HU182021B - Process for producing new 5,6-dihydro-prostacycline derivatives - Google Patents

Abstract

Compounds (I> <IMAGE> where R is a carboxyl group or a derivative thereof, D is C2-C18-alkylene chain; one of R1 and R2 a radical Z (which is hydrogen, deuterium, tritium, C1-C12 alkyl, C2-C4alkenyl, C2-C4alkynyl or phenyl) or a -X-C1-C6-alkyl group where X is -O- or -S-, and the other is hydrogen, deuterium, tritium, halogen, hydroxy, -X-C1-C6alkyl, with X as defined above, or a R7-COO- or R7-SO2-O- group in which R7 is C1-C6alkyl, C6-C10aryl or C7-C12arylalkyl, R1, R2 and the carbon atom to which they are bound form a <IMAGE> group, with X as defined above, a <IMAGE> group in which R8 is hydrogen, C1-C8alkyl or aryl, or a <IMAGE> group in which X1 and X2, whether the same or different, are oxygen or sulfur and A1 is C2-C18alkylene, unsubstituted or substituted with halogen; R3 is hydrogen or C1-C6alkyl; and q, R4, Y, R5, R6, E and G are various groups and the symbol ----- is a single or double bond with various provisos; and the corresponding lactones of compounds wherein R is COOH and one of R1 and R2 is hydroxy; and the usual salts and isomers thereof. These compounds are substitutes for natural prostaglandins with various advantages thereover in terms of slower metabolization and more selective therapeutic action. They are prepared by introducing the chain containing R, D, R1, R2, and R3 in place of a hydroxy group initially occupying the chain attachment point. A process is disclosed for preparing compounds (I) where one of R1 and R2 is a radical Z and the other is hydrogen deuterium or tritium by reducing the corresponding compound where R1 and/or R2 is other than Z. <IMAGE>

Description

(57) EXTRAS

The present invention relates to bronchodilator compounds of formula I and their human and veterinary acceptable salts, optical antipodes, i.e. enantiomers, racemic mixtures, geometric isomers of optical antipodes and their compounds, and their lactone derivatives and mixtures of diastereomers thereof.

In the general formula (I)

R is

the)

-C00H or -COO (C1-C4 alkyl),

b) a radical of formula -C (O R _a ) ₃ wherein R _a may be _the same or different and represents a C 1-4 alkyl group;

(c) cyano; or

d)

-C0NH ₂ groups,

D is a straight or branched alkylene group having 2 to 4 carbon atoms, i

One of R 1 and R ₂ is hydrogen or deuterium, C 1 -C 4 alkyl or C 2 -C 4 alkenyl, the other is hydrogen, deuterium or halogen, hydroxy or R ₇ -SO-O-, wherein R ₇ is a C 6 -C 7 carbocyclic aryl group or R 1 is hydrogen; and R _{2, taken} with the carbon atom to which they are attached, forms an oxo group of 1 or 2,

Y is a group of 1,2-ethylene, -C = C-, the group -CH = CZ- containing hydrogen and Z in a cis or trans position relative to one another, wherein Z is hydrogen or halogen;

R _s and R ₆ groups is hydrogen and the other is OH,

E is a group of the formula - (CH ₂ ) _m -, wherein m is 1 to 7 and one of the hydrogen atoms may be replaced by a fluorine atom,

G is hydrogen, C 1 -C 4 alkyl or, when m is 2, phenyl, a single and a dashed line represent a single or double bond, provided that when one of R 1 and R ₂ is hydrogen, other than hydrogen and halogen meaning - and the formula of (I) from compounds of formula I, wherein R is free carboxyl group, and R, and R _2: one of a hydroxyl group.

-1182.021

This invention relates to 5,6-dihydro-9-deoxy-6,9a1ÍZ wood-epoxy-Δ FGF ^ _a ^^ _a / 11alfa, 15-dihydroxy-6,9alfa-epoxy prostanoic additional names: 5 » 6-Dihydro-prostacyclin, 5,6-dihydro-PG 1/2 derivatives.

The present invention relates, on the one hand, to a process of formula I, wherein

R is -COOH or -C00 (C1-C4 alkyl), b -C / OR _a (j) wherein the R groups may be the same or different and are (C1-C4) alkyl, Cyano or d / -CONH ₂ , which is a linear or branched C 2 -C 4 alkylene group.

R. one of R and Rp is hydrogen or deuterium;

M · - Á. <A Λ 1 * Λ. Ír Λ X · »η 1 Irish 4 1» · Α A · WV / ι Λ »Λη η 4 Α Μ Α Μ η Ί L ΑΊΑ 4 Ί Α π Α Μ represents a C 1 -C 4 alkyl or C 2 -C 4 alkenyl group. and the other is hydrogen, deuterium, halogen, hydroxyl or Rrj-SOp-O- represents a group of formula wherein R ₉ is 6-7 carbon atoms form a carbocyclic aryl group or R and _R2 together with the carbon to which they are attached, an oxo group , represents 1 or 2, represents a 1,2-ethylene group, a -CH2- group having the formula -CH = CZ- containing a hydrogen atom and Z in a cis or trans position with respect to each other, wherein Z represents a hydrogen or halogen atom, and

One of these groups is hydrogen and the other is OH * is ^- / 0H ₂ / _m - group of the formula wherein m is from 1 to 7 and up to one of the hydrogens substituted for a fluorine atom, a hydrogen atom, C1-4 alkyl or - if m is a phenyl group, one continuous and a dashed line —-— / represents a single or double bond, provided that when one of R 1 and R ₂ is hydrogen, the other is hydrogen and halo, bicyclic / bicyclic / prostaglandin derivatives.

Also included within the scope of the invention are all lactones prepared by esterification of the free carboxyl group R in the compounds of formula I intramolecularly (within the molecule) with the free hydroxy group R 1 or R 8. Also included within the scope of the invention are the human and veterinary salts, optical antipodes (or enantiomers) and racemic mixtures, diastereomers and diastereomers of the compounds of general formula I and their lactones derived from 2182.021, and their racemic mixtures and diastereomers mixtures thereof.

The present invention also relates to a process for the preparation of formula II wherein B ₁ 'and R ₂ ' are hydrogen or deuterium, R 1 Β R R 9 9 γ, _{R 1} Βθ, E and G are as defined above and consisting of a continuous and a dashed line. denotes a single or double bond for the preparation of bicyclic prostaglandin derivatives *

The dotted line in the formulas of the present specification indicates that the moiety is attached in endo configuration to the 2-oxabicyclooctane ring system of A and B, and in the S configuration to the side chain. However, the wedge line ( ^{-1 to} 53) means that the moiety is exo-configuration with respect to the 2-oxabicyclooctane ring system and the carbon atom of the side chain to which this moiety is attached is a R-configurator. . The wavy line (zw / w) means that the position of the moiety is undefined, i.e. the 2-oxabicyclooctane ring system moiety may be either endo- or exo-configurator or the carbon atom of the side chain to which it is attached. a given group may be in either the R or the S configuration.

In the compounds of the formulas 1 'and II, the heterogene ring B and the cyclopentane ring A are in the cis position. are bonded to each other, i.e. the two bonds in the ring B are cis relative to each other and both are either under the state of the cyclopentane ring A (i.e. in the alpha position) or above the plane of the ring (i.e. in the beta position) .

The side chain attached to the cyclopentane ring A is in a trans-position relative to the heterogene ring B; that is, if the ring B is located below the plane of the ring A / alpha, it is exo-configuration of the side chain, and if the ring B is above the plane of the ring A / beta el, then the side-chain configuration is endo.

If the side chain of the -CHR 1 -CR 1 -D-R is endo-configuration, then the hydrogen atom attached to the side-chain carbon atom of heterocycle B is exo-configuration and its absolute configuration is beta. If, on the other hand, the side chain exo configuration is ju, then the hydrogen atom is in the endo position and its absolute configuration is alpha.

Thus, the present invention relates to a process for the preparation of compounds of formula Ia, Ib, Ic and Id and mixtures thereof.

Compounds of formula Ib and Id have higher chromatographic motility / Rf / higher and lower optical rotation than the corresponding fibers of formulas Ia and Ic.

In the alkyl, alkenyl and acyloxy groups of the compounds of the invention, the carbon chains may be straight or branched.

In the compounds of the invention, R is preferably a free or esterified carboxyl group.

C 1-6 alkyl moieties are preferably methyl, ethyl or propyl.

-3182.021

When one of R 1 and R ₂ is halogen, it is preferably iodo; When Z is halogen, it is preferably chlorine or bromine.

The group Ry-SO ₂ -O- is preferably tosyloxy- / p-toluoyl-sulphonyl-oxy - / - cs.

Preferably, the compounds of the formulas Ia and Ib have the configuration endo; and the compounds of formulas Ic and Id are preferably exo.

The human and veterinary acceptable salts of the compounds of formula I may be formed with either organic or inorganic bases.

The human and veterinary acceptable inorganic bases are hydroxides of alkali metals and alkaline earth metals, as well as cyclohydroxide and aluminum hydroxide. Acceptable organic bases include amines, such as methylamine, diethylamine, trimethylamine, ethylamine, d-butylarain, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allyl. amine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, alpha-phenyl-ethylamine, beta-phenylethylamine, ethylenediamine, diethylenetriamine, and the like, aliphatic, cycloaliphatic, aromatic or heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine and the latter may also be substituted such as 1-methylpiperidine, 4-ethyl-morpholine, 1-isopropyl-pyrrolidine, 2-methylpyrrolidine .

1,4-dimethyl-1-piperazine or 2-raethyl-piperidine. Such bases also include amines having hydrophilic groups, such as mono-, di- or triethanolamine, 2-amino-2-butanol, 2-amino-2-ethyl-1,5-butyl-ethanolamine, 2-amino- 1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris- (hydroxymethyl) -araino-methane, N-phenylethanol, amine, N- (p-tertiary-amyl-phenyl) -diethanolamine, ephedrine, praine, and alpha or beta amino acids such as lysine or arginine.

Salts of the compounds of formula I according to the present invention are preferred, wherein R is -COOR ₂ , wherein R ₂ is a human or veterinary acceptable cation derived from one of the above-mentioned bases.

As regards the nomenclature of the compounds of the invention, those compounds of formula Ia in which q is

1, 5, 6beta-dihydroPGl2, also called 6alphaH-6,9alpha-oxido-prostanoic acid, or again 2'-oxabicyclo [5.3.3] octane-J'-exo-yl-alkanoic acid derivatives. And compounds of formula Ia wherein q is

It is referred to as 2 derivatives of 5 ⁹ H, 5 H, ⁹ H, 5-oxo-prostanoic acid, also known as 2'-oxa-bicyclo [4.5.0] 7nonan-5'-exo-yl-alkanoic acid. When such a compound is represented by the term "8,12-diiso," it refers to compounds of formula Ic, wherein q is 1 or 2, respectively.

Compounds of formula Ib wherein q is 1 are 5,6 alpha-dihydro-PGI ₂ , also known as 6betaH-6,9alpha-pxidQ-prostanoic acid, or alias 2'-oxabicyclo [5.3.3]. octane-5 * -endo-yl-alkanoic acid derivatives. And compounds of formula Ib wherein q is 2 are 5betaH-5, 9alpha-oxalprostanoic acid, also known as

-4182.021 o'-oxabicyclo [3.3.1] nonane-5'-endoyl-alkanoic acid derivatives ² ° If 8,12-di- _;

As a term, it is a compound of general formula M. _; . ^letela, If ^U e6y'vegjüllt'lama wlaml ^ Bswehasonlité compound JnuKoFtópesb contains one, two, bar or more 5 «nat °», then this homo-, dihomo-, trinomo answ. with prefixes. whereas if a carbon chain contains less than one, two, three or more carbon atoms in the carbon chain of the reference substance, this is the case with nor, dinor, trinor, etc. with prefixes.

The compounds of the invention are prepared according to the invention by reacting a compound of general formula III wherein _s &quot; is a hydroxy group or a known ring-linked ether linker.

One of R1 and R1 is hydrogen and the other is 3 »H or a known ether-bonded protecting group and q, Y, E, and G are reacted with a compound of formula IV, wherein R and D

L a and / CgH ^ / ^ P- above formula or / R 0 _E / ₂ P / - ^ - 0 / - group of the formula wherein R is alkyl of 1-6 carbon atoms talmazó Taro, and the two R groups are the same Removing or different, ^e is the optionally present protecting groups

Y, R 1, R 8, E, G, and the continuous and dashed line and Hg, and, if desired, and R _{2, with} the carbon atom to which they are attached, form an oxo group to form compounds of formula I wherein R 1 and R ₂ one of which is hydroxy or the group Rr-SOg-O-, wherein R? is as defined above and the other is hydrogen or deuterium, C 1-4 alkyl or C 2-4 alkenyl, and if desired, compounds of formula I wherein one of R 1 and R ₂ is is a hydroxy group and the other is an alkenyl group having 2 to 4 carbon atoms, is converted to compounds of the formula I in which one of R ₁ and R 2 is alkene substituted with 2 to 4 carbon atoms and the other is R 6 -. S0 ₂ -0- group of the formula wherein R is as defined above; or if desired, a compound of formula I, where R _T and R _2: one of a hydrogen atom or a hydroxyl group R-O- SOG group of the formula wherein R is as defined above, and the other is hydrogen, A compound of formula I, wherein I, D, q, Y, R 1, R 8, E, G, and the continuous labeled bond are as defined above, and R 1 and R ₂ are carbon atoms are obtained. to which they are attached form an oxo group and undergo compounds of the formula I in which R

-5182.021 wherein one of R ₁ and R ₂ is halogen, preferably iodine and the other is hydrogen or, if desired, a compound of formula I _? wherein Y represents -OH = CZ- and Z represents a halogen atom is also converted to compounds of formula I wherein Y is -CSC- or, if desired, compounds of formula I wherein Y is -CH = Z is hydrogen and is converted into compounds of formula I wherein Y is -CH ₂ -O ₂ - or, if desired, compounds of formula I wherein R is -000- / 1- C4 alkyl, is also converted to compounds of formula I wherein R is -COOH, or, if desired, compounds of formula I wherein R is -C / OR-; _is converted to compounds of formula I, wherein R is -C1- (C1 -C4) alkyl or an optional compound of formula (I). wherein R is -C = N, is also converted to compounds of general formula I wherein R is -NH ₂ and optionally converted to a lactone derivative or salt thereof.

In addition to the process described above, the compounds of formula II may also be prepared by a novel process which, as mentioned above, is also within the scope of the present invention. Accordingly, a compound of formula V wherein R, D, q, Y, R 4, R 8, Ξ and G are as defined above and R 1 'is one of R 1 and R p is hydrogen or deuterium and the other is halogen, preferably iodine or R 1 * and R 6 * together with the carbon atom to which they are attached form a group of formula> = O = N-NHR 8, where R _g is -SOgR? wherein R 'is as defined above is reduced.

Said known protecting groups are groups which can be cleaved from the hydroxyl groups under mild conditions, for example by acid hydrolysis; such as acetal ethers, enol ethers and silyl ethers. Preferred groups include those of formulas VI, VII, and VIII, wherein W is oxygen or methylene and Alk is C 1-6 alkyl, as well as trimethylsilyloxy, dimethyl tert-butylsilyloxy, and 1-cyclohexenyloxy. .

In a preferred embodiment of the process of the invention, a compound of formula III is reacted with 1.05 to 2.5 equivalents of a compound of formula IV in an inert solvent such as a straight-chain or cyclic ether such as diethyl ether, tetrahydrofuran , in dioxane, dimethoxyethane base; an aliphatic or aromatic hydrocarbon such as n-heptane, n-hexane, benzene, toluene, a halogenated hydrocarbon such as dichloromethane, tetrachloroethane, or

182,021 in a mixture of these solvents. The reaction temperature may vary between the freezing point and the boiling point of the solvent used. When reacting a compound of formula IV wherein L is / ΟθΗ ^ / ^ Ρ-, the reaction is preferably carried out at the boiling point of the solvent used, while reacting a compound of formula IV wherein L is / ΗθΟ ^ Ε / - is preferably at room temperature (i.e., between 10 ° C and 25 ° C).

In a further preferred embodiment of the process of the invention, the protecting groups attached to the ring or side chain via an ether oxygen atom can be removed by mild acidic hydrolysis, e.g. with an acid containing one or more carboxyl groups such as formic acid, acetic acid, citric acid. or tartaric acid in water, acetone, tetrahydrofuran, dimethoxyethane or a low molecular weight alcohol as a solvent; and with a sulfonic acid, such as p-toluenesulfonic acid, in a small molecule alcohol as a solvent, or with an ion exchange resin of the polystyrene sulfonate type. For example, 0.1-0.25 normal polycarboxylic acid (e.g. oxalic acid or citric acid) solution may be used in the presence of a suitable water-miscible solvent which can be readily removed under reduced pressure.

In a further preferred embodiment of the process of the invention, a compound of formula I wherein one of R 1 and R ₂ is hydroxy and the other is hydrogen or deuterium may be prepared by reacting a compound of formula I wherein R 1 and R 2 together are oxo are reduced with a suitable reducing agent such as a mixed hydride or lithium alkyl. The mixed hydrides are preferably alkali metals and alkaline earth metals. for example, borohydrides of sodium, lithium, calcium and magnesium, and zinc borohydride or lithium aluminum hydride. The reducing agent is used in an amount of 0.5 to 6 moles per compound of formula I in an aqueous or anhydrous solvent such as a straight chain or cyclic ether such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane; an aliphatic or aromatic hydrocarbon such as benzene, n-heptane; a halogenated hydrocarbon such as dichloromethane; in an alcohol such as methyl, ethyl or isopropyl alcohol, or a mixture thereof as a solvent. The reaction may be carried out at a temperature of about -40 ° C to the boiling point of the solvent used, but preferably at a temperature of -20 ° C to 25 ° C.

This reduction results in a mixture of two epimeric alcohols, in which the hydroxyl group is attached to a carbon atom of S or R configuration. If desired, these epimers may be separated by any suitable method, for example by fractional crystallization (e.g. diethyl ether, n-hexane, n-heptane or cyclohexane) or by column or preparative thin layer chromatography on silica gel or —Fciíiju J.1 * · A; _ Oluenskénb ped to, dichloromethane, diethyl ether, m.p. diizopj ... i - 'storage, ethyl acetate, meti1 acetate, benzene, n-cikloh.í'' · _-. J used as a mixture thereof.

According to another preferred embodiment of the process according to the invention, a compound of the formula I in which one of R 1 and R 9 is C 1-4 alkyl or C 2-4 alkenyl and the other is hydroxy or

Rrj-SOg-O- wherein R? as defined above, may be prepared by reacting a compound of formula I wherein R 1 and R 8 together are oxo with a Grignard reagent of formula R 1 - MgHal where Hal is halogen, preferably bromine or iodine, and R 4 is C 1-4 alkyl or C 2-4 alkyl. The Grignard reaction was from 1.05 to 2.0 based on the compound of formula I. moles of a magnesium compound in an anhydrous solvent such as a linear or cyclic ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; or in an aliphatic or aromatic hydrocarbon such as n-heptane, n-hexane, benzene or toluene. The reaction is carried out at a temperature of from about -70 ° C to the reflux temperature of the solvent used, but preferably from -60 ° C to 10 ° C.

Freezing the Grignard reaction with water or diluting a dilute acid such as hydrochloric acid, sulfuric acid or acetic acid or decomposing the reagent still present yields a compound of formula I wherein one of R 1 and R ₂ is hydroxy and another is C 1-4 alkyl or C 2-4 alkenyl.

Conversely, if the reaction is quenched in the presence of a chloride of a sulfonic acid (R 1 -SO 8 -OH / '), a compound of formula I is obtained wherein one of R 1 and R ₂ is R ₂ -SO ₂ -O- and the other is C 1 -C 4 alkyl or C 2 -C 4 alkenyl.

; In a further preferred embodiment of the process of the present invention there is provided a compound of formula I wherein one of R 1 and R ₂ is R ₂ -SO ₂ -O-, wherein R _{2 is} -O-. is the same as above and the other is an alkenyl group containing from 2 to 4 carbon atoms. may be prepared by conventional esterification of a compound of formula I wherein one of R 1 and R ₂ is hydroxy and the other is C 2 -C 4 alkenyl: for example, a sulfonic acid / R p -SO ₂ - Treatment with 0H / chloride in the presence of a base.

According to a further preferred embodiment of the invention there is provided a compound of the formula I in which one of R 1 and R ₂ is one.

The other 182.021 is hydrogen, may be prepared by treating a compound of formula I wherein one of R 1 and R ₂ is hydroxy and the other is hydrogen with at least two equivalents of a suitable phosphorus. in the presence of at least two equivalents. All other hydroxyl groups present in the starting molecule used for this reaction must be in the protected form mentioned above.

In a further preferred embodiment of the process of the present invention, a compound of formula I wherein one of R and R 8 is halogen and the other is hydrogen is prepared by preparing a compound of general formula I wherein

is hydrogen, as is known in the art. Chem. Soc., 77, 4899/1955/0, is treated with a halide of an alkali metal or alkaline earth metal.

The compounds of Formula I can be converted into other compounds of Formula I by methods known per se, for example by preparing lactones, salts and separating isomers of a compound.

For example, a compound of formula I wherein Y is ethylene may be prepared by catalytic hydrogenation of a compound of formula I wherein Y is -CH = CH- or -C = C, preferably in an alkaline solution of platinum or palladium on carbon. in the presence of a catalytic lyser at a temperature of -40 ° C to -20 ° C.

On the other hand, a compound of formula I wherein Y is -C = C- may be prepared by dehydrohalogenation from a compound of formula I wherein Y is -CH = C 2 - wherein Z is halogen; the reaction is carried out using a dehydrohalogenating agent such as methylsulfoxonium methylide, diazabicyclo-undecene, diazabicyclo-nonene, an alkali metal amide or an alcohol in an amount of 1.5 to 1.8 moles per compound of formula (I). The reaction is preferably carried out under an oxygen-free atmosphere, in an inert solvent such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, dimethoxyethane * tetrahydrofuran, dioxane, benzene, toluene, liquid ammonia or mixtures thereof. The reaction is carried out at a temperature of from about 100 ° C to a condensation temperature of ammonia, and preferably at room temperature.

In a further preferred embodiment of the process of the invention, a compound of formula I wherein R is an esterified carboxyl group such as an alkoxycarbonyl group containing from 1 to 4 carbon atoms may be prepared by known methods from a compound of formula I wherein R is a free carboxyl group; for example, in the presence of an acidic catalyst, such as p-toluenesulfonic acid, with an aliphatic alcohol having from 1 to 4 carbon atoms, or with a diazoalkane, reacting the starting material containing the free carboxyl group.

-9182.021

In a further preferred embodiment of the process of the invention, a compound of formula I wherein R is free carboxylic acid is prepared by conventional hydrolysis methods from a compound of formula I wherein R is an esterified carboxyl group; for example, the starting ester is treated with an aqueous or alcoholic solution of a hydroxide of an alkali metal or alkaline earth metal and the mixture is acidified.

In a further preferred embodiment of the process of the present invention, compounds of formula I wherein R1 and one of which is hydroxy and R is carboxyl, the lactones obtained by intramolecular esterification can be readily prepared by heating the starting compounds in the presence of an acidic catalyst such as p-toluenesulfonic acid. The same conversion, i.e., the conversion of compounds of formula I having R 1 or R 4 as hydroxy and as the free or esterified carboxyl group as R, can also be effected by the corresponding lactone / spontaneous transformation of certain compounds of formula I so substituted the pH or temperature used in the conversion is favorable for ester formation.

Salts of compounds of formula I are prepared by conventional methods.

Isomers, such as diastereomers, of the compounds of the invention may also be separated by conventional methods. The separation can be accomplished by fractional crystallization from diethyl ether, n-hexane, n-heptane, cyclohexane or benzene, or by adsorbent on silica gel or magnesium silicate with diethyl ether, n-hexane, n-heptane, cyclohexane, ethyl acetate, methyl acetate. , column or preparative thin layer columns using benzene, chloroform and the like as eluent were chromatographed 1.

In a further preferred embodiment of the process according to the invention, for the reduction of a compound of the formula V, for example, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, a trialkyltin hydride such as tributyltin anhydride, nickel II-boride. Raney nickel, and the corresponding deuterated derivatives such as lithium aluminum deuteride, sodium boron deuteride, sodium cyanoborode deuteride and the like may be used, and after reduction, the mixture is quenched with water or deuterated water. .

In a further preferred embodiment of the process of the present invention, a compound of formula I wherein R 6 and R 1 are hydrogen or deuterium, preferably a compound of formula V wherein one of R p and R p is hydrogen, and the other is a halogen atom, i.e., maintaining the starting material in dimethylformamide at room temperature to the reflux temperature of the solvent, but preferably below 100 ° C, with a reducing agent or a dehalogenating agent such as sodium borohydride or sodium boron. deuteride. Good results may also be obtained by using nickel (II) boride or tributyltin anhydride (or deuterated variants thereof) in an inert, anhydrous solvent such as a straight chain or cyclic ether such as diethyl ether, tetrahydro- furan, dioxane or dimethoxyethane.

In a further preferred embodiment of the invention there is provided a compound of formula II wherein R 1 is and R 1, each being hydrogen or deuterium, may be prepared from a compound of formula V wherein R 6 * and R 6 ', together with the carbon atom to which they are attached, are represented by the formula: C 8 = N-NHR 9 where R 8 is -SO ^ Ry group and R? is as defined above, wherein the starting compound is water, a mixture of water and alcohol, or dimethylformamide with sodium borohydride or sodium cyanoborohydride (or deuterated variants thereof); or in anhydrous solvent, such as diethyl ether or tetrahydrofuran, with lithium aluminum hydride or a deuterated version thereof. In general, the reaction is carried out at room temperature to about 100 ° C.

Compounds of formula III are known and are, for example, described in J.3. They can be prepared as described in Bindra and R. Bindra, Prostaglandin Synthesis, New York, 1977.

An IV Compounds of general formula wherein L is a / R _p 0 / P / - ^ 0 / - group of formula where as defined above, in the present invention, R knockdown was prepared to a IX of the formula wherein R, D and R is as defined above, the phosphonate is a hydride of a base, preferably an alkali metal or an alkaline earth metal such as sodium hydride, potassium hydride, lithium hydride or calcium hydride; an alkali metal alcohol such as sodium tert-butylate or potassium tert-butylate; an amide of an alkali metal or alkaline earth metal, such as sodium amide; a carboxamide such as sodium acetamide; or reacting with at least one equivalent amount of sodium succinimide.

Compounds of formula IV wherein L is a group of the formula: wherein R and D is as defined above and Hal is halogen are first prepared by a compound of formula X wherein R and D are as defined above. 1 to 1.2 equivalents of triphenylphosphine in an inert organic solvent such as benzene, acetonitrile or diethyl ether and then the triphenylphosphonium halide thus obtained is treated with an equivalent amount of an inorganic base such as sodium hydroxide, potassium hydroxide, carbonate or sodium bicarbonate.

Compounds of formula IX may be prepared by conventional methods such as those described in E.J. Corey £ j.Amer.Chem.Soc. 9θ 3247/1968/7 and E.J.Corey and G.W.Kwiatkowsky D .Amer.Chem.-Soc. 88, 5, 54 (1966,7).

Compounds of formula X may also be prepared by known methods, such as those described in J.S.Bindra and R. Bindra, Pros taglandin Synthesis, New York, 1977.

The preparation of compounds of formula V has already been described for the preparation of compounds of formula I.

-11182,021

The compounds of the invention may be used in human and veterinary medicine in general for the same therapeutic purposes as natural prostaglandins. However, the compounds of the invention have the advantage over natural prostaglandinol that they are metabolized much slower and have a more selective therapeutic action.

The compounds of the present invention exhibit a pronounced bronchodilator effect and may be useful in the treatment of bronchial asthma. For this purpose, they may be administered in various ways: orally / in the form of tablets, capsules or pills, or in liquid dosage forms such as syrups or drops; rectally / rectally / in the form of suppositories; intravenously (intravenously); intramuscularly (intramuscularly); subcutaneous (under the skin); as an inhalation / inhalation / aerosol or nebuliser solution; or in powder form, as an insufflation / infusion / nasal agent. Doses of 0.01 mg / kg to 4 mg / kg may be administered 1-4 times daily, depending on the age, weight and physical condition of the individual being treated 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 sympathomimetics1 (sympathetic nervous system stimulators) such as isoproterenol, ephedrine and the like; xanthine sarra derivatives such as theophylline or aminophylline; or corticosteroids such as prednisolone or AGTH (adrenocorticotropic hormone).

The compounds of the invention also have an oxytocin-like action and can be used in place of oxytocin to induce childbirth or to expel the dead fetus from the uterus in both human and veterinary medicine. For this purpose, the compounds of the present invention may be administered as an intravenous infusion at a dose of 0.01 µg / kg or until delivery, or may be administered orally.

The compounds of the present invention are valuable for their luteolytic activity and contraception, their e-activity being combined with the advantage that they stimulate smooth muscle contraction very little and thus have no side effects (such as vomiting and diarrhea) as natural prostaglandins.

However, the most important pharmacological activity of these compounds is their antiplatelet and anti-gastric effect. By virtue of their effects, the compounds of the present invention can be used to reduce and control excessive gastric acid secretion. These compounds inhibit the development of ulcers in the gastrointestinal tract and accelerate the healing of existing ulcers in the gastrointestinal tract. For this therapeutic purpose, the compounds of the invention are administered by intravenous infusions or by intravenous, subcutaneous or intramuscular injection; For infusion dosing, dosages are in the range of 0.1 µg / kg / min to 500 µg / kg / min, with total daily doses ranging from 0.1 mg / kg to 20 mg / kg for both infusions and injections. fall. The actual dose will depend on the age, weight and condition of the human or animal being treated, and the route of administration.

As noted above, the compounds of the present invention also inhibit platelet aggregation / platelet density, reduce platelet adhesion, promote the absorption of blood clots, and inhibit the formation of clots. For example, it can be used for the prevention and treatment of myocardial infarction and heart thrombosis, and for the treatment of atherosclerosis, arteriosclerosis, and generally hyperlipidemic conditions. '

The compounds of the invention actually inhibit ADP, AA, collagen and adrenaline-induced platelet aggregation even at low doses, for example in the order of 5-10 ng / ml.

For the above purposes, the compounds of the invention may be administered by conventional means, for example, intravenously, subcutaneously, intramuscularly, or otherwise. In urgent cases, they are preferably administered intravenously at doses of 0.005 mg / kg / day to 20 mg / kg / day; again, the actual dose will only depend on the age, weight and condition of the individual being treated and the route of administration.

Of particular importance is the vasodilatory activity of the compounds of the present invention, which may be potentiated by their anti-platelet aggregation inhibitory activity by the addition of phosphodiesterase inhibitors.

As noted above, the compounds of the invention may be administered in various forms, depending on the route of administration: intravenous, intramuscular, subcutaneous, oral; endovaginally (in the vagina), rectally or locally. Various excipients and carriers are used to formulate each dosage form. Formulations for oral use include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium or magnesium stearate, glycols, amides, acacia, gum adragate, polysaccharide, alginic acid or alginates. and the like. For spray application, these compounds may be dissolved or suspended in water in the form of their salts, such as their sodium salts. Alternatively, if they are to be dispensed as an aerosol from a pressurized container, they may be dissolved or suspended in a conventional liquid propellant such as dichlorodifluoroethane or dichlorotetrafluoroethane. If the compound is not soluble in the propellant, a cosolvent can be added / solubilized as a vehicle (e.g. ethanol or dipropylene glycol) and / or a tensioactive / vaporizer.

For the preparation of parenteral formulations, the compounds of the invention may be dissolved, for example, in deionized water, lidocaine hydrochloride solution, physiological saline, dextrose solution, or any other solvent conventionally used in the preparation of such formulations.

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

Example 1 3.8 g, for example, S.M.McElvan and J.P. Schroeder, f.Amer.Chem.Soc. 21? The ortho-methyl ester of beta-methoxycarbonyl-propionic acid (40/1949) is dissolved in 100 ml of anhydrous tetrahydrofuran. 49.6 g of dimethyl methane phosphonic acid dimethyl ester are treated with 38.4 g of butyl lithium at -70 ° C, at which temperature the above tetrahydrofuran solution is added and the mixture is stirred for another

-13182.021 is stirred at this temperature n. The mixture is allowed to warm to 10 ° C and 40 ml of acetic acid are added. The solvent was distilled off under reduced pressure, the residue was dissolved in water (300 ml), the aqueous solution was extracted with diethyl ether, the diethyl ether solution was dried and the solvent was distilled off first. and then the halls. This gave 52 g of dimethyl 2-oxo-5-methoxycarbonyl-1-pentane phosphonic acid, b.p. 160 ° C / 2.5 mmHg.

Example 2 A solution of 68 mg of sodium ethyl acetate and 355 mg of 2-oxo-5-methoxycarbonylpentane phosphonic acid dimethyl ester in 10 ml of dimethoxyethane is stirred for half an hour, and then 315 mg of 3 alpha-hydroxy-5-alpha is added. tetrahydropyran-2'-yloxy / -2.beta.-Q '/ S / -tetrahydro-pyran-2'-yloxy / -l'transz-octen-l-yl] cyclopentane--lalfa propionaldehid- delta-lactol in 2 ml of benzene. The mixture was stirred for another half hour, then acidified with acetic acid, allowed to stand overnight, then diluted with water and extracted with diethyl ether. The diethyl ether solution is washed neutral with water and the solvent is distilled off. The residue is chromatographed on silica gel, eluting with a 7: 3 mixture of cyclohexane and diethyl ether. There were thus obtained 312 mg of 9alpha-hydroxy-11alpha, 15S, bis-tetrahydropyran-2'-yloxy, -5,9-oxido-3-oxo-4,5 / alpha, beta / 2- homo-prost-13-trans-enoic acid methyl ester is obtained.

b / 312 mg 9aifa-hydroxy-lla, 15 / S / bis / ^{tetrahydro-pyran-2-yloxy} / -5.9 ~ oxido-3-oxo-4,5 / θlfa beta / 2a To a solution of homo-prost-13-trans-enoic acid methyl ester in 8 mL of acetone was added 4 mL of 0.1 N oxalic acid and the mixture was heated at 40 ° C overnight. The acetone was then distilled off under reduced pressure and the residue was partitioned between diethyl ether. The diethyl ether solution was washed with sodium bicarbonate solution, then with water, dried over sodium sulfate and the solvent was distilled off. The residue was chromatographed on silica gel, eluting with 6: 4 benzene: ethyl acetate. In this way, 220 mg of 9alpha, 11a1a, 15S / trihydroxy-5,9-oxido-3-oxo-4,5 / alpha, beta / 2a-homo-prost-13tra ns z-ens avraet II and and we win ter.

The product mass spectrum exhibits characteristic peaks at 396, 378, 360, and 316. After separation by TLC, 112 mg of 9 alpha, 11a-alpha, 15S-trihydroxy-5,9-oxido-3-oxo-4,5 / alpha / 2a-homo-prost-13-trans-enoic acid methyl ester are obtained from the above product. ester and 61 rags of 9θlfa, Halfa, 15S-trihydroxy-5,9-oxido-3-oxo-4,5 / beta / 2a-homo-prost, -13-trans-enoic acid methyl ester are obtained.

EXAMPLE 3 9 g of 9 alpha-hydroxyl-11 alpha, 15 S, bis-tetrahydropyran-2 * -1-OXX-6,9-oxido-4-oxo-5,6 (alpha, beta) To a solution of the bromo-prost-13-trans-enoic acid orthoester in 20 mL of methanol and 0.4 mL of water is added 20 mL of 25% trichloroacetic acid. After 4 hours at room temperature, the reaction mixture was neutralized with 2N sodium carbonate solution. The methanol was then distilled off and the remaining aqueous solution was extracted with ethyl acetate. The residue obtained after distillation of ethyl acetate was chromatographed on silica gel using a 7: 3 mixture of benzene and diethyl ether as eluent. In this way, 35θ mg of 9alpha, Halfa, 15β, 5β-tetrahydroxy-6,9-oxido-4-oxo-5,6α, αβ-14-bromo-prost-13-trans-enoic acid methyl ester and 235 mg of 9αα , Halfa,

-14182,021

15 (S) -trihydroxy-6,9-OXido-4-oxo-5,6,6-beta-14-bromo-prost-13-trans-enoic acid methyl ester is obtained. Typical mass spectra appear at 460/462, 380, 362, and 344.

In a similar manner, methyl esters corresponding to the ortho esters described in Example 2 are obtained.

Example 4

500 mg 9alpha-hydroxy-11alpha, 15S (bis) -tetrahydropyran; To a solution of -2'-yloxy / -6,9-oxido-4-oxo-5,6 (alpha-beta) -16-fluoro-prost-13 ^: trans-enoic acid nitrile in 8 ml acetone was added 0 ml 0 2N oxalic acid solution and the mixture was heated at 40 ° C for 8 hours. Then acetone under reduced pressure. distillate and extract the aqueous solution with diethyl ether. The diethyl ether solutions were squeezed, the solvent was distilled off and the residue was chromatographed on silica gel, eluting with a 2: 8 mixture of diethyl ether and dichloromethane. There were thus obtained 180 mg of 9alpha, 11alpha, 15S / trihydroxy-6,9-oxido-4-oxo-5,6 [alpha] -16-fluoroprost-13-trans-enoic acid nitrile and 110 mg of 9alpha, 11alpha, 15 (S) -trihydroxy-6,9-oxido-4-oxo-5,6 (beta) -16-fluoroprost-13-trans-enoic acid nitrile is obtained. Typical peaks in the mass spectrum are at 367, 349, 331 and 302. s.

Example 5

275 9alpha, 11alpha, 15S, 3'-trihydroxy-6,9-oxido-4-oxo-5,6 [alpha] -16-fluoro-prost-13-trans-enoic acid nitrile, 0.3 ml 30% hydrogen peroxide solution, 0.4 ml of 95% ethanol and 0.3 ml of 6N sodium hydroxide solution were kept at 40 ° C for 4 hours, with cooling in cold water for the first hour. The mixture was then neutralized with monosodium phosphate and extracted with ethyl acetate. The ethyl acetate solution was washed with water, followed by sodium bicarbonate solution and then again with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by TLC eluting with ethyl acetate / benzene (1: 1). There are thus obtained 245 µl of 9alpha, Halfa, 15β, 3β-trihydroxy-6,9-oxido-4-oxo-5β, 6α-α-16-fluoroprost-13-trans-enoic acid amide. Typical peaks of its mass spectrum occur at 385, 36, 350 and 340.

Starting from the prostenic acid nitriles obtained in Example 4 and analogously, the corresponding 4-oxo-prostenic acid amides are obtained.

Example 6

200 mg 9alpha, Halfa, 15 S, 3-trihydroxy-6,9-oxido-4-oxo-5,6 [alpha] -16-fluoroprost-13-trans-enoic acid nitrile, 50 rag 5% charcoal A mixture of palladium and 0.5 ml of triethylaraine in 10 ml of ethanol was hydrogenated for 1 hour. The catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel to give 196 mg of 9alpha, Halfa, 15S / trihydroxy-5,9-oxido-4-oxo-5,6 [alpha] -16-fluoro-prostanoic acid nitrile.

Characteristic peaks in its mass spectrum occur at mass numbers 369, 351, 333 and 304.

Starting from the compounds obtained in Example 4, analogously to the analogous prostanoic acid nitriles, following the procedure described in this Example, starting from the amides obtained according to Example 5.

-15182.021 vol. And the like yields the corresponding prostanoic acid amides.

7. General a

400 mg of a solution of 9alpha, 11alpha, 15S, 3'-trihydroxy-6,9-oxo-4-oxo-5,6 [alpha] -16-fluoroprost-1-trans-enoic acid amide in 10 ml of ethanol At 80 ° C, 80 mg of sodium borohydride are added. The mixture was stirred for half an hour at -10 ° C, then allowed to warm to room temperature and neutralized with acetic acid. The methanol was then distilled off and the residue was partitioned between ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was distilled off to give a mixture of 4 / S / - and 4 / R / - primary alcohols. This mixture was chromatographed on silica gel (80 g) eluting with ethyl acetate / benzene (1: 1). In this way, 180 rags of 9alpha, Halfa, 15S, 4S, -tetrahydroxy-6,9-oxido-5,6, alpha-16-fluoroprost-ll-trans-enoic acid aramide, and 110 rags of the corresponding 4 / The R isomer is obtained. Typical peaks in the mass spectrum appear at 387, 369, 351, 333 and -288.

AJ., 4th _? Starting from the prostaglandin lock coatings obtained in Examples 5 and following the procedure described in this example, a mixture of the corresponding 4 / R / - and 4 / S / epimeric alcohols is obtained, followed by 4 / R / - and 4 / S. / iscers are separated.

Example 8

150 mg of 9alpha, 11alpha, 4S, 15Setrahydroxy-6,9-oxido-5,6 [alpha] -16-fluoroprost-13-trans-enoic acid amide in 5 ml methanol and 0.2 ml lithium hydroxide (50 ml) was added and the mixture was heated at 50 ° C overnight. It is then acidified to pH 4 with sulfuric acid and allowed to stand for 2 hours. Methanol was distilled off and the aqueous residue was partitioned between diethyl ether. The diethyl ether solution was washed with water, then the diethyl ether was distilled off and the residue was chromatographed on silica gel, eluting with a 1: 1 mixture of diethyl ether and ethyl acetate. There was thus obtained 135 mg of 9alpha, Halfa, 4/3, 15S-tetrahydroxy-6,9-oxido-5,6 [alpha] -16-fluoro-prost-13-trans-enoic acid gamma-lactone. Characteristic peaks of its mass spectrum occur at 370, 352, 334 and 290.

Starting from the amides obtained in Example 7 and following the procedure in this Example, the corresponding lactones are obtained.

Example 9 To a solution of 0.05M zinc borohydride in 0.05M diethyl ether at 400C was added 400 mg of 9alpha, 11alpha, 15S / trihydroxy-6,9-oxido-4-oxo-5,6 / alpha. A solution of methyl-14-bromo-prost-13-trans-enoic acid in 5 ml of dimethoxyethane. The reaction mixture was stirred for 1 hour and then quenched by careful addition of 2N sulfuric acid. The organic layer was separated, washed with water, followed by sodium bicarbonate solution and then again with water, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue, containing a mixture of 4 / R / - and 4 / S / epimeric alcohols, is chromatographed on 80 g of silica gel, eluting with diethyl ether / benzene 8: 2. In this way, 180 mg of Salfa, 11a-alpha, 4S, 15S and et al-hydroxy-6,9-oxido-5,6 / alpha-14-bromo-prost-13-trans-enoic acid methyl ester and 170 mg of the corresponding 4-R isomer are obtained. Characteristic peaks of the mass spectrum occur at 462/464, 382, 364 and 346.

-16182,021

Example 10

Methyl 9alpha, 11alpha, 4β, 3β, 15β, 5β-tetrahydroxy-6,9-oxido-5,6α, α-14-bromo-prost-15-trans-enoic acid methyl ester (460 mg) in 10 ml of dimethyl · - of sulfoxide solution was treated with 115 mg of potassium tert-butylate and the mixture was stirred at room temperature for 4 hours. The pH of the mixture was then adjusted to 5 with 2N sulfuric acid and extracted with diethyl ether. The diethyl ether solution was washed with water, dried and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel, eluting with a 1: 1 mixture of diethyl ether and dichloromethane. There was thus obtained 245 mg of 9alpha, 11alpha, 4S, 15SS-tetrahydroxy-5,6 [alpha] -prost-13-acetic acid methyl ester. In its mass spectrum, the characteristic peaks appear at 582, 564, 546 and 528.

Example 11

Methyl 9alpha, 11alpha 4β, 3β, 15β, 5β-tetrahydroxy-6,9-oxido-5,6α, αα-16-fluoroprostatransenic acid methyl ester (200ml) with 4ml methanol and 1ml 25 mg of lithium hydroxide was added to a solution of water and the mixture was stirred for 4 hours. It was then acidified with 1N sulfuric acid and allowed to stand at room temperature overnight. The methanol was then distilled off and the residue was partitioned between diethyl ether. The diethyl ether solution was washed with water and the solvent was distilled off. There was thus obtained 185 mg of 9alpha, 11alpha, 4S, 15Setrahydroxy-6,9-oxldo-5,6 [alpha] -16-fluoroprost-13-trans-eno-gamma-lactone. Typical peaks in the mass spectrum occur at mass numbers 570, 552, 554 and 290.

Starting from the esters obtained in Example 9 and hydrolyzing them as described in this Example and then ring closure, the corresponding gamma-lactones are obtained.

Example 12

500 mg of a solution of 9alpha, 11alpha, 4S, 15SS-tetrahydroxy-6,9-oxido-5,6 [alpha] -14-bromo-prost-15-trans-enoic acid methyl ester in 5 mL of methanol 2 ml of 2N sodium hydroxide solution are added and the mixture is stirred for 12 hours at room temperature. The methanol was then distilled off, the pH of the remaining aqueous solution was adjusted to 4 with raonon sodium phosphate, stirred for a further 2 hours and extracted with diethyl ether. The diethyl ether solution was washed with water, dried and the solvent was distilled off. There was thus obtained crude 9alpha, 11alpha, 4S, 15SS-tetrahydroxy-6,9-oxido-5,6 [alpha] -14-bromo-prost-15-trans-enoic acid gamma. ma-lactone is obtained. Chromatography on silica gel gave 264 mg of pure product. Characteristic peaks of the mass spectrum occur at 450 / 452,550, 552, 514 and 270.

15 «Example

To a solution of 500 mg of 9alpha, 11alpha, 4S, 15SS-tetrahydroxy-6,9-oxido-5,6 [alpha] -prostanoic acid methyl ester in 5 mL of methanol is added 2 mL of 2N sodium hydroxide and the mixture was stirred for 12 hours at room temperature. The methanol is then distilled off, the remaining aqueous solution is acidified with monosodium phosphate and extracted with diethyl ether. The diethyl ether solution was washed with water, dried and the solvent was distilled off under reduced pressure. This gives 220 mg of 9alpha, Halfa, 4S, 15S, tetrahydroxy-6,9-oxido-5,6 (alpha) -propanoic acid.

-17182,021

The product is dissolved in diethyl ether and treated with 20 mg of Amberlyst 15 ion exchange resin for 12 hours at room temperature. The resin is then filtered off and the solvent is distilled off under reduced pressure. This gives 200 mg of 9alpha, Halfa, 4S, 15SS-tetrahydroxy-6,9-OXido-5,6 / alpha-prostanoic acid gamma-lactone. In its mass spectrum, the characteristic peaks appear at 554, 55θ → 318 ®s and 274

Example 14

650 mg of 9β1-hydroxy-11α-alpha, 15 S, bis-tetrahydropyran-2'-yloxy-4-oxo-6,9-oxido-14-bromo-5,6 (alpha) -prost To a solution of -15-trans-enoic acid orthomethyl ester in 5 ml of tetrahydrofuran is added 4 ml of a solution of methyl magnesium bromide in diethyl ether at -20 ° C. After half an hour, ammonium chloride solution was added, diluted with diethyl ether and the phases were separated. The diethyl ether solution was washed with brine, dried and the solvent was distilled off. The residue was dissolved in a mixture of 10 ml of methanol, 5 ml of water and 0.1 ml of hydrochloric acid. The mixture was stirred for 1 hour at room temperature and most of the solvent was distilled off. The residue was dissolved in diethyl ether, washed with water, followed by sodium bicarbonate solution, closed and the solvent was distilled off. The crude product containing a mixture of 15 / S / - and 15 / R / - alcohols is chromatographed on 120 g of silica gel, eluting with a 1: 1 mixture of diethyl ether and benzene. In this way 295 mg of 9θIfa, Halfa, 4/3 /. 15S-Tetrahydroxy-6,9-oxido-4-methyl-14-bromo-5,6-alpha-pro-15-trans-enoic acid methyl ester was obtained and 268 mg of 4R-epimeric alcohol were obtained. THE . characteristic peaks at 476/478, 458/460, 396, 378, and 560.

Starting from the compounds listed in Examples 9 and 10 and analogously, 9,11,4 / S, 15 / S -tetrahydroxy-6,9-oxido-5,6 (alpha) -propanoic acid methyl was prepared. 4-methyl, 4-ethyl, 4-vinyl and 4-ethyl derivatives of their esters and their 5,6 (beta) isomers.

Example 15

1.2 g of 9 alpha-hydroxy-11a-alpha, 15 S, bis-tetrahydropyran-2 * -yloxy-4-oxo-6,9-oxido-20-methyl-5,6a-alpha To a solution of N -prost-15-trans-enoic acid orthomethyl ester in 10 ml of dioxane is added 7 ml of a 1 molar solution of vinyl magnesium bromide in dioxane at -50 ° C. After stirring for 2 hours at -30 ° C, 7 ml of a 1 M tosyl chloride solution is carefully added and the mixture is stirred for another half hour. The mixture was then allowed to warm to room temperature and diluted with diethyl ether. The organic solvent solution was washed with ammonium chloride solution, dried and the solvent was distilled off. The residue was dissolved in diethyl ether, the diethyl ether solution was washed with sodium bicarbonate solution, water, dried and the solvent was evaporated. The crude product containing 4 (S) - and 4 (R)-tosyl ester is chromatographed on silica gel, eluting with 8: 2 diethyl ether: cyclohexane. There were thus obtained 710 mg of 9alpha, Halfa, 4S, 15SS-tetrahydroxy-6,9-oxido-4-tosyloxy-4-vinyl-20-methyl-5,6 (alpha) -prost-13-trans-enoic acid. methyl ester and 675 mg of the corresponding 4R-tosyl ester. Analysis: Calculated: C, 63.571; H, 8.18; S, 5.66. Found: C, 63.51; H, 8.21; S, 5.65.

Starting from the compounds obtained in Example 14 and following the procedure described above, the tosyl and mesyl esters of these compounds are obtained.

-18182021

Example 16

580 mg of '18,19,19,2O-trinor-9alpha, 4S-dihydroxy-11alpha, 15S-bis (tetrahydropyran-2 * -yloxy) -17-phenyl-6,9-oxo To a solution of 5.6 (beta) -prost-13-trans-enoic acid orthomethyl ester in 5 ml of pyridine is added 276 mg of tosyl chloride. After 1 hour, the mixture was diluted with ice water and extracted with diethyl ether. The diethyl ether solution was washed with 1 N citric acid solution, dried and then added to a mixture of 0.184 g of magnesium and 1.97 g of iodine; start the reaction by adding a drop of methyl iodide. After stirring for 1 hour, the mixture was cooled to +5 ° C and 0.5 ml of water was added dropwise. The diethyl ether solution was separated and washed with brine. The aqueous solution was partitioned between ethyl acetate and the solvent was evaporated from the combined organic solvent solutions. The crude product is dissolved in 9 mL of 5θ% aqueous methanol and treated with 20 mg of ρ-toluenesulfonic acid for 3 hours. The methanol was then distilled off under reduced pressure and the aqueous residue was partitioned between diethyl ether. The final crude product was chromatographed on silica gel using dichloromethane: cyclohexane (8: 2) as eluent. There were thus obtained 540 mg of 18,19,20-trinor-9alpha, 11a-alpha, 15S-trihydroxy-4 (R) -iodo-17-phenyl-6,9 * -oxido-5,6 (beta) -prost. 13-Trans-enoic acid methyl ester is obtained. Typical peaks in the mass spectrum appear at mass numbers 528, 510, 492, 400 and 364.

Starting from the 4 (R) -epimer and proceeding analogously, the 4 / S1A-iodine derivative is obtained.

Starting from the compounds obtained in Example 2 and analogously, the corresponding 4-iodo, 4-bromo and

Price of 4-chlorine.

Example 17

350 mg of 18,19,20-trinor-9alpha, 11alpha, 15S (trihydroxy-4R) -iodo-17-phenyl-6,9-oxido-5,6 (beta) -prost-13-trans-enoic acid To a solution of methyl ester in 15 ml of benzene was added 350 mg of a solution of tributyltin hydride in 10 ml of benzene and 10 mg of 2,2 ^U- azobis (2-methylpropionitrile). After stirring for 24 hours at 55 ° C, the mixture is diluted with diethyl ether and the diethyl ether solution is washed with Seignette salt / potassium sodium tartrate solution and then with water. The solvent was distilled off under reduced pressure and the crude product was chromatographed on silica gel, eluting with a 1: 1 mixture of cyclohexane and diethyl ether. There were thus obtained 260 mg of 18,19,2O-trinor-9alpha, 11alpha-trihydroxy-17-phenyl-6,9-oxido-5,6 (beta) -prost-13-tranaz

methyl ester. In the mass spectrum, typical peaks appear at the close of masses 402, 384, -366 and 261.

Starting from the prostaglandin derivatives obtained as described in Example 16 and analogously, the corresponding 5,6-dihydro-PO2 derivatives are obtained.

Example 18

214 mg of a solution of 9alpha, 11alpha, 15S-trihydroxy-6,9-oxido-4-oxo-5,6 [alpha] -propyl-13-trans-enoic acid orthomethyl ester in 5 mL of tetrahydrofuran 102 mg of p-toluenesulfonyl hydrazine and the mixture is stirred for half an hour. The solvent was distilled off and the crude tosylhydrazone was purified by thin layer chromatography. Thus 285 mg of ^the LFA 9, Hal Tree. 15 (S) -Trihydroxy-6,9-oxido-4-oxo-5,6 (alpha) -prost-13-trans-enoic acid orthomethyl ester-4-tosylhydrazone is obtained. This product, 15 / SA Acid19

-19182.021 is dissolved in 2 ml of deuterochloroform, and 20 mg of sodium boron deuteride is added to the solution. The reduction takes place in half an hour. Then 0.2 ml of deuterium oxide was added, the organic solvent layer was separated, washed with deuterium oxide, dried and the solvent was distilled off under reduced pressure. 123 mg of 4,4-dideutero-9alpha * llalfa, 15 / S / trihydroxy-6,9-oxido-5,6 / alpha-prost-13-trans-acid ortho-methyl ester is obtained. _r = + 25 / c = 2, chloroform /, ° CJ ₅₆₅ ° _{+ g 4} °

19 »Example

200 mg ^of 9-alpha, llölfa 4 / S / 15 / S / tetrahydroxy-6,9-oxido-4-methyl-14-bromo-5,6 / alpha / prost-13-enoic acid methyl ester

To a solution of 2.5 mL of dimethyl sulfoxide in 2.5 mL of methanol was added 50 mg of sodium methylate in 2.5 mL of dimethyl sulfoxide and 2.5 mL of methanol. After stirring for 1 hour at room temperature, the pH was adjusted to 5 with monosodium phosphate and extracted with diethyl ether. The diethyl ether solution was washed with water, dried and the solvent was distilled off. The residue was chromatographed on silica gel, eluting with a 1: 1 mixture of diethyl ether and dichloromethane. 145 mg of 9alpha, 11alpha, 4S, 15SS-tetrahydroxy-6,9-oxldo-4-methyl-5,6 [alpha] -prost-13-insic acid are obtained. Typical peaks in the mass spectrum appear at 382, 364, 328, 284 and 257.

As an alternative to the method described therein, the compounds already described in Example 10 above may be prepared by the method described in the present Example.

Example 20

320 mg of 9alpha, 4S, 15S, trihydroxy-6,9-oxido-5,6-beta-prostta-10,13-trans-dienoic acid methyl ester, 3.5 mL of methanol and 0.8 mL to a solution of water in water is added 50 mg of lithium hydroxide. The mixture was stirred at room temperature for 5 hours, then diluted with water, acidified with sodium hydrogen sulfate and extracted with diethyl ether. The diethyl ether solution was washed with water and the solvent was distilled off to give 3x5 mg of 9alpha, 4S, 15S, trihydroxy-6,9-oxido-5,6 / beta -prost-10,13-trans. diene acid is obtained. In its mass spectrum, the characteristic peaks appear at mass numbers 352, 334, 316, 290 and 253.

Example 21

191 mg 931fa, II added ^ice LFA 15 / S / trihydroxy-4-oxo-6,9-oxido-20-methyl-5,6 / alpha / prost-13-enoic acid in 5 ml of methanol cooling bath 5 ml of 0.1 N sodium hydroxide solution. The solvent was distilled off, and thus the form of white crystals, 200 mg ^{of 9-f,} Halfa, 15 / S / trihydroxy-4-oxo-6,9-oxido-20-methyl i1-5,6 / alpha / The sodium salt of -pros zt-13-enoic acid is obtained.

IR spectrum (KBr): δ = 3320 (-OH), 1715 (O) = 0,

1740 (-C00).

The corresponding salts are obtained from the prostgglandin derivatives obtained as described in Examples 2, 3, 9, 10, 14, 19 and 20 and analogously.

Claims (3)

Patent claims A process for the preparation of a compound of formula I wherein: -20182.021 means a / b / c / d / You are -000H. -COO (C 1 -C 4 alkyl) ·, -C / OR _a / j in which the _RQ groups may be the same or different and represent a (C1-C4) alkyl group, a cyano group or -C0NH ₂ groups, D is a straight or branched carbon chain having from 2 to 4 carbon atoms, R, and R2 is one of hydrogen, deuterium, 1-4 ^{x ώ} alkyl or C2-4 alkenilesoportot means, and the other is hydrogen, deuterium, or halo * hydrogen; and, .hidroxilcsoportot or R? -S0 ₂ Oh - represents a group of the general formula wherein R? is a C 6 -C 7 carbocyclic aryl group or R 4 and R 8 together with the carbon atom to which they are attached form an oxo group, q is 1 or 2, Y is a group of 1,2-ethylene-diphenyl, -ΌΞΟ-, wherein the hydrogen atom and Z are in the cis or trans position with respect to each other, where Z is hydrogen or halogen, One of Re and R are each hydrogen, and the other ⁷ hydroxyl group, E is a group of the formula - / CH ₂ / _m -, wherein m is 1 to 7 and one of the hydrogen atoms may be replaced by a fluorine atom, G is hydrogen, (C1-C4) -alkyl, or - when m is 2 - phenyl, denotes a single and a dotted line (-----) a single or double bond, provided that when R1 is One of R ₂ is hydrogen, and the other of hydrogen and halo is not further represented by the compounds of formula I wherein R is a free carboxyl group and one of R 1 and R ₂ is hydroxy, the lactones to be derivatized by intramolecular etherification and for the preparation of optical antipodes, i.e. enantiomers, racemic mixtures, geometric isomers and mixtures of optical antipodes and mixtures of diastereomers thereof, of compounds of formula I and their lactone derivatives, azzaX a compound of the general formula wherein R ₄ is hydroxy or a known protecting group attached to the ring via an ether linkage; ^- One of R 6 and R 8 is hydrogen and the other ⁷ is hydrogen or a known protecting group attached to the ring via an ether linkage, -21182.021 and q, Y, E and G are as defined above for a compound of formula IV wherein R and Ό are as defined above and L is a group of formula /θΗ ^ / ^ Ρ- or / R _Q 0 / gP / - ^ 0 / -, wherein R is a C 1-6 alkyl group and the two R _Q groups are not necessarily the same, and removing the protecting groups, if any, to give a compound of formula I wherein R, D, q, Y, R6, Βθ, E, G and the bond with a continuous and dashed line are as defined above, and R6 and Rg is the carbon atom to which they are attached to form an oxo group and optionally is one. Compounds of formula I wherein R 1 and R 8 together with the carbon atom to which they are attached form an oxo group are also converted to compounds of formula I wherein one of R 6 and R 8 is hydroxy or R 6 is hydrogen _. A group of the formula -SOg-O-, wherein R? is as defined above, and the other is hydrogen or deuterium, C 1-4 alkyl or C 2-4 alkenyl, and if desired, compounds of formula I wherein one of R ₂ is hydroxy group and the other represents 2-4 carbon atoms, is converted to compounds of formula I wherein one of R 1 and R 8 is C 2 -C 4 alkenyl and the other is R 4 -SO 8 -O - a group of the formula wherein R? has the meaning given above; or, if desired, a compound of formula I wherein one of R 1 and R 8 is hydroxy or R 6 -SO 8 -O- wherein R? is as defined above and the other is hydrogen, compounds of the formula I in which one of R 1 and R 8 is halogen, preferably iodine and the other is hydrogen or, if desired, one of the general formula I Compounds of formula wherein Y is -GH = CZ- and Z represents halogen are also converted to compounds of formula I wherein Y is -O-O- or, if desired, compounds of formula I wherein Y- CH = CZ- and Z represents hydrogen, converted to compounds of formula I wherein Y is -CH8-GHg- or, if desired, compounds of formula I wherein R is -C00- / 1- C4 alkyl is also a compound of formula I into compounds wherein R is -Ό00Η or, if desired, compounds of formula I wherein R is -C / OR · and R _{ö is} as defined above. -22182.021 is also converted to compounds of formula I wherein R is -C0- (C1-C4) alkyl or, if desired, compounds of formula (I). wherein R is -C = N, is converted, also compounds of formula I wherein R ₂ represents -C0NH group, and optionally reacting the compound of formula I is converted into a lactone derivative or its salt, or b / the compounds of formula I narrower for the preparation of compounds of the general formula II, which have the formula R 1 and R 8 * are hydrogen or deuterium and R, D, q, Y, R 6, R 8, E, G and -rzm are ^as defined above for a compound of formula V wherein R, D, q, Y, R 1, R, E and G have the meanings given above and one of the groups Rp 'and Rp *' represents a hydrogen or deuterium atom and the other a halogen atom or Forming N-NH-R ₈ group, wherein R ^ is -SOgR Rp 'Rp' * and the carbon atom to which they are attached, 3 is> C =? a group of formula wherein R? with the meanings given above - reduced. A process for the preparation of a medicament for human or veterinary use, characterized in that the compounds of the formula I according to claim 1, wherein R, D, q, R p, R ₂ , R 4, R 9, Y, E, G and α, as defined in claim 1, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, are formulated in a pharmaceutical composition in admixture with carriers and / or other excipients, as is customary in the pharmaceutical formulation. 3 drawings F.k .: Zoltán Hlmer National Office of Invention 70 - OTH - 84.070