6 mL of methanol was refluxed with 1.2 mL of 0.0 N oxalic acid for 2 hours. The methanol was then distilled off under reduced pressure and the residual aqueous solution was partitioned between ethyl ether to give 0.42 g of the corresponding methyl ester.

A solution of the product obtained above in 6 ml of anhydrous diethyl ether was added dropwise to 10 ml of a stirred solution of 0.1 molar zinc borohydride in 10 ml, and the mixture was stirred for 1 hour at room temperature, and the reaction was quenched by the addition of 2 N aqueous solution. . The organic solvent solution was separated, washed to neutral and the solvent was distilled off. In this way, 0.4 g of 4 / S, E, 11,15, 15S-trihydroxy-9a-deoxy-9a-methylene-prostacyclate-5,13-transz-dienoic acid methyl ester is interpreted. . This product was chromatographed on silica gel, eluting with a mixture of diethyl ether and ethyl acetate, to give 0.11 g of 4S, 11S, 15S-trihydroxy-9a-des-oxy-9a-methylene-prostatic z-5. 13-transz-diene -? -Methyl ester (IR spectrum / flmm): 3400 cm- ¹ (wide), M-2 H ₂ O: 344 m / e / and 0.14 g of 4R-. epimer.

The latter product was dissolved in methanol (5 ml) and a solution of lithium hydroxide (0.05 g) in water (0.3 ml) was added and the mixture was stirred at room temperature for 6 hours. Subsequently, the methanol is distilled off under reduced pressure, the remaining solution is acidified to pH 5.6 and then rapidly extracted with ethyl acetate. In this way, 4R, 11β, 15S-trihydroxy-9a-deoxyl-9a-methylene-prostacyclo-5.13-trans-dienoic acid is obtained. This product in ethyl acetate was half the amount of hydrogen in ionic form | stirring EVO szulfofasav polystyrene-type ion exchange resins in quantitative yield the 4R, II ', ^{15S-trihydroxy-9-deoxy-9-methylene-prosta-5,13-trans} 1,4-v-lactonic acid. M.p. 51-52 _L ° C, Μ * -H ₂ 0. 550 m / e.

The AS-epimer-T? Form is produced by the analog analogue of the sheet.

Example 34

0.8 g of 4-oxo-llz, 15S-bis-benzyloxy-tetrahydropyran-2'-yl / / 20-meth yl-9 but ^a- z oxy-9a-meth ylene-pr os zt c i kla- To a solution of the trimethyl orthoester of 5,13-1r-anenedioic acid in 20 ml of dichloromethane: ethanol was added 50 mg of sodium borohydride with stirring at -20 ° C and the mixture was stirred for half an hour.

-42182,726

The reaction was then quenched by the addition of 2 mL of acetone and 5 mL of saturated sodium dihydrogen phosphorate solution. The organic solvents were distilled off under reduced pressure and the residue was extracted several times with diethyl ether. The combined diethyl ether solutions were dried and the solvent was distilled off to give 0.75 S 4 / S, B-hydroxy-11,15S-bis / tetrahydropyran-2'-yloxy / -20-methyl- Trimethyl ortho ester of 9a-deoxy-9a-methylene-proaza-5-aza-5,13-trans-diacid is obtained.

The crude product obtained above was dissolved in methanesulfonic acid chloride (2.2 mL) and allowed to stand at room temperature overnight. The reaction mixture was partitioned between ice-cold 2N sulfuric acid and diethyl ether, the organic solvent was washed with saturated sodium chloride solution, dried and the solvent was distilled off at low temperature. In this way, 4 / S, B-mesylloxl-11 · 1; 15S-bis (tetrahydro-pyran-2 * -yloxy) -20-methyl-9a-deoxy-9a-methylene-prostacyclo-5,13-trans-dienoic acid trimethyl orthoester is obtained.

The product obtained above was dissolved without purification in anhydrous diethyl ether and 50 mg of lithium aluminum hydride dissolved in diethyl ether were added. The mixture was stirred at room temperature for 2 hours and then for 1 hour, and then the excess reagent was quenched by addition of ethyl acetate (2 mL) and water-saturated diethyl ether. The solution was dried over sodium sulfate and the solvent was distilled off. In this way, 0.5 g of crude 11cx, 15S-b is z / l-tetrahydro-pyran-2 * -yloxy / -20-methyl-9a-deoxy-9a-me ethylene-propyl ac kla-5,13-tr ans z-di ens av-1r ims t1-or ester is obtained.

The product thus obtained was boiled in 12 ml of methanol as a solvent by boiling in 4 ml of 0.2 N aqueous oxalic acid solution, and the mixture was worked up "as usual" with 0.2 g of 11 ', 15S-dihydroxy-20-methyl-9a-deoxy -9a-methylene-prostacyclo-5,13-tr ans z-dienoic acid methyl ester is obtained _. 0 = 360 /, consisting of 85% trans and 15% cis isomer by liquid-liquid chromatography.

Example 35

A suspension of 0.4 g of sodium hydride / 75% mineral oil dispersion / 13 x 5 ml of dimethylsulfoxide was stirred at 60-65 ° C for 4 hours under stirring in a neutral gas atmosphere, then cooled to room temperature and 20-22 ° C. A solution of 2.6 g of 4-carboxybutyl / triphenylphosphonium bromide in 6 ml of dimethyl sulfoxide is added at 0 ° C followed by 0.85 g of 2-exo / 3 ^, 5-tetrahydropyran-2 ^M - 11-oxy-non-1'-trans-en-1'-yl-7-dihydro-tetrahydro-pyran-2'-yloxy-bicyclo [3.2.0] octan-7-one. The reaction mixture was stirred for 3 hours. After stirring, the mixture is diluted with 25 ml of water and the aqueous solution is washed with 5 ml of diethyl ether (5 times) and 12 ml of diethyl ether (7 times). shake with benzene. The combined organic solvent solutions are shaken three times with 15 ml of sodium hydroxide solution and washed with neutral water each time. The aqueous wash was discarded, the aqueous alkaline solutions were acidified to pH 5.3 and extracted with diethyl ether / pentane 1: 1. The organic solvent solutions were washed neutral with water, dried over sodium sulfate and the solvent was distilled off. Thus, 0.86 g of _t IIx 15S-bis / Pirahã ^{people-tetrahydro-2'-yl-oxy} / deoxy-9a-9a-meüiIén-2-O-methyl-prosztaoikla-5,13-trans-dienoic acid. This au

The product -43182.726 is treated with diazomethane to the corresponding methyl ester and the tetrahydropyranyl protecting groups are removed as follows:

The methyl ether was dissolved in anhydrous methanol and treated with 0.01 molar equivalent of p-toluenesulfonic acid for 4 hours. The p-toluenesulfonic acid is then neutralized with pyridine and the solvent is distilled off. The residue was chromatographed on silica gel with 11,15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-pro-taclla-5,13-tr ans z-di-ene-thi ester. / M - H ~ 0 i 360, M ⁺ - HpO - ^C 2 ^H 4 ° * ⁵⁰² , and the pure 5 - cis, 13 - trans and 5 - trans, 13 - is separated by liquid chromatography. trans-isomer.

Example 36 ·

To a solution of freshly sublimed potassium tert-butylate in 12 ml of anhydrous dimethyl sulfoxide was added first with stirring and external cooling at 20-22 ° C, 8 g of 4-carboxybutyl / triphenylphosphonium bromide in 10 ml of dimethyl -szulfoxiddal was added, and then 0.65 S 2-exo / 2'-bromo-3'S / tetrahydropyran-2 "-yloxy / ^oct-l, trans-en-l ^'r -il7" 3 endo / '/ ^{tetrahydro-pyran-2-yloxy} solution / -bicyclo / 3.3.07oktán-7-one in 5 ml of dimethyl sulfoxide. The reaction mixture was stirred at room temperature for 8 hours, then diluted with an equal volume of water, acidified to pH 5 and extracted with diethyl ether: pentane (1: 1). The acidic aqueous solution was discarded and the combined organic solvent solutions were extracted five times with 20 ml of 0.8 N sodium hydroxide solution and washed with water until neutral. The organic solvent solution is discarded, the aqueous alkaline solutions are acidified to pH 5-ϊθ and extracted with diethyl ether / pentane (1: 1). The combined organic solvent solutions were sprinkled over sodium sulfate and a solution of diazomethane in diethyl ether was added until the yellow color of the solution remained. The solvent was distilled off to give crude 11β, 153-bis (tetrahydro-pyran-2'-yloxy) -9a-deoxy-9a-methylene-prostacycl-5-ene-13-acetic acid methyl ester. After removal of the tetrahydropyranyl protecting groups, 11,15S-dihydroxy-9a-deoxy-9a-methylene-prosttaicycl-5-ciazene-13-insacid methyl ester, after separation by liquid-liquid chromatography / 11: HO: 344, Μ Η ~ 0

-O ₂ H ₄ O: 300, M ⁺ - H ₂ O-C ₂ H ₂ O 3: 273 / and the corresponding 5-trans-geometric isomer is obtained. Similarly, the product of Example 36 was prepared.

37 · example

Starting from the protected bicyclo [2,3,5,7] octan-7-one derivatives obtained as described in Examples 27, 28, 29 · and 30 and following the procedures described in each of Examples 35 · and 35, the following acids are prepared: methyl ester:

$ 11, 15S-dihi dr őxi-9á * cLe zo'xf * 9a-me t ill ^ pf „“'άζ t ác i1Qa-5-i i £ 2713 = ··

trans-dienoic acid;

11,10,15S-Dihydroxy-9α-deoxy-9α-methylene-16β-fluoroprostacycl-5-cis-en-13-acid;

lla, 15S-dihydroxy-9-deoxy-9-methylene-16S-fluoro-prosta-cis-5-ene-13-ynoic acid;

11? -? 15S-Dihydroxy-9a-deoxy-9a-methylene-17?, 2 * -tetrahydrofuryl / t? -18,19? 20-trifluoromethyl-5-cis-ene- 13-ins av;

-44182,726

15S-moiety oxy-9a-d.-ethoxy-9a-methylene-prodacycl-5-cis-en-13-linic acid;

III, 15S-Dihydroxy-9a-des-oxy-9a-methyl-1-ene-methylac-5-cis, 13? -Tranazadiene acid; M-H 8 O: 346;

ll ^f '' ^r, 15S-dihydroxy-9-deoxy-9a-methyl-16S * proaztadikla-methyl-5-cis-13-trans-dienoic acid; M-HO: 360;

117.155-dihydroxy-9a-deoxyl-9a-methylene-20-methyl-prostacyclo-5-cis-13-trans-dienoic acid; M-H 8 O: 360;

lh /, ^{15S-dihydroxy-9-deoxy-9-methylene-17-cyclohexyl-18,19,20} -trinor-t-prosta-5-cis, 13-dienoic tranaz; M-HgO s 372;

LII <, ^{15S-dihydroxy-9} "deoxy-9-methylene-17-phenyl ~ horse, 19,20-tr Inor-prosta-5-cis, 13-trans-dienoic acid; M-H ₂ 0: 380;

11,10,15S-Dihydroxy-9a-deoxy-9a-methylene-16- (m-trifluoromethyl-methyl-oxy) -17,18,19,20-tetranor-prostaclkla-5-ol, 13-tranazo- di-acetic acid; Ki-HgO ^: 11,15S-dihydroxy-9a-deoxy-9a-methylene-16-methyl-16-butoxy-18,19,20-trinor-prostacyclo-5-ciaz, 13-trans-2-dienoic acid; KT-HgO 552 as biaz (trimethylsilyl) ether and their 5-tris-geometric isomers.

Example 38

0.45 6 2-oxo-3 * S- / tetrahydro-pyran-2 '-yloxy-oct-1 * -transen-1 * -yl] -3-endo- / tetrahydropyran-2 A solution of '-yloxy / -bicyclo / 3 · 3 · θ7-octane-7-one in ethyl acetate was hydrogenated at room temperature and standard pressure in the presence of 5% palladium on carbon (0.1 g) until the mixture was treated with 1.01 molar hydrogen does not record. The catalyst is then filtered off and the solvent is distilled off from the filtrate. 0.42 g of 2-exo- (3 * S - / tetrahydropyran-2-yloxy) -oct-1'-yl] -3-endo / tetrahydro-pyran-2 * -yloxy- Bicyclo [3.3.0] 07-octan-7-one is obtained. This was treated with the Wittig reagent of 4-carboxybutyl-phosphenumummonium bromide as described in Examples 35, 36, and 37 to give a product which was subjected to esterification with diazomethane followed by tetrahydropyran Removal of the L-groups gave 0.12 g of 11,15S-dihydroxy-9a; desosyl-L-9a-methylene-prostacycl-5-enoic acid methyl ester ZM 352 m / e. The 5-cis and 5-trans isomers are separated by Liquid Liquid Chromatography.

Example · Starting from (3-Carboxypropyl) -phosphonium bromide and

Proceed as in Examples 37 and 38 to obtain the following 9 £ LV & l ££ Ltj ·

117,155-dihydroxy-9a-deoxy-9a-methylene-2-nor-pro-tacyclo-5-cis, 13trans-z-dinic acid; M -H ₂ 0 ^! ^ 1-8;

II 7,15S-hydroxy-9α-azole-9α-methylene-2-fluoro-prostacifla-5-cis-enflav; M + 338;

11 <, 15S-dihydroxy-9-deoxy-9-methylene-2-nor-pros ztacikla-5-cis-13-ene-iusav, M-H ₂ 0 and 316th

Example 40 Starting from (5-carboxypentyl) -phosphonium bromide and following the procedure described in Examples 37 · and 3θ ·

-45182,726

15S-Dihydroxy-9a-deoxy-oxy-9a-methylene-2a-homo-pro-taclcla-5-claz, 13-trans-dienoic acid / M: 580, M-CH ₃ : 565 tris tris arylmethyl 11,15S-Dihydroxy-9a-deoxy-9a-methylene-20-methyl-2a-homo-prostacyclo-5,13-trans-dienoic acid as the III ether / M 594,

M -CH3 579 as tris-methylmethylsilyl ether.

Example 41

To a solution of 0.37 g of 11c15S-dihydroxy-9a-deoxy-9a-methylene-prostacyclo-5-cis, 13-trans-dienoic acid methyl ester in 10 ml of benzene was added 250 mg of 2,3-dichloro-5,6- dicyanobenzoquinone and the mixture was heated at 50 ° C for 8 hours. The precipitate was filtered off and the benzene solution was purified by passing through a short column of alumina. 0.29 g of 11? -Hydroxy-15-oxo-9a-deoxy-9a-methylene-pro-tacyclo-5-cis, 13-trans-dienoic acid methyl ester are obtained / M 362, 1Γ-HgO 344. m / e /.

This product is dissolved in a mixture of diethyl ether and toluene and 1.2 ml of a 1M solution of methyl magnesium bromide in diethyl ether are added at -20 ° C. The mixture

After 2.5 hours at -20 ° C, the reaction was quenched by the addition of ammonium chloride solution. The organic solvent solution is then separated, concentrated and the residue is chromatographed on silica gel, eluting with a mixture of diethyl ether and ethyl acetate. Thus, 0.1 g of lll, 15S-dihydroxy-15-methyl-9a-deoxy-9a is obtained. methylene-prostacyclo-5-cis, 13-trans-dienoic acid methyl ester (M * -IIpO 360 m / e) and 0.072 g of 15R-hydroxy epimer were obtained.

Example 42

To a solution of 2.2 g of 3-dihydroxybicyclo [3.2.0] octane-7-one in 100 ml of anhydrous benzene was added 4 ml of ethylene glycol and 0.2 g of p-toluenesulfonic acid monohydrate, followed by the mixture is refluxed for 12 hours while the reaction water is continuously removed. Pyridine (0.25 mL) was added and the mixture was cooled. The mixture was washed with water, sodium bicarbonate solution and water again, and the solvent was distilled off; There are thus obtained 2.32 g of 3-endo-hydroxy-7,7-ylenedioxybicyclo [3.3.0] octan-7-one. IR / film / t 3450 cm ^-1, 1745 ^- f cm-en no absorption. ™ '.................

This product is dissolved in 40 ml of acetone and 4.1 ml of Jones reagent is added at -5 v. After 20 minutes at -5 ° C, the excess oxidant was quenched by the addition of 4 mL of isopropyl alcohol. Benzene (150 mL) was added and the benzene solution was washed with 20% ammonium sulfate solution, water, then 5% sodium bicarbonate solution, and finally water. The solvent was distilled off, yielding 2.1 g of dl-7,7-ethylenedioxybicyclo [5,3,7,7-octane-3,7-yl] melting at 40-42 ° C. .This. ater ⁼ _ azl. d) 1-7,7-ethylene-dioxylcyclo [3- (3-O) -octane-3,7-di-η-2-carboxylic acid methyl] ester, A _max : 254 "myu = 7000 *

This product was reduced to 1.72 gd, 1-3-endo-hydroxy-7 in 20 ml of dichloroethane / 20 ml of ethanol as a solvent in sodium borohydride at -20 ° C. 7-ethylenedioxybicyclo [3.3.0] octane-2-exo-carboxylic acid methyl ester is obtained; IR / film /: 3400, 1720 ^οπΓ χ.

-46182,726

A solution of 1.57 gd, 1- 3-endo-hydroxy-7,7-ethylenedioxybicyclo [3.3.0] octane-2-exo-carboxylic acid methyl ester in 1 ml of dimethylformamide was treated with 1.3 g of dimethylformamide. t-butylsilyl chloride is treated with 0.885 g of imidazole EA, EA, the mixture was heated for 5 hours at O ^O C. Water is added thereto under cooling and the product is isolated in the usual manner. This gives 2.3 gd of methyl 1- (3-endo-dimethyl-tert-butylsilyloxy) -7,7-ethylenedioxybicyclo [3.3.07] octane-2-exo-carboxylic acid, m.p. spectrum / film / t 1710 ^- · · ^1. This product is reduced in anhydrous diethyl ether as solvent in lithium aluminium hydride as in Example 3 to give quantitative yield of dl-3-endo- / dimethyl-tert-butylsilyloxy / -7,7-ethylenedioxy-2. exo-hydroxy-methyl-bicyclo / 3 "3" 07oktánt.

43 · example

1.8 g of dl-3-endo- (dimethyl-tert-butylsilyloxy) -2-exo-hydroxymethyl-7,7-ethylenedioxy-biocyclo [3.3.0] octane were oxidized as described in Example 18. the corresponding 2-formyl derivative is obtained. This was then reacted with (2-oxo-heptyl) -dimethyl-phosphonate as in Example 20 to give 1.23 g of dl-3-endo / dimethyl-tert-butylsilyloxy / -2-exo / 3'-oxo. oct-l-en-l * ^-trans, -ll / etiléü -7,7-dioxa-bicyclo / 3 "3" 07oktánt / ^s 228 m / u «8960 / * give

This product was reduced to 1.22 g of dl-3-endo / dimethyl-tert-butyl-3-yloxy-2-exo-3 ^, 5S, R, - in a solvent such as diethyl ether, as described in Example 22. ^{hydroxy-oct-l-trans-en-l--il7-7,7} ethylenedioxy biciElo / "3.3" 07oktánt Kajo.

To a solution of the product thus obtained in 25 ml of methanol is added 10 ml of 1 N sulfuric acid solution under reflux for 50 minutes. The methanol is then distilled off under reduced pressure, the residue is extracted with diethyl ether and the solvent is distilled off from the diethyl ether solution. Thus 0.72 g of the crude dl-3-endo-hydroxy-2-exo- / 3 '/ S, R / hydroxy-oct-l * -trans-en ~ ^l-yl / bicyclo- / 3 "3:07 octane-7-one is obtained. The pure isomers of this compound were separated by chromatography on silica gel eluting with hexane / diethyl ether. The pure isomers are converted to the corresponding dihydropyranyl ethers by treatment with dichloromethane as the solvent in Example 25 as the solvent. With this method of 3'S-hydroxy-isomer obtained analogously to Example 28 from 2-exo / ³ ~ / tetrahydro-pyran-2 "-yloxy / ^{oct-l'-trans-en-l} -il7-3 endo / ^{tetrahydro-pyran-2-yloxy} / -bicyclo / 3.3 "07oktán-7-one was obtained in the same compound in all respects.

Similarly, following the procedure described in Examples 42 and 43 ·, it can be obtained as described in Examples 27, 28 and 29; all compounds

Example 44

4.8 g of methyl dl-3-endo-hydroxy-7? 7 "pentylene dioxybicyclo [3.3.0] octane-2-exo-carboxylic acid in 100 ml of 2.5% methanol: The mixture was treated with potassium carbonate (80:20) for 40 minutes and worked up as described in Example 2. 4.02 g of dl-3-endo-hydroxy-7,7-ethylenedioxybicyclo [3.3.3] octane-2-exo-carboxylic acid are thus obtained. This product is dissolved in 8D ml of anhydrous tetrahydrofuran and the solution is cooled to -10 ° C, at which temperature a solution of 2.1 g of triethylamine in 12 ml of anhydrous tetrahydrofuran is added dropwise at -10 ° C. A solution of ethyl chloroformate (2 g) in dry tetrahydrofuran (12 ml) was added. The mixture was stirred at -10 ° C for 1 hour and then added slowly

A solution of 1.4 g of sodium azide in 12 ml of water was added and the mixture was stirred for a further 25 minutes. The mixture was then concentrated under reduced pressure and the residue was diluted with water. The 2-exo-carboxylic acid azide was filtered off rapidly and dried under reduced pressure.

A solution of 4.01 g of the 2-exo-carbohydrate azide thus obtained in 8 ml of pyridine is treated with 4 ml of acetic anhydride and the mixture is kept at 5-8 ° C for 24 hours. The mixture was then partitioned between ice water, diethyl ether and 2N sulfuric acid. The organic solvent solution was separated, washed with neutral and the solvent was distilled off. 4.1 g of 3- ^l- endo-acetoxy-7,7-ethylenedioxybicyclo [5.3.3] octane-2-exocarboxylic acid azide are thus obtained. IR Spectrum (Film): 2215 cmA of the product obtained above was suspended in a mixture of 50 ml of acetic acid and 8 ml of water * and heated to 40 ° C. After the evolution of gas had ceased, the mixture was heated at 60-70 ° C for a further 2 hours and then excess acetic acid was removed by steam distillation. After cooling, the mixture was partitioned between diethyl ether and ethyl acetate, and the aqueous solution was basified to pH ~ 9 with sodium hydroxide. 1.92 g of 3-endoacetoxy-2-exo-aminobicyclo [3.2.0] octan-7-one are obtained, m.p. 111-113 ° C. The latter product is reacted with a mixed anhydride of ethyl formate of chloroformate and 2S-acetoxy-heptanoic acid to give 3-endo-acetoxy-2-exo- [2 ^{, 5} -acetoxy-heptanol-amino] -bicyclo [3.3.0] octane-7 we get to. A solution of this product in dimethyl sulfoxide was obtained by treating with Ilidd from 4-carboxy-butyl-triphenylphosphonium bromide and then hydrolyzing the resulting product with 11,15S-dihydroxy-9β-deoxy-9α-methylene-13-aza- 14-oxo-prostacyclo-5-trans-enoic acid is obtained. Nuclear Magnetic Resonance Spectrum (free acid / CDCl3), ppm: 0.89 (3H, t), 3.64 (1H, m), 4.10 (1H, m), 5.33 (1H), broad t / 7.52 (1H, broad t); IR Spectrum: 3360, 3300, 1705, 1630, 1545 cm ^-1 ; Tris (trimethylsilyl ether); M ⁺ 583.

Analogously, 15R-epi analog is prepared using 2'R-hydroxyheptanoic acid.

Example 45

To a benzene solution of 2-Exo-bromo-3-endo-hydroxy-bicyclo [3.2.0] heptan-6-one was added 15 ml of ethylene glycol and 0.9 g of p-toluenesulfonic acid, and the mixture was stirred for 12 min. The mixture is heated to reflux for 1 hour while the reaction water is continuously removed. Then 0.6 ml of pyridine was added and the mixture was cooled. The solution was washed with water, 2.5% aqueous sodium bicarbonate solution and water again, dried and distilled under reduced pressure with 100 ml of benzene. To the concentrated solution was added tributyltin hydride (41 g) under nitrogen and the mixture heated at 55 ° C for 8 hours. The reaction mixture was cooled to room temperature, washed with saturated aqueous sodium dihydrogen phosphate solution, dried and the solvent was distilled off. The residue was chromatographed on 240 g of silica gel. eluent is a mixture of benzene and diethyl ether. In this way, 14.9 g

-48182,726

3-endo-hydroxy-6,6-ethylenedioxybicyclo [3.2.07] heptane is obtained. IR spectrum (film): 3460 cm ^-1 ; tris (trimethylsilyl ether): M ⁺ 242.

Example 46

To a solution of 12.75 g of 3-endo-hydroxy-6,6-ethylenedioxybicyclo / 3.2.07heptane in 340 ml of benzene and 112 ml of dimethylsulfoxide are added 46.35 g of dicyclohexylcarbodiimide,

5.9,8 pyridine and 5.4 g trifluoroacetic acid. After standing for 6 hours, 600 ml of benzene and 50 ml of water are added, the dicyclohexylurea is filtered off, the organic solvent solution is washed with water, dried over magnesium sulfate and the solvent is distilled off. In this way, 6,6-ethylenedioxybicyclo [3.2.07] heptane -3- is obtained. IR spectrum (film): 1742 cm <-1>; M ⁺ 168. ~

The product obtained above is dissolved in 70 ml of dimethyl carbonate and added to a solution of 4 g of sodium hydride / 80% in a mineral oil dispersion / suspension. The mixture was stirred at room temperature until hydrogen evolution ceased and then at 75-80 ° C for an additional 40 minutes.

The mixture was cooled, benzene (350 mL) and acetic acid (8.4 g) were added, washed with water, dried and the solvent was distilled off. In this way, dl-6,6-ethylenedioxybicyclo [3.2.0] heptane-3-one-2-carboxylic acid methyl ester (p = 0, q = 1 / M ⁺ 226) and dl-6.6 ethylene dioxybicyclo [3.2.0] 2,7] heptan-3-one-4-carboxylic acid methyl ester (p = 1, q = 0 / M ⁺ 226/1: 1); and chromatographed on iron / III / ion-free silica gel eluting with a mixture of hexane and diethyl ether.

Example 47

Starting from 14.85 g of 3-endo-hydroxy-7,7-ethylenedioxybicyclo [4.3.07-nonane and oxidizing it as described in Example 46, 13.9 g of 7,7-ethylenedioxybicyclo / 5.3.07 nonan-3-one (IR spectrum / film): 1740 cm -1; 196 m / e of 4.2 g of dl-7,7-ethylenedioxybicyclo [4.3.07] nonane-3-one-2-carboxylic acid methyl ester with dimethyl carbonate (M 254) / p = 1, q = 2, 4.8 g of dl-7,7-ethylenedioxybicyclo [4.3.07] nonane-3-one-4-carboxylic acid methyl ester, also known as dl-8,5-ethylene- dioxybicyclo [5.3.07] nonane-3-one-2-carboxylic acid methyl ester (p = 2, q = 1). 2 ^ 4 m / e.

Example 48 To a suspension of sodium hydride / 80% mineral oil dispersion / 550 ml dimethyl carbonate was added 90 g bicyclo / 4.3.07non-7-en-3-one in 350 ml dimethyl carbonate. . After hydrogen evolution ceased, the mixture was heated at 75-80 ° C for 4.5 hours, then cooled and diluted with 2.7 L of benzene at room temperature. The solution was washed with 25% aqueous sodium dihydrogen phosphate solution, dried and the solvent was distilled off. 91 g of bicyclo (4.3.07non-7-ene-3-one-2-carboxylic acid methyl ester) are obtained (= 252 µm, u = 8200).

IucLX /

The product obtained as above, with 1.2 liters of dichloromethane and

To a solution of 1.2 L of ethanol is added 14.4 g of sodium borohydride with stirring at -20 ° C. Then it is

After stirring for half an hour at -20 ° C, acetic acid (23 ml) was added, the mixture was allowed to warm to room temperature and the solvent was distilled off under reduced pressure.

The residue was partitioned between ethyl acetate and water, the organic solvent was dried, and the solvent was distilled off under reduced pressure. There was thus obtained 64 g of dl-3-endo-hydroxybicyclo [4.3.07] non-7-ene-2-exo-carboxylic acid methyl ether, trimethylsilyl ether. This product is dissolved in anhydrous tetrahydrofuran, 33 g of 2,3-dihydropyran and 0.63 g of p-toluenesulfonic acid are added and the mixture is kept at room temperature for 3 hours. 0.4 g of pyridine is then added, followed by stirring at 0 ° C over a period of 45 min, with a 1.2 molar solution of borane in tetrahydrofuran. The mixture was stirred for an additional hour at 0 ° C and the excess hydride was quenched by addition of water. The resultant borane is then oxidized by vigorous stirring in a slow, parallel addition of 110 ml of 3M sodium hydroxide solution and 110 ml of 30% hydrogen peroxide solution at 0-5 ° C in an internal cooling bath. The reaction mixture was then diluted with 2 L of benzene, the aqueous solution was separated and extracted twice with 50 mL of benzene. Each benzoloa solution was combined, washed with 1% sodium carbonate solution, then with saturated sodium sulfite solution and finally with saturated sodium chloride solution, dried over magnesium sulfate and the solvent was distilled off.

The crude mixture of 7-hydroxy and 8-hydroxy derivatives thus obtained is chromatographed on 300 g of silica gel, eluting with diethyl ether, to give 24 g of dl-3-endo- / tetrahydropyran-2'-11-OXI / -. 7'-Hydroxy-bicyclo [5.3.07] nonane-2-exo-carboxylic acid methyl ester (M 370 as trimethylsilyl ether) and 27 g of dl-3-endo / tetrahydropyran-2 * -yloxy / 8-Hydroxybicyclo ^[ 3.1.0] nonane-2-exo-carboxylic acid methyl ester is obtained. (M 370 as trimethylsilyl ether).

To a solution of the 7-hydroxy compound (g) in dry dimethylformamide (30 ml) was added dimethyl tert-butylsilyl chloride (15.8 g) and imidazole (8.85 g), and the mixture was heated at 60ΟΟ for 5 hours. The reaction mixture was cooled to room temperature, diluted with 90 ml of water and extracted with diethyl ether.

The organic solvent solutions were combined, washed with water and the solvent was distilled off. In this way, dl-3-endo- (tetrahydropyran-2'-yloxy) -7- (dimethyl-tert-butylsilyloxy) -bicyclo [4.3.0] nonane-2-exo-carboxylic acid methyl ester is obtained. M 412.

To a solution of this product in anhydrous toluene (220 mL) was added a 1.4 molar solution of diisobutylaluminum hydride in toluene at -70 ° C to -60 ° C over 45 minutes, and the mixture was stirred for an additional 2 hours. The excess hydride was then quenched by addition of 2M toluene in isopropanol. The mixture was then warmed to room temperature and 60 ml of a 30% aqueous sodium dihydrogen phosphate solution were added, followed by 50 g of sodium sulfate. The insoluble material is filtered off, the organic solvent solution is washed with water and then the solvent is distilled off to give dl-2-exo-formyl-3-endo- (1-tetrahydropyran-2'-yloxy) -7- / dimethyl- tertiary-bu £ ylsilyloxy / bicyclo / 5.3.07 nonane (p = 2, q, -1) is obtained.

Starting from 8-hydroxy-s zármazékból, the same procedure as described above dl-3-endo / tdro ^{{tetrahydro-pyran-2-yloxy} / -8 - / er c ier dimethyl-1-but-s i1 z111ioxy / -b ici at / 4.3.07nonan-2-exo-kar b ona av50

-50182,726

methyl ester (12 412), followed by dl-2-exo-formyl-3-endo- (tetrahydropyran-2 * -yloxy) -8- (dimethyl-tert-butylsilyloxy) -bicyclo /4.3.o7nonan won. / M 382 /

49 · example

To a suspension of 43.5 g of sodium hydride / 80% mineral oil dispersion / 10 ml of anhydrous benzene is added a solution of 0.33 g of 2-oxo-heptyl-dimethylphosphonate in 5 ml of anhydrous benzene with stirring. After 1 hour, N-bromo-succoinimide (260 mg) was added and 5 minutes later, 0.4 g of 2-exo-formyl-3-endo- (tetrahydro-pyran-2'-yloxy) -8- / dimethyl- solution of tert-butylsilyloxy / bicyclo / 4.3.07nonane in 5 ml of toluene.

The reaction mixture was stirred for an additional quarter hour, then washed with 15% aqueous sodium dihydrogen phosphate solution, dried, and the solvent was distilled off under reduced pressure. Thus 2-exo- (2'-bromo-3'-oxo-oct-1 * trans-en-1'-yl) -3'-endo / tetrahydropyran-2 * -yloxy--8 ^; - (dimethyl tert-butylsilyloxy) -bicyclo (4.3.07nonane) is obtained ( _max . 251 m / u, d). = 8900 /.

Example 50

To a suspension of 0.33 g of sodium hydride / 80% mineral oil dispersion / 50 ml of benzene is added with stirring a solution of 2.85 g of 3-phenoxy-2-oxopropyl / dimethylphosphonate in 10 ml of benzene , then. the mixture is stirred for 45 minutes and then 3.82 g of 2-exo-formyl-3-endo- (tetrahydropyran-2 * -yloxy) -7- (dimethyl-tert-butylsilyloxy) is added. solution of -bicyclo / 4.3. After stirring for an additional 20 minutes, the organic solvent solution was washed with 20% aqueous sodium dihydrogen phosphate solution, water, dried and the solvent was distilled off. The residue was chromatographed on silica gel (38 g), eluting with a mixture of benzene and diethyl ether. Thus, 3.97 g of 2-exo- (3 * -oxo-4'-phenoxy-but-1'-trans-en-1 * -yl) -3-endo- / tetrahydropyran-2 * -yl- oxl -7- (dimethyl-tert-butylsilyloxy) -bicyclo [4.3.0] non-nane is obtained. M ⁺ -102 412 m / e.

The following compounds were prepared as the phosphonate (5-cyclohexyl-2-oxobutyl) -dimethylphosphonate and the aldehydes obtained as described in Example 49 and as follows:

2-exo- (3'-oxo-5'-cyclohexyl-pent-1'-trans-en-1 * -yl) -3-endo- (tetrahydropyran-2'-yloxy) -7- dimethyl tert-butylsilyloxy / bicyclo / 4.3.07 nonane, _max = 228 m / u, λ = 9300;

2-exo- (3'-oxo-5'-cyano-hexyl-pent-1'-trans-en-1'-yl) -3-endo-tetrahydro-pyran-2'-yloxy / -8- / dimethyl-t-butylsilyloxy-bicyclo / 4.3.07nonán \ _max = 228.6 m / u = 9450 ·

Example 51 ........... .............

The dimethyl-tert-butylsilyl-protected, N-unsaturated ketones obtained as described in Examples 49 and 50 are: a) reduced to the corresponding allylic alcohols, b) the newly formed hydroxyl alcohol is protected as tetrahydropyranyl ether;

c) deprotecting the hydroxyl group protected by dimethyl tert-butylsilyl;

-511872726 d) oxidizing the secondary hydroxyl group liberated as described in c / d to an oxo group; and finally, after removal of the additional protecting groups present, f) the epimer allyl alcohols are separated by high performance liquid chromatography or by silica gel chromatography on silica gel.

To perform these operations at 0.01 M, proceed as follows:

a) Reduction: To a stirred solution of 0.02 mol dimethyl tertiary-butylsilylated / unsaturated ketone in 90 ml dichloromethane and 90 ml ethanol at -10 to -15 ° C was added 0.01 mol / 0.32 g / sodium borohydride and its mixture! stir for another half hour. The excess hydride was then quenched by addition of 10 ml of acetone and 25 ml of a saturated aqueous sodium dihydrogen phosphate solution, the solvent was distilled off under reduced pressure and the residue partitioned between dichloromethane and water. The organic solvent solution was separated, dried, and the solvent was distilled off. In this way, a mixture of 3'S and 3 * R allyl alcohols (0.02 mol) was obtained.

b / Protection of allyl alcohols as tetrahydropyranyl ether: A mixture of the 3'S and 3 * R allyl alcohols (0.02 mol) was dissolved in 30 ml of dichloromethane and 2 g of 2,3-dihydro was added with stirring. pyran and 0.038 g of p-toluenesulfonic acid.

After 2 hours, 0.5 ml of pyridine was added and the solvent was distilled off under reduced pressure. In this way, a mixture of 3'S and 3'R tetrahydropyranyloxysilyl ethers is obtained.

c / Distillation: its products obtained as described in (b); dissolved in 80 ml of anhydrous tetrahydrofuran, 14 g of anhydrous tetrabutylammonium fluoride are added and the mixture is kept at room temperature for 12 hours. The solvent was distilled off under reduced pressure and the residue was chromatographed on 40 g of silica gel using diethyl ether as eluent. In this way, the 3'S, 3'R-tetrahydropyranyloxy derivatives of the corresponding secondary alcohols are obtained (about 0.02 mol).

d / Oxidation: To a solution of the tetrahydropyranyloxy-secondary alcohol obtained in (c) in a mixture of 45 ml of benzene and 15 ml of dimethyl azulphoxide is added first 6.5 g of dicyclohexylcarbodiimide, followed by 1 ml of pyridine and finally 0.5 ml trifluoroacetic acid, the mixture was diluted with benzene (100 mL) and a solution of oxalic acid (3 g) in water (100 mL) was added. The dicyclohexylurea formed was filtered off, the organic solvent solution was washed to neutral, dried and the solvent was distilled off.

......... e, f / Cleavage of pyranyl groups and chromatography.

Separation: A solution of 3'S, 3'B-tetrahydropyranyloxy-ketone in 30 ml of methanol was stirred for 3 hours with 0.18 g of p-toluenesulfonic acid at room temperature. Pyridine (0.5 mL) was added and the solvent was distilled off. The residue was dissolved in a 80:20 mixture of cyclohexane and ethyl acetate and injected into a high performance liquid chromatograph.

The following keto alcohols are obtained:

-52182,726

2-exo / ^{2-bromo-3-S-hydroxy-oct-l} * ^{trans-en-l-yl} / -3-endo-hydroxy-bicyclo / 4.3.07nonán-8-one; Μ-H ₂ O: 341, 342;

2-exo- (2 * -bromo-3 * R-thioxy-oxo-1'-tranaz-eD-1'-yl) -3-endo-hydroxybicyclo [4.3.07] nonan-8-one ; M - H 8 O: 340, 342;

2-exo- (3'S-hydroxy-4 * -phenoxy-butt-1? -Transz-1'-yl) -3-endo-hydroxybicyclo [4.3.07] nonan-7-one ; M ⁺ 460 as bis (trimethylsilyl ether) 7;

2-exo / ^{3'R-hydroxy-4-phenoxy-but-l, trans-en-l-yl} / -3-endo-hydroxy-bicyclo / 4.3.07nonán-7-one; M-460 as bis (trimethylsilyl ether); "

2-exo- (3 * S -hydroxy-5'-cyclohexyl-penyl-1'-yl) z-en-1'-yl] -3-endo-hydroxy-bicyclo / 4,3.07 nonan-7-one; M ⁺ - H ₂ O: 302;

2-exo- [3'R-hydroxy-5'-cyclohexylpent-1 * -tranazen-1'-yl] -3-endo-hydroxybicyclo [4.3.07] nonan-7-one; M ⁺ - H ₂ O: 302;

2-exo- [3 * 5-hydroxy-5 * -cyclohexyl-pent-1 * -tranazen-1'-yl] -3-endo-hydroxybicyclo [4.3.07] nonan-8-one; M - H ₂ O: 302;

2-exo- (3'R-hydroxy-5'-cyclohexylpent-1'-trans-en-1'-yl) -3-endo-hydroxybicyclo [4.3.07] nonan-8-one. M ⁺ - H ₂ 0: 302 m / e

Example 52

A suspension of 2.1 g of sodium hydride / 80% mineral oil dispersion / 70 ml of anhydrous dimethylsulfoxide was stirred under nitrogen at 65 ° C for 4 hours. After cooling to 25-30 ° C, 13 g of dry 4-carboxybutyl / triphenylphosphonium bromide are added to give a dark red solution of Ilid.

To this ylide solution was added 1.79 S 2-exo / 2 * ^{-bromo-3'S-hydroxy-oct-l, trans-en-l-yl} / -3-endo-hydroxy-bicyclo /4.3*07nonán At -8, a solution of 6 ml of anhydrous dimethylsulfoxide was added and the mixture was stirred at 28 ° C for 1 hour and then at 40 ° C for 4 hours. Cool to room temperature, dilute with water (80 mL), adjust to pH 4 with 4 N sulfuric acid and extract with ethyl acetate (4 x 50 mL, then 2 x 25 mL). The combined organic solvents were washed first with water, then with 10 ml of 1 N sodium hydroxide solution (5 times), and finally washed with water until neutral. The combined alkaline aqueous solutions were acidified to pH 5 and extracted with diethyl ether. 11,15,15S-Dihydroxy-9a-deoxy-9a, 9b-dimethylene-pro-azacyclo 5 / Z, E-ene-13-acetic acid (a mixture of 5-ol and 5-trans-isomers) is thus obtained. Mi: 362 M - Ho0: 344 M - 2H90: 326, M ⁺ - H20 - C ₅ H _{i; l:} 273a pure geometric isomers may be isolated by Chromatography on with forty-fold amount of silica from the raw product weight, using cyclohexane: ethyl -acetate mixture.

53 «Example

To a solution of 3.36 g of freshly sublimed potassium tert-butoxylate in 36 ml of anhydrous dimethyl sulfoxide is added 6.5 g of 4-carboxybutyl / triphenylphosphonium bromide under nitrogen. and thus a solution of Ilid dark red is obtained. Then, 0.8 g of 2-exo- (3 * R -hydroxy-4 ^, -phenoxyl-but-1'-transz-en-1'-yl) -3-endo-hydroxybicyclo [4.3.0] nonane is added. -7 at 3 ml with anhydrous dimethyl sulfoxide and the mixture was stirred at 42 ° C for 5 hours. Then cool down53

-53,182,726, diluted with 50 ml of water, acidified to pH 5 and extracted four times with 10 ml of diethyl ether. The combined diethyl ether solutions were washed with water, the washings were discarded, and the solution was extracted four times with 6 ml of 0.5 N sodium hydroxide solution and washed with water. The combined aqueous alkaline solutions were acidified to pH 5 and extracted with diethyl ether. The organic solvent solutions were combined, dried and the solvent was distilled off. In this way, 11β, 15R-dihydroxy-9α-deoxy-9α, 7α-homodedimethylene-16-phenoxy-17,18,19,20-tetranor-prestacyclo-5 / Z, E, 13-trans-dienoic acid / 5-ciaz- and 5-trans-isomer mixture of / is recovered, Li: 400, M - H ₂ 0: 382nd

The pure geometric isomers were separated by chromatography on forty times the weight of the crude product on silica gel eluting with a mixture of cyclohexane and ethyl acetate.

Example 54

Starting from the keto alcohols described in Example 50 and following the procedure described in Examples 52 and 53, the following prostacyclanic acid derivatives are obtained:

11 "?, 15S-Dihydroxy-9a-desoxy-9a, 9b-dimethyl-1-en-tosticl-5-cis-en-13-acetic acid; M 362, M - H ₂ 0_0 ₅ H _u 273;

IV ', 15S-dihydroxy-9-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17,

18.19.20- tetranor-prostacyclo-5-cis, 13-trans-dienoic acid; M ⁺ 400;

IV, 15S-Dihydroxy-9a-desoxy-9a, 9b-dimethylene-17-cyclohexyl-18,9,9,20-trinoroprostacyclo-5-cis, 13-trans-dienoic acid; 404 N, N, 15 S -dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-17-cyclohexyl-18,19,20-iorphenylacyl-5-cis, 13-tr an s z-di ens av; M 404;

N, N, 15S-dihydroxy-9a-deoxy-9a, 7a-hormone-dimethylene-prostacyclo-5-trans-ene-13-acid; M 362, M - HgO-O ^ H ^^ 273;

IIx, 15S-dihydroxy-9a ~ deoxy-9a, 7a ~ homo-dimethylene-16-phenoxy ~ 17,

18.19.20- 1 etr anor-pr os zt eye kla-5-1 r ans z, 13-tr ans z-di en-s av;

M 400;

^ll-r 5,15S dihidX'oxl-9a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18-trinor-Í9,20 prosztaoikla-5-trans, 13-trans-diénaav; M 404;

11c <,15S-Dihydroxy-9a-de-oxy-9a, 7a-homo-dimethyl-yl-17-cy clohexyl-18,19,20-trinor-prostacyclo-5-trans, 13-trans-dienoic acid , M * 404 m / e.

Example 55 g of 2-acetoxy-perhydro-azulen-6-one, or aliased

5-endo-hydroxy-bicyclo [5,3,7] decan-8-one acetate (described by D.K. Banerjee Method / Indian. J. Chem., 10, 1/1972/7, starting from and. EXAMPLE 45 Prepares the ethylene dioxl derivative of the starting compound (29.1 g) This product is treated with potassium carbonate in 2% aqueous methanol. hydrolyzing the product to give 3-endo-hydroxy-8,8-ethylenedioxybicyclo [5.3.3] decane, which is oxidized in the same manner as in Example 46 and then treated with dlethyl carbonate in the same manner as in Example 46, and 21.2 g of dl-8,8-ethylenedioxy-bicyclo [5.3.0] decane-2-carboxylic acid is obtained. A = 254 nm, = 7000.

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Example 56

The ethylenedioxybicycloalkane keto esters obtained as described in Examples 46, 47 and 55 · were reduced as follows:

To a solution of 0.025 mol of ethylenedioxybicycloalkane-ketoester in 75 ml of ethanol and 75 ml of dl of chloromethane is added 0.9 g of sodium borohydride in portions at -20 ° C. After stirring, the unreacted hydride was quenched by addition of 12 ml of acetone. The mixture was warmed to room temperature, treated with 20% aqueous potassium dihydrogen phosphate, and the solvent was evaporated. The residue was diluted with water (20 mL) and extracted with dichloromethane. The combined organic solvent solutions are washed with water, dried and the solvent is distilled off. The residue was allowed to stand at room temperature for 12 hours with a solution of 0.54 g of sodium methylate in 20 ml of anhydrous methanol. Then 0.59 g of acetic acid is added, the solvent is distilled off and the residue is extracted with dichloromethane. In this way, about 0.022 mol of the ethylene dioxybicycloalkane hydroxy ester listed below is obtained:

dl-3-endo-hydroxy ~ 6,6 ~ ethylenedioxy-bicyclo / 3.2.07heptán-2-exo-carboxylic acid methyl ester; 300 as trimethylsilyl ether;

dl-3-endo-hydroxy-6,6 _T et ylene-dioxy-bicyclo / 3 · 2.O / heptane-4-exo-carboxylic acid methyl ester *? r, also known as DL-3-endo-hydroxyphenyl -7,7- © methylene-dioxy-bicyclo / 3 «2.Q7heptán-2-exo-carboxylic acid methyl ester; M ⁺ 300 as trimethylsilyl ether;

dl-3-endo-hydroxy-7,7-ethylenedioxy-bicyclo [4.3.07] nonane-2-exo-carboxylic acid methyl ester; 3 323 as trimethylsilyl ether;

dl-3-endo-hydroxy-8,8-ethylenedioxy-bicyclo [5.3.0] nonane-2-exo-carboxylic acid methyl ester, M323 as trimethylsilyl ether;

dl-3-endo-hydroxy-8,8-ethylenedioxy-bicyclo [5.3.0] decane-2-exo-carboxylic acid methyl ester, 342 as trimethylsilyl ether.

0.02 mol of the above compounds in 25 ml of anhydrous dichloromethane as a solvent are treated with 2 g of 2,3-dihydropyran and 38 mg / 0.0002 mol / p-toluenesulfonic acid at room temperature for two hours. The reaction was quenched with rich pyridine (0.1 mL), evaporated under reduced pressure to give the corresponding 3-tetrahydropyranyl ethers, which were used without further purification.

57 · example

The 3-endo-hydroxybicycloalkane-2-exo-carboxylic acid methyl esters and their 3-tetrahydropyranyl ethers obtained as described in Example 5θ are reduced to the corresponding 2-exo-hydroxymethyl as described below. compounds with an:

To a solution of 0.02 mole of keto-ester (in either 3-hydroxy or 3-tetrahydropyran-2 * -yloxy) form in 25 ml of diethyl ether in water is added dropwise 0.4 g lithium aluminum hydride in a stirred suspension of 50 ml of anhydrous diethyl ether and stirred for a further half an hour. The excess hydride was then quenched by addition of 5 ml of acetone and water-saturated diethyl ether, 12 g of anhydrous magnesium sulfate was added and the solvent was distilled off from the organic solvent. In this way, the following compounds were obtained:

-55182,726

3-endo-hydroxy-2-exo-hydroxymethyl-6,6-ethylenecarboxylic acid (3-hydroxy-2H) -heptane M 342 as bis / trimethylsilyl ether / sulfur ;

3-en-dehydroxy-2-oxohydroxymethyl-7,7-e 11 -enedioxy-bis (2-hydroxy) -3,3-heptane; M 342 as bis (trimethylsilyl ether) sulfur;

3-endo-Eidroxy-2-oxo-hydroxymethyl-7,7-ethylene-dioxy-bis-chloro / 5,3·θ7ηοηάηϊ M 370 as bis / trimethylsilyl ether

3-Endo-oxy-2-exo-hydroxy-methyl-8,8-ethylene-di-oxybic chloro-4,3 * 7-nonane; M 370 as bis (trimethylsilyl ether); ^-

3-endo-hydroxy-2-exo-hydroxymethyl-8,8-ethylenedioxy-bicyclo [3,3,7,07] as M 384 as bis (trimethylsilyl ether)?

and their 3-endo- (tetrahydropyran-2 ^, 3-yloxy) analogs in racemic form or, if the starting material for the reduction is an optically active compound obtained from the partial reading described below, then the optically active compound / nat and self / form®

Example 58 To a solution of g / 0.02 mol / 3-endo-hydroxy-2-exo-hydroxymethyl-8,8-ethylenedioxybicyclo / 5.3.07 decane in 20 ml of methanol and 2 ml of water was added. 3 g of p-toluene azulfonic acid and reflux for 2 hours. The solvent was distilled off under reduced pressure and the residue was filtered through a short pad of silica gel to give the free ketone.

4.7 g of 3-endo-hydroxy-2-exo-hydroxymethyl-1-b 1 -cyclo [5. A solution of anhydrous dimethylsulfoxide (1 mL) was reacted with Ilide from 27 g of potassium tert-butylate in 280 mL of dimethyl sulfoxide (3-carboxypropyl) -phosphonium bromide for 5 hours at 40 ° C. The mixture was then diluted with 300 ml of water. and partitioned between diethyl ether and benzene 80:20 to remove triphenylphosphine oxide. The aqueous alkaline solution was acidified to pH * 5 and extracted eight times with 200 ml of diethyl ether 4 and then five times with 100 ml of diethyl ether: ethyl acetate 3: 9. The combined organic solvent solutions were combined, dried, concentrated to a volume of 100 ml, and the concentrated solution was treated with diethyl ether diazomethane and the solvent was distilled off.

The crude methyl ester was chromatographed on 100 g of silica gel eluting with ethyl acetate. In this way, 4.1 g _X. - (20 - 12) -oct an or-12 -hydroxymethyl 1-11 ^λ -hydroxy-9a-de-oxy-9a, 9b, 7-homo-1-trimethylene-2-n or-pr os zt ac i kl-5 / Ζ.E / -en-a av-me t i1 and z * space are obtained. M 426 as biSz (trimethylsilyl ether).

The product thus obtained was treated with 12 ml of anhydrous dimethyl fumaramide, 2.2 g of dimethyl tert-butylsilyl chloride and 1.55 g of imidazole for 24 hours at 15 ° C. With stirring, the mixture is diluted with 24 ml of water and extracted with diethyl ether, and the residue obtained after distilling off the solvent was chromatographed on 25 g of silica gel, eluting with a mixture of cyclohexane and diethyl ether. Yield: 4.31 g (80%) of the corresponding 12-dimethyl-11'-tertiary-butylsilyloxy derivative. M 39θ m / e.

This product was reacted in pyridine (10 ml) with acetic anhydride (5 ml) at room temperature for 12 hours and then hydrolyzed with p-toluenesulphonic acid in two aqueous methanol to give (2S, 12S) -octane-12 - * - hydroxymethyl-11Y-acetoxy 9a-deoxy-9a,

9b, 7a-homo-trimethylene-2-nor-prostalicyclo-5 [beta] -en-a-methyl-ester is obtained (M 324 m / e). Pure 5o-5 and 5-trans-56

-56182.726 meridians were chromatographed on silica gel support, treated with 3% silver nitrate solution in a high performance liquid chromatography apparatus using dichloromethane and ethyl acetate as eluent, and the chromatograph was separated by refractive index measurement. apart.

Similarly, instead of the corresponding perhydro-azulene derivative, 3-endo-hydroxy-7,7-ethylenedioxybicyclo [4.5.07] nonane-2-exo-carboxylic acid methyl ester and [beta] -carboxy Instead of -propyl / phosphonium bromide, starting from 4-carboxybutyl / phosphonium bromo, N * - [20- (12) -octanor-12-hydroxymethyl-11-acetoxy-9a] is prepared. deoxy-9a, 7a-homo-dimethylene-proscyclac-5 / Z, N-ene-4-methyl ester (M 324 m / e) and its pure 5-cis and 5-trans isomers.

59 · example

Starting from the 2-exo-hydroxymethyl-tetrahydropyranyl ether derivatives obtained in Example 57, or the 12'-hydroxymethyl-11-acetoxy derivatives obtained in Example 58, the following oxidation step is carried out: the corresponding aldehydes;

To a stirred solution of the hydroxymethyl derivative (0.002 mol) in benzene dimethylsulfoxide (75 ml) (6 ml) was added dicyclohexylcarbodiimide (0.64 g), pyridine (0.1 ml), trifluoroacetic acid (0.05 ml), and stir for an hour. It is then diluted with 20 ml of benzene and 10 ml of water and stirred for a further half an hour. The dicyclohexylurea was filtered off and the organic solvent solution was washed with water to neutral and then concentrated to a volume of 10 ml. Thus, a solution of the aldehydes listed below in anhydrous benzene · obtained: 3 endo / ^{tetrahydro-pyran-2-yl-oxy} / -2-exo-formyl-6,6-ethylene-di-oxy-azoniabicyclo · * / 3.2.0 / heptane; M ⁺ 102: 180 m / e; 3 endo / ^{= tetrahydro-pyran-2-yl-oxy} / -2-exo-formyl-7,7-dioxin-ethyl-bicyclo / 3.2.0 / heptane; M ⁺ 102: 180 m / e; 3 endo / ^{tetrahydro-pyran-2-yl-oxy} / -2-exo-formyl-7,7-ethylene-di-oxy-bicyclo + / 4.3 »0 / nonane; BT - 102: 208 m / e;

3 endo / o ⁼ tetrahydrobenzimidazole pyran-2'-yloxy / -2-exo-formyl-8,8-ethylene-di-oxy-bicyclo ·· / 4.3 «0 / nonane; M - 102: 208 m / e; 3-endo- (tetrahydro-pyran-2 * -yloxy) -2-exo-formyl-8,8-ethylenedioxy-bicyclo [5.0.0] decane; M - 102: 222 m / e.

61- (2O-12) -octanor-12'-formyl-H-acetoxy-9a-deoxy-9a, 9b, 7-homo-trimethylene-2-nor-prostacyclo-5Z, E-enoic acid methyl- ester;

M, 322 m / e;

U- (20/12) -Octor-12-formyl-11-acetoxy-9a-deoxy-9a, 7a-ho-dimethylene-prostacycl-5 / Z, E-enoic acid methyl ester, M 322 m / e.

All of these compounds were used in the Wittig-Horner reaction without further purification.

Example 60 To a stirred suspension of mg / 0.0022 mol / sodium hydride / 80% in mineral oil dispersion / 15 ml in benzene, 0.49 g of 2-oxo-heptyl / dimethylphosphonate is added. of benzene, the mixture was stirred for 45 minutes, and 0.002 moles of '- (2'-12'-octanor-12j-formyl-1'-acetoxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor) were added. methyl ester of prostacyclo-5-trans-enoic acid was prepared with 10 ml of benzene

-57182.726. The reaction mixture was stirred for an additional hour and quenched by the addition of acetic acid (132 mg) in benzene (5 mL). The organic solvent solution was washed with water to neutral, dried and the solvent was distilled off.

The residue (1.2 g) was chromatographed on silica gel (10 g), eluting with a mixture of cyclohexane and ethyl acetate. In this way, 0.76 g of HX-acetoxy-15-oxo-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-n-ortho acyl-5-tr an 13-1trans.z-4R-diethyl methyl ester is obtained, _max = 228 m / l, ε = 9800.

Starting from the other aldehydes obtained in the same manner as in Example 59 and following the procedure described above, the following <y, ^ - unsaturated ketones are obtained:

11 _T acetoxy-15-oxo-9a-desoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prosttaicyclo-5-cis, 13-trans-dienoate, ethyl ester, λ =

228 m / u, ≤ 10,000 and a mixture of the compound 5 / Z, E / isomer; M 418, Μ - CH COPh 358 »ll - <- acetoxy-15-oxo-9-deoxy-9a, 7a ~ prosztaciklaX homo-dimethylene-5-trans, 13-trans-dienoic acid methyl ester, A _max» 229 m / u ^ A a

000, as well as a mixture of the 5-cis isomer and the 5 Z-β isomer; M 418, M - CH, CO 2 H 358, and the following compounds: 2

2-exo / 3'-oxo-oct-l-trans-en-l-yl / -3-endo / tetrahydropyran * ^-2, yl »oxy / 6,6-ethylene-dioxo bicyclo / 3.2.07heptán; M 102: 276;

2-exo- (3 * -oxooct-1 * -trans-ene-1'-l'-3-endo- (tetrahydropyran) -2 ^{, 3} -yloxy) -7,7-ethylenedioxy bicyclo / 3.2.07heptán; M 102:

'276;'' ......... ^;

2-N- (3'-oxo-oct-1'-tr ans z-en-1 * -yl) -3-endo-3-endo-dro-pyran * -2'-yloxy-7'-y- ötilén-dioxabicyclo / Í.J.07nonan; M -102: 304;

2-exo- (3 * -oxo-oct-1? -Tr ans z-en-1 * -1? - 3? - endo- (1'-trihydro-pyran) -2'-yloxy) -8 8 ~ azabicyclo dioxin-ethylene / 4.3.07nonán; M -102: 504;

2-exo / ^{3-oxo-oct-l, trans-en-l-yl} / -3-endo / * tetrahydro-pyran -2-yloxy / -8,8-ethylenedioxy -bicyclo / 5.3.07 decane, M -102:

...... 318 .------------------------------------------ -------------------------------------------------- ----------------

Example 61

Starting from various dimethylphosphonates and following the procedure described in Example 60, the following γ-sheets are prepared: -? 0.002 mole of 3-endo- (tetrahydropyran-2'-yloxy). -2-exo-formyl-7,7-e ^, 0.4 g of ethylenedioxybicyclo [3.2.0] heptane reacted with 2-oxo-3 (S), R-fluoroheptyl-dimethylphosphonate-OT72 ~ g * 3 endo / tetrahydro-pyran-2-yloxy * / -2-exo / ^3-oxo-4 / S, R / -fluoro>oct-l'tranaz-en- 1,1,7 - ^, 7,7-ethylenedioxybicyclo [3.2.07] heptane was obtained, λλ &gt; = 229 m / u = 9900, [α] _D = + 98 ° (chloroform).

b / 0.002 mole of 3-endo- (tetrahydropyran-2 * -yloxy) -2-ex-formyl-6,6-ethylenedioxybicyclo [3.2.07] heptene / 2-oxo-octyl] - Reaction of dimethylphosphonate with 3-endo-7-tetrahydro-plran-2H-yloxy-2-exo- (3'-oxonone-1'-trans-en-1'-yl) -6 , 6-ethylenedioxy | 58

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-bicyclo / 3.2.07 heptane, 7 = 228 m / u. . £ = 9300. M ⁺ 102: 290 m / e7 ^max * c / 3-Endo- / tetrahi dr o-pyran-2 * -yloxy / -2-exo-formyl-7,7 · * - ethylenedioxy-bicyclo / 3.2.07heptánt 0.565 g / 2-oxo-4-phenylbutyl / -dimetll phosphonate obtained: 3 endo / tetrahydrobenzimidazole o-pyr an- ^»-2, -yloxy / -2- exo / ^{3-oxo-5-phenyl-pent-l »-tranaz-en-l-yl} / 7, ^l 3-ethylenedioxy-bicyclo / 3.2.07heptánt obtained. Irish - 102: 310 m / ^.

0.52 g of 2-oxo-d-3-endo-tetrahydropyran-2 * -yloxy-2-exo-formyl-7,7-r-ethylenedioxy-cyclohexyl-3-ol nonane. -3S-methylheptyl / - or / 2-oxo-3R-methylheptyl / dimethyl phosphonate re- »agáltatva 3- endo / ± flro ^{tetrahydro-pyran-2-yl-oxy} / -2- exo / ^3-oxo-4, 4-methyl-oct-l-trans z-en-1'-yl / 7,7-ethylenedioxy-bicyclo / 5.3 · 07 Nonant / M - 102 318 m / e, respectively 3-endo- (tetrahydropyran-2-yloxy) -2-exo- (3 * -oxo-4 ^, N-methyl-oct-1 ^, trans-en-1 ^, - il-7,7-ethylenedioxybicyclo [5.3.07] was obtained, M + - 102: 318 m / e

Example 62

3-Endo- (1-ethanahydro-pyran-2 * -1-oxy) -2-exo- (3'-oxo-4 *) R, 21'-fluorooct-1'-tranazene-en- To a solution of i-yl-7,7-ethyl-ee dioxybicyclo [3.2.0] heptane in 15 ml of anhydrous pyridine was added 0.8 g of pyridine-hydrobromide perbromide / Cl-HcN.HBr.B^/ under stirring. The mixture was stirred at room temperature for 4 hours, then the precipitate was filtered off and the filtrate was partitioned between ice-cold 2N sulfuric acid and ethyl acetate. Is this? methyl acetate solution was chilled 0.5N sulfuric acid solution, washed with brine and aqueous sodium carbonate solution, 1% and then with water until neutral to give 0.71 g of ^2-bromo-4 * / R, S N-fluoroferament * is obtained which is a mixture of the 4'S and 4'R derivatives of the two diastereomers. The pure isomers were separated by silica gel high performance liquid chromatography (85:15) dichloromethane: diethyl ether to give 0.22 g of 3-endo- / tetrahydropyran-2'-yl. oxy / -2-exo / ^{2-bromo-3-oxo-4-fluoro} * R * -trans-oct-l-en-l-yl / 7,7-ethylenedioxy-bicyclo / 3 »2.p7heptánt / A _max = 250 m / u = 9830 / 0.19 g 4'S-fluoro isomer / \ = 251 m / u £ = 9750 /.

Starting from various N-unsaturated ketones and following the procedure described above, the following compounds are obtained:

3 endo / tetrahydropyran-2'-yl-oxy / -2-exo / ^{2-bromo-3'-oxo-non-1'-tr} ans z-en-1 »-i1 / -6 , 6-ethylenedioxybenzo [3,2,7] heptane;

M - 102: 368.370 m / e

3 endo / tetrahydropyran-2'-yloxy / -2-exo / ^{2-bromo-3-oxo-oct-l} »trans-en-l" yl / -7> 7 ethylene dioxybicyclo [4.3.07] nonane, 1T - 102: 382, 384 m / e.

63 · example

---------------- 0.4 g of iBX-hydroxy-1, 4-oxo-4-a-deoxy-baryloxycarbonyl-dimethyl.

To a solution of mevil-prostacyclo-5-trans, 13-trans-dienoic acid in 8 ml of dir ethyl ether and 4 ml of toluene is added 5 ml of 5% diethyl ether in diethyl ether with stirring at -30 ° C. iodide solution and the mixture was stirred for 4 hours. After heating to 0, the excess reagent was quenched by addition of 20% aqueous ammonium chloride solution. The serum solvent solution was washed with water, dried, and after the addition of 0.1 in. Of pyridine, the solvent was distilled off. Marass

The precipitate was dissolved in 10 ml of anhydrous methanol and stirred in 0.1 g of anhydrous potassium carbonate for two hours. The insoluble material is filtered off, the solvent is removed from the filtrate under reduced pressure, and the residue is partitioned between ethyl acetate and 20% sodium dihydrogen phosphate solution. The organic solvent solution is worked up in the usual manner and concentrated to a small volume. The residue is chromatographed on 20 g of silica gel, eluting with 80:20 diethyl ether / diisopropyl ether. 0.1 g of 11-, 15S-dihydroxy-15-methyl-9a-deoxy-9a, 7a-homodimethylene-rrostacyclo-5-tr ans z, 13-tr ans z-dienoic acid methyl ester / M 392 and 0.085 g of the 15R isomer were obtained.

Similarly, methyl 11β, 15S-dihydroxy-15-methyl-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacyclo-5-trans, 13-trans-dienoic acid is obtained in a similar manner. 392 / and its 15R eplmer ice.

The free esters from the above esters are obtained by boiling a 80:20 solution of the methyl esters in methanol / water in the presence of 2% potassium carbonate. The solvent was distilled off under reduced pressure and the residue was partitioned between diethyl ether and water. The product was extracted from the diethyl ether solution with 0.5% potassium carbonate solution, acidified to pH 6 and extracted with diethyl ether. The combined diethyl ether solutions were washed, dried over magnesium sulfate and the solvent was distilled off to give the free acids.

Example 64

The N-unsaturated ketones obtained as described in Examples 59, 60 and 61 were converted to the corresponding allylic alcohols by the following procedure:

To a stirred solution of zinc borohydride (0. 25 mol) in anhydrous diethyl ether (0.002 mol) in anhydrous diethyl ether (20 ml) was added dropwise with stirring over half an hour. After stirring for a further 2 hours, the excess hydride was quenched by the addition of saturated sodium chloride solution. The organic solvent solution was washed neutral, dried over sodium sulfate and the solvent was distilled off. The residue was purified on silica gel using a mixture of dichloromethane and ethyl acetate as the eluent to give 11-acetoxy-15S-hydroxy-9a-deoxy-9 & alpha, 9b, 7a-homo-trimethylene-2-nor-pr. z-diacyl-5-c is also z, 13-trans z-dienoic acid methyl ester (M 420), and its 5-trans and 5 / Z, E-geometric isomeric signal and '-acetoxy -15S-hydroxy-9a-deoxy-9a, 7a-homodimethylene-prostacyclo-5-trans, 13-trans-dienoic acid methyl ester (M 420), and its 5-cis and 5 / Z, E-geometries an isomeric signal is obtained.

In a similar manner, the following compounds were prepared:

3 endo / ^{PIRQ-tetrahydro-2-yloxy} / -3'S-hydroxy-oct-l? -Trans-en-l-yl / 6,6-ethylene-dioxin-bicyclo / 3 »2.07heptán ; M 380 /

3-endo- / tetrahydropyran-2 »-yloxy / -2-exo-73 ^, S-hydroxy-oct ₇

l ^{»trans-en-l-yl} / 7,7-ethylenedioxy-bicyclo / {3-2.07heptan

-60182,726

-1'-trans-en-1 * -yl / -8,8-ethylenedioxybicyclo [5.3.0] nonane;

M 408;

3 endo / tetrahydro-pyran-2-yloxy * / -2-exo / ^{2, bromo-3,} S-hydroxy -4'R-fluoro-oct-l-en-l * -tranaz * -yl (-7,7-ethylenedioxybicyclo [2,3-2,7] heptane); M 476, 478;

3-endo-7-tetrahydro-pyran-2'-yloxy / -2-exo-2H-bromo-3 ^{, 5} -hydroxy-4'S-fluoro-oct-1'-tranazen-1'-yl N, N-ethylenedioxybicyclo [3.2.2.0] heptane; M 476, 478;

3 semen / ^{EetrahidEo-pyran-2-yl-oxy} / -2-exo / ^2'-bromo-3, S-hydroxy-non-l-en-l * -tranaz »yl / -6, 6-ethylenedioxy-bicyclo / 3 «2.07héptán; M 472, 4? 4;

3-endo- (tetrahydropyran-2 * -yloxy) -2-exo- (3'S-hydroxy-non-1H-trans-en-1'-yl) -6,6-ethylenedioxy bicyclo / 3.2.07heptán; M ⁺ 394; . ₄

3 endo / o tetrahydrobenzimidazole-pyran-2 "yl-oxy / -2-exo / 3'S-hydr oxy-5-phenyl-pent-l * * ^{-tran3z-en-l-yl} / 7, 7-ethyl-dioxa-bicyclo / 3.2.0 / heptane; M 414;

3 endo / tetrahydro-pyran-2-yloxy * / -2-exo / 2'-bromo-3-S-hydroxy-oct-l-en-l-tranaz-yl / 7, 7-ethylenedioxy-bicyclo / 5.3.07nonán; M 486, 488;

3 endo / o tetrahydrobenzimidazole-pyran-2-yloxy * / -2-exo / 3 * S-hydr oxy-4'S-methyl-oct-l * ^{-trans-en-l-yl} / -7 7-ethylenedioxybicyclo _[ 5.3.3.0] nonane; M 422;

3-end'o- / tetrahydro-pyr. * -2-yl-oxy / -2-exo / 3 * S * R-hydroxy-4-methyl-1 ο ^ ^ -1 '- ^ 1 * 3η3ζ-βη -ΐ1 / -7,7-- θ ^ 1έη-ά1οχ1-1ιίο1 ^ ο / 5.3 · 07 nonane; ΪΛ 422;

-acetoxy-15R-hydroxy-9a-deoxy-9a, 9b _? 7α-homo-trimethylene-2-nor-pro-taclla-5-cis, 13β-di-ena av-me thi ester, M 420 and its 5 / Z, E / - and 5tranaz - geometric isomers;

-acetoxy-15R-hydroxy-9a-deoxy-9a, 9a-h.-dimethylene-prostate-cyclo-5-tranazole, 13-tranazenedioic acid methyl ether, M 420 and its 5 / Z, E / - and 5cis-geometric isomers;

3 endo / tetrahydro-pyran-2-yloxy * / -2-exo / 3-R-hydroxy-oct-l-en-l * * -trans-yl / 6,6-ethylenedioxy bicyclo / 3.2.07heptán; M 380;

3-endo- (tetrahydropyran-2 * -yloxy) -2-exo- (3'R-hydroxy-oct-1 * -bren-1 * -yl) -7,7-ethylenedioxy -b ici cl / 3 · 2.07heptane; M 380; .

3-endo- (tetrahydropyran-2'-yloxy) -2-exo- (3R) -hydroxyoct-1'-tranazen-1'-yl / -8,8-ethylene- dioxabicyclo / 4.3 Ö7iionan; M 408;

3-endo- (tetrahydro-pyran-2 * -yloxy) -2-exo- (3'R-hydroxy-oct-1 * -tranazen-1'-yl) -8,8- ethylenedioxy-bicyclo / 4.3 »07nonan; M 408;

3-endo- (1'-tertrahydropyran-2-yloxy) -2-exo-2'-bromo-3'R-hydroxy-4 * R-fluorooct-1'-tranazene-en- 1-yl-7,7-ethylenedioxybicyclo [3.2.2] heptane; M ⁺ 476, 478;

3-endo-7 tertrahydro-pyran-2 * -yloxy-2-exo-2 * -bromo-3 * R-hi-oxy-4 * S-fluoro-oct-1 ? -tranazen-1'-yl? -7,7-ethylenedioxybicyclo [3.2.2] heptane; M 476, 478;

3-endo-7tetrahid.ro-pyran-2'-yl-oxy / -2-exo / 2'-Bromo-3'R-hydroxy-non-l * - ^{'fcranaz-en-l-yl} / - 6,6Tetilén-dioxa-bicyclo / 3 »2.07heptán; M 472, 474;

3-endo- (tetrahydropyran-2'-yloxy) -2-exo- (3'R-hydroxynon-1 * -transen-1 * -yl) -6,6-ethylene- dioxy-bicyclo / 3 »2.07heptán; li 394;

-61182,726

3-endo- (tetrahydropyran-2 * -yloxy) -2-exo- (3 * R) -hydroxy-5'-phenyl-pent-1'-trans-en-1 * -11 / -7 , 7-ethylenedioxybicyclo [3.2.0] heptane; M ⁺ 414;

3-endo / tetrahydropyran-2'-11-oxy-2-exo-2'-bromo-3'R-hydroxy-1 * -oct-1 * -trans z-en-1 * -yl /-7,7--ethylene-dioxy-bicyclo/4.3 · 07ηοηέ4;

M * 486, 488;

3 endo / ~ tetrahydro-pyran-2'-yl oxy / -2-exo / 3 * R * S-hydroxy-4-mefcil-oct-l-trans-en-l-yl * / -7 7-ethylenedioxybicyclo / 5.3.07 nonane; M 422; "

3-en do- / tetr ahidr op and an-2 * - i l-oxl / -2-exo- / 3 * R ~ hl dr oxy -4 · R-methyl-oct-1 * -tr ans z-en -1 * -yl / -7,7-ethylenedioxybicyclo [Z. 3.07 nonane, M 422.

65 · example

The (tetrahydropyranyloxy) ethylene dioxybicycloalkane derivatives obtained in Example 64 were converted to the corresponding pro-aza-cyclenic acids as follows:

0.001 mol (tetrahydropyranyloxy / ethylenedioxy) biocyclo *

A solution of the alkane derivative in 15 ml of acetone was refluxed in 10 ml of 1 N aqueous oxalic acid for 8 hours. The acetone is then distilled off under reduced pressure and the remaining aqueous solution is extracted with diethyl ether. The diethyl ether solution was worked up in the usual manner, and after distilling off the solvent, about 0.0006 to 0.001 mol of hydroxy ketone were obtained. This product is dissolved in 2 ml of anhydrous dimethyl sulfoxide and added to a dark red solution of bridge solution of 1.35 g of potassium tert-butylate and 2.6 g of 4-carboxybutyl / triphenylphosphonium bromide in 15 ml of anhydrous dimethyl sulfoxide under nitrogen atmosphere. . The reaction mixture was heated at 40-42 ° C for 6 hours, cooled, diluted with water (20 mL), acidified to pH 5.1 and extracted with diethyl ether (5 x 25 mL). The aqueous solution was discarded, the organic solvent solution was washed with 5 mL of water and this wash water was discarded. The organic solvent solution was then extracted six times with 6 ml of 0.5 N sodium hydroxide solution and washed with water until neutral. The aqueous alkaline solutions were combined, acidified to pH 5 and extracted with diethyl ether. The combined diethyl ether solutions were washed with water (2 mL), dried over sodium sulfate and the solvent was evaporated. This gives a mixture of 5E-isomeric acids 52.

The pure isomers were separated by chromatography on iron (II) and iron (III) ion-free silica (150 times by weight), eluting with a mixture of dichloromethane and ethyl acetate.

The following compounds were prepared in the same manner as described above for 11 ', 15S-dihydroxy-9a-deoxy-9a-trifluoromethylene-prostacyclo-5-tranis,

13-trans-dienoic acid; ΙΓ 552, M ⁺ - CH, 537, M ⁺ -0 _{ς 48} .. 481 Tris / 1-im 1-s 1-1-e t er / - sulfur; ---------------_ ξ_ ~ ^{ll, y,} 15S dihydrochalcone oxy-9a-de oxy-9a-nor -met 11 énr20-meth 1-i c i pr os zt kla- trans-5, 13-dienoic traúsz; M 566, M -CH, 551, Μ σ _β Η _Ί ,

481, as trimethyl azilyl ether; ² ylthio ² (15S-dihydroxy-9-deoxy-9a-nor-20-methylene metilTpiosztacikl-5-trans-en-13-inaav; M ⁺ 564, M-CH, 5 R 9, M-C _fi H 479 as trimethylsilyl ether; ^{2 ', 11} ', 15S-dihydroxy-9a-deoxy-9a-methylene-7a-normethylene-prostacyclo-5-trans, 13-tBans-dienoic acid, M 552 Tris-trimethyl- szi62

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As 111-ether, NMR (CDCl3), ppm: 0.89 (3H, t), 3.33 (1H, m),

4.05 (2H, m), 5.15 (1H, m), 5.55 (2H, m);

31,155-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prestacyl-5-tranaz, 13-tranazadiene; M 364, M -H _o 0 346, M -2H _n 0 328, μ -Η ₂ ο-σ ₅ Η _η 275; . ²

-, 15S-dihydroxy-9-deoxy-9a, 9b-dimetilénTprosztacikla tranaz-5, 13-dienoic tranaz; Μ-H ₂ 0 3 ^ 6, M - 2 H ₂ 0 348;

, 15S-dihydroxy-9-deoxy-9-methylene-7a-nor-16S-methylene-5-fluoro-proaztacikl tranaz-en-13-inaav; M 352; .............

15S-Dihydroxy-9a-deoxy-9a-methylene-7a-normethylene-16R-fluoro-pro-aza-cyclo-5-trans-ene-13-acid; M ⁺ 352;

, 15S-Dihydroxy-9a-deoxy-9a-methylene-7a-normethylene-17 '-phenyl · * -18,19,20-trinoropropyl-5-trans-13-trans-dienoic acid ;

M ⁺ 370;

, 15S-dihydroxy-9-deoxy-9a, 7a-dimethyl-homp-16S-methyl-5, trans-proaztacikla, 13-dlénsav; M 378, M-H ₂ 0 360;

15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16R-methyl-proactacyclo-5-trans, 13-trans-dienoic acid; M ⁺ 378, M-H ₂ 0360;

, 15S-dihydroxy-9-deoxy-9a, 7a-homo-dimethylene proaztacikla-5-trans-en-13-ynoic acid; M 362;

11 ', 15S-dihydroxy-9a-deoxyl-9a-nor-methylene-prostacyclo-9cis, 13-trans-dienoic acid; M 336, M - H ₂ 0 247;

15S-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl-prestacyclo-5-cis, 13-trans-dienoic acid; M 350;

, 15S-dihydroxy-9-deoxy-9-methylene-20-nor-methyl-prosta-5 ~ I ~ 13 ~ ciaz-ynoic acid; M 348;

11,15S-Dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-pro-tacyclo-5-cis, 13-trans-dienoic acid; M ⁺ -H ₂ 0 318; 15'-dihydroxy-9a-deoxyl-9a, 7a-homo-dimethylene-pro-aza-cyclase-5-cis, 13-tranazadiene; M -H _? 0 364;

, ^{15S-dihydroxy-9} -des oxy oxy-9a, 9b-AIME ylene pr o z tacikla 2-5-cis, 13-tranaz diénaav; M ⁺ H ₂ 0 346;

ll <, 15S-dihydroxy-9-deoxy-9-methylene-7a-nor-16S-methylene-5-fluoro-proaztacikl ci3z-en-13-inaav; M 352;

·, 15S-dihydroxy-9a-deoxy-methylene-7a-nor-methylene-fluoro-16R proaztacikl-5-cis-en-13-ynoic acid.; M ⁺ - H ₂ O: 334;

15S-Dihydroxy-9a-desoxy-9a-methylene-7a-nor-methylene-17-phenyl-18,19,20-trinor-prostacyclo-5-ol, 13-trans-dienoic acid; ΜΓ H ₂ 0 352;

117,155-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16S-methyl-prostacyclo-5-cis, 13-trans-dienoic acid; M 378;

11 / 15S-dihydroxy-9-deoxy-9a, 7a-homo-dimethylene-16R-methyl-prosta-cis-5, 13-dienoic biansz; M 378;

11 <, 15S-Dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-claz-en-13-ynoic acid, M ⁺ 362, -------------- ---------------- ----------------------------- and their 15R isomers .

Example 66

0.39 g of 11,15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene *

To a solution of -15-methyl-pro-tacl-kl-5-tr ans, 13-tr-z-di-en-methyl and z, 6 ml of benzene dimethyl azulfoxide in 75-25 was added 0.32 g of dicyclohexyl with stirring. DCC |

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Pyridine (0.044 mL) followed by trifluoroacetic acid (0.022 mL) was stirred for 5 hours. Dilute with benzene (20 mL), add a solution of oxalic acid (1.2 g) in water (10 mL) and stir for a further 20 min. The solids are then filtered off, the organic solvent solution is washed to neutral, dried and the solvent is distilled off.

The residue was chromatographed on silica gel (4 g), eluting with diethyl ether, to give 0.26 g of 11-oxo-15S-hydroxy-9a-deoxy-9a, 7a-homodimethylene-15-methyl-prostacyclo-5-trans. Methyl 13-trans-dienoic acid (M ⁺ 390) is obtained which is hydrolysed to the free acid with 2% aqueous potassium carbonate solution.

Example 67

To a solution of 11.42 g of bicyclo [3.2.0] non-7-en-3-one in 80 ml of ethanol was added 2.5 g of sodium borohydride in portions and the mixture was stirred for 2 hours. Thereafter, 5 ml of acetic acid are added and the solvent is distilled off. The residue was partitioned between water and dichloromethane and the solvent was distilled off from the organic solvent. 11 g were thus obtained

3-h, hydroxy-bicyclo / ^z i.3.07non-7-ene in anhydrous DMF was added 15.6 g ~ dimethyl-t-butylsilyl chloride, and 10.85 g of imidazole, the mixture for 6 hours The reaction mixture was heated at 60 ° C, cooled and diluted with water (66 ml). The solution was subjected to extensive extraction with diethyl ether to give 3- (dimethyl-tert-butyl-3-acyloxy) -bicyclo [5.3.0] non-7-ene (19.1 g) after usual work-up. The product thus obtained was dissolved in 100 ml of anhydrous tetrahydrofuran and 75 ml of a 1M solution of borane in tetrahydrofuran were added at 0 ° C under nitrogen. After 2 hours at 25 ° C, 25 ml of 1 N sodium hydroxide solution and 25 ml of 30% hydrogen peroxide solution are added. The mixture was heated at 60 ° C for 2 h, cooled and diluted with benzene (400 mL). The organic solvent solution was washed with 1% sodium carbonate solution, saturated sodium sulfite solution and saturated sodium chloride solution, dried, and the solvent was distilled off. 20.3 g of crude 3- (dimethyl-tert-butylsilyloxy) -7 / 8,7-hydroxybicyclo [3.1.0] nononone are obtained. To a solution of the alcohol obtained above in 150 ml of a 75:25 mixture of benzene-dimethylsulfoxide was added 16 g of dicyclohexylcarbodiimide, 2 ml of pyridine, followed by 1 ml of trifluoroacetic acid, and the mixture was stirred for a further 5 hours. The reaction mixture was diluted with 400 ml of water, 50 ml of water and 6 g of oxalic acid in 75 ml of water were added and the mixture was stirred for half an hour; stir and then filter the insolubles. The organic solvent solution was washed with water until neutral to give 18.25 S 3-dimethyl-tert-butylsilyloxy-bicyclo [4.3.07] nonane-7 / 87-0nt. This product was dissolved in methanol (60 mL), p-toluenesulfonic acid (1.8 g) was added and the mixture was kept at room temperature for 12 hours. Then 1.95 µl of pyridine are added and the solvent is distilled off. The residue was filtered through silica gel eluting with a mixture of diethyl ether and ethyl acetate to give 10 g of 3-hydroxybicyclo [4.3.0] nonane-7/8 / one.

The product obtained in the above manner is dissolved in 50 ml of benzene,

Anhydrous ethylene glycol (5.264 g) and p-toluenesulfonic acid (0.62 g) were added and the mixture was refluxed for 14 hours while the reaction water was continuously removed. Pyridine (2 mL) was added and the solution was cooled, washed with water, 2% sodium carbonate solution, then brine, and the solvent was distilled off to give 3-hydroxy-7.7 / 8.8 N-ethylenedioxybicyclo [4,3.0] is obtained. Oil, IR (film): 3400 cm; M 198. "·«

4.5 g of dl-3-endo-b-hydroxy-8,8-ethylenedioxybicyclo [4.3.07] nonane-2-exo-carboxylic acid methyl ether in 2%, 80% aqueous hydrolysis with potassium carbonate in methanol gave 4.2 g of free acid.

To a solution of 4.2 g of the free acid obtained above in 120 ml of acetonitrile is added 2.3 g of d - / + / - ephedrine. After standing at room temperature for 2.8 hours, 2.8 g of salt crystallize out, which is recrystallized from acetonitrile to 2.15 g of (+) - 3-endo-hydroxy-8,8-111-dloxybicyclo [3.3.0] nonane-2- Exo-carboxylic acid d - / + / - ephedrine salt is obtained. The mother liquors were combined and the solvent was distilled off. The residue was dissolved in water and adjusted to pH 12-13 with 1 N sodium hydroxide solution. The d - / + / - ephedrine is recovered by extraction with diethyl ether, then the basic aqueous solution is acidified to pH 5, extracted with ethyl acetate and the solvent is distilled off from the organic solvent solution. Dissolve the residue in aoe * · tonitrile and repeat the procedure using / - / - ephedrine. In this way, 7 - [[beta] -N-hydroxy-8,8-ethylenedioxybicyclo [5.3.0] nonane-2-exo-carboxylic acid] - [-] - ephedexine salt is obtained. The salts obtained above are dissolved separately in water, basified with sodium hydroxide, and the optically active base is extracted by extraction with diethyl ether. The aqueous alkaline solution was then acidified to pH 5-5.1 and extracted with ethyl acetate to give +/- 3-endo-hydroxy-8,8-ethylenedioxy-bicyclo [3.3.0]. of nonanone-2-exo-carboxylic acid and N - [3- (3-endo-hydroxy-8,8-ethylenedioxy) -bio [5.3] -nonan-2-exo-carboxylate. These two acids are treated with dlazomethane to form the corresponding methyl ester.

69 »Example g Methyl dl-3-endo-hydroxy-7,7-stile-dioxyl-bicyclo [4.3.07] pentane-2-exo-carboxylic acid methyl olefinate in 100 ml of acetone 20 ml of 2N sulfuric acid. solution for 4 hours.

The acetone is then distilled off under reduced pressure and the remaining aqueous solution is extracted with ethyl acetate. The organic solvent extracts were combined, washed to neutral, dried and the solvent was distilled off. There was thus obtained 21.2 g of dl-3-endo-hi-hydroxy-Hfcl / 10,3'.O7nonan-7-one-2-exo-carbonyl-9-yl-ethyl ester. To this solution of KetorT250 in anhydrous acetonitrile (12 ml) was added 12.1 g of d-1-phenyl-1-ethylamine and 50 ml of solvent was slowly distilled off over half an hour. The remaining solution was slowly cooled to room temperature, followed by precipitation of - [+] - 3-endo-hydroxy-7,7- [1 * -phenyl-1 »-ethylimino] -bicyclo [4.3 *] - nonane-2 -exocarbon-3-acid methyl ester (12.12 g) was filtered off. The mother liquor was concentrated to give 6 g of racemic material. Finally, the latter was concentrated to a volume of 80 ml by 11.42

-65182.726 g of - (-) - 3-endo-hydroxy-7,7- (1'-phenol-1'-eth) -I-imino / -bicyclo [4.3.07] ηοηάη-2-exo-carboxylic acid- methyl ester is obtained.

The two Schiff bases obtained in the above manner were separated by boiling one with a mixture of 160 ml of methanol and 40 ml of 2N sulfuric acid for 2 hours. The methanol was distilled off under reduced pressure, and the remaining aqueous solution was extracted with ethyl acetate. Are the combined organic solvent solutions washed neutral and dried? and distilling off the solvent under reduced pressure salt. In this way, 8.1 g of [+] - 3-endo-hydroxybicyclo [5.3.3] nonane-7-one-2-exo-carboxylic acid methyl ester and 7.2 g of [- (3-eno-3-hydroxy) Methyl 7-on-2-exo-carboxylic acid methyl ester of -bicyclo.

All ethylene dioxybicycloalkane-hydroxycarboxylic acid esters obtained as described in Example 5θ · were resolved as described above to give the following compounds:

[+] - 3-endo-hydroxy-bicyclo [3.2.0] heptan-6-one-2-exo-carboxylmethyl ester;

(+) - 3-endo-hydroxy-bicyclo [3.2.2] heptan-7-one-2-exo-carboxylic acid methyl ester;

/ +/-3- endo-hydroxy-bicyclo [05.3] O7 non-nano-7-on-2-exo-carboxylic acid methyl ester;

/ + / - 3-endo-hydroxy-bicyclo / ^z i.3.07nonán-8-on-2-exo-carboxylic acid methyl ⁱ ^ methyl ester;

(+) - 3-endo-hi-hydroxy-bicyclo [5,3,7] decan-8-one-2-exo-carboxylate;

Methyl 3- (3-endo-hydroxy-bicyclo [3.2.0] heptan-6-one-2-exo-carboxylate);

(-) - 3-endo-hydroxy-bicyclo [3.2.0] heptan-7-one-2-exo-carboxylate methyl ester - [3-dihydroxy-bicyclo] 5.3-O 7 -nonan-7-one-2-exo-carboxylate;

N - [3- (3-endo-hydroxy-bicyclo [3.1.0] nonane-8-one-2-exo-carboxylic acid methyl ester);

/ - / - 3-endo-hydroxy-bicyclo / 5 "3" 07dekán-8-on-2-exo-carboxylic acid methyl ester. *

Starting from the ketones listed above and following the procedure described in Example 55, the corresponding ethylene dioxide derivatives are obtained.

Example 70

With stirring and external cooling, the temperature of the reaction mixture is maintained at 20-22 ° C.

12.7 g of dicyclohexylcarbodiimide, 1.65 ml of pyridine and 0.83 ml of trifluoroacetate are added with 12 g of 2-exo-hydroxymethyl-3-endo-hydroxy-bicyclo [3.3.0] octan-7-one. -7,7-ethylene-3-THP-ether in a solution of 80 ml of benzene / dimethylsulfoxide in a 75/25 solvent mixture. The reaction mixture was diluted with 50 mL of benzene, filtered, washed with water to neutral, dried over sodium sulfate, and the solvents were evaporated to a small volume (30 mL) and this solvent was added with stirring to the sodium phosphonate solution. A solution of 10.8 g of 2-oxooctyldimethylphosphonate in 30 ml of benzene was added to a suspension of 1.35 g of sodium hydride / 80% / 12 ml of benzene. After 15 minutes, the reaction was quenched and the reaction mixture was heated with 6 mL of acetic acid. wash with water to neutral, dry over sodium sulfate. The solvent was evaporated in vacuo to a residue

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Chromatography on SiOp gel. -Etilacetát using n-hexane / 80: 20 applied / diluent oil aárga 12.7 g of 2-exo / 3 ^{-oxo-non-l'-trans-l-enyl} / -3-endo-hydroxy-bicyclo / 3 * 3.0 / octane-7-one-7,7-ethylenedioxy-3-THP-ether is obtained. IR / dilution "without / cm ^-1: 2970-1690-1670-1625 - NME / CDC1 _X / '= 0.88 73H, t / -3,2-4,2 / 7H, m / 4.60 to 4 , 75 / 1H, m / 6.18-6.20 / 1H <d / 6.79 6.89 / 1H, dd /.

The above compound was dissolved in 10 ml of anhydrous pyridine and 24 g of pyridine bromide hydrobromide were added with stirring.

After 1.30 hours, the reaction mixture was diluted with 500 mL of 30% aqueous NaHPPO 4 and extracted with ethyl acetate.

The organic extracts were collected, washed neutral, dried over Na 2 SO 4 and evaporated to dryness in vacuo.

The residue was purified on SiOp / Eluent: hexane: ethyl ether 80:20 solvent /: 1.3 g of 2-exo / ^{2'-bromo-3-oxo-non-l, trans-l-enyl} / - 3-endo-hydroxy-bi-cyclo [3,3,7] octan-7-one-7,7-ethylenedioxy-3-THP-ether is obtained, IB (without dilution) - (cm @ ^-1 ): 2940-1685-1610.

The resulting 12.6 g brómketont methanol dissolved in 32 ml of methanol was added dropwise to a solution of 4.2 g ml NaBFL'6 ^r and -20 Οθ cooled. The reduction takes place within 1 hour. The reaction mixture was then diluted with an excess of 30% aqueous NaHPPO 4 and extracted with ethyl acetate. The organic extracts were collected, washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue (12 g) was dissolved in acetone (100 mL) and treated with 1 N aqueous oxalic acid (50 mL) for 12 hours at 40 ° C. The acetone was evaporated in vacuo at 50 ° C and the aqueous slurry was extracted with ethyl acetate. The organic extracts were collected and washed with brine. After drying over Na2SO4, the solvent was evaporated and the residue was chromatographed on a silica gel column. Elution with n-Hexone-ethyl acetate (50:50 / solvent mixture) gave the following keto alcohols:

A mixture of 2-exo / ^{2-bromo-3-R-hydroxy-non-l,} l-trans-enyl / 3-en do-hydroxy-bicyclo ~ / 3.3 "07oktán-7-one and

4.2 g of 2-exo / 2 * ^{-Eróm-3'-S-hydroxy-non-l,} l-trans-enyl / endo -3-hydr oxy-azabicyclo b ic / 3.3 · O / October on - / - C.

To a solution of 18 g of sodium tert-butoxide in 180 ml of anhydrous DMSO under an inert gas / Np atmosphere is added 32.4 g of 4-carboxybutyl-triphenylphosphonium bromide to give a red solution of the ylide compound. Thereafter, 4.2 g of the above 3 * S-alcohol are added over 5 minutes. The reaction mixture was kept under stirring at room temperature for 15 hours under inert gas. The reaction mixture was in an excess of ca. Dilute with 350 ml of a 30% NaHpPO ₂ solution and extract with 5 x 50 ml of ethyl ether. The cerebral extracts were combined, washed with brine (15 mL) and washed neutral with 5 mL x 1 mL of 1 N NaOH. The basic extracts were combined, acidified to pH 5-θ and then extracted with 3 x 30 mL, 1 x 15 mL and 1 x 10 mL ethyl ether. These organic extracts were combined, washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The residue is chromatographed on a silica gel column eluting with 100: 0.5 ethyl ether / acetic acid. so

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1.21 g of 5 'Cis-11A, 15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycl-5-en-13-ynoic acid

Nuclear Magnetic Resonance Spectrum (CDC,), δ qppm: 0.90 (3H, t); 4.00 (1H, m); 4.40 (1H, t); 5.27 ^p / 1H, t /; and

1.84 g of 5-thiansz-11'-A-15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycl-5-en-13-ynoic acid are obtained without IR / dilution / v / cm 'Í / • 3350 2115 1705

NMR / CF, C0 D _o /, / = '0.9 / 3H, t / L 4.00 / H m /; 4.40 / 1H, t / j 5.30> ^a / 1H, t /; 6.38 (3H, m).

Similarly, starting from the above prepared alcohol Wittig reaction 3 * R 'for 4-carboxybutyl triphenyl foszfóniumbromiddal S10 and chromatography on ₂ -n separated ethyl ether-acetic acid / 99.5: 0.5 / solvent mixture to give the following compounds :

0.4 g of 5-cis-lLY, 15R-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycl-5-en-13-ynoic acid,

Nuclear Magnetic Resonance Spectrum (CBCl),? Ppm: 0.90 (3H, t); 4.00 (1H, m); 4.40 / 1H, t /; 5.28 ^p / 1H, t /; and

0.8 g of 5-tJans z-11,15R-dihydroxy-9a-deoxy-9a-methylene-20-methyl *

-pr os zt ac i kl-5-en-13-in-s av, _________________________________________________ _____________________________

Nuclear Magnetic Resonance Spectrum (CDCl3)? 4.00 (1H, m); 4.39 / lH, t / j $ 530 / lH, t /.

Example 71

Using the procedure of Example 70, but employing 2-oxononyldimethylphosphonate instead of 2-oxooctyldimethylphosphonate, the following compounds were obtained:

5-cis-11a, 15S-dihydroxy-9a-deoxy-9a-methylene-20-ethyl-prostacycl-5-en-13-ynoic acid, m / e 358 (M-2H ₂ O);

NME (CDCl3), 1-0.88 / 3H, t / 2.37 / 2H, t /; 3.98 / 1H, m /? 4.40 ---- / lH.t /; 5.30 (1H, broad t); 5.98 (3H, broad),

5-trans-10,15S-Dihydroxy-9a-deoxy-9a-methylene-20-ethyl-prostacyclo-5-en-13-ynoic acid, m / e 358 / M ⁺ -H ₂ O /, 340 / M -2H ₂ 0 /.

NMR (CDCl 3): 0.88 (3H, t); 2.36 (2H, t); 3.98 (1H, m); 4.39 (1H, t); 5.30 (1H, broad t); 5.62 (3H, broad), and their 15 R epimers:

5-cis z-11'-, 15R-Dihydro-bxi-9a-deoxy-9a-methylene-20-ethyl-prop acycl-5-en-13-yn acid, m / e 358 / M -H ₂ 0 /, 340 / M-2H ₂ 0/5 tiansz-llc <, 15R-Dihydroxy-9-deoxy-9a-methyl ~ 2Q "ethyl"'Pross"ta-embarrassing-5-en- 13-in-acid, m / e 358 / M -H ₂ 0 /, 340 / M-2H ₂ 0 /.

Example 72 To a solution of freshly sublimed potassium tert-butoxide (g) in water (30 ml) tea-dimethyl sulfoxide at room temperature under nitrogen atmosphere was treated with 5.4 g of 4-carboxyl-butyl-triphenylphosphonium bromide followed by 600 mg of 2-exo- ^{3'S-hydroxy-non-l-ynyl} / -3-endo-hydroxy-bioiklo / 3 "3" 27 ⁰ octan-7-one 5 & 1 dimethyl sulfoxide was added DOS * -------- * -----— ------—— ------ The reaction mixture was kept at room temperature under nitrogen for 15 hours and then poured into 30% aqueous sodium dihydrogen phosphate solution. The aqueous mixture was extracted with diethyl ether and the combined ethereal extracts were extracted with 1N aqueous sodium hydroxide solution.

The aqueous basic extract was then acidified to pH 5 and extracted again with diethyl ether. The organic phase lift

The mixture is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was purified by column chromatography on silica gel using diethyl etheracetic acid (95.5: 0.5) as eluent to give 90 mg of 11,15S-dibydroxy-9a-des-oxy-9a-methylene. -2-methyl-acyl-5-c is also z-en-13-inavate,

Nuclear Magnetic Resonance Spectrum (CDC1) 0.1 µm / ppm: 0.90 (3H, t, 4.00 (1H, m), 4.40 (1H), t ( ²⁾ and 5.27 (1H, t); and 130 mg of 11 ^y, 15S-dihydroxy-9-deoxy-9-methylene-20-methyl-trans-prosta-5-en-13-ipaayat ___________ ,, _

Nuclear Magnetic Resonance Spectrum (CDCl3). ppm: 0.90 / 3Η, t /, 4.00 (1H, m /), 4.40 ^p / 1H, t /, and 5.30 / 1H, t /.

In a similar manner, but replacing 2-exo / 3'R-hydroxy-non-1-ynyl * / 3-endo-hydroxy-bi cyclo / 3.3 · 07oktan-7-one was obtained starting from the II ^v, 15R- dlhydroxy-9a-deoxyl-9a-mefcylene-20-methyl-pros-4-tacyclo-5-cis-en-13-one-ina,

NMR / CLC1, · / r / ppm: 0.90 / 3H, t /, 4.00 / H, m /, 4.40 ² / lH.t / 5.28 / lH.t /; and the '''

11 <, 15R-Dihydroxy-9a-desoxy-9a-methylene-20-methyl-propacyclic-5-trans-ene-13-acetic acid /

Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.90 (3H, t), 4.00 (1H), m /, 4.39 ^p (1H), t /, and 5.50 (1H, t). .

In a similar manner, however, from 2-exo- [3 ^, 5-hydroxyoct-1'-ynyl] -3-endo-hydroxybicyclo [3.3.0] octan-7-one or its 3 * R-hydroxy starting from its isomer, 11?, 15S-dibydroxy-9a-deoxy-9a-methylene-prostacycl-5-cis-ene-13-acid,

Nuclear Magnetic Resonance Spectrum (δ _D / G) δ (ppm): 0.90 (3H, t), 4.00 (1H), m / 4.39 (1H), ² broad t /, 5.29 (1H), broad t / and

4,15 S-dibydroxy-9a-deoxy-9a-methylene-prestacycl-5-trans »** stv oil *

NMR / CDCl _x / c / ppm: 0.90 / 3H, t /, 4.00 /ll'.a/, 4.40 / IH, br t /, 5.28 / IH, br t /, and 11X, 15R-Dihydroxy-9a-deoxy-9a-methyleneprozac-5-cis-en-13-ynoic acid,

Nuclear Magnetic Resonance Spectrum (GDG1), δ ppm: 0.90 (3H, t), 4.00 (1H), m /, 4.40 (1H), broad t (5.28 (1H), broad t), and IIx). 15E-Dihydroxy-9a-de-oxy-9a-methyl-ene-acyl-5-tr ans z-en «<

-13-Inava, ____ ___ "___ _ ______ ______

Nuclear Magnetic Resonance Spectrum (CDCÍ,) δ ppm: 0.90 - 73H, t /, 4, θϋϋϋΪΗ, ^ΕΖ ^, 4759ΎΠΓ7, broad t /, and 5.29, 2H, broad t /.

Example 73

Following the procedure of Example 34, the following compounds were prepared from the appropriate starting material:

11,15S-Dibydroxy-9a-deoxy-9a-methylene-20-methyl-prostacyclo-5-trans-en-13-ynoic acid,

Nuclear Magnetic Resonance Spectrum (CDC1,) δ ppm: 0.90 (3H, t), 4.00 (1H), m /, 4.40- (πγ, γ) - - 5730 (1H), δ / m / a. the corresponding 5-cis 3Z isomer,

Nuclear Magnetic Resonance Spectrum? / CDClx / δ ppm: 0.90 / 3H, t /, 4.00 / 1H, m /, 4.40 / 1H, t /, 5.27 / ia, t / 5

U ^ 15R-dihydroxy-9-deoxy-9a-methyl-20-methyl-trans-prosta-5-en-13-ynoic acid,

Nuclear Magnetic Resonance Spectrum (CDC1,), δ ppm: 0.90 (3H, t), 4.00 (1H, m), $ 4.39 (1H), t /, 5.50 (1H, t);

and the corresponding 5-ciazomer,

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Nuclear Magnetic Resonance Spectrum (CDO11 _λ ) / ppm: 0.90 (pH, t /, 4.00 (1H), m /, 4.40 (1H), t /, 5.28 (1H, t)).

Example 74

Using the procedure described in Example 35, the following compounds were prepared from the appropriate starting materials:

, 15S-dihydroxy-9-deoxy-9-methylene-20-methyl-trans-prosta-5-en-13-ynoic acid,

NMR / CDO1, / _y ppm: 0.90 / 3H, t /, 4.00 / H, m /, 4.40 ⁵ / H, t /, 5.30 / H, t /, and the corresponding 5-cis isomer,

Nuclear Magnetic Resonance Spectrum (CDCl3), δ ppm: 0.90 (3H, t), 4.00 (1H), m /, 4.40 (1H), t (), 5.27 (1H), t /;

15R-Dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacyclic-5-transene-13-insic acid,

Nuclear Magnetic Resonance Spectrum (GDC1) / ppm: 0.90 (3H, t), 4.00 (1H), m /, 4.39 ^p / 1H, t /, 5.30 (1H), t /, and the corresponding δ -oisz isomer,

Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.90 (3H, t), 4.00 (1H), m /, 4.40 (1H), t /, 5.28 (1H, t).

Example 75

By proceeding as in Example 37, *, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-trans-ene-13-acetic acid methyl ester and the corresponding 15R-epimer were prepared from the appropriate starting materials.

The above methyl esters are saponified to give the free acids:

11,15S-Dihydroxy-9a-deoxy-9a-methylene-prestacyl-5-transz-ene-13-acid,

Nuclear Magnetic Resonance Spectrum (CDG1),? Ppm: 0.90 (3H, t), 4.00 (1H, m), 4.40 (1H)? wide t /, 5.28 / 1H, wide t /,

11- ', 15R-Dihydroxy-9a-desoxy-9a-methylene prenac tacyclo-5-trans-ene-15-acetic acid,

Nuclear Magnetic Resonance Spectrum (CDC1,), ppm: 0.90 (3H, t), 4.00 (1H), m /, 4.39 (1H), ^p broad t /, 5.29 (1H, broad t).

Example 76

Proceeding as in Example 70 using 2-oxo-decyl-dimethyl phosphonate, 2-oxo-isodecyldimethylphosphonate, 2-oxo-undecyldimethylphosphonate or 2-oxo-isoundecyldimethylphosphonate. the following compounds are obtained:

5E-11,15S-Dihydroxy-9a-deoxy-9a-methylene-20-n-propyl-prostacyclic-5-ene-13-acid; 372 m / e / M -H ₂ 0 /; Nuclear Magnetic Resonance Spectrum (CDCÜH) δ ppm: 0.88 (5H, t), 4.37 (1H), t (5.26 / 1H, t), 7.21 (3H, aze); 5Z-11 <, 15S-dihydroxy-9a-dezoxiv9a-methylene-2-O-n-propi1-prosta-5-ene-13 «-insav; 372 m / e / M -H _? 0 /; Nuclear Magnetic Resonance Spectrum (CDC1 -), δ ppm: 0.88 (3H, t), 4.36 (1H), t (5.23 / 1H, t), 7.34 (3H) broad;

5E-11,15S-Dihydroxy-9a-deoxy-9a-methylene-20-isopropyl-proscyclo-5-ene-13-acid; 372 m / e / M -H ₂ 0 /; Nuclear Magnetic Resonance Spectrum (GDCl ·), δ ppm: 0.86 (6H, d), 4.38 (1H), t (5.24 (1H), t (), 7.52 (3H, broad));

5Z-11 ', 15S-Dihydroxy-9a-deoxy-9a-methylene-20-isopropyl-prostacycl-5-ene-13-acid; 372 m / e / M -H ₂ 0 /; Nuclear Magnetic Resonance Spectrum (CDCl 3)

-70182726 delta, ppm: 0.85 / 6H, d /, 4.36 / 1H, t /, 5.25 / 1H, t /, 6.24 / 3H, broad /;

5E-11,15S-Dihydroxy-9a-deoxy-9a-methylene-20-n-butyl-prostacycl-5-ene-13-acetic acid; 386 m / e / _o 0 M-H /; NMR / CDC1 _X / delta: 0.89 / 3H, t /, 4.39 / lH.t /, 5.28 / lH.t / 7.88 Λ3Η, széXos / *

5Z-11 ', 15S-dihydroxy-9a-deoxy-9a-methylene-2O-n-butyl-prodrug tacyclo-5-ene-13-acetic acid; 386 m / e / M -H ⁺ _P 0 /} NMR / GDC1 _X / delta: 0.89 / 3H, t /, 4.39 / H, t / ^d 5.25 / lH.t /, 6.70 / 3H / szX09 / * '......

5E-11x, 15S-Dibydroxy-9a-deoxy-9a-methylene-20-isobutyl-prostacyl-5-ene-13-acid; 3θβ m / e / M -H _o 0 /; lü.íR NMR / CDC1 _X / delta: 0.86 / 6H, d /, 4.34 / lH.t /, 5.26 / lH, t /, 7.32 / ² 3H, br /;

5Z-yl ^<X, 15S-dihydroxy-9a-dezoxÍT9a oxy-methylene-20-isobutyl-5-pr o ztaci kl "en-13-ynoic acid; 386 m / e / _o 0 M-H /; Nuclear Magnetic Resonance Spectrum (CDC1 _X ) δ (ppm): 0.86 (6H, d), 4.32 (1H, V, 5.27 (1H), t /, 6.54Λ3Η, broad);

5E-11x, 15R-Dihydroxy-9a-des oxir9a-methylene-20-n-prop-1-pro-tacycl-5-ene-13-acetic acid; 372 m / e / M ⁺ H _p 0 /; Nuclear Magnetic Resonance Spectrum (CDC1 _X ) δ (ppm): 0.88 (3H, t), 4.38 (1H), t (5.26 / 1H, t), 6.25 (3H, δ);

5Z-11,15R-Dihydroxy-9a-deoxy-9a-methylene-20-n-propyl-prodacycl-5-ene-13-acid; 372 m / e / Μ -E ~ 0 /; Nuclear Magnetic Resonance Spectrum (CDC1,), δ ppm: 0.88 (3H, t), 4.38 (1H), t (5.24 / 1H), t (6.02 (3H), broad); 5E-11 *, 15R-Dib.hydroxy-9a-deoxy-9a-methylene-20-isopro-ophthalmic-cl-5-ene-13-acid; 372 m / e / M _o -E 0 /; NMR / CDC1 _X / delta: 0.86 / 6H, d /, 4.37 / lH.t // 5.27 / lH.t /, 6.58 / JH Wide / j 5Z-11X, 15R-Dihydroxy-9a-deoxy-9a-methylene-20-isopropyl-pro-tacyclo-5-ene-13-acid; 372 m / e / M _o -E 0 /; NMR /.CDC1 _X / delta: 0.86 / 6H, d /, 4.36 / lH.t /, 5.27 / lH.t /, 6.63 Λ3Η, br /;

5E-11x, 15R-Dihydroxy-9a-deoxy-9a-methylene-20-nbutyl-pro-tacyclo-5-ene-13-acid; 386 m / e / _o 0 M-H /; Nuclear Magnetic Resonance Spectrum (CDC1,), δ ppm: 0.89 (3H, t), 4.39 (1H, t), 5.26 (1H), t /, 6.40 (1H, broad);

11 ^X-5Z, 15R-dihydroxy-9-methylene-dezoxix9a ~ 20 ~ n búti1 prostacyclin-kl-5-en-13-ynoic acid; 386 m / e / M -H _? 0 /; Nuclear Magnetic Resonance Spectrum (CDC1,), δ ppm: 0.89 / 3H, t /, 4.39 / 1H, V, 5.25 / 1H, t /, 6.43 / 3H, δ Zβ Zβ3 /.

5E-11x, 15R-Dihydroxy-9a-desoxy-9a-methylene-20-isobutyl-pro-tacyclo-5-ene-13-acid; 386 m / e; / M H _o 0 /; NMR / CDC1 _X / delta: 0.86 / 6H, d /, 4.38 / lH.t / 5.25 / lH.t /, 6.58 / 3H br /;

5Z-11-S15R-dihydroxy-9a-deoxy-9a-methylene-20-isobutyl-prostacyl-5-ene-13-acid; 3θ6 m / e / M _o H 0 / I NMR / CDC1, / ppm: 0.8? / 6H, d /, 4.37 / 1Η, ϊ / _Λ 5.25 / 1H, t /, 6.04 / 3H, fiber / * 77. example

In the same manner as in Example 7θ and using 2-oxo-3R-methylheptyldimethylphosphonate and d, 1-2-exo / 2 * -bromo-3 * S-hydroxy-4'R-methyl-oct. -1'-tranaz-1'-enyl-4'-endo-hydroxybicyclo [3.2.0] octan-7-one, followed by bromination of the intermediate unsaturated ketone with pyridinium hydro-tribromide. product with sodium borohydride. reduced to remove the protecting groups

-71182.726 vol., After chromatographic separation, d, l-2-exo-2 »-bromo-3 * S-hydroxy-4'R-met11-oct-1 * -trans-1'-enyl / -3-endo- hydroxy-bicyclo [3.3.0] octan-7-one having an NMR (CDCl3), delta, 0.76 (3H, d), 1.00 (3H, d), 3.73 71H, d /, 5.83 / ΪΗ d / and 3 * R epimer.

These intermediates were also converted to the following compounds as described in Example 73:

d, 1-5 / cis, trans z-11, 15S-dlh-hydroxy-9a-deoxy-9a-methylene-16R-methyl-prostacycl-5-ene-13-acid and d, 1-5 / ciaz trans, trans -11 *, 15R-Dihydroxy-9a-deoxy-9a-methylene-16R-methyl-prostacycl-5-en-13-ynoic acid;

Nuclear Magnetic Resonance Spectrum (CDC1 _X /) δ ppm: 0.97 / 3H, δ V, 4.27 / 1H, broad d /, 5.25 / 1Ή, broad t /.

Example 78 - d, 1-16R, 5S-Fluoro-20-methylcarbaprostacycline or / dL-5-trans, 13-trans -115S-Dib.hydroxy-9a-deoxy-9a-methylene- Preparation of 16 (R, S) -fluoro-20-methyl-prostacyclo-5,13-dienoic acid:

320 mg of D, L-3 ^/ -hydroxy-2f; i-hydroxy-S-Z 3 * 4 * - / R, S / ^fluoro-l - <; Starting from trans-nonenyl / -7-oxobicyclo [3.2.0] octane and following the procedure of Example 36, 103 mg of the title compound and its 5-isomers, d, 1-5-cis, are obtained. 13-trangl-11,15S-dihydroxy-9a-deoxy-9a-methylene-16R, 5S-fluoro-20-methyl-prostacyl-5,13-dienoic acid and 15R-epimers of each. The title compound thin layer chromatography / diethyl ether + 2% acetic acid / received Rf: »0.25 · NMR / CDC1 _Z / delta: 0.89 / 3H, t /, 3.77 / 1H, m /, 4.0-4.3 71.5H, nZ,?, 67Z0.5H, _m /, 5.27 (i), {. '

H a in G ^ gJ ^ p = 50 Hz.

79 · example

The same procedure and using the appropriate Z3.3.07oktán ^{bicyclo-7-one-3,3--biaz} THP ethers are described in Example 35 · and 36, which are 27 to 30. The following esters were prepared:

5Z-1 i /, 5S-dihydroxy-9-deoxy-9-methylene-16R ~ prosztaclkl-fluoro-5-en-13-ynoic acid, methyl ester, M-H ₂ 0: 362;

5Z-11 <15S-dihydroxypiperidine-9a-deoxy-9a-fluoro-16S-methylene-5-ene-prosztaclkl I3 lnsav methyl ester, M-H ₂ 0: 362;

5E-] n <15S-dibLidroxi-9a-deoxy-9a-methylene-fluoro-16R proaztacikí-5-en-13-ynoic acid, methyl ester, M-H ₂ 0: 362

5E-LLX, 15S-dih.idroxi-9a-deoxy-9a-fluoro-16S-methylene-5-ene-prosztacikÍ ethyl 3-ynoic acid methyl ester, M-H ₂ 0: 362;

5Z'-LLU, 5R-dihydroxy-9a deáoxi oxy-9a-meth yl ene-16R-fluoro-pr os zt c i kl-5-ene-l3-lnsav methyl ester, M-H ₂ 0: 362;

· 5Z-ll /, 15R-dihydroxy-9-deoxy-9-methylene-16S-fluoro-prosta-5-ene-I3 lnsav methyl ester, M-H ₂ 0: 362;

5E llcx, 15R-dihydroxy-9-deoxy-9-methylene-16R-fluoro-pr oszfcaoikl-5-en-13-ynoic acid metllészter, Μ -H ₂ 0: 3θ2;

5E llcx, 5R-dihydroxy-9-deoxy-9a-fluoro-16S-methylene-pr osztacikl-en-13-ynoic acid metllészter, M-H ₂ 0: 362nd

-72182,726

The methyl ester is then saponified to the free acid.

Example 80 A solution of 11 mg of acetyl-15S-hydroxy-14-bromo-9a-deoxy-9a-methylene-prostacycl-5-cis, 13-trans-dienoic acid methyl ester in 1 ml of anhydrous dimethylsulfoxide treated with tert-butylate.

After stirring for a few minutes, the reaction mixture was poured into 30% aqueous sodium dihydrogen phosphate solution. The aqueous mixture was extracted with diethyl ether, and the combined ether extracts were washed with water and evaporated to dryness. The residue was treated with potassium carbonate in 80% aqueous methanol and worked up in the usual manner to give 11 *, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-ol-13-1-aaavav methyl.

M-H ₂ O: 344, M ⁺ -H ₂ O, C ₂ H ₄ O: 300; M -HgOiO ^ H · ^: 273 ·

Example 81

1.84 g of 5E-11.X prepared according to Example 75 ·

15S-Dihydroxy-9a-deoxy-9a-methylene-20-methyl-1-pro-acyl-5-ene-13-acid is dissolved in an equivalent amount of sodium hydroxide solution. . The solution is immediately evaporated to dryness. This gives 5E-11β, 15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycl-5-ene-13-insacid sodium salt as a hygroscopic solid. . .

IR: V = 3550 / OH /, 2200 / C = C /, 1565 ^cm-1 / salified carboxylic groups /.

Claims (2)

Patent claims A process for the preparation of compounds of formula I wherein: R is a carboxyl group that is free or is esterified with C 1 -C 4 alkyl or -C / OR '/ j where R * groups may be the same or different and are C 1 -C 4 alkyl, I) represents a methylene group, a hydroxymethylene group, a carbonyl group or an oxygen atom, One of R 1 and R ₂ is hydrogen and the other is hydroxy, or both are hydrogen or R 1 and R ₂ together form an oxo group, One of R 1 and R 4 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl-substituted C 2 -C 4 alkynyl, the other is hydroxy or C 1 -C 4 alkoxy, or R 1 and R _{4 taken} together is oxo, And Βθ Re is independently hydrogen, alkyl of 1-4 carbon atoms, or ^five halo, Y is-1,2-ethylene, -C = C, -CH = CH- in cis or trans position, -NH-CO- or -NH-CHg-, -73182,726 X is - / CH ₂ / _m - wherein m 2 is 0 or O, m ₂ and m ₂ are independently 0, 1 or 2 and n ₂ is independently 0, 1, 2 or 3 » p and q are each independently 0, 1 or 2, with the proviso that p and q may be an integer from 1 to 4 and are hydrogen, C 1-4 alkyl ^f, C 5-7 monocycloalkyl, unsubstituted or phenyl substituted with halo (C 1 -C 4) alkyl or a 3- to 7-membered saturated heterocyclic ring in which the heteroatom can be oxygen or sulfur, and the 1-4-lactones and their compounds derived from compounds of formula I or for the preparation of veterinary acceptable salts thereof, characterized in that: A. A compound of Formula III wherein p, q, Y, n 1, n ₂ , X, R 4, R 8 and R 6? is as defined above, and one of the groups R '^ and R * ₂ is a hydrogen atom and the other is a hydroxy group, or a protecting group attached to the bicyclic system via an ether linkage, or both are hydrogen or R' - ^ and R ' ₂ together represents an oxo protecting group, the One of R * 2 and R '' is hydrogen, (C 1 -C 4) -alkyl, (C 2 -C 4) -alkenyl or (C 2 -C 4) -alkynyl, and the other is hydroxy, (C 1 -C 4) -alkoxy, or is linked via ether or a protecting group, or R '' and R '' taken together are an oxo protecting group, alkylated with a compound of formula IV wherein D, m 'and m ₂ are as defined above, E is a group of the formula (GgH ^ AP) or (B ₂ O / ₂ P- / O) - wherein the R _e groups are the same or different and are 'C 1-6 alkyl or phenyl, and R 1 ^f represents a free carboxyl group esterified with a C 1-4 alkyl group or a salt thereof. -G / OR '/ z wherein R * is as defined above, and if necessary, protecting groups which may be present in the molecule are removed, or .............. ..... ..... B. A compound of formula V wherein: R '*, m ₂ , m-p, q, R 1 and R * ₂ are as defined above and D 'is methylene, oxygen, b, wherein X * is sulfur and R * and R 1 together form a C 2 -C 4 alkylene chain or CH-OCOR' where R * -74182.726 of the above meaning, or and - are taken together with the general formula c, wherein bu, is alkylated with a compound of the formula VI above, wherein E, n-, R 1, R 8, X, n ₂ and R? and Z is a halogen, and thus a compound of formula VII is prepared wherein R '*, m ₂ , D *, m ^, p, q, R * ^ and R * 2 »Z, ⁿ ]. R 1, R 8 »X» ⁿ 2 ® ^a are as defined above and, if desired, deprotecting the optional protecting groups of formula VII to give a compound of formula I ' ⁷ ' wherein Y is -GH = CZ- wherein Z is as defined above and R and R together are oxo and / or, if desired, carrying out any of the following steps: a / a compound of the formula I in which R 4 and R _{a taken} together is an oxo group, reduced and then deprotected to give a compound of formula I wherein R? and one of R 4 is hydrogen and the other is hydroxy; b / starting from the nucleophilic addition of a free carbonyl group on the β-side chain of a compound of the formula I in which R 1 and R 11 together represent an oxo group, then deprotecting the compound of the formula I in which R 1 and R 4 one is hydroxy and the other is C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl; c) etherifying a compound of formula I wherein one of R and R is a hydroxy group and any hydroxyl groups that may be present in the molecule, and then removing any protecting groups that may be present, such that a compound of formula wherein one of R 2 and R 4 is C 1-4 -alkoxyalkoxy; d) dehydrohalogenating a compound of formula I wherein Y is -CH = CZ-, wherein Z is halogen and all hydroxy, oxo and carboxyl groups optionally present in the molecule are dehydrohalogenated and then removing any protecting groups that may be present to form a compound of formula I wherein Y is -C = C; _e / _e w a compound of formula I, wherein m and R n of the groups represents a hydrogen atom and the other oxilösoportót and / or one of R and R ₂ groups represent a hydrogen atom and the other is hydroxy, and optionally the molecule optionally present additional hidroxilcsonort / is protected, oxidized and deprotected. I such a compound obtained in which R ea R ^ and / or R ^ and _R2 are oxo; R, hydr2 -75182726 f / a compound of formula I wherein D represents a carbonyl group and the other carbonyl groups which are not intended to be protected are reduced to give a compound of formula I wherein D represents CHOH; g / a compound of formula I wherein D. Represents a CHOH group and the other hydroxyl groups, which are not intended to be converted, are protected, converted to tosyl or mesylate, the tosylate or mesylate is reduced and the protecting group present is removed to give a compound of general formula I wherein D is methylene; h) esterifying a compound of Formula I wherein R is an oxyl group to give a chemical of Formula I wherein R is a carboxyl esterified with C 1-4 alkyl; 1) saponifying a compound of formula I wherein R represents an esterified carboxyl group to form a compound of formula I wherein R represents a carboxyl group; j / transesterifying an orthoester of formula I wherein R is -O / OR * / j to give a compound of formula r wherein R is -COOCHj; k) converting a compound of formula I into a lactone or salt; 1) converting a compound of formula I in the form of a salt to a free compound of formula I; m / a compound of formula I containing a protecting group is converted to the free compound and n / a mixture of cis-trans isomer compounds of formula I is separated into the individual isomers. 2. A process for the preparation of a medicament for human or veterinary use, characterized in that a compound of the formula I, wherein R, Rg, Rj, R ^, Rej, Rg, ^m 2 » ^η χ, ^η 2» Ρ »Q and R? or a lactone or a pharmaceutically acceptable salt thereof, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a carrier and / or other excipients conventionally used in the preparation of a pharmaceutical composition. 9 drawings