CS216842B2 - Method of making the 2-oxabicyklik prostaglandines - Google Patents

Description

The invention relates to a process for the preparation of 2-oxabicyclic prostaglandins of the general formula I

wherein R is (a) a free carboxyl group or a group of the formula -COORs wherein R represents Ci_i ₂ alkyl or C ₂ _ ^ alkenyl, (bj group of formula wherein the substituents R ', which may be the' same or different, denotes C 1-4 alkyl groups, (c) a group of the formula -Cl 2 OH, (d) a group of the formula

Ra /

—CON \

R _b in which R _a and R _b represent, individually, hydrogen, C ₆ alkyl group, C 2-6 ^Alk! Anoyl group or a phenyl group, a (ej group of formula

-ď H

STEED*

-C — OR ‘

OR ‘or (f) a cyano group,

Whether it represents a hydrogen or halogen atom, if it is zero or an integer from 1 to 7, q is 1 or 2,

Ri represents hydrogen, hydroxyl sku216842 pin, Cx- ^ alkoxy, Ο ₆ _ ₁₀ & Ϊ-γ (, _ ^ οxyskupinu η ₆ or C ₇ acyloxy3kupin ⁱ u,

Y represents a group of the formula —CH2 CH2—, —C = CH2

C = C (trans)

Zz wherein Z 2 přeďsitavuje hydrogen or halogen, one of the substituents on the R 2 and R is hydrogen, C ₆ alkyl'ovou group, a C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ group, and the second _Kjaryl'OVOu of R2 and R represents hydroxyl, C ^ -alkoxy or _C6-Cl ionophore receptor _least _joar alkoxy, or R and R together form oxoiskupinu,

R 3 and R 4, which may be the same or different, each represent a hydrogen atom, a C _1-6 alkyl group or a fluorine atom, or R 3 and R a together with the carbon atom to which they are attached form a radical of the formula "C"

II

CH2 or the rest of the formula

-C"

OF \

CHi ^CH Z ni and nz, which may be the same or different, individually denote zero or an integer from 1 to Θ,

X denotes oxygen or sulfur atom nebd group of formula - (CH _{2) m} -, wherein m is zero or 1,

R e denotes (a ') a hydrogen atom, (b') a C _1-4 alkyl group, (c ') a C ₃ -C ₉ aliphatic radical, optionally substituted with at least one C _1-6 alkyl group or a C 1-6 alkoxy group, (d') C ₆ _ioarylOfvou 'group optionally substituted by at least one halogen atom, halogenated C ^ alkyl, C ₆ alkyl group or a C ₆ alkbxýsikupinou, or (e') a saturated or unsaturated "or heteiromonocyklický heterobicyklioký ring containing at least one heteroatom selected from the group: nitrogen, sulfur and oxygen and having 1 to 10 carbon atoms optionally substituted with at least one halogen atom, a halogenated C ₆ alkyl, C ₆ al'kylovou group or a C _e alkoxy.

Also included within the scope of the invention are pharmaceutically or veterinarily acceptable salts as well as optical antipodes, i.e. enantiomers, racemic mixtures of optical antipodes, geometric isomers and mixtures thereof, and mixtures of diastereoisomers of the compounds of Formula I.

In the formulas of this disclosure, the dashed line (IIIUIU) indicates that the substituent attached to the cyclopentane ring is in the α-configuration, i.e. below the plane of the ring, the substituent bound to the 2-oxabicyclic system is in the ento configuration, and the substituent bound. the solid chain is in the S configuration, and the solid end-thickened line indicates that the cyclopentane ring-attached substituent is β-configuration, i.e. above the plane of the ring, the 2-oxabicyclic-rich substituent is exo- the carbon chain configuration and substituent is in the R configuration. Wavy line

indicates that the position of the line-attached substituent is not sterically defined, i.e., when the substituent attached to the cyclopentane ring may be in the α-position or in the β-position, the substituent bound to the 2-oxabicyclic system may be either endo-configuration or in the exo-configuration, and the substituent bonded to the carbon chain may be in either the S- or R-configuration.

In the compounds of formula I, the heterocyclic ring B is linked to the cyclopentane ring A cis, and the two bonds, indicated by the dotted lines (...), are both in the α-configuration with respect to ring A.

The side chain β-linked to the cyclopentane ring A is in the trans configuration with respect to the enému-linked heterocyclic ring and is consequently an exo substituent with respect to the 2-oxabicyclic system.

At the carbon atom of the heterocyclic ring B bearing the side chain of the general formula

Z, f

m = CH - (CH _z) p ^R is bonded to a hydrogen atom. If the side chain of the general formula * (CH3) p R is in the endo configuration relative to the 2-oxaibicyclic system, then said hydrogen atom is an exo substituent and its absolute configuration is denoted by β, and when the side chain of the general formula

Z <

In the exo configuration, said hydrogen atom is an endo substituent and its absolute configuration is referred to as.

Compounds of formula I wherein the side chain of formula z,

F 1 C 1 - / - (CH 2 p R is in the exo-configuration and in which the hydrogen atom bonded to and the same carbon atom of the ring B is necessarily of the absolute configuration α, are referred to as 6'-H-6,9a-oxide derivatives I, q = 1j and as derivatives of 5aH-5,9ia-oxide (general formula I, q = 2) of prositanoic acid (proistaglandin numbering, while compounds of general formula I wherein the side chain of general formula is in the endo-configuration and in which the hydrogen atom bonded to the same carbon atom in Book B thus necessarily has an absolute configuration of β are referred to as 6 /? H-6,9a-oxide derivatives (formula I, q = 1j and 5 / 3Ή-5,9a-oxide derivatives (general Alternatively, 6aH-6,9a-prostanoic acid derivatives are referred to as (2'-oxa-bicyclo [3.3.0] octane-3'-exo- acid derivatives of formula I, q = 2). yl) alkanoic, 5xH-5,9a-prostanoic acid derivatives as (2'-oxa-bicyclo [4.3, O-nonan-3'-exo-yl] alkanoic acid, 6 / 3H-6,9a-procanoic acid derivatives as (2'-oxaibicyclo [3.3.0] ok, tan-3'-endo-yl) alkanoic acid derivatives , and 5 / 3H-5,9'-Prostanoic acid derivatives as (2'-oxa-bicyclo [4,3,0] nonan-3'-endo-yl) alkanoic acid derivatives.

Derivatives 6aH-6,9a-oxide and derivatives 5qeH-5,9a-oxide prostanoic acid have higher chromatographic mobility (i.e. have a higher _Rf value) and less positive optical rotation ([ «] d) than the corresponding derivatives of 0 (3H- 6.9'-oxide and 5'H-5,9a-prostanoic acid.

All of the above data refer to natural compounds; d, 1-compounds are mixtures containing equimolar amounts of natural (nat) compounds having the absolute steric structure described above with respective enantiomeric (ent) compounds that are mirror images of said nat-compounds; in ent-compounds, the stereochemical configuration at all centers is opposite to the configuration of natural compounds, and the prefix ent denotes that fact.

In formula (I), the alkyl, alkenyl, afkinyl, alkoxy and alkanoyloxy groups may have a branched or straight chain.

Preferably R represents a free, salt-converted or esterified carboxyl group.

(C ₆ _iogair- (Ci-Ce) alkoxy group is preferably benzyloxy.

C ₆ _ _I0 aryl group is preferably a phenyl, α-naphthyl or β-naphthyl group.

A halogenated alkyl group having 1-6 carbon atoms is preferably a halogenated alkyl group having 1-8 carbon atoms, in particular a trifluoromethyl group.

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

The alkoxy of 1-6 carbon atoms is preferably methoxy, ethoxy or propoxy.

The C 2-6 alkenyl radical is preferably a vinyl group.

The C 2-6 alkynyl group is preferably an ethynyl group.

When R represents an esterified carboxyl group, it is preferably a group of the formula -COOR 5 in which R 5 represents an alkyl radical of 1-12 carbon atoms, in particular a methyl, ethyl, propyl or heptyl group, or an alkenyl radical of 2-12 carbon atoms, especially allyl.

Preferably Z 1 represents a hydrogen atom. When Z 1 represents a halogen atom, it is preferably a chlorine or bromine atom.

The index p is preferably an integer from 1 to 3.

When R1 is C1-yacyloxy, it is preferred that the group is alkanoyloxy having 2-7 carbon atoms (especially allanoyloxy having 2-6 carbon atoms, for example acetoxy or propionyloxy), or benzoyloxy.

When Z2 is a halogen atom, it is preferred that the halogen atom is a chlorine, bromine or iodine atom.

The substituents R 3 and R 4 are independently of one another

6842 is preferably selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms and fluorine.

The index n1 is preferably zero or an integer from 1 to 3; preferably is an integer from 1 to 3.

If R6 is a C 3-9 cycloaliphatic radical, it is preferred that the radical is a C 3-9 cycloaliphatic radical, for example a cyclopentyl, cyclohexyl or cycloheptyl radical, or a C 3-9 cycloalkenyl radical carbon, for example cyclopentyl, cyclohexenyl or cycloheptenyl.

Examples of preferred heteromonocyclic radicals include tetrahydrofuryl, tetrahydropyranyl, pyrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl groups.

Examples of preferred heterobicyclic radicals include 2-oxa-bicyclo [3.3.0] ocityl, 2-oxa-bicyclo [3.4.0] nonyl, 2-ithia-bicyclo [3.3.0] octyl and 2-thiabicyclo [3,4.0] nonyl and aromatic analogs thereof.

Pharmaceutically or veterinarily acceptable salts of the compounds of formula I are, for example, salts with pharmaceutically and veterinarily acceptable bases. As the pharmaceutically and veterinarily acceptable bases, either inorganic bases such as alkali metal hydroxides, alkaline earth metal hydroxides as well as aluminum hydroxide and zinc hydroxide, or organic bases, especially organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, N-methyl-N-hexylamine, decylamine, dodecylamine, allylamine, cyclopentylamine, cyclohexylamine, benzylamine, dibertzylaminu, α-phenylethylamine, C-I ^en yl ^e dimethylamine, ethylenediamine, diethylenetriamine, morpholine, piperidine, pyrrolidihu, piperazine, and also alkyl derivatives the latter four bases, mono-, di- and triethanolamine, ethyl-diethanolamine, N-methyl-ethanoliamine, 2-amino-1-butanol, 2-amino-2-methyl-1-propanol, N-phenylethanolamine, galaictamine , N-methylglucamine, N-methylglucosamine, ephedrine, procaine, dehydroabietylamine, lysine, arginine, and other α- or α-amino acids in. Preferred salts of the compounds of the invention are those of formula I wherein R is a group of the formula -COOR _d , wherein R _d is a pharmaceutically or veterinarily acceptable cation derived from one of the aforementioned bases.

Particularly preferred compounds of the present invention are the 6H-6,9'-oxides and 5 (3Η-5,9'-oxides of formula I) wherein R is a free carboxyl group and R6 is a C1-4 alkyl group, a cycloalkyl group C 5 -C 7 carbon atoms or an optionally substituted phenyl group.

The prefixes nor-, di-nor ·, tripor-, tetranor- etc. are used to denote compounds of formula I in which the side chain attached to the cyclopentane ring A is shorter by one, two, three, four, etc. carbon atoms than the analog side chain in natural prostaglandins.

The following are examples of some specific preferred compounds of Formula I (t denotes trans).

13t-6CH-6,9a-oxide-11a, 15S-dihydroxy-prost-13-enoic acid, 6CH-6,9a-oxide-11a, 15S-dihydroxy-prost-13-enoic acid, 13t-6 (3H) -6,9α-oxide-11a, 15S-dihydroxy-prostanoic acid, β, βΗ-θ-, 9α-oxide-11a, 15S-dihydroxy-15-methyl-prost-13-enoic acid, 6β-6,9a- oxide-11a, 15S-dihydroxy-15-methyl-prost-13-ynoic acid, 6β-6,9a-oxide-11a, 15S-dihydroxy-15-methyl-prostanoic acid, 6β-6,9a-oxld-11a, 15S-dihydroxy-15,20-dimethyl-prost-13-enoic acid, 6H-6,9a-oxide-11a, 15S-dihydroxy-15,20-dimethyl-prost-13-enoic acid, 6H-6,9 , .alpha.-oxide-11a, 15S-dihydroxy-15,20-dimethyl-prostaric acid, 13t-6H-6,9'-oxide-11 ', 15S-dihydroxy-20-methyl-prost-13-enoic acid, 6CH-6,9a-oxide-11a, 15S-dihydroxy-20-methyl-prost-13-ynoic acid, 6CH-6,9a-oxide-11a, 15S-dihydroxy-20-methyl-prostanoic acid, 13t-6CH 6,9a-oxide-15S-hydroxy-prost-13-enoic acid, 6CH-6,9a-oxide-15S-hydroxy-prost-13-ynoic acid, 6CH-6,9a-oxide-15S-hydroxy-prostanoic acid , 13t-6cH acid 6,9a-Oxide-15S-hydroxy-15-methyl-prost-13-enoic acid, 6H-6,9a-Oxide-15S-hydroxy-15-methyl-prost-13-enoic acid 5α-Oxide-15S-hydroxy-15-methyl-prostanoic acid, 13β-6β-6,9α-oxide-15β-hydroxy-15,20-dimethyl-prost-13-enoic acid, 6β-6, 9'-Oxide-15S-hydroxy-15,20-diinethyl-prost-13-ynoic acid, 6H-6,9a-oxide-15S-hydroxy-15,20-dimethyl-prositanoic acid, 13t-6H-6,9a -15S-hydroxy-20-methyl-prosit-13-enoic acid, 6H-6,9α-oxide-15S-hydroxy-20-methyl-prost-13-ynoic acid, 6H-6,9a-oxide- 15S-hydroxy-20-methyl-prostanoic acid, 13t-6H-6,9a-oxide-11a, 15S-dlhydroxy-14-bromo-prosph-13-enoic acid, 13t-6 / JH-6,9a-10xld -11a, 15S-dihydroxy-14-chloro-prost-13-enoic acid, 13t-6 / 3H-6,9a-oxide-11a, 15S-dihydroxy-1α-bromo-1S-methyl-prost-13-enoic acid , 13t-6 / 3H-6,9a-oxo-11a, 15S-dihydroxy-14-bromo-20-methyl-prost-13-enoic acid, 13t-6 / 3-6,9a-oxtd-11a, 15S dihydroxy-14-bromo-15,20-dimethyl-pro-13-enoic acid, 13it-6 (3H-6,9a-oxide-11a), 5S-dihydroxy-16,16-dimethyl-pro3t-13-enoic acid, 13t-6 / 3H-6,9a-oxide-11a, 15S-dihydroxy-16-methyl-16-butoxy-20,19,18-trinor -prost-13-enoic acid 13t-6 (3H-6,9o) -oxide-11a, 15S-dihydroxy-16 (S, R) -fluoro-17-cyclobexyl-20,19,18-trinor-prost -13-enoic acid and respective individual 16 (S) - and 16 [R] -fluoro-isomers, 13t-6,3H-6,9a-oxide-11a, 15S-dihydroxy-17-cyclohexyl-20,19,18-trinoric acid -prost-1S-enoic acid, 6 ₁ dH-6,9a-oxide-11a, 15S- ⁱ dihydroxy-17-cyclohexyl-20,19,18-trinor-prost-13-ynoic acid, 13t-6,3H- 6,9a-oxide-11a, 15S-dihydroxy-16-phenoxy-20,19,18,17-tetr, anor-13-eno and its p-fluoro, ρ-chloro, p-methoxy-, ο-fluoro -, m-fluoro-, m-trifluoromethyl and m-chlorophenoxy analog, 13t-6H-6,9a-Oxide-11a, 15S-dihydroxy-17- (2'-tetrahydrofuryl) -20,19,18-trinoric acid pros, t-13-enoic acid 13t-6 / 3H-6,9a-oxide-11a, 15S-dihydroxy-17- (2'-tetrahydrothenyl) -20,19,18-trinor-prost -13-enoic acid, 13t-6 (3H-6,9a-oxide-11a, 15S-dihydroxy-20-ethyl-prost-13-enoic acid, 13it-6 / 3H-6,9a) -oxa-11a, 15S-dihydroxy-16-henzyloxy-20,19,19,17-tetranor-13-eno and its p-fluoro, ρ-chloro, p-methoxy-, o-fluoro-, η-fluoro -, m-trifluoromethyl-, m-chlorobenzyloxyanaloga, 13't-5f3H-5,9a-oxide-11a, 15S-diliydraxy-pro-13-enoic acid, 5f1H-5,9'-oxide-11a, 15S- dihydroxy-prostanoic acid, 5 / 3H-5,9a-oxide-11a, 15S-dihydroxy-pro'st-13-ynoic acid, 13t-5 / 3H-5,9a-oxide-11a, 15S-dihydroxy-16S- methyl-prost-13-enoic acid, 13t-5,3H-5,9a-oxide-11a, 15S-dihydroxy-16R-methyl-prost-13-enoic acid, 13t-6 / 3H-6,9a-oxide-11a, 15S-dihydroxy-16S-methyl-prost-13-enoic acid, 13t-6 (3H-6,9a-oxide-11 ', 15S-dihydroxy-16R-methyl-prosit-13-enoic acid, 6 / JH-6 9α-oxide-11a, 15S-dihydroxy-16S-methyl-prost-13-ynoic acid, 6,3H-6,9a-oxide-11a, 15S-dihydroxy-16R-methyl-prost-13-ynoic acid;

and also the 5-bromo, 5-iodo and 5-chloro analogues of all the above-mentioned 6 (3H-6,9a-oxide) derivatives, as well as the 4-bromo, 4-iodo and 4-chloro analogues of all the above derivatives 5i (3H-5,9a-oxide, as well as the corresponding 15R-epimers, 15-oxo derivatives and the 6aH- and 5aH-diastereoisomers of all of the above compounds.

The compounds of formula I can be prepared according to the invention by reacting a compound of formula IV

wherein R 'is (a ") free carboxyl groups, or a group of the formula -COOR wherein R represents C i ^ lkylovou group or a C ₂ _ ^ alkenyl, (b' j a group of formula

STEED*

OF

-C — OR *, \

OR * in which the substituents R ‘are as defined above, (c") a group of the formula -CH 2 -R 2 in which R 2 represents a hydroxyl group or an ether-oxygen-bonded protecting group to a "CH 2" group, jd ") a group of the formula

E ^A '-a /

—CON \

R b in which R _a and R _b are as defined above, (e "j is a radical of formula ^X NH-N or (F") cyano,

R 'represents a hydrogen atom, a hydroxyl group, a C ₆ alkoxy, C ^^ ar-C ^^ alkoxy, C ₇ acyloxy group, or a protecting group bound to the ring with ethereal oxygen atom, etc., Z and q are as defined above, to a compound of formula V

wherein E represents a group of formula (+) (C 6 H 8 P 6 or a group of formula)

O t

(RCO) ₂ P, wherein R _e, which may be the same or different, each independently representing a C ₆ alkyl or C ₆ _ ₁₀ aryl group, and Z2, R3, Ri, Ni, Na, X and R6 are as defined above and after deprotection, if present, the compound of formula (I) in which R2 and R8 together represent oxo and Y represents a group of formula (CH = CZ2) in which Z2 is as defined above, optionally reduced to a compound of formula I wherein one of R 2 and R 5 represents a hydrogen atom and the other substituent represents a hydroxyl group and Y represents a group of the formula -CH = CZ 2 in which Z 2 is as defined above, or optionally a compound of formula I, wherein R 2 and R 5 together represent an oxo group and Y represents a group of formula - CH = CZ 2 - in which Z 2 is as defined above, is converted to a compound of formula I in which one of the substituents ents R 2 and R represents a hydroxyl group and the other represents a C subsítituent ^ alkyl, C ₂ _ ₆ alkenyl, C ₂ _. ₆ alkinyliovou group or a C ₆ _i ₀ aryl group, and the compound of formula I in which one of sulhstituentů R 2 and R represents a hydroxyl group and the other represents hydrogen, C ^ alíkylovou group, a C ₂ _ ₆ alikenylovou group, a C ₂ _ _an alkynyl group or a C ₆ -C ₆ arylovone group and Y represents a group of the formula "CH = C 2", in which Z 2 is as defined above, optionally etherifying to a compound of the formula I wherein one of R 2 and R 5 is C 1-6 C ^^ alkoxy or ar-C ^^ alkoxy, and the other substituent is hydrogen, C ^ alkyl, C ₂ _ _alkenyl group, C ₂ _ ₆ alkynyl or C ₆ _ ₁₀ aryl, or with an alkyl group and Y represents and / or a compound of formula I wherein Y is a group of formula - CH = CZ2 wherein Z2 is hydrogen or optionally hydrogenated to form a o of formula I in which Y represents a group of formula —CH2 — CH2, and / or a compound of formula I in which Z1 represents a hydrogen atom and Y represents a group of formula —CH = CZ2 in which Z2 represents a halogen atom, optionally dehydrohalogenates to a compound of formula (I) in which Y represents a group of the formula —C.dbd.C- and Z1 represents a hydrogen atom, or a compound of formula (I) in which R2 and R8 together represent an oxo group and Y represents a group of formula wherein Z 2 is hydrogen or optionally hydrogenates to a compound of formula I wherein R 2 and R 3 together are oxo and Y is -CH 2 -CH 2 - or a compound of formula I wherein Z 1 is hydrogen, R2 and R5 together represent an oxo group and Y represents a group of the formula --CH.dbd.CH2 - in which Z2 is a halogen atom or optionally dehydrohalogenates to a compound of the formula I wherein Z 1 is hydrogen, R 2 and R 5 together are oxo and Y is -C = C-, and the compound of formula I wherein R 2 and R 5 together are oxo is optionally reduced to a compound of formula I, wherein one of R 2 and R 5 represents a hydrogen atom and the other of the substituents represents a hydroxyl group, or a compound of formula I wherein R 2 and R 5 together represent an oxo group optionally converted to a compound of formula I wherein one of R 2 and R 5 represents a hydroxyl group and the other substituent represents C ^ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ _i ₀ aryl group, and a compound of formula I wherein one of R2 and R represents a hydroxyl group and the other substituent is hydrogen, C ₆ alkyl group, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ _ ₁₀ aryl Vou group, optionally etherified with a compound of formula I wherein one of R2 and R represents a C ₆ alkoxy or C ^ mar-C ^ íjalkoxyskupinu and the other substituent is hydrogen, C _'6 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ _ioarylovou group and / or a compound of formula I or into a different compound of formula I and / or a compound of formula I optionally converted into a salt, and / or optionally forming a free compound of a compound of formula I from a salt thereof, and / or optionally separating the mixture of isomers into the individual isomers.

In the individual steps of the above process, where only one of several of the present substituents of the compound of formula (I) is specifically mentioned, it is understood that all other substituents have the same meaning as previously given for formula (I).

The protecting groups (i.e., ether groups) used in the process of the invention are those which can be converted to hydroxyl groups under mild reaction conditions, i.e., by acid hydrolysis. For example, acetalethers, enol ethers can be used as such protecting groups. and silytethers, groups of general formulas are preferred

OAlk

OAlk

X

St-0-ι

CHfl ch ₃ -c _}

CH 1 in which W represents -O- or -CH 2 -, and Alk represents a lower alkyl group.

When in the compound of formula (V), E represents a group of formula

O t

(R _C OJ P-, wherein R _e is C ₆ _ ₁₀ aryl group, this is preferably a phenyl group.

The reaction of the aldehyde of formula IV with a compound of formula V is conveniently carried out using an excess of a compound of formula V, i.e. using at least 1.01 mol equivalents of the compound of formula V for each mole of the compound of formula IV. Any inert solvent such as linear and cyclic ethers, for example ethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, or aliphatic or aromatic hydrocarbons, for example n-heptane, n-hexane, benzene or toluene, or halogenated hydrocarbons, for example, can be used as reaction medium. methylene chloride or tetrachloroethane, as well as mixtures of these solvents. The reaction temperature may range from the freezing point to the boiling point of the solvent used.

When used in the reaction, a compound of formula V wherein E is a group of formula

O

T (R _& 0 ^ P-, it is preferably performed at about 10-20 ° C when used to react the compound of formula V wherein E represents SKUs (+) pin of the formula (CeHsjsP / it is preferably performed at the boiling point of the solvent used.

The product of the reaction of a compound of formula IV with a compound of formula

Y is a mixture of a compound of formula I wherein Y represents a group of formula tran-CH = CZ 2 - in which Z 2 is as defined above with a compound of formula I wherein:

Y represents a group of formula cis-CH = CZ 2 - in which Z 2 is as defined above, in a ratio varying between about 90: 10 to 95: 5.

A compound of formula (I) wherein:

Y denotes a group of the formula trans-CH = CZ 2 - in which Z 2 is as defined above, crystallization from a suitable solvent can be separated from the reaction mixture, while a compound of formula I in which Y denotes a group of the formula cis-CH = CZ 2 - as defined above, may be obtained by concentrating the mother liquors and subsequently separating the resulting mixture by either column chromatography or preparative thin layer chromatography using silica gel or magnesium silicate as carriers and, for example, methylene chloride, diethyl ether, isopropyl ether, ethyl acetate, benzene or cyclohexane, or mixtures thereof as eluents.

Protecting groups, if present, can be removed by mild acid hydrolysis.

As an optional reduction of a compound of formula I wherein R 2 and R 5 together are oxo, and Y represents a group of the formula "CH = CZ 2" in which Z 2 is as defined above to a compound of formula I where Y is a group of the formula —CH = CZz— in which Zz is as defined above, in which one of R2 and R5 represents a hydrogen atom and the other one represents a hydroxyl group, and optionally converting a compound of formula I in which R2 and R5 together represent oxo and Y represents a group of formula -CH = CZz- in which Z2 has the meaning shorauvedený to -compound of the formula I in which Y represents a group of WTOTCíe -ϋΗ = Ε2 ₂ -, Z ₂ is shorauvedený defined and one of the substituents R and R represents the hydroxyl group and the other one denotes an alkyl group having 1-6 carbon atoms, an alkenyl group having 2-6 carbon atoms, an alkynyl group having 2-6 carbon atoms or an aryl group n-6-10 carbon atoms, must be considered as different applications of only one reaction consisting of a 1,2 polar addition to the carbonyl group. Optionally reducing the obtained compound of formula I wherein R and R ₂ together represent an oxo group and Y denotes vzoree -CH = CZ ₂ -, wherein Z2 is shorauvedený defined, to a compound of formula I in which Y represents a group of formula - CH = CZ ₂ -, wherein Z 2 is as defined above, and wherein one of R 2 and R 5 is hydrogen and the other is hydroxyl, preferably alkali metal or alkaline earth metal borohydrides, preferably sodium, lithium, calcium borohydride , magnesium or zinc, using 0.5-6 moles of reducing agent for each mole of the compound of formula (I). The reduction can be carried out either in aqueous medium or in anhydrous inert solvents such as linear or cyclic ethers such as ethyl ether, tetrahydrofuran , dimethoxyethane or dioxane, or in aliphatic or aromatic hydrocarbons, for example d in n-heptane or benzene, or in halogenated hydrocarbons, for example in methylene chloride, or in hydroxylated solvents, for example in methanol, ethanol or isopropyl alcohol, or in mixtures of these solvents. The reaction temperature may range from about -40 ^° C to the boiling point of the solvent used, but the preferred reaction temperature is from about -20 ° C to about 25 ° C.

The reduction described above leads to a mixture of two epimeric alcohols,

S (-C -) & R (-C -) >

In which individual epimers can be separated, if necessary, by traction crystallization, for example from diethyl ether, n-hexane, n-heptane or cyclohexane, but more preferably by column chromatography on silica gel or magnesium silicates, or by preparative thin layer chromatography, for example on silica gel using, for example, methylene chloride, ethyl ether, isopropyl ether, ethyl acetate, methyl acetate, benzene or cyclohexane, or mixtures thereof, as eluents, or by high pressure liquid chromatography.

Optionally converting a compound of Formula I wherein R ₂ and R 5 are oxo and Y represents a group of the formula —CH = CZ ₂ -, wherein Z 2 is as defined above, to a compound of Formula I wherein one of R 2 and R 5 the group represents a hydroxyl group and the other one represents an alkyl group having 1-6 carbon atoms, an alkenyl group having 2-6 carbon atoms, an alkynyl group having 2-6 carbon atoms or an aryl group having 6-10 carbon atoms, and Y represents a group of the formula -CH = CZ ₂ -, in which Z ₂ is as defined above, may be carried out by treatment with a Grignard reagent of the general formula R "- MgHal, in which Hal denotes a halogen atom, preferably a thunder or iodine atom, and R" denotes an alkyl group with

1-6 carbon atoms;

2-6 carbon atoms, 2-6 alkenyl or 6-10 carbon atoms, preferably methyl, vinyl, ethynyl or phenyl. The Grignard reaction is carried out using 1.05 to 2 moles of magnesium compound per mole of ketone, and is operated in anhydrous solvents such as linear or cyclic ethers, for example, ethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, or aliphatic or aromatic hydrocarbons. , for example, in n-heptane, n-hexane, benzene or toluene, at a temperature in the range of about -70 ° C to the boiling point of the solvent used. A preferred reaction temperature is in the range of -60 ° C to 10 ° C.

Any etherification of a compound of formula I in which Y represents a group of formula -CH = CZ ₂ - ·, in which Z ₂ has the meaning shorauvedený, and one of R ₂ and R 5 represents a hydroxyl group and the other represents hydrogen, alkyl of 1 up to 6 carbon atoms, 2-6 carbon alkenyl, 2-6 carbon alkynyl or 6-10 carbon aryl, to a compound of formula I wherein Y is a group of formula —CH '= CZ ₂ - wherein Z ₂ is as defined above, and one of R ₂ and R 5 'is C 1-6 alkoxy or aralkoxy and the other is hydrogen, C 1-6 alkyl, C 2-6 alkenyl The C 6 -C 6 alkynyl group or the C 6 -C 10 aryl group can be carried out, for example, by reaction of an optionally aryl substituted or diazoalkane in the presence of a catalyst such as fluorine acid. or a reaction of a free or salt-converted hydroxyl group with an alkyl or aralkyl halide in the presence of a base such as silver oxide, in an inert solvent such as dimethylsulfoxide or dimethylformamide.

Any hydrogenation of a compound of formula I in which Y denotes groups of the formulas -CH = CZ2- in which Z ₂ is hydrogen to a compound of vzor216842 ce I in kterémΎ denotes the group -CH-CH2, is carried out catalytically, for example, preferably in an alcoholic medium, in the presence of platinum or palladium on activated carbon as a catalyst, at a temperature in the range of about -40 ° C to the boiling point of the solvent used. To prepare a compound of formula (I) wherein Z 1 is halogen and Y is -CH 2 -CH 2 -, hydrogenation is preferably carried out at a temperature between about -40 ° C and about -20 ° C. ^c Celsius.

Optional dehydrohalogenation of a compound of formula I wherein Z 1 is hydrogen and Y is —ch = c ₂ - wherein Z 2 is halogen to a compound of formula I wherein Z 1 is hydrogen and Y is - Preferably, this can be carried out using a dehydrohalogenating agent selected from the group consisting of dimethylsulfinylcarbanion of the formula CH 2 SOCH 2 -, diabicycloundecene, diazabicyclononene and alkali metal amides or alkoxides. For each mole of a compound of formula I in which Y is a group of the formula —CH-CZ2— in which Z2 is a halogen atom, 1-5 molar equivalents, preferably 1.5 to 1.5, are used.

1.8 mol equivalents of the basic dehydrohalogenating agent.

The dehydrohalogenation reaction is preferably carried out in the absence of atmospheric oxygen, in an inert solvent such as dimethylsulfoxide, dimethylformamide or hexamethylphosphoric triamide, or in a linear or cyclic ether such as dimethoxyethane, tetrahydrofuran or dioxane or an aromatic hydrocarbon such as benzene or toluene, or liquid ammonia, or mixtures of these solvents. The reaction temperature may range from ammonia liquefaction temperature to about 100 ° C, but the preferred reaction temperature is room temperature.

Depending on the solvent used, the reaction temperature and the molar ratio of the reactants, the reaction time may vary from a few minutes to several hours.

Optional reduction of a compound of formula I wherein R 2 and R 5 together are oxo and Y represents a group of formula —CH2 —CH2— or —C = C— to a compound of formula I wherein one of R2 and R5 is hydrogen and the other denotes a hydroxyl group, and Y represents a group of formula —CH2CH2— or —C = C—, may be carried out as described above for the analogous reduction of a compound of formula I wherein R2 and R5 together represent oxo and Y represents a group of the formula - CH = CZ 2 - in which Z 2 is as defined above.

Optionally converting a compound of formula I wherein R 2 and R 5 together are oxo and Y is -CH 2 -CH 2 - or -C = C- to a compound of formula i wherein one of R 2 and R 5 is hydroxyl and the other denotes an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2-6 carbon atoms, an alkynyl group having 2-6 carbon atoms or an aryl group having 6-10 carbon atoms, can be carried out under the same reaction conditions as described above for an analogous converting a compound of formula I wherein Y is --CH.dbd.Z @ 2 - and Z @ 2 is as defined above.

Also, an optional etherification of a compound of formula (I) wherein one of R2 and R5 represents a hydroxyl group and the other a hydrogen atom or a C1 -C6 alkyl group, a 2-6 alkenyl group, a 2-6 alkynyl group carbon or aryl of 6-10 carbon atoms, and Y is --CH2 --CH2 - or --C.dbd.C1 - may be carried out as described above for the etherification of a compound of formula (I) - wherein one of R2 and R5 is hydroxyl and the other is hydrogen or (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl or (6-10C) aryl, and Y represents a radical of formula

-CH-Z 2 -, wherein Z 2 is as defined above.

Optionally converting a compound of formula I to another compound of formula I, as well as converting a compound of formula I to a salt, preparing a free compound from a salt, and separating the mixture of isomers into the individual isomers can be accomplished by known methods.

For example, a compound of formula I wherein one of R ₂ and R ₅ is hydrogen and the other is hydroxyl can be converted to a compound of formula I wherein R ₂ and R ₅ together are oxo by oxidation. The oxidation can be carried out by treating an excess of activated manganese dioxide in an inert solvent, preferably a halogenated inert solvent such as dichloromethane or chloroform, at room temperature for a reaction time of several hours to one or more days.

Alternatively, the oxidation can be carried out by treating with 1.1-1.2 mol equivalents of dichlorodicyanobenzoquinone (DDQ) in an inert solvent such as dioxane, tetrahydrofuran or benzene, or mixtures thereof, at a temperature in the range of about 40 ° C to the boiling point of the solvent used.

A compound of formula (I) wherein:

R is a violet carboxyl group, can be converted to a compound of formula I in which R is an esterified carboxyl group, for example a C 1 -C 12 alkoxycarbonyl group, by known methods, for example by reaction with an appropriate alcohol, for example with a C 1-12 aliphatic alcohol carbon atoms, in the presence of an acid catalyst, for example p-toluenesulfonic acid, or also with diazoalkane.

Optionally, the conversion of a compound of formula I wherein R 1 is a hydroxyl group to a compound of formula I wherein R 1 is a C 6 acyloxy group may be accomplished by conventional means, for example by treatment with anhydrides or halides such as chloride of the appropriate carboxylic acid in the presence of a base. When one of R 2 and R 5 represents a hydroxyl group, the hydroxyl group may be protected by one of the known protecting groups mentioned above prior to acylation.

Optionally converting a compound of formula I in which R is an esterified carboxyl group to a compound of formula I in which R is a free carboxyl group can be carried out by conventional saponification processes, for example by treatment with an alkali metal or alkaline earth metal hydroxide in aqueous or aqueous-alkaline solution and subsequent acidification of the reaction mixture. For compounds of formula I in which R is an esterified carboxyl group and R 1 is a C _1-7 acyloxy group, the saponification can optionally be carried out selectively relative to the esterified carboxyl group, preferably by transesterification, i.e. by reaction with the same alcohol to which the esterified carboxyl group is in the presence of a base such as an alkali metal or alkaline earth metal alkoxide, or in the presence of potassium carbonate.

Optionally converting the compound of formula I in which R represents a hydroxy group, into a compound of formula I wherein R denotes an alkoxy group with 1-6 carbon atoms or C ₁ _ ₆ _ioarC ₆ alkoxy, any of the conventional methods of etherification, such as described above for etherifying a compound of formula I wherein one of R 2 and R 5 is hydroxyl.

If it is desired to etherify only one of the several hydroxyl functions present, it is expedient to protect the hydroxyl groups which are not desirable to be etherified prior to carrying out the actual etherification, for example with the known protecting groups mentioned above, and then remove them after the etherification.

Optionally converting a compound of formula I in which R is a free or esterified carboxyl group to a compound of formula I in which R is --CH2 --OH can be carried out, for example, by reducing the ester with lithium aluminum hydride in ethyl ether or tetrahydrofuran, the boiling point of the reaction mixture.

Optionally converting a compound of formula I wherein R is a free carboxyl group to a compound of formula I wherein R is a group of formula I

—CO — N \

R _b , wherein R _a and R _b are as defined above, may be carried out by treatment of the above acid with an amine of formula NHR a R _b in the presence of a condensing agent such as a carbodiimide such as dicyclohexylcarbodiimide and optionally converting a compound of formula I , to a compound of formula I wherein R is a group of formula

—CO — N \

Rb can be carried out by treating the ester with an amine of the formula NHRaRb in a suitable organic solvent at the boiling point of the reaction mixture for 2-3 hours.

Optionally converting a compound of formula I in which R is a free carboxyl group to a compound of formula I in which R is a radical of formula can be accomplished by converting the carboxyl group to the corresponding halide, preferably chloride, for example by reaction with thionyl chloride; oxalyl chloride in dioxane or dichloroethane at the boiling point of the reaction mixture, and the obtained halide is reacted with, for example, ammonia, the obtained amide is dehydrated to a nitrile, for example by treatment with p-toluenesulfochloride in pyridine medium at about 90 to 100 ° C. reaction with sodium azide and ammonium chloride in dimethylformamide at a temperature ranging from room temperature to 100 ° C. However, the above process for converting a carboxyl group to a cyano group or a group of formula is more preferably carried out using, for example, a compound of formula VI as the starting material.

The optional conversion of a compound of formula I into a salt is carried out in a conventional manner.

Also, the optional separation of the racemic mixtures into optically active compounds, as well as the optional separation of the diastereoisomers or geometric isomers from their mixtures, can be carried out by conventional methods.

A compound of formula IV wherein Z 1 is a halogen atom may be prepared by reacting a compound of formula VI ''

selectively oxidizing the —CH2OH to —CHO group.

Removal of the protecting groups from the aldehyde or alcohol group can be accomplished by mild acid hydrolysis.

The selective oxidation of the --CH2 OH group to the aldehyde group can be carried out in a conventional manner, for example by treating at least 3 moles of dicyclohexylcarbodiimide per mole of primary alcohol in benzene with dimethylsulfoxide and in the presence of an acid catalyst such as pyridinium trifluoroacetate or phosphoric acid.

Compounds of formula IV in which Z 1 is hydrogen may be prepared either by dehalogenating a compound of formula IV in which Z 1 is halogen as described above for converting compounds of formula I in which Z 1 is halogen to compounds of formula I wherein Z is hydrogen, or in such a way that a compound of formula VI is cyclized in the presence of Hg source ⁽⁺⁾ ions [as previously described for preparing a compound of formula III in which Q represents a group of formula ~~ Hg ^{( +)} Z ^(-) ] and the obtained compound is then reduced.

Compounds of formula V wherein E is a group of the formula wherein R 1, p, q, D and R 1 are as defined above, and G is a protected aldehyde group or a protected -CH 2 OH group, preferably a group of the formula

OR10 can be prepared by treating a phosphate of formula VII - CH

OR10 or

SR10 —CH

Ra.0 ι ι * q \ p - C-CO- ()μ) -Ο 'X-fCH 2 -Pe' / 1 *

Re-O h Rt (Vil)

SR10 in which R10 represents an alkyl group having 1 to 6 carbon atoms or a group of the general formula

-cZ \ cp,) _n . or '<CWpn _s \ G / ^C to 5 wherein n ₃ represents an integer of 2 to 4, preferably 2 or 3, or a group of formula -CH ₂ -O-CH2C6H5, or -CH2-O-CH2SCH3 halogenating cyclized, deprotecting the product obtained, and optionally wherein R _e , Z 2, ni, R 3, R a, X, ns and R e are as defined above, react with at least a base equivalent selected preferably from the group consisting of an alkali metal or alkali metal hydride soil, eg sodium, potassium, lithium or calcium hydride, alkali metal alkoxide, eg sodium or potassium tertiary butoxide, alkali metal or alkaline earth metal amide, for example sodium amide, alkali metal or alkaline earth metal derivative 3 carboxylic acid amide , for example, sodium acetamide or sodium succinimide.

A compound of formula V wherein (+)

E represents a group of formula (C 6 H 8 P 6 -)

Tlal -C-CO ~ (CH _{z) n} - C H from ^r- (VLN) wherein In, Ni, R, R, X, n 2, and R6 are shorauvedený meanings and Hal represents halogen, is reacted with 1 - 1.2 mol equivalents of triphenylphosphine in an inert solvent such as benzene, acetonitrile or diethyl ether, and the triphenylphosphonium halide obtained is reacted with an equivalent of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate.

The compound of formula VI can be prepared, for example, by the method described in Tetrahedron Letters, 42, 4307-4310 (1972).

The compound of formula VII wherein Z is halogen is obtainable by halogenation of a compound of formula VII wherein Z is hydrogen, in substantially the same manner as halogenation of β-keto esters.

Compounds of formula VII wherein Z is hydrogen can be prepared by known methods, for example, according to E.J. Corey et al., J. Am. Chem. Soc. 90, 3247 (1968), or by E.J. Corey and G.K. Kwiatkowsky, J. Am. Chem. Soc. 88, 5654 (1966).

The compounds of formula (VIII) are known or can be prepared by known methods.

The compounds of formula I can generally be used in the same therapeutic indications as natural prostaglandins, both in human and in veterinary therapy.

Particularly preferred are compounds of formula I having an acetylene bond at the 13,14 position instead of an ethylene bond and compounds mono- and disubstituted with a methyl or fluorine atom, as they have a higher resistance to degradation by 15-prostagandiine dehydrogenase enzymes that rapidly inactivate natural prostaglandins; another advantage is that they have more selective therapeutic efficacy as shown below.

In order to determine the preliminary biological profile of the compounds of formula I, i.e. to determine whether they have prostaglandin (PG) or thromboxane (TXAz) or PGX activity, the compounds were first tested by the superfusion cascade method as described by Piper and Van in Nature 223 29 (1969). To enhance the sensitivity of the biological experiment, it was added to the Krebs-Henseleitoy solution 24 to a mixture of antagonists [see Giimore et al., Nature 218, 1135 (1968)], and indomethacin (4 µg / ml) was added to prevent endogenous biosynthesis. prostagladin.

The contraction of rat colon (part of the colon) (RC), rat stomach strip (RSS) and coronary artery artery (BCA), and rabbit mesenterial artery relaxation (RbMA) are considered signs of prostaglandin activity. TXA2 activity is manifested by RbMA contractions and must be confirmed in vitro by pro-aggregation activity against platelets since compounds with PGF _2a activity, in contrast to prostaglandin PGE, also cause contraction of RmMA. Finally, PGX activity is manifested by BCA relaxation, and must be confirmed by in vitro antiplatelet activity against platelets.

Synthetic prostaglandins PGE2 and biosynthetic or thromboxane TXA2 and PGX were used as standard compounds; said standards were effective at concentrations of 1-5 µg / ml.

The compounds of formula I prepared by the process of the invention were dissolved in a few drops of ethanol just prior to testing; the stock solution was prepared in 0.1 M tris [tris (hydroxymethyl aminomethane and hydrochloric acid) pH 9.0 (1 mg / ml concentration) and this solution was diluted with Krebs-Henseleite solution to the desired concentration.

13-tr, ans-11a, 15S-dihydroxy-6S-6,9a-prostene oxide was chosen as the parent compound and is hereinafter referred to as 6 / 3H-6,9a-oxide; its diastereoisomer, 13-trans-11a, 15S-dihydroxy-6aH-6,9a-prostenoic acid, is referred to as 6aH-6,9a-oxide. The chemical names of the other test compounds are also referenced to these parent compounds. The substances were tested at concentrations up to 100 ng / ml.

The test results show that, in general, the 6βH-diastereoisomers, i.e. 6βH-6,9α-oxide, dl-6 (3β-5-bromo-6,9α-oxide, 6βH-6,9α-oxide-16) m-CF 3 -phenoxy-γ-tetranior and 6? 3H-6,9α-oxide-16-m-chlorophenoxy-γ-tetranor cause BCA relaxation and therefore have PGX activity.

Of the prepared 6 / 3H derivatives, only one compound, dl-6 / 3H-6,9a-oxide-16-methyl-16-butoxy-6-tetranor, caused BCA contraction. 6wH-derivatives, i.e. 6aH-6,9a-oxide, dl-6aH-5-bromo-6,9a-oxide, dl-6aH-6,9a-oxide-16-methyl-16-butoxy-n-tetranor, 6αΗ-6,9α-oxide-16-m-CF 3 -phenoxy-ω-tetranor and 6αH-6,9α-oxide-16-m-chlorophenoxy-ω-tetranor also caused BCA contractions.

In general, compounds with exo-configuration can be expected to cause BCA contractions.

In addition, the compounds of formula I have hypotensive activity in mammals, such as the natural compound PGX. Compared to PGX, however, the compounds of formula I are more advantageous as they are chemically more stable and can be used in pharmaceutical formulations.

1 Β 8 4 2

Hypotensive efficacy was demonstrated in a blood pressure test for limb perfusion. During the perfusion of the left leg of the rat, introduced by the femoral artery, at a constant perfusion pressure, both 6 / JH- and 6aH-6,9a-oxide caused a decrease in mean perfusion pressure at all doses ranging from 0.05 to 1pg (-42 pressure reduction). In addition, the systemic pressure, both systolic and diastolic, was reduced at doses ranging from 0.5 µg / kg to 5 µg / kg. kg (about -45 percent).

Due to the hypotensive and vasodilatory activity of the compounds of Formula I, they can be used to treat cases of gangrene of the lower limbs. They have been found to be more effective than PGE 1 and PGE 2 prostaglandins in this therapeutic use. The compounds of formula (I) may also be used in disorders of the peripheral vascular system, in particular for the prevention and treatment of diseases such as phlebitis, hepatorenal syndrome, ductus arteriosus (arteriosic ducej), non-obstructive mesenterial ischemia, arteriitis (arteritis) and ischemic ulceration of the feet.

The compounds of the formula I, in particular the 6H-derivatives, also have high anti-aggregation activity. The most potent of these 6βΗ-compounds are, in order of increasing potency, dl-6 (3H-5-bromo-6,9a-oxide, 6β-6,9α; -oxi'd-16-m-CF 3 -phenoxy) _? -ethanol, dl-5 / SH-6,9a-oxide and 6 (3H-6,9a-oxide).

Anti-aggregation efficacy testing was performed using platelet-rich blood plasma (PRPj) obtained from healthy human donors who had not taken any drugs for at least one week prior to blood collection, and platelet aggregation was monitored by continuous light transmittance registration in a Born aggregometer [Born GV R. Nature (London) 194, 927 (1962)], it was found that 6 / 3H-6,9a-oxide, dl-S / 1H-5-bromo-6,9a-oxide, 6 / SH-6, 9α-oxide-16-m-CF 3 -phenoxy-γ-tetranor and 6 (3H-6,9a-oxide-16-m-chlorophenoxy-ω-tetranor) are exactly similar to the biosynthetic PGX in their platelet anti-aggregation properties.

Evaluation of the anti-aggregation activity was performed by incubating the test compounds for 2-3 minutes at 37 ° C in PRP plasma and then adding the aggregating agent - arachidonic acid (0.4 mM, adenosine diphosphate (ADP) (10 μΜ),

Compound uterus collagen (38 μΜ) or adrenaline (15 μΜ). The ratio of potency of the test compound, compared to the biosynthetic PGX, is, for example, 1: 10 for arachidonic acid-induced aggregation, and 1: 100 for ADP-induced aggregation.

A very interesting increase in anti-aggregation activity will occur with both the 6/311-oxide and 6aH-6,9a-oxide base after substitution with the methyl group at the 20-position. Similarly, the 6 (3H-5-bromo-20-methyl- , 6 / 3H-5,14-dibromo, 6,11,13,14-didehydro-20-methyl- and then 6 / 3H-5-bromo-13,14-didehydro compound and their 6 / 3H-5 iodo-derivatives (but not 6aH-5-iodo-isomers i.

The compounds of formula (I) can therefore be used, particularly in mammals, to inhibit platelet aggregation, to prevent and inhibit thrombus formation, and to reduce the adhesion of blood vessels. The compounds of the formula I can be used in practice for the treatment and prevention of thrombosis and myocardial infarction, for the treatment of atherosclerosis, and generally in all syndromes etiologically based on or associated with lipid imbalance or hyperlipidemia, as well as in geriatrics to prevent cerebral ischemic events. and in the long-term treatment of myocardial infarction.

When the compounds of formula I are administered as antiplatelet agents, they can be administered by conventional means, for example, orally, intravenously, subcutaneously or intramuscularly. In sudden situations, intravenous administration is preferred, at dosages ranging from 0.005 to about 10 mg / kg per day. The exact dose level depends on the patient's condition, weight, age and route of administration.

The inventors have also studied the effect of the compounds of formula I on uterine contractions, both in vitro and in vivo, compared to prostaglandin PGF _2a as a standard.

For example, 6αH-8,9α-oxide-16-m-chlorophenoxy-ω-tetranorderivate and 6α-SH-6,9α-oxide-16-m-CF 3 -phenoxy-ω-tetranorderivate were effective in uterine estragenized rats in vitro 1.3 and 3 times, respectively, more potent than PGF _2a .

In in vivo tests in which the intrauterine pressure of ovariectomized rabbit females was measured, the latter compounds exhibited 5.9-fold and 5-fold, respectively. 8.25 times higher than PGF _2a (see table below).

Efficacy of in vitro ileum in vivo uterus

PGF _2a 1

6'-H-6,9'-oxi-10-m-chloro-1,3-phenoxy-n-tetranor

6 (SH-6,9a-oxide-16-m-CF 3 -phen, oxy-γ-tetranor

3.1

1

0.05 5.9

0.1

8.25

It can be seen from the table that said compounds of the formula I have a greater activity in the uterus than in the gastrointestinal tract.

The compounds of formula (I) may therefore be used to induce labor and to expel a dead fetus from the mother's body, both in human and in veterinary therapy, without the undesirable side effects of natural pirostaglandins such as vomiting and diarrhea.

In order to induce labor pain, the compounds of formula (I) may be administered by intravenous infusion at a dose of about 0.01 µg / kg / minute until the end of labor. When administered at the same dose, the compounds of formula I broaden the cervix (cervix uteri) to facilitate therapeutic labor; for this purpose, they are preferably administered in the form of vaginal tablets or suppositories.

The compounds of the formula I, in particular the dl-6 / 3H-6,9a-oxide-16-m-chlorophenoxy-.beta.-tetranorone compound, also have luteolytic activity and can therefore be used for fertility control.

The present inventors have also studied the effect of the 6H-6,9a-oxides and their 6H-isomers on the gastrointestinal tract. The following were investigated: a) cytoprotective effect against tissue damage caused by non-steroidal anti-inflammatory agents; (b) the ability to prevent ulcers induced by the Togagi-Okabe method [Japan J. Pharmac. 18, 9 (1968)], and c) antisecretory activity against gastric juices according to the method of Shay et al., Gastroenter. 26, 906 (1954).

Cytoprotective activity is a general feature of all compounds of the invention. For example, 6 / 3H-6,9a-oxide is slightly more effective (1.5- to 2-fold) than the PGE2 standard in antisecretory action against gastric juices when administered subcutaneously.

In general, the cytoprotective activity of 6 / 3H-compounds doubles when an acetylenic bond is present at position 13,14 of the molecule and increases fourfold when an alkyl group, usually a methyl group, is present at position 16 and at position 16 ( S) configuration.

As the substance with activity against ulcer formation is essential j3H 6 _t-6,9a-oxide at least as effective as prostaglandin PGE2, and by implementing an acetylenic bond in position 13,14, the methyl group or in position 16 S or 16 R, or fluorine atom to position 16 S or 16 R, the potency of effect is substantially increased (up to 30 times),

The antisecretory efficacy of the parent 6 / 3H-6,9a-oxide when administered orally is further increased significantly when the methyl group is introduced into the C-15 position or when two methyl groups are present at the 16-position, such as 6 (2H- 6,9--oxide-16-methyl-16-butoxy- ω -tetrano derivative.

As compounds having cytoprotective, anti-ulcer and antisecretory activity, the compounds of the formula I are preferably administered by intravenous injection or infusion, or subcutaneously or intramuscularly. For intravenous infusions, the agents may be used at a dosage of about 0.1 µg to about 500 µg per kilogram of body weight per minute. The total daily dose by injection or infusion is of the order of 0.1 to 20 mg / kg; the exact dose level will depend on the age, weight and condition of the patient or animal being treated, and the mode of administration of the drug.

The compounds of formula (I) also have significant bronchodilator activity and can therefore be used in the treatment of obstructive pulmonary diseases such as bronchial asthma.

For the treatment of obstructive pulmonary diseases, for example bronchial asthma, the compound of formula I may be administered in various ways, for example orally in the form of tablets, capsules or coated tablets, or in the form of liquid preparations such as drops or syrups; rectally in the form of suppositories; intravenously, intramuscularly or subcutaneously; by inhalation in the form of aerosols or solutions for inhalers; and inhalation in the form of powders.

The compounds of formula (I) may be administered in doses of the order of 0.01 to 4 mg / kg, times to 4 times daily, the exact dose being dependent on the age, weight and condition of the patient and the mode of administration of the drug. For use as an anti-asthma agent, the compounds of formula I may be combined with other anti-asthma agents such as sympathicomimetics such as isoproterenol, ephedrine and the like, with xanthine derivatives such as theophylline and aminophylline, or with corticosteroids.

When the compounds of formula I are used as hypo-sensitive and vasodilating agents, the dosages are about the same as when the compounds are used as anti-aggregating agents.

As mentioned above, the compounds of Formula I may be administered to humans or animals in various dosage forms, for example, orally in the form of tablets, capsules or solutions; or rectally in the form of suppositories; or parenterally, subcutaneously or intramuscularly, with intravenous administration being preferred in an emergency; or by inhalation in the form of aerosols or solutions for inhalers; or in the form of sterile implants with prolonged efficacy; or intra vaginally in the form of, for example, buffalo.

Pharmaceutical or veterinary preparations containing as active ingredient compounds of formula I may be prepared by conventional means using conventional carriers and / or diluents.

For example, sterile aqueous isotonic solutions of substances are suitable for intravenous injection and infusion. For subcutaneous or intramuscular injections, sterile solutions or suspensions in aqueous or non-aqueous media may conveniently be used / for tissue implants, sterile silicone rubber tablets containing or impregnated with the active ingredient may be used.

Suitable carriers or diluents are, for example, water, gelatin, lactose, glucose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium or magnesium stearate, glycols, starch, gum arabic, tragacanth, alginic acid or alginate, lecithin, polysoibbate, vegetable oils and the like.

Suspensions or solutions of the compounds of formula (I), preferably in the form of salts, such as sodium salt, in water, may be used for inhalation using inhalers. Alternatively, the pharmaceutical compositions may be used in the form of a suspension or solution of a compound of Formula I in one of the conventional liquefied propellants, such as dichlorodifluoromethane or dichlorotetrafluoroethane, and applied from pressurized containers such as aerosol bottles. If the active ingredient is not soluble in the propellant, an additional solvent such as ethanol, dipropylene glycol and / or a surfactant may be added to the pharmaceutical composition.

The process according to the invention is explained in more detail in the following examples. Abbreviations used in the examples have the following meanings: THF = tetrahydrofuran, DME = dimethoxyethane, DMSO = dimethylsulfoxide, THP = tetrahydropyranyl, Et 2 O = ethyl ether, TLC = thin layer chromatography, MeOH = methanol, EtOH = ethanol.

Example 1

To a solution of 1.0 g of 4-p-phenylbenzoate χ-lactone dl-5 (S-hydroxymethyl-2a, 4α-dihydroxy-cyclopentan-la-acetic acid in 8 ml of a mixture of benzene and DMSO (75:25) was added with stirring 0.89 g of dicyclohexylcarbodiimide and then, at room temperature, 1.42 ml of a solution of pyridinium trifluoroacetate (prepared by mixing 1 ml of trifluoroacetic acid with 2 ml of pyridine and making up to 25 ml with 75: 25 benzene / DMSO). The mixture is diluted with 19 ml of benzene and added dropwise to oxetic acid dihydrate (0.3 g) in water (3.8 ml), stirred for 15 minutes, then filtered, washing the organic portion with water until neutral, It is concentrated to 2 ml and the concentrated solution is diluted with 5 ml of isopropyl ether, and the precipitated product is filtered off and recrystallized from isopropyl ether to give 0.8 g of .alpha.-lactone 4-p-phenylbenzoate dl-5H-formyl-2a, 4a-dihydroxy. -cyclopentane-α-acetic acid, mp 129-131 [deg.] C. The solution of 800 mg To the reaction mixture in 2.8 ml of anhydrous methanol, 0.62 ml of methyl orthoformate and 18 mg of p-toluenesulfonic acid monohydrate are added. After 1 hour 0.01 ml of pyridine was added to the reaction mixture and the solution was evaporated to dryness. The residue was dissolved in ethyl acetate and the solution was washed with 1.0 N sodium hydroxide solution and then with a saturated aqueous sodium chloride solution until neutral. The solvent was distilled off under reduced pressure and the residue was recrystallized from methanol; to give 800 mg of 4-p-phenyl benzoate χ lactone of dl-5/3-dimethoxymethyl-2a, 4a-dihydroxy-cyclopentane-la-acetic acid, mp 108-110 ^C. 'C.

Example 2

To a solution of 5/3-formyl-2α-hydroxypentane-1-acetic acid χ-lactone (1 g) in 6.5 mL of anhydrous methanol was added 1.74 mL of methyl orthoformate and 52 mg of p-toluenesulfonic acid and the mixture is allowed to stand for about one hour. 0.04 ml of pyridine is then added, the solution is evaporated to dryness, the residue is taken up in ethyl acetate and the organic phase is washed with 1 N sodium hydroxide solution and then with saturated aqueous sodium chloride solution until neutral. After distilling off the solvent, 1 g of 5β-dimethoxymethyl-2a-hydroxy-cyclopentan-1-acetic acid β-lactone is obtained, [α] D = -16 °.

Example 3

To a solution of 1.8 g of 4-carboxybutyl-triphenylphosphonium bromide and 0.38 g of 4-tetrahydropyranyl ether of χ-lactol of 5/3- dimethoxymethyl-2, 4-dihydroxycyclopropane-ethanol in DMSO was stirred and cooled to A solution of 1.05 g of potassium tert-butoxide in 10 ml of DMSO is added dropwise at 20-22 ° C. The mixture is kept at room temperature for 1 hour and then diluted with 16 ml of ice-water. Shake the aqueous solution with ether (5 x 8 mL) and then with ether / benzene (70:30, 5 x 6 mL). The organic extracts were combined, shaken with 0.5 M sodium hydroxide solution (2 x 10 mL) and discarded. The combined aqueous alkaline extracts were acidified to pH 4.8 with 30% sodium dihydrogen phosphate solution and the product was shaken into a mixture of ethyl ether and pentane (1: 1, 5 x 15 mL). The organics were combined, dried over anhydrous sodium sulfate, and the solvents were distilled off; 0.45 g of 5-cis-7- (2α, 4α-dihydroxy-5α / 5-dimethoxymethylcyclopentan-1α-yl) hept-5-enoic acid 4‘-tetrahydropyranyl ether is obtained. The acid obtained is converted into the corresponding methyl ester by treatment with diazomethane in ether. An analytical sample of the methyl ester was prepared by chromatiography of 100 mg of crude product on silica gel, eluting with benzene / ethyl ether (85: 15).

NMR Spectrum:

\ Z c == c

OF \

Η H

5.46 ppm, multiplet.

Example 4

To a solution of 0.34 g of 5-cis-7- (2'-hydroxy-5 '/ 3-benzyloxymethyl-cyclopent-1-yl) -hept-S-enoic acid methyl ester in 6 ml of methanol is added a solution of 0.325 g of mercuric acetate in the mixture. water with methanol (1: 9, 6 mL) and stirred for 15 minutes, then concentrated under reduced pressure to a volume of 3 mL, saturated aqueous sodium chloride (5 mL) was added and the precipitate was extracted into methylene chloride. The mixture was washed with water and the solvents were distilled off to give 0.52 g of the crude methyl ester.

S-chloromercuric-S- (6 ex-exo-benzyl-oxymethy-1-oxo-bicyclo [3.3.0] octan-3'-yl) pentanoic acid.

To a solution of the latter compound in methylene chloride (10 mL) was added 80 mg of pyridine in 2 mL of methylene chloride, and then a solution of 150 mg of bromine in methylene chloride was added dropwise with stirring. The mixture was stirred at room temperature for 20 minutes, then the solution was washed with water, 7% potassium iodide solution and sodium thiosulphate and neutralized. After distilling off the solvent, 0.34 g of 5-bromo-5- (6‘-exo-benzyloxymethyl-2‘-oxa-ibicycloif 3,3,0] octan-3‘-yl) pentanoic acid methyl ester is obtained.

Mass spectrum:

M + 424.426 m / e,

M + - HB-r 344 m / e,

M ^{+ -} CHBr (CH 2) 3 COOCH 3 231 m / e. Example 5

To a solution of 0.26 g of 5'-iodo-5- (6'-exo-dimethoxymethoxy-7'-endo-hydroxy-2'-oxa-bicyclo [7'-tetrahydro-pyranyl-ether-methyl ester) [ 3,3,0] octan-3'-yl) pentanoic acid was added 10.5 mg of p-toluenesulfonic acid monohydrate and the mixture was allowed to stand at room temperature for 30 minutes. To the solution was added 10 mg of pyridine and the solvent was distilled off to dryness. The residue is taken up in ethyl ether-water, the organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off; to give 0.23 g of crude methyl 5-iodo-5- (6'-exo-dimethoxymeithyl-7 '-'^{end'0-hydroxy-2-oxa-bicyclo} [3.3.0] octan-3 ' (f-yl) pentane. Chromatography of the crude product on a silica gel column using methylene chloride / ethyl ether (75:25) as the eluent afforded 84 mg of 5-iodo-5- (6'-exo-dimethoxymethyl) -ethyl ether. 7'-en'do-hydroxy-2'-oxa-bicyclo [3.3.0] octan-3'-endo-yl) pentanoic acid and 55 mg of 3'-exo-somer.

With respect to spectral data, prostaglandin numbering will be used in the following; Thus, the above diastereoisomer-eryliz-e is termed as follows: the end-o-diastereoisomer is methyl ester 6, pH-6,9'-dioxide-11a-hydroxy-12β-dime32 thoxy-formyl acetal-20 (20 The 13'-tetranoropropanoate, and the -exo-diastereoisomer, is 6aH-6,9a-oxide-11a-hydroxy-12H-dimethoxy-1-hydroxy-acetyl-1-ω (20 → 13) tetranoropropanoate.

Analytical data:

Endo-diastereoisomer:

TLC: Polar uniform spot.

Mass spectrum (m / e;% fragment intensity):

442, 0.002 M +,

412 4 M + -CH ₂ O,

315/314, 3 M + - iodine / Hj,

283,11315 — CH3OH,

75, 100 CH (OCH 3) 2.

NMR (CDCl 3 solvent, TMS as internal standard j, ppm:

3.49 and 3.52 ~ s, 3H / 3H, CH (O ₅₎ 2,

3.64S, 3H, COOCH3,

4.00 m, 3H (Cs, C9, Cnj protons,

4.29 d, 1H, CH (OCH 3) 2,

4.60 111, 1H, OM1. .......

¹³ C — MR (at 20 MHz in CeDe solution, TMS as internal standard), ppm:

172.9, 36.5, 33.1, 25.6, 41.8, 81.0, 38.1, 55.5,

83.1, 41.5, 74.2, 44.6, 108.0, 54.2, 54.1, 51.0.

Exo - di astere o-i some-r:

TLC: less polar uniform spot.

Mass spectrum:

442, 0.01, M @ ⁺ ,

366, 3, M + -CH ₂ CH (OCH 3) 2,

315.4 M + - J,

283.10, M + - J - CH 3 OH,

75, 100, (CH (OCH 3) 2+).

NMR, ppm:

3.34 and 3.37 3H / 3H s, CH (OCH 3) 2,

3,5 and 4,1 m, 1H and 2H protons on C5, C9, C11, indefinitely expressed,

3.65, s, 3H, COOCH3,

4.21, d, 1H, C, H (OCH 3) 2,

4.35 m, 1 H, 60-H.

13 _C —MR, ppm:

173.0, 37.0, 33.1, 25.5, 40.1, 84.4, 39.7, 57.2,

83.7, 40.5, 75.9, 44.0, 107.3, 54.0, 53.8, 51.1.

Example 6

To a solution of 1.98 g of 5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxix-bicyclo] 3.3.0] octan-3'-yl-7'-tetrahydropyranyl ether methyl ester of pentanoic acid in 10 ml of n-aqueous methanol, 60 mg of p-toluenesulfonic acid are added, the mixture is allowed to stand at room temperature for 30 minutes and then 20 ml of 20% aqueous sodium bicarbonate solution are added. The solution was shaken with ethyl ether, the combined ether extract was dried over sodium sulfate and the solvent was distilled off. The residue is chromatographed on a column of 100 g of silica gel, eluting with methylene chloride / ethyl ether (94: 6); as eluent; 0.64> g of 5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] oiktan-3'-exo-yl) pentanoic acid methyl ester is obtained, 0.52 g endo-isomer and 0.12 g 3'-yl.

NMR (CDCl3):

endo isomer 4.6 ppm m, 1H, 6 / 3H, exo isomer 4.3 ppm m, 1H, ΘαΗ.

TLC:

endo isomer - more polar substance, exo isomer - less polar substance.

Example 7

Acetylation of 0.2 g of 5-iodo-5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octan-3'-endo-yl] -pentanoic acid methyl ester with acetic anhydride ( 0.3 ml) in pyridine (0.6 ml) gave 0.21 g of the corresponding 7'-acetoxy derivative.

NMR (CDCl3, ppm):

2.03 s, 3H, OCOCH ₃ ,

OCH3

OF

3.36-3.40 s, s, 3H / 3H, CH3

OCH3

3.66 s, 3H, COOCH3,

4.00 m, 2H, protons at C5, Cg

4.27 d, 1H, CH (OCH 3) 2,

4.6 m, 1H, [delta] (3H,

5.0 m, 1H, proton on C11.

[The respective NMR spectral data for the corresponding acetate of the 6H-isomer are as follows: 2.03, 3.34-3.38, 3.66 s + m, 4H, COOCH3 and one of the Cs, Cg 4.1 m protons, 1H ,. another of the protons Cs, Cg, 4.2, 4.4 m, 1H, 6H, 5.1.]

Example 8

A solution of 3.4 g of (2-oxo-heptyl) dimethoxyphosphanate in 50 ml of dimethoxyethane was added dropwise to a suspension of 0.45 g of 80% sodium hydride (dispersion in mineral oil), followed by stirring for 1 hour. 7 g of 5- (6'-exoformyl-7'-endo-hydroxy-2'-oxa-bicyclo] 3,3,0-octan-3'-yl) pentanoic acid methyl ester in 40 ml of dimethoxyethane ¹ After 10 minutes, the reaction mixture is diluted with 50 ml of a 30% aqueous sodium dihydrogen phosphate solution, the organic layer is separated, the aqueous portion is again shaken and the combined organic extracts are evaporated and the crude product is chromatographed on a 50 g silica gel column using cyclohexane / ethyl ether. 50:50 as eluent;

1.1 g of 5- {6'-exo- (3'-oxo-nkt-1'-trans-en-1'-yl) -7'-endo-hydroxy-2'-oxa-bicyclo acid methyl ester is obtained [3,3,0) octan-3'-endo-yl) pentanoic acid or methyl 13t-6 / 3H-6 (N) -oxide-11'-oxoxy-15-oxo-pr'ost-13-enoic acid methyl ester , and 0.98 g of 5- (6'-exo-3'-oxo-oct-1'-trans-en-1-yl) -7'-endo-hydroxy-2'-oxa-biphenyl [3] , 3,0] octan-3'-exo-yl} pentanoic acid or methyl 13t-6'H-6 (9a) -oxa-11a-hydroxy-15-oxo-prosit-13-enoic acid, and 0.9 g mixtures of the two isomers (3'-exo and 3'-endo, or 6aH and 6 / 3H) in a 1: 1 ratio. The latter mixture is separated into the individual isomeric compounds by preparative thin layer chromatography using ethyl ether.

Said isomers exhibit the following absorption:

λ “| ° ^H = 230 m ^, ε = 13,070;

λ = 228 m ₎ .

ε = 12 200.

NMR (CDCl3, ppm):

0.9 t, 3H, C20-CH3,

3.68 s, 3H, COOCH3,

6.16 d, 1H, vinylic proton at C-14 (J-14 ^H His 16 Hz)

6.71 q, 1H, vinyl proton on C13 (JH13 9 Hz.

In the same way, from the respective 5-H and

The 5-halo-compounds will prepare the following prostatic acid derivatives:

methyl 13t-6aH-6 (9'-oxide-15-oxoprost-1S-enoic acid),

M ⁺ 350

M ^{+ -} C 5 H 11 279, 13t-6aH-6 (9 ") -5-chloro-15-oxo-prost-13-enoic acid methyl ester,

M + 386/384

M ^{+ -} Cl 349,

M + - C2H4O 342/340, 13β-6 · α · 6 (9α) -σχΐύ-5-bromo-15-oxo-prost-13-enoic acid methyl ester,

M + 430/428

M + - C2H4O 386/384

M ^{+ -} Br 349, 13t-6aH-6 (9α-oxide-5-iodo-15-Oxo-prost-13-enoic acid methyl ester),

M ⁺ 476

M + - C2H4O 432

M + - C5H11 405

M + - J 349, 13t-6aH-6 (9 ') - 5-chloro-11-oxide, α-hydroxy-15-oxo-prop-13-enoic acid methyl ester,

M ⁺ 402/400

M ^{+ -} HzO 384/382

M + —Cl 365

M ^{+ -} H ₂ O - C ₂ H ₄ O 340/338, 13t-6aH-6 (9a) -oxide-5-bromo-11a-hydroxy-15-oxo-prost-13-enoic acid methyl ester,

NMR:

3.67 s, 3H, COOCH3,

3.95 m, 4H, protons on C5, C9, C11 and proton Hx / Hy on Ca,

4.3 m, 1 H, 6aH,

6.15 d, 1H, proton on C14,

6.63 q, 1H, proton on C13,

M + 446/444

M + —HaO 428/426

M + - HaO — C2H4O 384/382,

M + —Br 365,

M ⁺ - H 2 O-C 5 H 11 357/355, 13t-6'H-6 (9a) -oxide-5-iodo-11a-hydroxy-15-ox'O-prost-13-enoic acid methyl ester, NMR:

0.9 s, 3H, C20-CH3,

3.53 m, 1H, proton to Cs,

3.6 s, 3H, COOCH3,

3.9 m, 1H, proton on C4,

4.1 m, 2H, protons on C9, Cu,

4.4 m, 1 H, 6aH,

6.2 d, 1H, proton to C14,

6.75 q, 1H, proton 11a C13,

M + 492

M ^{+ -} H ² O 474,

M + —H2O — C2H4O 430,

M + - H 2 O — C 5 H 11 403,

M + - J 365, 13t-6 / 5H-6 (9a) -oxide-15-oxo-prost-13-enoic acid methyl ester,

M + 350

M + - C 2 H 4 O 306,

M + - C 5 H 11 279, 13t-6 / 3H-6 (9a) -oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester,

M ⁺ 386/384

M ^{+ -} Cl 349,

M + - C 2 H 4 O 342/340, 13t-6: 3H-6 (9a) -oxide-5-thromo-pro-13-enoic acid methyl ester,

M + 430/428

M + - C2H4O 386/384

M ⁺ - Br 349, 13Ϊ-6 / ΪΗ-6 (9a) -oxide-5-iodo-15-oxo-prost-13-enoic acid methyl ester,

M + 476

M + - C 2 H 4 O 432,

M + - C5H11 405

M @ + = 349, 13t-6 / 3H-6 (9a) -oxide-5-chloro-11a-hydroxy-15-oxO-prost-13-, methyl ester. -enoic, 13t-6 / 3H-6 (9a) -oxide-5-birome-11'-hydroxy-15-oxo-prost-13-enoic acid methyl ester,

M ⁺ 402/400

M + —H2O 384/382,

M + —Cl 365

M + -H ₂ O-C2H4 340/338,

NMR:

3.66 s, 3H, COOCH3,

4.00 m, 3H, C5 protons, Cg, Cu,

4.6 m, 1H, 6 / 3H,

6.2 d, 1H, proton on C14,

6.64 q, 1H, proton on C13,

M + 446/444

M + - H2O 428/426

M + - H2O — C2H4O 384/382

M + - Br 365, 13t-6 / 1H-6 (9a) -oxide-5-iodo-11'-hydroxy-15-oxo-prost-13-enoic acid methyl ester,

NMR:

3.65 s, 3H, COOCH3,

3.96 m, 3H, protons on C9, Cu and C5,

4.6 m, 1H, 6ft H,

6.21 d, 1H, proton on C14,

6.75 q, 1H, proton on C13,

M + 492

M + —HaO 474,

M ⁺ —H2O — C2H4O 430,

M + - H 2 O - C 5 H 11 430,

M + - J 365.

Example 9

A solution of 2.16 g of (2-oxo-octyl) dimethylphosphonate in 20 ml of benzene was added dropwise to a suspension of 292 mg of sodium hydrides (75% dispersion in mineral oil) in 30 ml of benzene. After stirring for 30 minutes, a solution of 2.6 g of 4-bromo-4- (7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo [3,4,0] methyl ester) was added dropwise to the reaction mixture. Nonan-3'-yl) butane in 20 ml of benzene and stirred for an additional 30 minutes. 24 ml of a 30% aqueous solution of sodium dihydrogen phosphate are then added, the organic layer is separated and the aqueous portion is shaken with benzene. The organic extracts were combined, the solvent was distilled off and the residue was chromatographed on silica gel (50 g) using methylene chloride / ethyl ether (120:40) as eluent to give 0.52 g of 4-bromo-4- {7 'methyl ester. -exo- (3'-oxo-ioct-1'-trans-1'-phenyl) -8'-endo-hydroxy-2'-oxa-bicyclo [3,4,0] nonan-endo-yl} butane was not 13-tris-4-bromo-5 / 3H-5 (9 ') -oxide-11a-hydroxy-15-oxo-prost-13-enoic acid methyl ester, and 1.45 g of 4-ibromo-4-methyl ester - {7'-exo- (3'-oxo-oct-1'-trs-1'-phenyl) -8'-endo-hydro.

xy-2‘-oxa-bicyclo [3.4.0] nonan-3R- exo-yl

butanoic acid was not 13-trans-4-bromo-5aH-5 (9a) -oxide-11a-hydroxy-15-oxo-priost-13-enoic acid methyl ester.

Methanolic solutions of the two compounds absorb in the UF region of the spectrum

A “eon ₌ 230 nm, ε = 10 640, or at Λ = 229 nm, ε = 11 600.

In the same way, using 4-H and 4-halo-bicycloderivatives as starting materials, the following prostenoic acids are obtained:

13-trans-5 / 3H-5α-α-15-oxo-prost-13-enoic acid methyl ester,

M ⁺ 350

M + - H 2 O 332,

M + -OCH ₃ 319,

M + - (CH 2) 4 CH 3 279, 13-trans-5./lH-5(9a)- 11a-hydroxy-15-oxo-prop-13-enoic acid methyl ester,

M + 366

M ^{+ -} H ² O 348,

M + —OCH3 335,

M + - (CH 2 J 4 CH 3 295) 13-trans-4-chloro-5 (3H-5 (9H) -oxide-15-oxo-ppost-13-enoic acid methyl ester,

M + 386/384

M + - Cl 349,

M + - CsHn 315/313, 13-trans-4-chloro-5 / 3H-5 (9α) -oxide-11a-hydroxy-15-oxo-prost-13-enoic acid methyl ester,

M + 402/400

M + - HzO 384/382

M + —Cl 365

M + -C5H11331/329, 13-trans-4-bromo-5 / 3H-5 (9'-oxide-15-oxo-pros't-13-enoic acid methyl ester),

M ⁺ 430/428

M ^{+ -} Br 349,

M + - C5H11 359/357, 13-trans-4-bromo-5 '/ 3H-´5 methyl ester (9α) -oxa-11a-hydrioxy * 15-oxo-prost-13-enoic acid,

M + 446/444

M + - HzO 428/426

M + —Br 365,

M + —C5H11 375/373, 13-tran8-4-iodo-5,3H-5 (9a) -oxide-15-oxo-prost-13-enoic acid methyl ester,

M + 476

M ⁺ - CsHti 405

M + - 349 J methyl ester, 13-trans-4-iodo-5 _l of 3H-5 (9a) -oxide-lla-hydroxy-l5-oxo-prosta-13-enoic acid,

M ⁺ 492

M + - H 2 O 474,

M + - H 2 O — C 5 H 11 430,

M ⁺ -J 365, 13-trans-5'H-5 (9'-oxo-15-oxo-prosit-13-enoic acid methyl ester),

M + 350

M ^{+ -} H ² O 332,

M + - OCHs 319,

M + - _(CH2) 4CH3 279 13-methyl-5 tran3-5aH (9aj-oxide-lla-hydroxy-S-oxo-S-priost-enoic acid, M ⁺ 366,

M + - H 2 O 348,

M + —OCH3 335,

M ⁺ - (CH ₂ ) 4 CH ₃ 295, 13-trans-4-chloro-5aH-5 (9 ') -oxide-15-oxo-pro-13-enoic acid methyl ester,

M + 386/384

M ^{+ -} Cl 349,

M + - C 5 H 11 315/313, 13-Tris-4-chloro-5H-5 (9a) -oxa-11-hydroxy-15-oxo-prost-13-enoic acid methyl ester,

M + 402/400

M + - HzO 384/382

M + —Cl 365

M + - CgHn 331/329, 13-trans-4-bromo-5aH-5 (9a) -, 15-axo-prosM3-enoic acid, methyl ester,

M + 430/428

M + - Br 349

M + - C5H11 359/357, methyl 13 trans-4-thunder-5a-5 (9a) -oxide-lla-hydroxy-15-oxo ^j pr OST-13-enoic acid,

M + 446/444

M + - HzO 428/426

M + - Br 365

M + —C5H11 375/373, 13-trans-4-iodo-5aH-5 (9a) -oxo-15-oxo-prost-13-enoic acid methyl ester,

M + 476

M + - C5H11 405

M ^{+ -} J 349, 13-trans-4-iodo-5a-5 (9a) -tetoxide-11a-hydroxy-15-oxo-prio-3'-13-enoic acid methyl ester,

M ⁺ 492

M + - H 2 O 474,

M + - H 2 O - C 5 H 11 430,

M + - J 365.

Example 10

As described in Example 8, by reaction

620 mg of (2-oxo-3-methyl-4 ^j butoxybutyl) phosphonate with 74 mg of sodium hydride (75% dispersion) and 0.43 g of 5- meithylesteru (6 '-'Oxoformyl-7'-endo-hydroxy-21'-oxa-bicyclo [3.3.0] octan-3'-yl-pentanoic acid in dimethaxyethane, after chromatography on silica gel (25 g), eluting with ethyl ether / hexane 1: 1 gives 0.15. g 13t-6aH-6 (9α-oxide-11'-hydroxy-15-ioxo-16-methyl-16-butoxy-18,19,20-trinoir-prost-13-enoic acid methyl ester (λ _max = 228 nm, ε = 14 500), and 300 mg of the corresponding 6 / 3H-isomer (λ _max = 227 nm, ε = 12 280).

Mass Spectrum: m / e 410 M ^& lt ^{; +} & gt ^; , m / 392 M &lt; + &gt; - H _&lt; 0 &gt;, m / e 379 M &lt; ⁺ &^gt;

CH ₃ \

m / e 115 C - O - C 4 H 9.

Z ch ₃

Both isomers have similar spectra, with minimal differences in the region of secondary fragmentation.

The same procedure gave methyl 5-chloro-, 5-bromo-5-iodo-13t-6H-6 (9a) -oxide-11a-hydroxy-15-oxo-16-methyl-16-butoxy-18 methyl ester. 19,20-trinor-prost-13-ene.

Mass spectrum for. 5-chloro compound:

M ⁺ 446/444, 428/426, 391, 276, for 5-ibromo compound:

M + 490/488, 472/470, 391, 276, for 5-iodo compound:

M + 536, 518,391,276.

Example 11

Following the procedure of Example 10, from methyl 4- (7'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.4.0] nonan-3'-f-yl) butanoate and bicyclic The following compounds are obtained from the 4-iodo derivative:

13t-5 (SH-5 (9, a) -oxide-11a-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester, mass spectrum :

M + 410, 392, 379, 295 (UV λ _max 229 nm, ε = 14,000), 13t-4-iodo-5,3H-5 (9α) -oxide-11a-hydroxy-15-oxo-16-methyl- 16-butoxy-18,19,20-trinor-13-ene,

M + 536, 518, 391, 276 (λ max 228 nm, ε = 12,400), 13t-5aH-5 (9a) -oxide-11a-hydroxy-15-oxo-16-methyl-16-butoxy-18 methyl ester, 19,20-trinor-prost-13-ene,

M + 410, 392,379,295,

UV λ _max 227 nm, ε = 11,800, 13t-4-iodo-5aH- (9α-oxide-11a-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinoric acid methyl ester) prost-13-ene,

M + 536, 518, 391,276,

Λ _max 226 nm, ε = 10 300.

Example 12

To a suspension of 45 mg of 80% sodium hydride in 10 ml of benzene was added a solution of 375 mg of (2-oxo-3,3-dimethylheptyl) dimethylphosphonate in 10 ml of benzene, followed by a solution of 0.305 g of methyl 5-iodo-5- (6'-exo-formyl-2'-oxa-bicyclo [3.3.0] octan-3'-yl) pentanoate The reaction mixture was stirred for 45 minutes then diluted with 10% aqueous sodium dihydrogen phosphate solution, organic layer After chromatography on a silica gel column using cyclohexane / ethyl ether (90:10) as the eluent, 0.12 g of methyl 13t-5-iodo-6) is obtained. 1 H-6 (9α) -oxide-15-oxo-16,16-dimethyl-pr ost-13-enoic acid (M + 504, M + -OCH 3 473, M + -99 405 and 0.095 g of methyl 13t-5-iodo-6iaH) -6 (9a) -oxo-15-oxo-16,16-dimethyl-prost-13-ene, M + 504, M ⁺ -OCH 3 473, M ⁺ -99 405.

Example 13

To a suspension of 178 mg of sodium hydride (75% dispersion in mineral oil) in 15 ml of benzene is added dropwise a solution of 1.55 g of [2-oxo-3 (S, R) -fluoro-4-cyclohexylhutyl] dimethylphosphonate in 10 ml of anhydrous benzene. and after 30 minutes of stirring, a solution of 1 g of 5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octan-3'-4-yl) methyl ester is added The reaction mixture is stirred for an additional hour for one hour, then neutralized with 30% aqueous sodium dihydrogen phosphate solution, the organic layer is separated, concentrated and chromatographed on silica gel using methylene chloride / ethyl ether (90: 1).

10) as eluent. 0.62 g of methyl 13t-6aH-6 (9a) -oxide-11a-hydroxy-15-oxo-16 (S, R) -fluoro-17-cyclotiexyl-18,19,20-trinor-prost- 13-enové,

A = 238 nm,> ε = 12 765, and 0.31 g of the respective 6 / JH-isomer, λ MeOH _{= 238 nm} , ε = 9870.

The NMR spectrum of the first compound is as follows (CDCl3, ppm):

3.64 s, 311, COOCH3,

3.8 m, 1H, proton at C9,

4.03 q, 1H, proton on C11,

4.3 m, 1H, 6'H,

5.00 and 5.55 t, t, 1/2 H, 1/2 H, proton at C 16, Ihf 55 Hz,

6.54 q, 1H, proton at C14,

6.9 q, 1H, ^C 13 proton, J H ₁₄ -h ₁₂ 3.5 Hz, J ^H 13 ^-H 12 7.5 Hz, H ₁₃ -h ₁₄ 15.5 Hz.

Treatment of this compound with acetic anhydride in pyridine affords the corresponding 11a-acetoxy derivative having the following NMR spectrum (CDCl 3, ppm):

2.02 s, 3H, OCOCl 3,

3.64 s, 3H, COOCH3,

3.8, proton per Cg,

4.25 m, 1H, 6'H,

4.66, 5.22 t, t, 1/2 H, 1/2 H, proton to Cie,

4.97 q, 1H, proton on C11,

6.51, proton on C14,

6.90, proton on C13.

The above diastereoisomeric hydroxyketones have the following mass spectrum:

M ⁺ 424 m / e, and then M ⁺ - H2O,

M + - HF

M + - CH 3 OH / CH 2 O,

M ⁺ - CH 2 '= CHOH (base ion),

M + - 115

M + - 44-59 a

M + - (CHF-CH2-CeHn).

In the mass spectrum of the exo-diastereoisomer the following masses predominate:

M + - CH3OH and M + - 44–28, and masses predominate in the endo-diastereoisomer spectrum

M + - CH 3 O and M + - 44-18.

From the corresponding 5-bromo derivative, 13t-5-bromo-6 (SH-6 (9 ') -oxide-11a-hydroxy-15-oxo-16 (S, R) -fluoro-17-cyclohexyl-18) methyl ester is obtained. , 19,20-trinor-prost-13-ene, λ = 235 nm, ε = * 12 900.

Example 14

Substituting (2-oxo-4-cyclohexylbutyl) dimethylfoefonate or (2-oxo-4-phenylbutyl) dimethylphosphonate as described in Example 2 gives:

13t-6 (3H-6 (9 ') -oxyl-11-hydroxy-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-1,3-enoic acid methyl ester),

Λ _max 223 nm, ε = 9780, 13t-6 methyl ester (3H-6 (9H-Oxide-11'-hydroxy-15-oxo-17-phenyl-18,19,20-trinoro-prosit-13-) enové,

A _rn; <238 nm, ε = 9950, and their 6aH isomers,

Λ _max 230 nm, ε = 11,950.

Example 15

To a suspension of 178 mg of sodium hydride (75% dispersion in mineral oil) in anhydrous tetrahydrofuran was added dropwise a solution of 1.63 g of 2-oxo-3- (m-chlorophenoxy) propyl-dimethylphosphonate in 10 ml at 0 ° C, with stirring. anhydrous THF, and after stirring for 30 minutes, a solution of 1 g of methyl ester is added

5- (6‘-exo-formyl-7‘-endo-2‘-oxa-bicyclo [3.3.0] octan-3‘-yl) pentanoic acid. The reaction mixture was stirred for an additional hour, then diluted with aqueous sodium dihydrogen phosphate solution, the organic layer was separated and the aqueous portion was shaken again with benzene. The organics were combined, the solvent was distilled off and the crude product was chromatographed on silica gel using methylene chloride / ethyl ether (95: 5) as eluent. 0.43 g of 13t-6aH-6 (9a) -oxide-11a-hydroxy-15-oxo-16-m-chlorophenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester is obtained, λ = 227 nm, ε = 16,800, and 0.11 g of the corresponding 6βH-isomsr λ /// = 224 nm, ε = '16,900.

Both diastereoisomers have a molecular ion of m / e 436 corresponding to the sum formula C23H29CIO6 in the mass spectrum, which ion has the following fragmentation:

M + - H2O

M + - (CH 2) 4 CQOCH 5,

M ⁺ - OCH 3 / CH 3 OH,

M ⁺ - 44

M + - (O-C 5 H 6 Cl),

M + - HaO - (O - C 6 H 4 Cl), which further confirms the assumed structure.

There are the following differences between the two diastereoisomers: The 6 H-exo isomer shows a peak at M ⁺ -32 and the less intense peak at M ⁺ -44, and the endo 6 / 3H-isomer shows a peak at M ⁺ -31 and the intense peak at M ⁺ - 44.

Example 16

Following the procedure of Example 15, but starting from 2-oxo-3- (m-trifluoromethylphenoxy) propyl dimethyl dimethyl phosphonate or 2-oxo-3- (fluorophenoxy) propyl dimethyl phosphonate, the following compounds were obtained :

13t-6SH-6 (9a) -oxide-11a-hydroxy-15-oxo-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-pro-13-enoic acid methyl ester, 13t-6 methyl ester JH-6 (9a) -oxid 11a-hydroxy-15-oxo-16-pfluorophenoxy-17,18,19,20-tetranor-prost-3-ene, and their 6aH-isomers.

The mass spectra of all the above compounds are in agreement with the assumed structure, and show, for example, a peak at M + - 115. An interesting difference between endo, and exo-trifluoromethylanalogues is that the exo-isomer shows maxima at

M + - CH 3 OH and M ⁺ - CF 3 - C 6 H 4 - OH, and the endo-isomer of maximum at

M + - CH 3 O and M + - CF 3 - C 6 H 4 - O.

Example 17

Using the procedure described in Example 13, but starting from (2-oxo-3S-methylbutyl) -dimethylphosphonate, 13t-6 (3H-6 (9a) -oxide-11a-hydroxy-15-Oxo-16S) methyl ester was obtained. methyl-prost-13-e, new and its 6H-isomer.

To a solution of 2.2 g of the 6 / 3H-isomer in 2.6 ml of pyridine was added 1.05 ml of acetic anhydride while cooling to 0 ° C. The solution was allowed to stand overnight at 0 ° C, then poured into excess cold 0.05 N sulfuric acid and the product was shaken into ethyl ether. After distilling off the solvent, 2.3 g of 13t-6SH-6 (9a) -oxide-11a-hydroxy-15-oxo-16S-methyl-prost-13-enoic acid 11-acetate methyl ester are obtained, λ 'θ ° ^Η = 229 nm, ε = 12050.

To a solution of the latter compound in 10 ml of glacial acetic acid was added dropwise a solution of 875 mg of bromine in glacial acetic acid until the solution turned pale orange. To the solution was then added 1.52 g of anhydrous potassium carbonate, and the mixture was heated at 80 ° C for 4-5 hours until the excretion of potassium bromide was complete. Excess acetic acid is distilled off under reduced pressure, water is added to the residue and the pH is adjusted to 6.8 with sodium hydroxide. The mixture was shaken with ethyl ether, the solvent was distilled off and the residue was chromatographed on silica gel, using methylene chloride / ethyl ether (70:30) to elute the substances; 2.01 g of 13t-6H-6 (9α) -oxide-11a-hydroxy-14-bromo-1S-oxo-1S-methyl-pro-1S-enoic acid 11-acetate methyl ester are obtained,

Λ = 249 nm, ε = 11450.

The 6aH-isomer was prepared in the same manner.

Example 18

To a suspension of 0.265 g of sodium hydride (80% dispersion in mineral oil) in dimethoxyethane (10 ml) was added dropwise a solution of 2.06 g of (2-oxo-3S-methylheptyl) -dimethylphosphonate in 20 ml of DME and stirred for 30 minutes. 1.6 g of brom-bromosuccinimide are added. The mixture was stirred vigorously for 10 minutes and then a solution of 1.35 g of 5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octane-3-methyl ester) was added. 5-yl) pentanoic acid in 5 ml of dimethoxyethane. The reaction mixture is stirred for 1 hour, then acidified with 20 ml of a 30% aqueous solution of sodium dihydrogen phosphate and worked up in the usual manner. The crude 14-bromo-enone was chromatographed on silica gel with ethyl ether (85: 15) as eluent; 0.9 g of 13t-6H-69 ([alpha]) -oxide-11a-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoic acid methyl ester and 0.92 g of the corresponding 6aH-isomer are obtained.

0.2 g of the 6 / 3H-isomer is reacted with 0.2 ml of acetic anhydride in 0.4 ml of pyridine to give 0.205 g of 11-acetoxy derivative which is identical on all sides to the compound prepared as described in Example 17.

Example 19

A solution of 0.43 g of (2-oxo-octyl) -dimethylphosphonate in 10 ml of benzene was added dropwise to a suspension of 54 mg of sodium hydride (80% dispersion in mineral oil) in 5 ml of benzene. After 1 hour, when the evolution of hydrogen ceased, 0.32 g of N-bromosuccinimide was added in one portion to the reaction mixture. To this carbanion prepared (l-bromo-2-oxo-octyl) -dimethylfosfonátu was added a solution of 270 mg of 5- (6'-exo-formyl-7'-endo-hydroxy-2 ^<-oxabicyklo [3,3, Ooctan-3'-yl) penitanium in 8 ml of benzene. After 30 minutes, the reaction is quenched by the addition of 20 ml of 10% sodium dihydrogen phosphate solution, the organic layer is separated, washed neutral and the solvent is distilled off. 0.31 g of a mixture of isomeric methyl esters of 13t-6H-6 (9 ') -oxa-11a-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid is obtained, _λ mooh _{= 245} nm, ε = 13 500, which is then separated into the 6aH- and 6 / 3H-isomers.

Example 20

Using the method described in Example 19, but using (2-oxo-4-cyclohexylbutyl) -dimethylphosphonate or (2-oxo-4-phenylbutyl) -dimethylphosphonate instead of (2-oxooctyl) -dimethylphosphonate, the following compounds were prepared:

13t-6 / 3H-6 (9a) -oxide-11a-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-pro-13-enoic acid methyl ester,

A weoH 248 nm, ε = 12,000, 13t-6 / 3H-6 methyl ester: (9a) -oxa-11a-hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-trinor- prost-13-ene, _λ MeoH = 247 nm, ε = 14,500.

Example 21

As described in Examples 18, 19, 20, but using 5-iodo-5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octane methyl ester) -3'f-yl) pentanoic acid, 4-iodo-4- (7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo [3,4,0] nonane-3'f methyl ester) -yl) butane and the corresponding 4-H derivatives instead of the above formyl derivatives the following compounds were prepared:

13t-5-iodo-6 / 3H-6 (9a) -oxa-11-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoic acid methyl ester, _λ M ( _{OHOH = 243 niD) )} ε = 12 350, 13t-4-iodo-5H-5 (9a) -lahydroxy-14-bromo-15-oxo-16S-methyl-pro-3'-13-enoic acid methyl ester, λ = 235 nm,

850 13 t-Methyl-5 5j3H (9a) -oxide-llia-hydro xy ^{i-14-bromo-15-oxo-16S-meithyl} prios! T-13-enoic acid, ^Mu0H λ = 245 nm, ε max = 10,350, 13t-5-iodo-6 / SH-6 (9a) -oxide-11-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester,

^{: Ι: 0Η} = 241 nm, max 'ε = 12 650, 13t-5 / JH-5 (9a) -oxa-11a-hydroxy-14-bromo-15-oxo-20-methyl-prost-13- anic acid, λ = 245 nm, ε = 14,500, 13t-5-iodo-6,5H-6 (9 ') - 11a-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19-oxide, 20-trinor-prost-13-enoic acid, λ λ = 235 nm, ε = 12,100, 13t-5 methyl ester, SH-5 (9α-oxide-11a-hydroxy-14-bromo-15-oxo-17) -cyclohexyl-18,19,20-trifluoro-prost-13-enoic acid, λ = 231 nm, ε = 11,750, 13t-5-iodo-6 / SH-6 (9a) -oxide-IIIa-methyl ester hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoic acid, λ = 248 nm, ε = 13,000, 13t-5 / JH-5 methyl ester (9a) 11a-hydroxy-14-bromo-15-ox9-17-phenyl-18,19,20-trinor-prost-13-enoic oxide, λ = 245 nm, ε = 14,100.

Example 22

A solution of 0.61 g of 2-oxo-ocityl-triphenylphosphonium bromide in 6 ml of DMSO was added to a solution of 0.15 g of potassium tertiary butylate in 3 ml of DMSC, while cooling the reaction mixture to 16-19 ° C, and then a solution of 0.27 g was added dropwise. 5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octan-3'-yl) -pentanoic acid methyl ester in 8 mL of anhydrous tetrahydrofuran. The reaction mixture was stirred for 30 minutes, then an equal volume of water was added and the mixture was shaken with ethyl ether. The combined organic extracts were washed until neutral, the solvent was distilled off and the residue was chromatographed on silica gel using cyclohexane / ethyl ether (40:60) as eluent; 0.21 g of 13t-6H-H-6 (9a) -oxide-11'-hydroxy-15-oxo-20-methyl-prO-St-13-enoic acid methyl ester is obtained,

M + 380

M + - H 2 O 362,

M + —OCH3 349

M + - 4436,

M + - CsHi 3 295.

The mixture of 6H- and 6 / 3H-isoiner obtained was separated by preparative thin layer chromatography on silica gel, eluting with ethyl ether.

Example 23

A solution of d, l-13t-6aH-6 '(9'-oxid-11a-hydroxy-15-, oxo-13-enoic acid methyl ester (exo-isoimer with the highest R _p ) (0.9 g) in anhydrous ether) A solution of zinc borohydride (10.1 ml) in anhydrous ethyl ether (30 ml) was added dropwise with stirring over 15 minutes, and after 2 hours the excess reducing agent was quenched by the careful addition of saturated aqueous sodium chloride solution and 2N aqueous sulfuric acid. The organic portion was separated, washed until neutral, the solvent was distilled off and the residue was chromatographed on silica gel using ethyl ether to elute the materials to give 0.38 g of 13t-6aH-6 (9a) -oxide-11a, 15R methyl ester. droxy-prostenoic aldehydes in the form of an oily product, and 0.42 g of d, l-13t-6aH-6 (9a) -oxide-11a, 15S-dihydroxy-prostenoic acid methyl ether, mp 69-71 ° C, mass spectrum m /E

350 M + - 18

319 M + - 18 —CH 2 O,

318 M @ + - 18 - CH2 OH.

The methanolic solution of the latter ester (4 ml) was treated with a solution of 60 mg of lithium hydroxide in water (0.8 ml) at room temperature for 8 hours. The methanol was distilled off under reduced pressure, the residue was diluted with water and shaken with ethyl ether to remove neutral impurities. The alkaline aqueous phase was acidified to pH 5 with saturated aqueous sodium dihydrogen phosphate solution and then shaken with ethyl ether. The organic extracts were combined and the solvent was distilled off; 105 DEG-106 DEG C .; the free d, l-13t-6aH-6 (9a) -oxide-11a, 15S-dihydnoxy-prostenoic acid, m.p.

The respective 15R-hydroxy acid is a non-crystallising oily product.

In the same way, but using the nat-compound in the reduction with zinc borohydride, in addition to the 15-epi-alcohol, the methyl ester of nat-13t-6aH-6 (9a) -oxide-11a, 15S-dihydroxypropenoic acid, mp 71-72 ^C C, [α] _D = + 10.2 °, [α] 365 = + 32.2 ° (in chloroform),

218842, which after saponification gives the free acid of m.p. 101-102 ° C, [α] D = + 6.34 °, [α] 365 = + 33.2 ° (in chloroform).

Using the endo-diastereoisomers (more polar compounds) as starting materials, the following esters are obtained:

13t-6, 13H-6 (9 ') -oxa-11a, 15R-dihydroxy-prostenoic acid methyl ester of (d, 1-, nat-, ent-; oily substances), 13t-6; 3H-6 (9') methyl ester -oxide ^11a-1, 15S-dihydroxy-prostenoic (d, L, NAT- [cíJd • = + 24.5 °, [• a] 365 = +52,9 (in chloroform), an oily substance, ent- , [α] _D = -22 °, oily substance and, after saponification, the following free acids:

13T-6 / 3H-6 (9a) -oxide-11a, 15R-dihydroxy-prostenoic acid (d, l-, nat-, ent-, oily substances), 13t-6 / 3H-6 (9a) -oxide -11a, 15S-dihydroxy-prostene (d, l-, oily substance, nat-, mp 78-80 ° C), [α] D ⁼ + 32.5 °, [α] 365 = + 11.6 ° ( 78 DEG-79 DEG C., [ _.alpha. ] _D = -31 DEG (in ethanol).

The following compounds were prepared in an analogous manner:

13t-15S-hydroxy-16R-methyl-6H-6 (9a) -propenoic acid methyl ester,

M ⁺ 366

M + - H2O 348

M + —CeHi3 281, 11a, 15S-dihydroxy-6aH-6 (9a) -pentenoic acid methyl ester and the corresponding 6 / 3H-6 (9a) -oxide-isomer,

M + 368

M + —HaO 350,

M + - 2 H ₂ O 332,

M + - H 2 O — C 2 H 4 O 306, 11a, 15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-6aH-6 (9a) -prop-13-ynoic acid methyl ester, [α] _D = +17, 2 °, [α] 365 = + 54 ° and the corresponding 6H-6 (9a) -oxide isomer, [α] D ⁼ + 26.5 °, [α] 365 - +84 ° (in ethanol).

Mass spectrum:

M + 406

M + - H ₂ O 388, 11a, 15S-dihydroxy-16S-methyl-6aH-6 '(9a) -prop-13-ynoic acid methyl ester and its 6 / 3H-6 (9a) -oxide-isomer,

M + 366

M + - H2O 348

M ^{+ -} 2? -? 330, 13t-11a, 15S-dihydroxy-6aH-6 (9α-oxide-16-methyl-16-butoxy-20,19,18-trinorotenoic acid methyl ester),

M + 412

M + - H2O 394,

M + —2 H2O 376,

M + - C 7 H 15 O 297, 13t-11a, 15S-dihydroxy-6 / 3H-6 (9a) -17-phenyl-20,19,18-trinorotenoic acid methyl ester, [α] _D = + 28 °, 13t-11a, 15S-dihydroxy-6βΗ-θ (9a) -oxide-16-m-chlorophenoxy-20,19,18-trinorotenoic acid methyl ester, [α] _D = + 31 °, 13t-11a methyl ester 15S-dihydroxy-β-β-6 (9α) -oxide-16-pfluorophenoxy-20,19,18-trinoropropenoic acid, [α] D - + 30 °, 13t-11a methyl ester, 15S-dihydroxy -6) 1H-6 (9α) -oxide-16-m-trifluorophenoxy 20,19,18,17-tetranor-prostene, [α] _D = + 33 °, and their 6aH-6 '(9a) ] -oxide isomers which exhibit an optical rotation in the range of [α] _D + 8 ° to + 12 ° (in chloroform), 13t-11a, 15S-dihydroxy-6αΗ-6 (9a) -oxide-16S- trans-17-cyclohexyl-20,19,18-trinoroprost-13-eno [α] _D = + 18 ° (in ethanol) and its 6] / 3H-6 (9a) -oxide diastereoisomer, [ α] _D = + 7 ° (in ethanol).

Example 24

To a solution of 0.332 g of anhydrous calcium chloride in propan-2-ol (7 ml) was added successively a solution of 159 mg of sodium borohydride with 7 ml of propan-2-ol while cooling the reaction mixture to about -5 ° C to -8 ° C. a solution of 0.38 g of 13t-6aH-6 (9α-oxide-11a-hydroxy-15-oxo-16 (S, R) -fluor-17) methyl ester is then added to the calcium borohydride thus prepared, with stirring, over 40 minutes. -cyclohexyl-18,19,20-trinor-prost-13-ene in 3 ml of propan-2-ol The reaction mixture is stirred at a temperature within ± 5 ° C, then the excess reducing agent is quenched by addition of 5 ml of acetone and ml of water, the solvents are distilled off under reduced pressure, and the residue is partitioned between water, 0.1 N sulfuric acid and ethyl acetate, the organic extracts are combined, washed until neutral, the solvent is distilled off and the residue is chromatographed on silica gel (30 g). eluent methylene chloride / ethyl ether (70:30) to give 0.21 g. 13t-6aH-6 (9a) -oxide-11a, 15R-dihydroxy-16 (S, R) -fluoro-17-cyclohexyl-18,19,20-thirinor-prost-13-enoic acid methyl ester, and 0, 14 g of the corresponding 15S-epimer, mp 83-84 ° C (from ethyl ether),

M + 426

M + - H 2 O 408,

M + - H 2 O - HF 388,

M + - 44 382.

In the same way, by reduction of the 6 / 3H-isomer (220 mg), 0.1 g of methyl 13β-6 / 3Η-6 (9α) -ιοχΙά-11α, 15Κ-ύΛγ (ΐΓΌχγ-16 (S, R) - Fluoro-17-cyclohexyl-18,19,20-triinor-prost-13-ene, mp 63-64 ° C (from isopropyl ether), and 60 mg of the corresponding 15S-alcohol.

From this 6H-15S-alcohol, a single isomer was obtained:

[Α] _D = +7 ³ (EtOH).

Mass spectrum:

M + 426

M + - H 2 O 408,

M + - H 2 O - HF 388,

M + - 44 382.

The following compounds are obtained in an analogous manner:

13t-5-iodo-6aH-6 (9α-oxide-11a, 15S-dihydroxy-prost-13-enoic acid methyl ester, [α] _D = + 21 ° (c = 1, chloroform), 13t-5- methyl ester iodo-6 / 3H-6 (9a iodide-11a, 15S-dihydroxy-prost-13-ene),

M + 494

M ⁺ —H7O 476,

M + - 2 H ₂ O 458,

476 — C2H4O ⁺ 432

476 — C5H11 + 405

405 — HzO 387,

M-J + 367, [α] _D - + 22 (c = 1, chloroform), 13t-16S-methyl-5-iodo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-pr methyl ester osite-13-ene,

M + 508

M + - H2O 490,

M + -2 HzO 472, 13t-20-methyl-5-iodo-6H-6 (9α-oxide-11a, 15S-dihydroxy-prost-13-enoic acid methyl ester), [α] D - + 23 °, [ α '] 365 = + 78 ° (in chloroform), 13t-5-iodo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-18,19,20-trinoro-17-cyclohexyl- pro'st-13-enoic, [α] _D = + 26 ° (in ethyl alcohol), 13t-5-iodo-6aH-6 (9α-oxide-11a, 15S-dihydroxy-18,19,20-trifluoro) methyl ester -17-cyclohexyl-piOSt-13-enoic acid, [α] D = + 17 ° (in ethanol), 13t-5-iodo-6 / 3H-6 (9 ") -oxide-11a, 15S- dihydroxy-18,19,20-trinor-17-phenoxy-prost-13-enoic acid, (α) _D = + 21 ° (in ethyl alcohol), 13t-5-iodo-6aH-6 (9a) -O 'methyl ester X1d-11a, 15S-dihydroxy-18,19,20-trifluoro-17-phenoxy-prost-13-enoic, [α] _D = + ⁸ ° ( ^c = 1, ⁱⁿ chloroform, 13t-5-iodo-methyl ester) 6 / 3H-6

- 15S-hydroxy-prost-13-enoic oxide,

M + 478

M + - H 2 O 460, 13t-5-iodo-6aH-6 (9α-oxide-15S-hydroxy-prost-13-enoic acid methyl ester),

M + 478,

M ⁺ —H2O 460, 13t-5-iodo-6 (3H-6 (9α-oxide-11a, 15S-dihydroxy-prost-13-ynoic acid) methyl ester,

M + 492

M + - H 21 O 474, 13t-5-iodo-6aH-6 (9a) -Oxide-11a, 15S-dihydroxy-prost-13-ynoic acid methyl ester,

M + 492

M + - H 2 O 474, 5-iodo-6 / 3H-6 (9a) -oxide-16S-methyl-11β, 15S-dihydroxypropyl-13-ynoic acid methyl ester,

M + 506

M + -H 2 O 488, 5-iodo-6 / 3H-6 (9a) -oxide-20-methyl-11 ', 15S-dihydroxy-pro-13-ynoic acid methyl ester, [α] _D = +20 ^c ( in chloroform,

M + 506

M + - H 2 O 488,

M ⁺ -2 H 2 O 480, 13t-15-methyl-5-iodo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydnoxy-p'Poat-13-enoic acid methyl ester,

M + 508

M + - H 2 O 490,

M + -2 H 2 O 472, 16,16-dimethyl-5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxypropanoic acid methyl ester and the corresponding 6H-diastereoisomer,

- M + 478/476

M ^{+ -} HzO 460/458,

M + -2 H 2 O 442/440, 13t-16,16-dimethyl-5-bromo-6H-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 476/474

M + - HzO 458/456,

M + - 2 HzO 440/438, 13t-16,16-dimethyl-5-bromo-6aH-6 (9a) -oxide-11a, 15S-dihydroxy-priost-13-enoic acid,

M + 476/474

M + - HzO 458/456,

M ⁺ -2 H 2 O 440/438, 13t-5-bromo-6aH-6 (9a) -oxide-11, α, 15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-, methyl ester ene and the corresponding 5-bromo-6 / 3H-6 (9a) -oxld,

M + 488/486

M + —H2O 470/468, 5-bro-6, 13H-6 (9a) -oxidium methyl ester, 15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-ynoic acid methyl ester,

M ⁺ 486/484

M + - H2O 468/466, 5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-prostanoic acid,

M + 450/448

M + -II2O 432/430, 13t-5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-prosit-13-enoic acid,

M + 448/446

M + —H2O 430/428,

M + -2 HaO 412/410, 13t-20-methyl-5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 462/460

M + —H2O 444/442, 13t-15-methyl-5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid, M + 462/460,

M + -H ₂ O 444/442, 13t-15-methyl-5-bromo-6aH-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 462/460

M + - H ₂ O 4442442, 13t-16S-methyl-5-bromo-6S-6 (9a) -oxide-11, α, 15S-dihydroxy-prost-13-enoic acid,

M + 462/460

M + - H2O 444/442, 13,5-5-bromo-6H-6 (9a) -oxide-11a, 15S-dihydiroxy-18,19,20-trinor-17-cyclohexyl-prosit-13-enoic acid (methyl ester),

M + 488/486

M + - H2O 470/468, 13t-5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-17,18,19,20-tetrano-16-m-trifluoromethylphenoxy-prost- 13-en,

M + 538/536

M ^{+ -} H a O 520/518.

Example 25

A solution of 0.15 g of 13t-6aH-6 (9a) -oxide-11a-hydroxy-15-keto-16-methyl-16-butioxy-18,19,20-trinorothenoic acid methyl ester in methanol (5 mL) was cooled to -5 ° C to -10-10 ° C and reduced by adding a solution of sodium borohydride (30 mg) in water (0.5 mL). After 15 minutes, the reaction mixture was neutralized by the addition of a 15% aqueous solution of sodium dihydrogen phosphate and the solvent was distilled off under reduced pressure. The remaining aqueous solution was shaken with ethyl ether and the solvent was evaporated to give a crude mixture of epimeric 15R, 15S-alcohols. Chromatographic separation of the above mixture on silica gel, eluting with methylene chloride / ethyl ether (70:30) gave 13t-6aH-6 (9a) -oxide-11a, 15R-dihydroxy-16-methyl-16- butoxy-18,19,20-trinor-prostene (45 mg) and the corresponding 15S-hydroxy-epimer (62 mg).

M + 412

M ^{+ -} H2O 394,

M + - 2 H 2 O 376.

Example 26

Reduction of 13t-5aH-5 (9a) -oxide-11a-hydroxy-15-keto-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester under the same experimental conditions as described in the Example 25, after chromatographic separation of the obtained mixture of epimeric alcohols (300 mg) on silica gel (12 g), eluting with methylene chloride / ethyl ether (75:25), 100 mg of methyl 13t-5aH-5 (9a) - oxld-11a, 15R-dihydroxy-16-methyl-16-butoxy-18,19,20-trinoropropene, and 110 mg of the corresponding 15S-epimer.

M ⁺ 412

M + - H 2 O 394,

M + - 2 HaO 376.

Example 27

To a 0.12 M solution of zinc borohydride in ethyl ether (8 mL) was added dropwise a solution of 0.135 g of 13t-5-bromo-6aH-6 (9a) -oxa-11a-hydroxy-15-oxo-prostenoic acid methyl ester in 2 mL with stirring. of anhydrous ethyl ether. The reaction mixture was stirred for 2 hours, then the excess reducing agent was quenched with water and 2 N sulfuric acid solution, the organic layer was separated, washed neutral and the solvent was distilled off. The crude product was separated by preparative thin layer chromatography on silica gel using a 90:10 ethyl ether-ethyl acetate solvent system to give 38 mg of 13t-5-bromo-6aH-6 (9a) -oxide-11a, 15R-dihydroxy-propylene acid methyl ester and 46 mg of the respective 15S-epimer.

M + 448/446

M ⁺ —H2O 430/428,

M + 2 H ₂ O 412/410,

M + —H2O — C2H4O 386/384,

M ^{+ -} Br 367.

Example 28

Using 13t-5,14-dibromo-6 (SH-6 (9a) -oxa-11a-hydroxy-15-oxo-prostenoic acid methyl ester (0.2 g) as starting material) and using a mixture of methylene chloride and ethyl216842 ether as eluent on silica gel chromatography of the mixture to give 0.056 g of 13t-5,14-dibromo-6,3H-6 (9a-oxide-11a, 15R-dihydroxy-prostenoic acid methyl ester) and 0.098 g of the corresponding 15S-isomer,

M + 528/526

M + 528/526/524

M + - HzO 510/508/506

M + 2 HzO 492/490/488,

M + —Br 447/445,

M + - 2 Br 366.

A solution of the latter methyl ester in methanol is then hydrolyzed with aqueous lithium hydroxide solution to give 72 mg of 13t-5,14-dibromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-prostenoic acid.

Example 29

As described in Example 25, using isopropanol as a solvent and sodium borohydride (45 mg) as a reducing agent, reducing the 13t-6, 3H-6 (9a) -oxide-11a-hydroxy-15-oxo-16- (m- trifluoromethyl) phenoxy-17,18,19,20-tetranor-prost-13-enoic acid (0.47 g) yields 0.20 g of 13t-6./SH-6 (9a) -oxide-11a, 15S methyl ester. -dihydroxy-16- (m-trifluoromethyl) phenoxy-17,18,18,20-tetrahydro-pro-13-eno [α] _D = + 33.3 ° (in methanol), and 0.18 g of the respective 15R-epimer. The 6aH-15S epimeric alcohol is an oily substance having an optical rotation of [α] _D = + 12 ° (in methanol).

Example 30

A solution of 13t-16S-methyl-6aH-6 (9 ') -oxa-11a-hydroxy-15-oxo-priost-13-enoic acid methyl ester (0.002 M, 0.72 g) was added to an ethereal solution of zinc borohydride with stirring (0.01 M, 100 mL). After 30 to 45 minutes, the excess reducing agent is quenched by the addition of a 2 N solution of sulfuric acid in saturated aqueous sodium chloride solution, the organic layer is separated, washed until neutral and the solvent is distilled off. The residue is chromatographed on silica gel (25 g), eluting with methylene chloride / ethyl ether (80: 1).

: 20) as an editing agent; give the 15R-hydroxy isomer (7,5.10 ^_4 M, 0.27 g) and the corresponding 15S-alcohol (I, 1.10 ^-4 M, 0.38 g), i.e. methyl ester 13 t-16S-methyl-6aH- 6 (9a) -oxide-11a, 15S-dihydroxy-pro-13-enoic acid.

The following methyl esters are obtained by this procedure:

13Ϊ-Θ / 3Η-6 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 382

M + —HaO 364,

M ^{+ -} 2 H ₂ O 346,

M + -H 2 O-44 320, 13it-6 / 3H-6 (9a) -oxide-16R-methyl-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 382

M ^{+ -} H ² O 364,

M + - 2 HzO 346,

M + - H ₂ O - C ₂ H ₄ O 320, 13t-6 (3H-6 (9a) -oxide-16,16-dimethyl-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 396

M ⁺ - H2O 378

M + 2 HzO 360,

M ^{+ -} H ² O - C ² H 4 O 334, 13t-6aH-6 (9a) -oxide-20-methyl-11a, 15S-dihydroxy-prost-13-enoic acid, mp 57-59 ° C, [α] _D = +14 ^c , [α] 365 = + 47 ° (in chloroform),

M + 382

M + —HaO 364,

M ^{+ -} 2 H ₂ O 346,

M + - H 2 O - OCH 2 333,

M + -H ₂ O-44 320, 13t-6SH-6 (9a) -oxide-20S-methyl-11a, 15S-dihydroxy-prost-13-enoic acid,

mp 38-39 ° C, [α] _D = + 21.7 °, [α] _D = + 77 ° (in chloroform),

M + 382

M + - H 2 O 364,

M + —2 H2O 346,

M + - H 2 O - OCH 3 333,

M + - H 2 O - 44 320, 13t-5-bromo-6 / 3H-6 (9a) -oxide-16S-methyl-11a, 15-dihydroxy-prost-13-enoic acid, M + 462/460,

M + - Hao 444/442

M + -2H ₂ O 430/434,

M + - H ₂ O - C ₂ H ₄ O 404/402, 13t-5-bromo-6 / 3H-6 (9a) -oxide-16R-meithyl-11a, 15S-dihydroxy-prost-13-enoic acid, M + 462/460,

M ^{+ -} HzO 444/442

M ⁺ 2H ₂ O 436/434

M + - H 2 O - C 2 H 4 O 404/402, 13t-5-brioma-6 / SH-6 (9a) -oxide-16,16-dimethyl-11a, 15S-dihydroxy-prosit-13-enoic acid,

M + 476/474

M + —H ₂ O 458/456,

M + —2 H2O 440/438

M + - H ₃ O - C ₂ H ₄ O 418/416, 13t-5-iodo-6 (3H-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 494

M + - H ₂ O 476

M + —2 PI2O 458,

476 — C2H4O ⁴ - 432,

476— C5Hh + 405

405 — HzO 387,

M-J + 367, [α] _D = + 22 ° (c = 1, CHCl 3), 131-16S-methyl-5-iodo-6 (SH-6 (9a) - * oxide-11a, 15S-dihydroxy- prost-13-ene,

M + 508

M + —HaO 490,

M + -2 H 2 O 472, 13t-20-methyl-5-iodo-6,3H-6 (9a) -oxide-11a, 15S-dihydroxy-pro5t-13-enoic acid, [α] π = + 23 °, [a] 365 = + 73 ° (CHCl 3), 13t-5] z-6,3H-6 (9a) -oxide-11a, 15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoic acid, [α] _D = + 26 ^c (EtOH), 13t-5-iodo-6aH-6 (9a) -oxid-11a, 15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13- eno, [α] _D = + 17 ° (EtOH), 13t-5-iodo-6 / 3I-I-6 (9a) -oxide-11a, 15S-dihydroxy-18,19,20-trinone- 17-phenoxy-prost-13-enoic, [α] _D = + 21 ° (EtOH), 13t-5-iodo-6H-6 (9a) -oxide-11a, 15S-dihydroxy-18,19, 20-trinor-17-phenoxy-prost-13-enoic, [α] _D = + 8 ° (EtOH), 13t-5-iodo-60H-6 (9a) -oxide-15S-hydroxy-prost-13- enové,

M + 478

M + —H ₂ O 460, 13t-5-iodo-6aH-6fa) -oxide-15S-hydroxy-prost-13-enoic acid,

M + 478

M + - II2O 460, 131-5-iodo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-ynoic acid,

M + 492

M + -H 2 O 474, 131-5-iodo-6aH-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 492

M + - H2O 474, 5-iodo-6 (3H-6 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-prost-13-ynoic acid,

M + 506

M + - H 2 O 488, 5-iodo-6 / 3H-6 (9a) -oxide-20-methyl-11a, 15S-dihydroxy-prost-13-ynoic acid, [α] D = + 20 ° (CHCl 3),

M + 506

M + - H, 0 488,

M ⁺ -2 HaO 470, 13t-5-hromo-6aH-6 (9a) -oxide-11a, 15S-dihydnoxy-18,19,20-trifluoro-17-cyclohexyl-prst-13-enoic acid and derivatives of 5- bromo-6,3H-6 (9a) -oxide,

5S

M + 488/486

M + —H2O 470/468, 5-bromo-6SH-6 (9a) -oxide-11a, 15S-dillydethoxy-18,19,20-trinor-17-cyclohexyl-prost-13-i.noic acid,

M + 486/484

M + - H ₂ O 468/466, 5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydrioxyprostanoic acid,

M + 450/443

M @ + - H2 O 432/430, 13t-5-bromo-6,3H-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 448/446

M + —H2O 430/428,

M ⁺ -2 12 O 412/410, 13t-20-methyl-5-bromo-6 (3H-6 (9a) -oxide-11a, 15S-dihydroxy-pr'Ost-13-enoic acid,

M + 462/460

M + - H2O 444/442, 13t-15-methyl-5-bromo-6 / SH-6 (9a) -oxide-11α, 15S-dihydroxy-prost-13-enoic acid,

M ⁺ 462/460

M + - H 2 O 444/442, 13t-15-methyl-5-bromo-6aH-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid, M + 462/460,

M + -H ₂ O 444/442, 13I-16S-methyl-5-bromo-6H-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-enoic acid, M + -H 2 O 444/442, 13t-5-bromo-6,3H-6 (9a) -oxide-11a, 15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoic acid, m-methyl ester mass spectrum:

M ⁺ 488/486

M + 1-I 2 O 470/468, 13t-5-bromo-6pH-6 (9a) -oxide-11a, 15S-dihydroxy-17,18,19,20-tetranor-16-m-trifluoromethylphenoxy-prost- 13-enové,

M + 538/536

M + - H ₂ O 520/518, 13t-5-bromo-6,3H-6 (9a) -oxide-11a, 15S-dihydroxy-20-methyl-prost-13-enoic acid, [α] D = + 38 °,

M ⁺ 462/460

M + - H2O 444/442

M + —2 H2O 436/434

M + - H 2 O - C 2 H 4 O 404/402, 13t-5-iodo-6 / 3H-6 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-pro-13-enoic acid, M + 508,

M + - H2O 490

M + - ₂ H ₂ O 472, 13t-5-iodo-6 / 1H-6 (9 ') -oxide-16R216842 acid

-methyl-11a, 15S-dihydroxy-prost-13-ene, M + 508,

M + - H 2 O 490,

M + - 2 HzO 472, 13t-5-iodo-6H-6 (9a) -oxide-16,16'-dimethyl-11a, 15S-dihydroxy-ppoet-13-enoic acid,

M + 522

M + - H 2 O 504,

M ⁺ 2 HzO 486,

H + - H 2 O - 44 460, 13t-5-} οΰ-6 / 3Η-6 (9a) -oxide-11a, 15S-dihydroxy-20-methyl-prost-13-enoic acid,

L =] + 23 °, [α] 365 = + 78 ° (in chloroform),

M + 508

M + - H 2 O 490,

M ⁺ 2 HzQ 472,

M ^{h -} HzO - CzHdO 446,

M ⁺ - J 381, 13t-5-Chloro-6H-6 (9a) -oxide-16S-methyl-11H-dihydroxy-proSt-16S-enoic acid, M ⁺ 418/416,

M + - Hz 400/398,

M + 2 HzO 382/380,

M + - H 2 O - C 2 H 4 O 356/354, 130-5 / 35 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-prost-13-enoic acid,

M + 368

M + - HzO 350,

M + - 2 HzO 332,

M + - C ₆ Hi ₃ 283, 13t-5 / 3H-5 (9a) -oxide-16,16-dimethyl-11a, 15S-dihydroxy-prost-13-enoic acid,

M ⁺ 382

M + - H 2 O 364,

M + —2 H2O 346,

M + - C ₇ H ₁₅ 283, _13t -4-bromo-5H-5 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-prost-13-enoic acid,

M ⁺ 462/460

M + —H ₂ O 444/442,

M + —2 HaO 436/434,

M + - Br 381, 13t-4-bromo-5S-5 (9a) -oxide-16R-methyl-11a, 15S-dihydiroxy-prost-13-enoic acid,

M + 462/460

M ⁺ —H2O 444/442,

M + 2 HzO 436/434,

M + - Br 381, 13t-4-bromo-5 / 3H (9a) -oxide-16,16-dimethyl-11a, 15S-dihydroxy-poxy-prost-13-enoic acid,

M + 476/474

M + - HzO 458/456,

M + 2 HzO 450/448,

M ⁺ -Br 395, 13t-4-iodo-5 / 3H-5 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-prost-13-enoic acid, M + 508,

M + - H 2 O 490,

M ⁺ 2 HzO 472,

M ^{+ -} J 381, 13t-4-chloro-5H (9a) -oxide-16S-methyl-11'-SS-dihydroxy-prost-1S-enoic acid, M + 418/416,

M + —H2O 400/398

M + - 2H ₉ O 382/380

M + -Cl 381, 13t-6 / SH-6 (9a) -oxide-16'S-methyl-11a, 16S-dihydroxy-14-bromo-prost-13-enoic acid,

M + 462/480

M + - HzO 444/442

M + - 2 HzO 426/424, 13β-6 / 3Η-6 (9α) -oxide-16R-methyl-11a, 15S-dihydroxy-14-bromo-prost-3-enoic acid,

M + 462/460

M + —H2O 444/442,

M + -2 H 2 O 426/424, 13t-6H-6 (9a) -oxide-20-methyl-11a, 15S-dihydroxy-14-bromo-prost-13-enoic acid,

M + 462/460

M + - HzO 444/442

M ⁺ -2 H 2 O 426/424, 13t-6 / 3H-6 (9a) -oxide-15 (S, R) -20-dimethyl-11a, 15S-dihydroxy-14-bromo-prost-13-enoic acid,

M ⁺ 476/474

M + - HzO 458/456,

M + - 2 HzO 440/438, 13t-5β-5 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-14-bromo-prost-13-enoic acid,

M ⁺ 448/446

M + - HzO 430/428

M + - 2 HzO 412/410,

M + - Br 367, (free acid) M ⁺ 462/460,

M ⁺ —H2O 444/442,

M + - CH3O 431/429

M + -2 H 2 O 426/424, 13t-5 / 3H-5 (9a) -oxide-16R-methyl-11a, 15S-dihydiroxy-14-bromo-prost-13-enoic acid,

M ⁺ 448/446

M + - HzO 430/428

M + - 2 HzO 412/410,

M + - Br 367, (free acid) M ⁺ 462/460,

M + —H2O 444/442,

M + —CH3O 431/429,

M + -2 H 2 O 426/424, 13t-5 / 3H-5 (9a) -oxide-20-methyl-11a, 15S-dihydroxy-14-bromo-prost-13-enoic acid,

M + 448/446

M + —H ₂ O 430/428,

M + —2 HaO 412/410,

M + - Br 367, (free acid) M ⁺ 462/460,

M + - HZO 444/442

M + —CH ₃ O 431/429

M + 2 H ₂ O 426/424, 13t-5 / 3H-5 (9a) -oxide-16 (S, R) -methyl-20-methyl-11a, 15S-dlhydroxy-14-bromo-prost- 13-enové,

+ 462/460,

M + - H ₂ O 444/442

M + -2H ₂ O 426/424,

M + - Br 381, (free acid) M + 476/474,

M + - HaO 458/456

M + —CH 2 O 445/443,

M + —2 H2O 440/438, 13t-5-bnomo-6 / 3H-6 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-14-bromo-prost-13-enoic acid,

M + 542/540/538

M + —H ₂ O 524/522/520

M + 2 H ₂ O 506/504/502,

M + —Br 461/459,

M + -2 Br 380, 13t-5-bromo-6H-6 (9a) -oxide-16R-methyl-11a, 15S-dihydroxy-14-bromo-pig-13-enoic acid,

M + 542/540/538

M + —HaO 524/522/520

M + -2 Br 380, 13t-5-bromo-6 / 3H-6 (9a) -oxide-20-methyl-11a, 15S-dihydroxy-14-bromo-prost-13-enoic acid,

M + 542/540/538

M + —H2O 524/522/520

M + 2 H ₂ O 506/504/502,

M + —Br 461/459,

M + -2 Br 380, 13t-5-bromo-6 / 3H-6 (9a) -oxide-16 (S, R) -20-dimethyl-11a, 15S-dihydroxy-14-bromo-prost-13-enoic acid ,

M + 556/554/552,

M + —HaO 538/536/534

M + —2 H2O 520/518/516

M + -2 Br 394, 13t-4-bromo-5 / 3H-5 (9a) -oxide-16S-methyl-11a, 15S-dihydroxy-14-bromo-prosit-13-enoic acid,

M + 542/540/538

M + —H ₂ O 524/522/520

M + 2 H2O 506/504/502,

M + —Br 461/459,

M + -2 Br 380, 13 t-acid-4 BRIO-5/3 H-5 (9a] -oxide-16R-methyl-lla, 15S-dihydroxy-14 ^J-proet bromo-13-enoic acid,

M + 542/540/538

M + IbO 524/522/520

M + 2 H ₂ O 506/504/502,

M + —Br 461/459,

M + -2 Br 380, 13t-4-bromo-5H, 3H (9a) -oxide-20-methyl-11a, 15S-dihydroxy-14-bromo-prost-13-enoic acid,

M + 542/540/538

M + —HaO 524/522/520

M + 2 H ₂ O 506/504/502,

M + —Br 461/459,

M + -2 Br 380, 13t-4-bromo-5H-5 (9a) -oxide-16 (S, R) -20-dimethyl-11a, 15S-idihydroxy-14-bromo-prost- 13-enové,

M + 556/554/552,

M + - H2O 538/536/534

M + --2 HaO 520/518/516

M + - 2Br 394, as well as their 15R-epimeric alcohols, when the respective 15-keto starting compounds are subjected to reduction and subsequent chromatographic separation.

Using the appropriate 6aH and 5aH diastereoisomeric 15-keto compounds, the corresponding 15S- and 15R-alcohols were prepared.

All of the above methyl esters are then saponified to give the corresponding free acids.

Example 31

A solution of 13t-5-iodo-6 / 3H-6 (9a) -oxide-16R-methyl-15-oxo-prost-13-enoic acid methyl ester (0.32 g) in ethyl ether (8 mL) was added with stirring to solution of zinc borohydride in ethyl ether (25 mL). After 30 minutes, the excess reducing agent was quenched by addition of saturated sodium chloride solution and 1 N sulfuric acid solution. The organic portion was worked up in the usual manner and the crude residue was chromatographed on silica gel using methylene chloride / ethyl ether as eluent. 0.16 g of methyl 13t-5-iodo-6 (SH-6 (9a) -oxo-16R-methyl-15S-hydroxy-prost-13-enoic acid) is obtained,

M + 492

M + - H2O 474,

M + - OCH3 461

M + - H 2 O - C 2 H 4 O 430, and 0.095 g of the respective 15R eplmer.

In the same way, the following methyl esters are obtained:

13t-6H-6 (9a) -oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid,

M + 366

M + —H ₂ O 348,

M + - OCH3 331

M + - H ₂ O - C ₂ H ₄ O 304, 13t-6 / SH-6 (9α-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid),

M ⁺ 366

M ^{+ - I} -hO 348,

M + —OCH3 331,

M ^{+ -} H ² O - C ² H 4 O 304, 131-6 µl 11- (9a) -oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid,

M + 380

M + - H 2 O 362,

M + —OCH3 349

M + - H 2 O - C 2 H 4 O 318, 13t-5 / 3H- (9a) -oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid,

M + 352

M ^{+ -} H ² O 334,

M ^{+ -} C 6 H 13 267, (free acid) M ⁺ 366,

M + - H 2 O 348,

M + —CH3O 335,

M + —CeHis 281, 13t-5SH-5 (9a) -oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid,

M + 352

M + —H2O 334,

M + - C 6 H 8 O 267, (free acid) M ⁺ 366,

M + - H 2 O 348,

M + - CH3O 335

M + - C 6 H 13 281, 13t-50H-5 (9a) -oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid,

M + 366

M + —H2O 348,

M + - C 7 H 15 267, (free acid) M ⁺ 380,

M + - H 2 O 362,

M + —CH3O 349,

M + - C 7 H 15 281, 13,5-bromo-6,10H-6 (9a) -oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid,

M ⁺ 446/444

M + - HzO 428/426

M + —CH3O 415/413,

M + -Br 365, 13t-5-bromo-6,3H-6 (9a) -oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid,

M + 446/444

M + —H2O 428/426

M + —CH3O 415/413,

M + -Br 365, 13t-5-bromo-6,3H-6 (9a) -oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid,

M + 460/458

M + - HzO 442/440

M + —CH3O 429/427,

M + - Br 379, 13t-5-bromo-6 / 3H-6 (9a) -155-hydroxy-20-methyl-prost-13-enoic acid,

M + 446/444

M + —H2O 428/426

M + -CH3O 415/413

M + -Br 365, 13'-5-broim-6 / 3H-6 (9a) -oxide-15S-hydroxy-16S, 20-dimethyl-prost-13-enoic acid,

M + 460/548

M + - HzO 442/440

M ⁺ - CH 3 O 429/427, as well as their 15R-epimeric alcohols, when the corresponding 5-keto starting materials are subjected to reduction and subsequent chromatographic separation.

Using the appropriate 6aH and 5aH diastereoisomeric 15-keto compounds, the corresponding 15S- and 15R-alcohols were prepared.

Example 32

The following 15S-hydroxy-9a-procenenoic acid methyl esters, as well as their 15R-epimeric alcohols, were obtained by the method described in Examples 23-31 by reduction of the respective 15-keto starting compounds: 13t-6 / 3H-6 (9a) -oxide- 11a, 15S-dihydroxy-13-pirostene, [α] _D = + 32 '(EtOH),

M + 368

M + - HzO 350,

M + -2 H2O 338, 13t-14-bromo-6 / SH-6 (9a) -oxide-11a, 15S-dihydroxy-13-prostenoic acid,

M + 448/446, 430/428, 412/410, 13t-14-chloro-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-13-prostenoic acid,

M + 404/402, 386/384, 368/388, acid 13 ^! t-5,14-dibromo-6 (SH-6 (9a) -oxide-11a, 15S-dihydroxy-13-prostene),

M + 528/526/524, 510/508/506, 492/490/488, 13t-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-20-methyl-13-prostenoic acid,

M + 382, 364, 352, 13t-14-bromo-6 / 3H-6 (9a) -oxide-11a, 16S-dihydroxy-20-methyl-13-prostenoic acid,

M + 462/460, 444/442, 426/424, 13-5-5-dibromo-6 ', 3H-6 (9a) -oxide-11a, 15S-dihydroxy-20-methyl-13-prostenoic acid,

M + 542/540/538, 524/522/520, 506/504/502, 13t-5-iodo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-20-methyl-13-prostenoic acid ,

M + 508, 490, 472, 13t-5-iodo-14-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-20-methyl-13-prostenoic acid,

M + 588/586, 570/568, 552/550, 13t-14-birom-6 (3H-6 (9 ') -oxide-11', 15S-dihydroxy-16 (S, R) -fluoro-17- ^{cyclohexyl-18,19,20-trinor-simple!} t-13-enoic acid,

M + 506/504, 438/486, 470/468, 13t-5,14-dibromo-6 / 3H-6 (9 ') -oxide-11a, 15S-dihydroxy-16 (S, R) -fluoro- 17-cyclo-hexyl-18,18,20-trinor-prost-13-ene,

M + 586/584/582, 568/566/564, 13'-5-bromo-6 / 3H-6 (9 ') -oxide-11a, 15S-dihydroxy-16 (S, R) -fluoro-17 acid -cyclohexyl-18,19,20-thirinior-prost-13-9 new,

M ⁺ 506/504, 488/486, 13t-6 (3H-6 (9?) -Oxa-11a, 15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-tirinor-prosit-13 acid) -enové,

M + 444, 426, 408, 13t-14-bromo-6 / 3H-6 (9 ') -oxide-11a, 15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-trinoro- prois1: -13-ene,

M + 524/522, 506/504, 488/486, 13t-6 $ H-6 (9a) -oxide-11a, 15S-dihydroxy-16 (S, R) -fluoro-17-phenyl-18, 19,20-trinnr-prost-13-ene,

M + 420, 402, 384, 13t-14-bromo-6 / 3H-6 (9a) -oxide-11 ', 15S-dihydroxy-16 (S, R) -fluoro-17-phenyl-18,19 acid , 20-trinor-prost-13-ene,

M + 500/498, 482/480, 464/462, 13t-6 / 1H-6 (9a) -oxide-11a, 15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-proBt-13-enoic acid , [α] _D = + 25 ° (EtOH),

M + 394, 376, 358, 13 t-6 acid (6-SH (9 a) -oxide-lla, L5S Γ7-dihydroxy-cyclohexyl-18,19,20- Trina ^i! R pΓ03t-13-enoic acid [ α _D = + 26 ° (EtOH),

M + 408, 390, 372, 13t-14-bromo-ββ-6 (9a) -oxa-11a, 15S-dihydroxy-17-cyclohexyl 1-18,19,20-trinor-pro-13-enoic acid ,

M + 488/486, 470/468, 13t-5,14-dibromo-6 / 3H-6 (9a) -oxide-11, a, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinior-prost -13-enes,

M + 568/566/564, 550/548/546, 13t-5-biroma-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-17-cyclohexyl-18,19,20-thinothioic acid -pros't-13-ene,

M + 488/486, 470/468, 13t-5-chloro-6 (3H-6 (9a) -oxide-11a, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid ,

M + 444/442, 426/424, 418/416, 13t-5-iodo-6 / SH-6 (9 ') -oxa-11a, 15S-dihydroxy-16-methyl-16-butoxy-18, 19,20-trinor-prost-13-ene,

M ⁺ 510, 482, 454, 131-5-iodo-6I / SH-6 (9a) -oxide-11a, 15S-dihydroxy-16-methyl-16-propoxy-8,19,20-trinor-prost- 13-enové,

M + 496, 468, 440, 13t-5-iodo-6 / 3H-6 :( 9a) -oxide-11 ', 15S-dihydroxy-16-methyl-16-amyloxy-18,19,2O-trinoropyrim -13-en0vé,

M + 524, 496, 468, 13t-5-iodo-6 (3H-6 (9a) -oxide-11a, 15S-dihydroxy-17-cycloheptyl-18,19,20-trinorepor-13-enoic acid) ,

M + 548, 530, 512, 13t-6/3 Η - 6 (9α) -oxide) - 11a, 15S-dihydroxy-16- (pfluoro) -phenoxy-17,18,19,20 -tetranor-13 -prostenové,

M + 422, 404, 386, [α] π = +30, 13t-6 / 3H-6 (9α) -oxide-11a, 15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor- 13-room,

M + 404, 386, 368, 131-6 (3 + 1-6 (9a) -oxide-11a, 15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranior-13-prestenoic acid,

M + 410, 392, 374, 13t-6, 3H-6 (9a) -oxide-11a, 15S-dihydiroxy-16- (m-chloro) -phenoxy-17,18,19,20-tetranor-13- pro3tenové,

M + 440/438, 422/420, 404/402, [α] D - + 31 °, 13t-6 / 3H-6 (9α) -oxide-11a, 15S-dihydroxy-16- (m-trifluoromethyl) acid (1) phenoxy-17,18,19,20-tetranor-13-prostene;

M + 472, 454, 436, [α] D = + 33 °, 13t-14-bromo-6 (3H-6 '(9a) -oxa-11a, 15S-dihydroxy-16- (pfluoro) phenoxy- 17,18,19,20-tetranor-13-prosle;

M + 502/500, 484/482, 13t-14-bromo-6 (3H-6 (9a) -oxide-11a, 15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13- pirostenové,

M + 484/482, 466/464, 13'-14-bromo-0 / 3H-6 (9a) -oxide 11a, 15S-dihydroxy-16- (m-chloro) phenoxy-17,18,19,20- tetranor-13-latent,

M ⁺ 520/518/516, 502/500/498, 13t-14-bromo-6 (SH-6 (9a) -oxide-11a, 15S-dihydroxy-16- (m-trifluoromethyl) phenoxy-17,18) , 19,20-tetranor-13-prositenQvé,

M ⁺ 555/550

M + -HaO 534/532, 13t-5-iodo-6 / 3H-6 (9a) -oxid-11a, 15S-dihydroxy-16- (p-fluoro-phenoxy-17,18,19,20-tetranor-13) -pirostenové,

M ⁺ 548

M + - H 2 O 530, 13t-5-iodo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydr, oxy-16-phenoxy-17,18,19,20-tetranor13-prostenoic acid,

M + 530

M ^{+ -} H ₂ O 512, acid 13, 5-iodo-6 / 3H-6 (9a) -oxide-11a, 15S-dlhydroxy-1-cyclohexyloxy-17,18,19,20-> tetra , anor-13-prostene,

M + 536

M ^{+ -} M ² O 518, 13t-5-iodo-6 / 5H-6 '(9a) -oxide-11a, 15S-dihydroxy-6- (m-chloro) phenoxy-17,18,19,20-tetiranoric acid -13-prosten,

M + 566/564

M + - HxO 548/546, 13t-5-joid-6,3H-6 (9a) -oxid-11a, 15S-dlhydroxy-16- (m-trifluoromethyl) phenoxy-17,18,19,20-tetranar- 13-pr, barbed,

M + 598, 580, 562, 13Í-5 / 3H-5 (9 ') -oxide-11a, 15S-dihydroxy-13-prostenoic acid,

M ⁺ 368, 350, 338, 13t-14-bromo-5 / 3Η-5 (9α) -oxide-11a, 15S-dihydroxy-13-prostenoic acid,

M + 448/446, 430/428, 412/410, 13t-14-chloro-5 / SH-5 (9a-oxide-11a, 15S-dihydnoxy-13-procenoic acid),

M ⁺ 404/402, 386/384, 368/366, 13t-4,14-dibromo-5 / JH-5 (9a) -oxide-11a, 15S-dihydroxy-13-prostenoic acid,

M + 528/526/524, 510/508/506, 492/490/488 acid 13 t-5/3 H-5 (9a] -oxide-lla, 15S-dihydroxy-20-methyl-13-heptenoic free ^of the ^L,

M + 382, 364, 352, 13t-14-bromo-5 / SH-5 (9a) -oxide-11a, 15H-dihydroxy-20-methyl-13-prostenoic acid,

M + 462/460, 444/442, 426/424, 13t-4,14-dibromo-5 / 1H-5 (9a) -oxide-11a, 15S-dihydroxy-20-methyl-13-prostenoic acid,

M + 542/540/538, 524/522/520, 506/504/502, 13t-4-iodo-5 <3H-5 (9a) -oxide-11a, 15S-dihydrioxy-20-methyl-13 -prostenové,

M + 508, 490, 472, 13t-4-iodo-14-bromo-5H-5 (9a) -oxide-11 ', 15S-dihydroxy-20-ethyl-13-prostenoic acid,

M + 588/586, 570/568, 552/550, 13t-14-bromo-5 / 1H-5 (9a) -oxide-11a, 15S-dihydroxy-16 '(S, R) -fluoro-17-cyclohexyl acid -18,19,20-trinor-prast-13-enoic acid, M + 506/504, 488/486, 131-4,14-dibromo-5 / 3H-5 (9a) -oxide-11a, 15S-dihydroxy- 16- (S, R) -fluoro-17-cyclohexyl-1 H-O-trinor-prosyl-15-enoic acid,

M + 586/584/582, 568/566/564, 13t-4-bromo-5 / 3H-5 (9a-oxide-11a, 15S-dihydroxy-16 (S, R) -fluoro-17-cyclohexyl- 18,19,20-trinor-prost-13-eno,

M + 506/504, 488/486, 13t-5H-5 (9a) -oxide-11a, 15S-dihydroxy-16 (S, R) -fluoro-17-phenyl-18,19,20 -trinor-prost-13-ene,

M + 420, 402, 384, 13t-14-bromo-50H-5 (9a) -oxide-11a, 15S-dihydroxy-16 (S, R) -fluoro-17-phenyl-18,19,20-trinoric acid -prost-13-eine,

M + 500/498, 482/480, 464/462, 131-5 / 3H-5 (9a) -oxide-11a, 15S-dihydroxy-17-cyclopentyl-18,19,20-trinoir-pr, 9t-13 -enové,

M ⁺ 394, 376, 358, 13H-5 / 3H-5 (9a) -oxide-11a, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinoroposit-13-enoic acid,

M + 408, 390, 372, 13t-14-bromo-5β-5 (9a) -oxide-11a, 15S-dihydiroxy-17-cyclohexylic acid 1-18,19,20 -'trinor-prio ^, s' t-13 - ene,

M + 488/486

M ^{+ -} H ₂ O 470/468, 13t-4,14-dibromo-5 / 3H-5 (9a) -oxide-11a, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinone-prost- 13-enové,

M + 568/566/564

M + -HaO 550 / 548/546, 131-5S-5 (9a) -oxide-11a, 15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid,

M + 404

M + —H ₂ O 386,

M + -2 H 2 O 368, 13t-4-yl-5H-5 (9a) -oxide-11a, 15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid ,

M + 530

M + —H ₂ O 512,

M + -2 H 2 O 494, 131-4-iodo-5 / 2H-5 (9a) -oxide-11a, 15S-dihydroxy-16-cyclohexyl-oxy-17,18,19,20-tetranor-13-prositenoic acid ,

M + 536

M + —H ₂ O 518,

M + 2 HzO 518,

M + —3 H2O 500

216642 13ΐ-4-} ύύ-5βΗ-5 (9α) -οχ1ύ-11α, 153-dihydroxy-16- (m-chloro) phenoxy-17,18,19,20-tetranor-13-prostenoic acid,

M + 566/564

M + - H 5 O 548/546, 13t-4-iodo-5H-5 (9a) -oxid-11a, 1,5S-dihydroxy-16- (m-trifluoromethyl) phenoxy-17,18,19,204 etranor-13-steep, M + 598,

M + —H ₂ O 580,

M ^{+ -} 2 H ₂ O 562.

In the same manner, using αH-9α-oxo-15-keto-diastereoisomers as starting materials, diastereoisomeric α-9α-oxide-15S- and αH-9α-oxide-15R-alcohols were prepared.

All of the above esters are saponified to give the corresponding free acids.

Example 33

To a solution of 0.46 g of 13t-5 (3H-5 [9a) -oxide-16S-methyl-11a-hydroxy-15-oxo-proet-13-enoic acid methyl ester in pyridine (2 mL) is added acetic anhydride (1 mL). The reaction mixture was allowed to stand for 6 hours at room temperature, then diluted with brine, acidified to pH 4.5 to

4.8 and shake with ethyl ether. The combined organic extracts were evaporated to dryness; 0.48 g of 11-acetoxy derivative is obtained, λ = 229 nm, ε = 11 058.

A solution of the latter compound in ethyl ether was added dropwise to a solution of zinc borohydride in ethyl ether. After 30 minutes, the excess reducing agent was quenched with N sulfuric acid solution, and after usual work-up, 0.47 g of 13t-5 / 2H-5 (9a) -oxide-16S-methyl-11a-methyl ester, 11 (acetate), was obtained. R) dihydroxy-13-prostene.

M + 424

M ⁺ - H ₂ O 406

M ^{+ -} C ₆ H ₁₃ 339.

A solution of the latter mixture of isomers in methylene chloride (5 mL) was cooled to about -5 ° C to -10 ° C, a solution of boron trifluoride etherate (1.2 χ 10 ^-4 M) in methylene chloride was added, followed by a 5% solution of diazomethane in methylene chloride until the yellow color persisted. The reaction mixture was concentrated under reduced pressure to half its original volume, washed with 5% aqueous sodium bicarbonate solution and water until neutral and the solvent was distilled off. 0.47 g of 11t-5 / 3H-5 (9α) -oxide-1S-methyl-11a-hydroxy-15 (S, R) -methoxy-prost-13-enoic acid methyl ester 11-acetate is obtained,

M + 438

M + - CH 3 CO 2 379,

M + - C 6 H 13 353, which was chromatographed on silica gel using a mixture of benzene and ethyl ether (85:

15) as the eluent, separated into the individual isomers.

In contrast, 0.21 g of a mixture of 15 (S, R) -methoxy derivatives was dissolved in anhydrous methanol (4 ml) and selectively deacetylated by treatment with 20 mg of anhydrous potassium carbonate for 4 hours at room temperature. The reaction mixture was neutralized by the addition of aqueous sodium dihydrogen phosphate solution, methanol was distilled off under reduced pressure, and the residue was extracted with ethyl ether (2 x 5 ml) and ethyl acetate (2 x 6 ml). The organic extracts were combined and the solvents were distilled off. 180 mg of crude 13H-5 / 1H-5 (9 ') -oxide-16S-methyl-11a-hydroxy-15 (S, R) -methoxy-prostenoic acid methyl ester are obtained,

M + 396

M ⁺ —I-IO 378,

M + - C 6 H 13 311 which was then separated by silica gel column chromatography using methylene chloride / ethyl ether as eluent to give two pure isomers: the 15S-methoxy derivative and the 15R-methoxy derivative.

In the same way, the following methyl esters are obtained:

13t-6i / 3H-6 (9a) -oxide-16S-methyl-11a-hydroxy-15S-methoxy-prost-13-enoic acid, M + 396,

M + —H2O 378,

M + - C 6 H 13 311, 13t-6H-6 (9a) -oxide-16R-meithyl-11a-hydroxy-15S-methoxy-prost-13-enoic acid,

M + 396

M + - HsO 378,

M + - C 6 H 13.3 311, 13t-6 / 5H-6 (9α-Oxide-20-methyl-11a-hydroxy-15S-methoxy-prost-13-enoic acid),

M + 396

M '- IIO 378,

M + - C 6 H 13 311, 13t-5-bromo-6 / 3H-6 (9a) -oxide-20-methyl-11a-hydroxy-15S-methoxy-priost-13-enoic acid,

M + 476/474

M + —HZO 458/456,

M + —CH3O 445/443

M + - Br 395, 13t-5-bromo-6,3H-O (9a) -oxa-11a-hydroxy-15S-methoxy-prost-13-enoic acid,

M + 462/460

M + - HZO 444/442

M + - CH3O 431/429

M + - Br 381, 13t-5-bromo-6 / 3H-6 (9a) -oxide-16S-methyl-11a-hydroxy-15S-methoxy-prost-13-enoic acid,

M + 476/474

M ⁺ —HsO 458/456

M + —CH3O 445/443

M + - Br 395, 11a-hydroxy-15S-methoxy-6) 3H-6 (9α) -oxide-16S-methyl-prost-13-ynoic acid, [α] _D = + 24 ° (in ethanol), 11a-hydr, oxy-15S-ethoxy-6 (3H-6 (9a) -oxide-16S-ethyl-prost-13-ynoic acid (ethyl ester), [α] _D = + 26 ° (in ethyl alcohol), and their epimeric 15R-methoxy derivatives, using the appropriate 11-acetoxy-15-keto compounds as starting materials.

In the same way, but using the corresponding αH-diastereoisomers instead of the HH-isomers as starting materials, the corresponding Η-15-methoxy derivatives are also obtained.

The same procedure can also be applied to any of the 15-keto compounds described above, and analogously other diazoalkanes may be used instead of diazomethane.

Example 34

To a solution of 0.26 g of methyl 13-6 / 3H-6 (9a) -oxide-15 (S, R) -hydr, oxy-16S-methyl-prost-13-enoic acid in methylene chloride is added 0.3 ml of a solution of boron trifluoride etherate in methylene chloride and then, with cooling to -10 to -8 ° C, a solution of diazoethane in methylene chloride until a permanent yellow color is obtained. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, eluting with ethylleither with methylene chloride (10:90); 0.115 g of methyl 13t-6 (3H-6 (9a) -oxide-15S-ethoxy-1S-methyl-prost-16-enoic acid) and 0.1 g of the corresponding 15R-ethoxyisomer are obtained,

M + 394

M + —OCH3 363,

M + - C 2 H 4 O 350,

M ^& lt ^{; +} &^gt;

When 15S, 15R-alcohols are used as starting materials in the process described in Examples 68 and 69, for example 13t-6 / 3H-6 (9a) -oxil-11a, 15 (S, R) -dihydroxy-16'S At the same time, the alkoxylation of the alcoholic function at the 11-position also occurs with methyl 11-hydroxy-prostenoic acid and, for example, using diazomethane gives, after chromatographic separation, 13t-6 / 3H-6 (9a) -oxide-11a, 15S methyl ester. -dimethoxy-16S-methyl-postenene; a decent 15R-epimeric derivative,

M + 410

M + —OCH3 379,

M + - C2H4O 366

M @ + - CeHn 325.

In a similar manner, the following 15S-alkoxy-prostenoic acid derivatives are obtained:

13t-5 / 3H-5 (9α-Oxide-11a, 15S-dimethoxy-prostenoic acid),

M + 382

M + - C5H11 311

M + 396

M + —OCH3 365

M ⁺ - C 5 H 11 325 (methyl ester), 13t-6H-6 (9a) -oxide-11a, 15S-dimethoxy-prostenoic acid,

M + 396

M + —OCHs 365

M ⁺ —C2H4O 352,

M + - CsHi 325, 13t-6SH-6 (9a) -oxide-5-bromo-11a, 15S-dimethoxy-prostenoic acid,

M + 476/474

M + - OCH3 445/443

M + - C2H4O 432/430

M ^{+ -} Br'395, 13t-6 / SH-6 (9a) -oxide-5-iodo-11a, 15S-dimethoxyprostenoic acid,

M + 522

M + —OCH3 491,

M + - C2H4O 478

M + - J 395, 13t-5 (3H-5 (9a) -oxide-15S-methoxy-16S-methyl-prostenoic acid,

M + 366

M + —CeHn 281, 13t-6H-6 (9a) -oxide-15S-methoxy-1S-methyl-prostenoic acid,

M ⁺ 394

M + —OCH3 363,

M + - C 2 H 4 O 350,

M + —CeHn 309, 13t-6 (3H-6 (9a) -oxide-15S-methoxy-16R-methyl-prostenoic acid,

M + 394

M + - OCH3 363

M + - C 2 H 4 O 350,

M ⁺ —CeHn 309, 13t-6 / 3H-6 (9a) -oxide-15S-methoxy-16-methyl-16-butoxy-18,19,20-trinoropropenoic acid,

M + 396

M + - C 7 H 15 O 281, as well as their respective 15R-epimers, and after saponification with lithium hydroxide in methanol, the corresponding free acids are prepared.

Using the same procedure, diastereoisomeric αH-9α-oxide derivatives can be obtained.

Example 35

To a solution of 13t-6aH-6 (9a) -oxide-11a-hydroxy-15-oxo-prost-13-enoic acid methyl ester 11-acetate (1.33 g) in a mixture of toluene (6 ml) and benzene (54 ml) was stirred and a solution of 1.67 g of methylmagnesium iodide in ethyl ether was added under cooling to +4 ° C. After 20 minutes, the excess Grignard reagent was decomposed, while cooling with ice, with a 20% solution of ammonium chloride in water. The reaction mixture was then diluted with an equal volume of ethyl ether, the organic layer was separated, washed with water, sodium bicarbonate solution and again with water, and dried over anhydrous magnesium sulfate. Pyridine (0.1 ml) was added to the solution and the solvent was distilled off to dryness; 1.2 g of 13t-6H-6 (9a) -oxide-11a, 15 (S, R) -dihydnoxy-15-methyl-prostenoic acid methyl ester 11-acetate are obtained. From this amount, 0.2 g was separated into pure components by thin layer preparative chromatography on silica gel, eluting with benzene / ether (60:40).

To the solution. 1 g of the above mixture of two epimeric alcohols in anhydrous methanol (20 ml) was added 0.25 g of anhydrous potassium carbonate and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off and the residue was partitioned between ethyl ether and 15% aqueous sodium dihydrogenphosphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel (200 g), eluting with ethyl ether / isopropyl ether (80:20) to give 0.20 g of 13t-6aH-6 methyl ester. (9a) -oxide-11a, 15R-dihydroxy-15-methyl-prost-13-enoic acid and 0.36 g of the corresponding 15S-epimer,

M + 382

M + - H 2 O 364,

M + —CH3O 351,

M + - H 2 O - C 2 H 4 O 320.

To a solution of 0.16 g of the latter compound in 12 ml of methanol was added 0.8 ml of water and 0.2 potassium carbonate. After 5 hours at room temperature, methanol was distilled off under reduced pressure and the residue was partitioned between a 20% aqueous sodium dihydrogen phosphate solution and ethyl acetate. 0.14 g of 13t-6'H-6 (9a) -oxide-11a, 15S-dihydroxy-15-methyl-prost-13-enoic acid, [α] _D (methyl ester) is obtained from the organic fraction after distilling off the solvent. + 6.2 ° (in chloroform).

The corresponding 6 / SH-isomers were prepared by the same procedure. [α] _D for 13.t-63H-6 (90) -oxide-11a, 15S-dihydroxy-15-methyl-prost-13-enoic acid methyl ester is + 19.62 ° (in chloroform).

Example 36

To a solution of 1.79 g of 13t-5aH-5 (9a) -oxide-11a-hydroxy-15-oxo-prost-13-enoic acid 11-acetate methyl ester in 20 ml of anhydrous tetrahydrofuran is added 50 ml of a 0.3 M solution of ethinylmagnesium bromide in anhydrous tetrahydrofuran and the mixture was shaken for one hour. Excess Grignard reagent was quenched with saturated aqueous ammonium chloride and the solvent was distilled off under reduced pressure. The residue is triturated with ethyl ether to give 1.62 g of 13t-5aH-5 (9a-oxo-11a), 15 (S, R) -dihydroxy-15-ethynyl-prost-13-enoic acid 11-acetate,

M ⁺ - H ₂ O 416

M + - C 5 H 11 363.

The latter compound was dissolved in anhydrous methanol, 250 mg of anhydrous potassium carbonate was added thereto, and the mixture was shaken for 3 hours. After distilling off the solvent from, and under reduced pressure, the residue was partitioned between a 20% aqueous solution of sodium dihydrogen phosphate and ethyl ether. 1.41 g of 13t-5αΗ-5 (9a) -oxide-11a, 15 (S, R) -dihydroxy-15-ethynyl-prostenoic acid methyl ester are obtained from the organic fraction after distillation of the solvent,

M + 392

M + - H 2 O 374,

M + C 5 H 11 321, which was separated by chromatography on silica gel, using 1: 1 benzene / ethyl ether as the eluent, to give pure 15S-hydroxy and 15R-hydroxy-epimers.

After saponification of 15S-hydroxyepimer with potassium carbonate in methanol, 13t-5aH-5 (9a) -oxide-11a, 15S-dlhydroxy-15-ethynyl-prostenoic acid is obtained,

M + 378

M ^{+ -} HzO 360,

M + - C 5 H 11 307.

Example 1 and d 37

To a solution of 1.41 g of methyl 5-13 t-BNome-6- (3H-6 (9a j ^j oxide-15-: pr ost-oxo-13-enoic acid ethyl ester in anhydrous THF (25 mL) at 0-5 ° C A 0.5 M solution of vinylmagnesium bromide in tetrahydrofuran (25 mL) was added and the mixture was allowed to stand at room temperature for 4 hours, excess Grignard reagent was quenched with saturated aqueous ammonium chloride, the tetrahydrofuran was distilled off under reduced pressure and the product was taken up in ethyl ether. was chromatographed on silica gel using methylene chloride: ethyl ether as eluant to give 0.41 g of methyl ester 13 _t-5-bromo-6 and SH-6 (9a) -oxide-15R-hydroxy-15-vinyl-prostenoic ,

M + 428/426

M + - H ₂ O 410/408

M + —CH3O 397/395

M + - Br 347, and 0.62 g of the corresponding 15S-isomer.

The latter compound, after saponification with lithium hydroxide in methanol, yields 0.49 g of 13t-5-brm-6 / SH-6 (9a) -oxide-15S-hydroxy-15-vinyl-prostenoic acid,

M ⁺ 414/412

M + —H2O 396/394

M + - Br 333.

Example 38

To a solution of 0.98 g of 11-acetate, 13 tons of methyl 5-bromo-6- (3H-6 (9a) ^{-oxide-lla-hydroxy-15-oxo-20-methyl-i} for the wall in 30 ml of benzene toluene (85:15) was added

A solution of 0.92 g of phenylmagnesium bromide in ethyl ether / benzene 1: 1 is added while cooling to 3-4 ° C. The reaction mixture is allowed to stand for 5 hours at room temperature. Excess Grignard reagent was decomposed under ice-cooling with a 15% aqueous ammonium chloride solution, the organic layer was washed repeatedly with water until neutral, and the solvent was distilled off. The crude 15-phenyl-15 (S, R 1 -hydroxy derivative) was dissolved in anhydrous methanol, 0.25 g of anhydrous potassium carbonate was added and the mixture was shaken for 2 hours. The solvent was distilled off under reduced pressure and the residue was partitioned between 20%. An aqueous solution of sodium dihydrogen phosphate and ethyl ester, and the solvent was distilled off from the organic portion, to give 0.81 g of 13t-5-bromo-6 (3H-6 (9H) -oxide-11a, 15 (S, R) -dihydroxy acid methyl ester). -15-phenyl-20-methyl-prostene,

M + 538/536

M ⁺ - H ₂ O 520/518

M + —CH3O 507/505,

M + - Br 457, which, after chromatography on silica gel, using ethyl ether as eluent, affords the corresponding individual 15S- and 15R-epimers.

Example 39

Reaction of the appropriate 15-oxo derivatives with a Grignard reagent selected from the group consisting of methylmagnesium-, ethylmagnesium-, vinylmagnesium-, ethinylmagnesium, and phenylmagnesiumhalagenide, after treatment of the reaction mixture with one of the procedures described in Examples 70-73, affords the following methyl esters of acids:

13t-6 / 3H-6 (9α) -oxide-15S-hydroxy-15-methyl-prostenoic acid,

M ⁺ 366

M + —H2O 348,

M + —CH3O 335,

M + - C 5 H 11 295, 13t-6 / JH-6 (9a) -oxide-15S-hydroxy-15,20-dimethyl-prostenoic acid,

M + 380

M + —H2O 362,

M + —CH3O 349,

M ⁺ —C ₆ Hi3 295, 13t-6 / SH-6 (9α-oxide-15S-hydroxy-15-ethyl-prostenoic acid),

M + 380

M + - H 2 O 362,

M + —H ₂ O 362,

M ⁺ —CH _S O 349,

M + - C 5 H 11 309, 13t-6 / JH-6 (9a) -oxide-15S-hydroxy-15-ethynyl-prostenoic acid,

M ⁺ 376

M + —H2O 358,

M + —CH3O 345,

M ^{+ -} C 5 H 11 305, 13t-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-15-methyl-prostenoic acid,

M + 382

M + - H 2 O 364,

M + - 2 HzO 346,

M + - H 2 O - C 2 H 4 O 320,

M + - C 5 H 11 311, 13t-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-15-ethyl-prostenoic acid,

M + 396

M ^{+ -} H ² O 378,

M + —2 H2O 360,

M + - H 2 O - C 2 H 4 O 334,

M + - C5H11 325, 13t-6 / 3H-6 (9a-oxide-11a, 15S-dihydroxy-15-vinyl-prostenoic acid),

M + 394

M + —H2O 376,

M + 2 HzO 358,

M + - H 2 O - C 2 H 4 O 332,

M + - C 5 H 11 327, 13t-6H-6 (9a) -oxide-11a, 15S-dihydroxy-15-ethynyl-prostenoic acid,

M + 391

M + -HZO 374,

M + 2 HzO 356,

M + - H 2 O - C 2 H 4 O 330,

M + - C 5 H 11 325, 13t-6 / SH-6 (9a) oxide-11a, 15S-dihydroxy-15-phenyl-proetenoic acid,

M + 444

M + - H 2 O 426,

M + - 2 HzO 408,

M + - H 2 O - C 2 H 4 O 382, 13t-6 (3H-6 ^: (9a) -oxide-11a, 15S-dihydroxy-15,20-dimethyl-prostenoic acid),

M + 396

M + —H2O 378,

M + 2 HzO 360,

M + - H 2 O - C 2 H 4 O 334, 13t-5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-15-methyl-prostenoic acid,

M + 462/460

M + - HzO 444/442

M + -2 HzO 436/434, 13t-5-briom-6 (SH-6 [9a) -oxide-11a, 15S-dihydroxy-15-vinyl-prostenoic acid,

M + 474/472

M ^{+ -} HzO 456/454

M + -2 H 2 O 438/436, 13t-5-bromo-6H-6 (9a) -oxide-11a, 15S-dihydroxy-15-ethynyl-pentenoic acid,

M + 472/470

M + - HzO 454/452

M + 2 HzO 446/444,

7S 13t-5-bromo-6 / 3H-6 (9a) -oxide-11 ', 15S-dihydroxy-15-ethyl-prostenoic acid,

M + 476/474

M + —H ₂ 0 458/456,

M ^{+ -} 2 HzO 450/448, 13t-5-bromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-15-phenyl-prostenoic acid,

M + 524/522

M + —H2O 506/504

M @ + - 2 HzO 488/486, 13t-4-bromo-5H-(9a) -oxide-11a, 15S-dihydroxy-15-methyl-prostenoic acid,

M + 462/460

M + —H2O 444/442,

M + -2 H 2 O 426/424, 13t-4-bromo-5 / 3H-5 (9a) -oxide-11a, 15S-dihydrioxy-15,20-dimethyl-prostenoic acid,

M + 476/474

M ^{+ -} HzO 458/456,

M + -2 HzO 440/438, 13t-4-hromo-5 / 3H-5 (9a) -oxide-11a, 15S-dihydroxy-15-ethynyl-prostenoic acid,

M + 472/470

M + - HzO 454/452

M + -2 H 2 O 446/444, 13t-5 / JH-5 (9a) - Oxide-11, α, 15S-dihydroxy-15-methyl-prostenoic acid,

M + 368

M + - HzO 350,

M + - 2 HzO 332,

M + - C 5 H 11 297, (free acid) M ⁺ 382,

M + —H ₂ O 364,

M @ + - 2 HzO 346, 13t-5 / SH-5 (9a) -oxide-11, 15S-dihydroxy-15,20-dimethyl-prostenoic acid,

M ⁺ 382

M + - H 2 O 364,

M + —2 H2O 346,

M + - C 6 H 13 297, (free acid) M + 396,

M + - H 2 O 378,

M + - 2 HzO 360, 13t-5 / 3H-5 (9a) -oxide-11a, 15S-dihydroxy-15-phenyl-prostenoic acid,

M + 430

M + —H ₂ O 412,

M ⁺ 2 HzO 394,

M ^{+ -} CsH11 359, (free acid) M + 444,

M + - H 2 O 426,

M + - 2 HzO 404, 13t-5 / 3H-5 (9a) -oxide-11a, 15S-dihydroxy-15-ethynyl-prostenoic acid,

M + 378

M + —HaO 360,

M + —2 H2O 342,

M ⁺ - C 5 H 11 307, (free acid) M + 392,

MA —HZO 374,

M + —2 H2O 356, ´J · substance 5 / 3H-5 (9a) -oxide-11a, 15S-dihydroxy-15-carboxylic acid,

M + 380

M + —HaO 362,

M ⁺ —2 H2O 344,

M + - C 5 H 11 309, (free acid) M ⁺ 394,

M + - H 2 O 376,

M ^h HZO 358 -2, 131-5 acid / 3H-5 (9a) -oxide-lla, 15S-dihydroxy-15-methyl-for: wall,

M + 382

M + —HaO 364,

M ⁺ -2 H 2 O 346, and their 15R-hydroxyepimers.

Analogously, using the appropriate αH- (9a) -oxide-15-ketos compounds as starting materials, the corresponding αH- (9a) -oxide-15-suibstituted alcohols are obtained.

Example 40

To the ri thiocyte of 131-14-bromo-6 / 3H-6 '(9a) -oxo-15S-methoxy-16S-methyl-proet-13-enoic acid methyl ester (0.46 g) in anhydrous dimethylsulfoxide (5 mL) was added. potassium tertiary butylate (0.15 g) is added under stirring under an inert gas atmosphere and the mixture is stirred for 30 minutes. The reaction mixture was then diluted with 2 volumes of water, stirred for 15 minutes and shaken with ethyl ether. The organic extracts are shaken again with 2 x 5 ml of 0.2 N sodium hydroxide and then with water until neutral, and the solvent is distilled off. 30 mg of 6 * 3H-6 '(9') -15S-methoxy-16S-methyl-prost-13-ynoic acid methyl ester, [α] _D = + 21 ° (in ethyl alcohol), are obtained.

The combined aqueous-alkaline fractions were acidified to pH 5.1 and shaken with ethyl ether. After distilling off the solvent, 0.28 g of 6 / 3H-6 (9a) -oxide-15S-methoxy-16S-methyl-prost-13-ynoic acid is obtained, [α] _D = + 19 ° (in ethanol).

Example 41

To a solution of 0.445 g of 13t-5'H-5 (9a) -oxide-14-bromo-16R-methyl-pro-st-13-enoic acid in anhydrous dimethylsulphoxide under an inert gas atmosphere while stirring and strictly excluding air humidity, 0.84 g of trimethylsilylimidazole is added, the mixture is stirred for 30 minutes and then a solution of 0.19 g of potassium tertiary butylate is added. After stirring for an additional 30 minutes, the reaction mixture was diluted with 3 volumes of water and stirred for an additional 2 hours. The solution is acidified to pH 5.2, shaken with ethyl ether-hexane 80:20, the organic extracts are combined, dried and the solvent distilled off; There was obtained 5aH-5 (9a) -oxide-16R-methyl-prost-13-ynoic acid, [ _.alpha. ] _D = + 21 DEG (in ethanol).

Example 42

To a solution of methylsulfinylcarbanion sodium salt, prepared by heating a suspension of 50 mg of 80% sodium hydride with 8 ml of anhydrous dimethylsulfoxide at 60 ° C for 3 hours and 30 minutes, is added under stirring under an inert gas atmosphere at 18-20 ° C. solution of 0.86 g of 13t-6 (SH-6 (9a) -oxide-11a, 15S-dimethoxy-14-briom-16 (S, R) -fluoro-20-methyl-pros't-13-enoic acid methyl ester) The mixture was stirred for 40 minutes, then an excess of 25% aqueous sodium dihydrogen phosphate solution was added and the solution was shaken with ethyl ether to give 0.51 g of 6 / 3H-6 (9a) -oxide-11a acid methyl ester after evaporation of the solvent. , 15S-dimethoxy-16 (S, R) -fluoro-20-methyl-prosta-13-ynoic [a] _D = + 21.4 DEG (in ethyl alcohol).

Example 43

To a solution of 80 mg of sodium amide in 10 ml of dimethyl sulfoxide is added a solution of 0.65 g of 11,15-bis-tetrahydropyranyl ether of 13t-14-bromo-5aH-5 (9a) -oxld-11a, 15S-dihydroxy-16-m- trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-ene in 5 ml of dimethylsulfoxide. The reaction mixture was stirred for 2 hours then diluted with water and shaken with ether. The ethereal extracts are again shaken with sodium hydroxide solution and set aside. The alkaline aqueous portions were combined, acidified to pH

4.5 and shaken with ethyl ether; after evaporation of the solvent, 0.54 g of 5αΗ-5 (9α) -oxld-11a, 15S-dihydroxy-16-m-trifluoromethylphenoxy-17,18,19,20-tetranorone-prost-, 11,15-bis-tetrahydropyranyl ether, is obtained. 13-in.

A solution of the latter compound (0.3 g in anhydrous ethanol (5 ml) and 2,2-diethoxypropane (3 ml) was treated with 20 mg of p-toluenesulfonic acid. After standing at room temperature for 5 hours, the reaction mixture was neutralized with an aqueous solution. sodium bicarbonate, the solvents were distilled off under reduced pressure, and the residue was partitioned between water and ethyl ether, the solvent was evaporated from the organic portion and the crude product was chromatographed on silica gel to give 0.1 g of 5'-H-5 (9a-oxide) ethyl ester. 11a, 15S-dihydroxy-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-yne, [α] _D = + 15 ° (in ethanol).

An additional 0.2 g of acetal ether was deacetalized by dissolving in 5 ml of acetone, 3.5 ml of a 0.2 N oxalic acid solution was added to the solution, and the mixture was heated at 40 ° C for 8 hours. The acetone was distilled off under reduced pressure, the aqueous solution was extracted with ethyl ether and the product was chromatographed on silica gel, eluting with a 95: 5 mixture of ethyl ether and ethyl acetate; 95 mg of the corresponding free acid is obtained, [α] _D = + 16.5 ° (in ethanol).

In the same manner, using 11,15-bis-dioxanyl ether of 13t-14-chloro-6a; H-6 ^; (9a) -oxa-11a, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinoir-prost-13-enoic acid, starting from 6αΗ-6 (9a) -oxide-11a, 15S-dihydroxy acid -17-cyclohexyl-18,19,20-trinior-prost-13-yne, (? Z) + 27.2 ° (in ethyl alcohol), methyl ester: [α] _D = + 17.2 ° (in ethanol) ], [α] 365 = + 54 °.

Example 44

To a solution of 0.48 g of 13t-14-thromo-6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13- methyl ester After 30 minutes, a solution of 1,5-diazabicyclo [5.4.0] undec-5-ene (0.25 g) in 2 ml of anhydrous dimethylforimamide is added and the reaction mixture is heated at 65 ° C for 6 hours. C. The solution was diluted with water, acidified to pH 4.5 and shaken with ethyl ether, the solvent was distilled off from the organic portion and the residue was chromatographed on silica gel using benzene / ethyl ether 80:20 as eluent to give 0.29 g of the methyl ester. 6H-6 (9a) -oxide-11a, 15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-ynoic acid, [α] _D = + 17.1 ° (in ethyl alcohol].

Example 45

By one of the methods described in Examples 40-44, using the appropriate 13t-14-halo-prost-13-enoic acids as starting materials, the following prost-13-ynoic acids are prepared:

6 (3H-6 (9a) -oxide-11a, 15S-dihydroxy-prost-13-ynoic acid, [[alpha]] D = + 25 [deg.] (in ethanol j, 6 / 3H-6 acid: (9a) -oxide-11a), 15R-dihydroxy-prloet-13-ynoic, [α] _D = + 37 ° (in ethyl alcohol), 6β 6-6 (9 α) -oxide-15-methoxy-prost-13-imoic acid, [a] _D = + 27 ° (in ethanol), 6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-16S-methyl-prost-13-ynoic acid, [α] _D = + 22.5 ° (in ethanol) 6 (SH-6 (9a) -oxide-11a, 15S-dihydroxy-16S, 20-dimethyl-prost-13-ynoic acid, [α] _D = + 23 ° (in ethanol), acid 6; (9 ') -oxide-11a, 15S-dihydroxy-16R-methyl-prost-13-ynoic acid, [α] _D - + ³⁷ ° (in ethanol), 0 / 3H-6 (9a) -oxide- 11a, 15S-dihydroxy-6S-fluoro-prost-1S-ynoic acid, [α] _D = + 25 ° (in ethyl alcohol), 6H-6 (9 ') -oxa-11a, 15S-dihydroxy-16, 16-difluoro-prost-13-inactive, [α] _D = + 16.5 ° (in ethanol), 6 / 3H-6 (9a) -oxide-11a, 15S-dihydroxy-20-methyl-prost-13 ynoic [· α] _π = + 16 ° (in ethanol), acid 6jSH-6 (9a) -oxide-lla, 15S-dihydroxy-17-cyclohexyl-18,19, 20-trinor-pro-13-yne, [α] _D = + 21 ° (in ethyl alcohol), methyl ester [α] _D = + 26.5 ° (in ethanol), [α] 385 = + 84 ° [ in ethyl alcohol), 6H-O (9a) -oxide-11a, 15S-dihydroxy-16-fluoro-17-cyclohexyl-18,19,20-trinor-prost-15-ynoic acid, []] d = + 23 ° (in ethanol), 6H-6 (9a) -oxide-11a, 15S-dihydroxy-16-p-fluoro-phenoxy-17, 18,19,20-tetranor-prost-13-ynoic acid, [α] _D = + 17 ° (in ethanol), 6SH-6 (9a) -oxide-11a, 15S-dihydroxy-17-phenyl-18,19,20-trinor-prost-13-ynoic acid, [α] _D = + 15 ° (in ethyl alcohol), 5βH-5 (9α) -oxide-11a, 15S-dihydroxy-16S-methyl-prosit-13-ynoic acid, [α] _D = + 19 ° (in ethanol), acid 5 3 H-5 (9a) -oxide-11a, 15S-dihydroxy-16S, 20-dimethyl-prost-13-inn ^; _.alpha. , [ _.alpha. ] _D = + 20.5 DEG (in ethanol); 5H-5 (9a) -oxide-11a, 15S-dihydroxy-16R-methyl-prost-13-ynoic acid, [a] _D = + 39 ° (in ethyl alcohol), 5βΗ-5 (9α) roxid-11a, 15S-dihydroxy-16S-fluoro-prost-13-ynoic acid, [α] _D = + 23.5 ° (in ethanol), 5j3H acid -5 (9a) -oxa-11a, 15S-dihydroxy-prost-13-ynoic acid, [α] _D = + 29 ° (in ethanol), 5 / 311-5 (9a) -oxide-11a, 15S -dihydrioxy-20-methyl-prost-13-yne, [α] _D = + 27 ° [in ethanol].

In the same way, but using αΗ- (9α) -oxide derivatives, the epimeric αΉ- (9α) -oxiu-13-ynoic acid is prepared.

Example 46

A solution of 0.12 g of methyl 13t-11a, 15S-dihydroxy-6 / 3H-6 (9a) -oxide-pro-13-emoate in 6 ml of methanol was treated with 0.5 N aqueous hydroxide solution for 6 hours. The methanol was removed under reduced pressure, the residue was diluted with water (2 ml) and the solution was shaken with ethyl ether to remove neutral impurities. The ethereal extracts were combined, washed with water (2 x 1 mL) and dried to give 91 mg of 13t-11a, 15S-dihydroxy-6 / 3H-6 (9a) -prost-13-enoic acid after distilling off the solvent. mp 78-80 ° C, [α] D = + 31 ° (in ethanol).

In this way, the esters obtained in the preceding examples are saponified to the corresponding free acids.

Example 47

To a solution of 11a, 15S-dihydroxy-6 / 3H-6 [9a) -16S-methyl-propyl-13-ynoic acid (0.11 g) in methylene chloride was added a solution of

1.5 mol equivalents of diazomethane in methylene chloride. After 15 minutes the solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel. Elution with a mixture of ethyl ether and benzene (70:30) gave 12 mg of 11a-hydroxy-15S-methoxy-6 / 3H-6 (9a) -16S-methyl-prost-13-ynoic acid methyl ester, respectively. [α] _D = + 24 ° (in ethanol), and 78 mg of 11a, 15S-dihydroxy-6 / SH-6 (9α) -oxide-16S-methyl-prost-13-ynoic acid methyl ester, [a] _D = + 21.5 ° (in ethanol).

Using the same procedure, but using 11'-hydroxy-15S-ethoxy-6 / 3H-6 (9α) -oxide-16S-methyl-prost-13-ynoic acid, [α] _D = + 26 ° (in ethyl alcohol) .

Claims (4)

A process for the preparation of 2-oxabicyclic staglandins of the general formula I, C - (CHghf 6 - x - (CH 2 R 6, Rit- (U wherein R is (a) a free carboxyl group or a group of the formula -COORs wherein R represents a C ^^ alkyl or C ₂ -i2alken, yloviou group, (b) a group of formula or OR ‘—C = C—, HZ ₂ —C — 0R ', STEED* C = C (cis) C = C (trans) Z ₂ in which the substituents R ', which may be the same or different, denote a C _1-6 alkyl group or a phenyl group, (cj a group of the formula -CH 2 OH, (d) a group of the formula / - CON \ R _b in which R _a and R _b is individually hydrogen, C ^ alkytoViOU group, a C _2-6 alkanoyl group or a phenyl · (e} a group of formula (f cyano, Z 1 is a hydrogen or halogen atom, p is zero or an integer from 1 to 7, q is 1 or 2, Ri is hydrogen, hydroxyl, C ^ alkioxyskupinu, C ₆ _ _{10 ares 1-e "6} alkoxy or C ₁ _ ₇ acyloxy, Y represents a group of the formula --CH2 CH2 - in which Z2 is hydrogen or halogen, one of R2 and R is hydrogen, C galkylovou group, a C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ ~ ₁₀ aryl group and the other of the substituents R and R5 represents a hydroxy group or a C tfalkioxyskupinu _C6 _i _{0 ares} alfeoxýskupinu-C _6, or R ₂ and R together form oxo, R 3 and R 4, which may be the same or different, each represent a hydrogen atom, a C _1-6 alkyl group or a fluorine atom, or R 5 and R 4 together with the carbon atom to which they are attached form a radical of the formula "C" II CH 2 or a radical of formula -cCHf- ^CH Z. ni and _{n 2} , which may be the same or different, denote zero or an integer individually · 1 to 6, X represents an oxygen atom or a sulfur atom or a group of the general formula 83 84 - (CH ₂ ) _m - in which m is zero of 1, R is (a ') hydrogen, (b) C ₁ _ ₄ alkyloviou group, (c') a cyclo-C _{3 _?} aliphatic, optionally substituted with one C alesipoň. ^ alkyl or C ^^ alkoxyiskupinou, (d) C ₆ aryl _i ₀ 'group optionally substituted by at least one halogen atom, C ^ haloigenlovanou alkyl, C ^ alkyl or C ₆ or (e ') a saturated or unsaturated heteromonocyclic or heterobicyclic ring containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen and having 1 to 10 carbon atoms, optionally substituted by at least one halogen atom, halogenated with C _1-6 alkyl, C _1-6 alkyl or C _1-6 alkoxy, and pharmaceutically or veterinarily acceptable salts and isomers thereof, characterized in that the compound of formula IV wherein R 1 is (a ") a free carboxyl group or a group of the formula -COOR 5 wherein: R ₂ represents Ci_i alkylovdu group or a C ₂ _ ₁₂ alkenyl ^and vioíu group, (b 'j Grp of formula OR ') —C — OR ', wherein R' is as defined above, (c ') a group of the formula —CH2 — R7, wherein R7 represents a hydroxyl group or an ether-oxygen-bonded protecting group on a —CH2 — group, (d “ ) is a group of the general formula / —CO — N \ R b in which R _a and R _b are as defined above, (e "j a radical of the formula ^X NH-N (f") cyano, R 1 represents a hydrogen atom, a hydroxyl group, a C 1-6 alkoxy group, a C 8-14 -alkoxy group, a C _1-7 acyloxy group or a ring bonded with an ethereal oxygen atom, ap, Z 1 and q are as defined above, with a compound of formula V Z ^ 3 E-C- CO- (Cty) _n - C- X- (CH / _n - ^R 6 ^{H R} 1 (V)) wherein E represents a group of formula (+) ( ^C 6 ^H 8 ^P or a group of general formula O t (R _e O) ₂ P, wherein R _e, which may be the same or different, each independently representing a C ₆ alkyl or C ₆ _ioarylovou group and Z, R 3, R, ni, n2, X and R6 are as defined above and, when deprotected, if present, the compound of formula (I) in which R2 and R5 together represent an oxo group and Y represents a group of formula (CH = CZ2) in which Z2 is as defined above, optionally reduced to a compound of formula I wherein one of R2 and R is hydrogen and the other substituent represents a hydroxyl group and Y represents a group of formula -CH = CZ ₂ - wherein Z 2 is as hereinbefore defined, or optionally a compound of vzor216842 ce I, in which R 2 and R 5 together represent an oxo group and Y represents a group of the formula -CH = CZ ₂ -, in which Z 2 is as defined above, is converted to a compound of the formula I in which n of the substituents R 2 and R represents a hydroxyl group and the other R represents a C alkyl _group, a C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ _ ₁₀ arylovlou group, and the compound of formula I in which one of R2 and Rs represents a hydroxyl group and the other zniačí hydrogen, C ^ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ _ ₁₀ aryl group, and Y represents a group of formula -CH = CZ2-, wherein Z2 is as defined above, optionally etherified with a compound of formula I in which matches one of R2 and R represents a _Cj-C6 or galkoxyskupinu _i _{0 ares-C 1} _ ₆ alkoxy, and the other substituent is hydrogen, C ^ alkyl group, a C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C _6-10 aryl group, and Y represents a group of formula -CH = CZ ₂ - wherein Z 2 is as defined above, and / or a compound of general The compound of formula (I) wherein Y represents a general formula --CII-CZ 2 - in which Z 2 denotes a hydrogen atom or optionally hydrogenates to a compound of formula I in which Y represents a group of formula -CH ₂ -CH 2, and / or a compound of formula I in which Z 1 denotes a hydrogen atom and Y is --CH.dbd.Z @ ₂ wherein Z @ 2 is halogen, optionally dehydrohalogenates to a compound of formula I wherein Y is --C-- .dbd.C, and Z @ 1 is hydrogen or a compound of formula I wherein R 2 and R 5 together are oxo and Y is 'CH = CH 2' wherein Z 2 is hydrogen or hydrogen to the compound of formula I wherein R 2 and R 5 are together oxo and Y is the formula -CH ₂ -CH 2 or a compound of formula I in which Z represents a hydrogen atom, R2 and R together represent an oxo group, and Y represents a group of formula -CH = CZ 2 - in which Z 2 represents a halogen atom or optionally dehydrohalogenates to a compound of the formula I in which Z 1 represents a hydrogen atom, R 2 and R 5 together represent an oxo group and Y represents a group of the formula "C = C"; R 2 and R 5 together are oxo, optionally reduced to a compound of formula I wherein one of R 2 and R 5 is hydrogen and the other substituent is hydroxyl, or a compound of formula I wherein R ₂ and R 5 are together oxo optionally converting a compound of formula I wherein one of R ₂ and R represents a hydroxyl group and the other substituent represents C ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ _ ₁₀ aryl group , and a compound of formula I wherein one of R ₂ and R 5 is hydroxyl and the other is is hydrogen, C ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ _i ₀ aryl group, optionally etherified with a compound of formula I wherein one of R ₂ and R represents C ^ galkoxyskupinu or C ₆ _ _{1 ()} Ar-C galkoxyskupinu and the other substituent is hydrogen, Oj ^ alkyl, C ₂ _ ₆ alkenyl, C ₂ _6alkinylovou group or a C ₆ _ ₁₀ aryl group and / or a compound of formula I optionally converting to another compound of formula I, and / or optionally converting a compound of formula I to a salt, and / or optionally preparing a free compound of formula I from a salt thereof, and / or optionally separating the mixture of isomers into individual isomers. 2. The process of item 1 for preparing 2-oxabicyclic prostaglandins of formula I Wherein R is a carboxyl group or a group of formula —COOR5, wherein R @ ₁ is a C1-12 alkyl group, Z 1 and Z 2, which may be the same or different, represent a hydrogen atom or a halogen atom, R 1 represents a hydrogen atom, a hydroxyl group or C 1 ^ acyloxy, R 5 and R _{6 are} each hydrogen, C 1-6 alkyl, or fluoro, X represents an oxygen atom or a sulfur atom or a group of the general formula - _(CH2) m -, wherein m is zero or 1, nz is zero or an integer from 1-7, q is 0 or 2, p is an integer of 1-7, Re is (a) hydrogen or methyl, (b) a cyclo-C ₃ _ ₉ aliphatic group optionally substituted with a C! _ ₆ alkyl or C ₆ alkoxy, (c) a saturated or unsaturated heteromioniocyklický or heterobicyclic ring containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen and having 1 to 10 carbon atoms optionally substituted with at least one halogen atom, trifluoromethyl group, C ₆ alkyl or C ₁ _ ₆ alkoxy, (d) C ₆ _ ₁₀ aryl group, optionally substituted with at least one halogen atom, trifluoromethyl group, CR_ ₆ alkyl or C _ò alkoxysikupinou, and the pharmaceutically or veterinarily acceptable salt thereof, wherein the compound of formula IV E-C 2 CO -C-X- (CH) _n - 6 ^{R 11} (V) (+) in which E represents a group of formula (+> (C6H5) 3P- or a group of the formula O t (ReO) ₂ P-, in which the substituents R _{e are} individually □ [. the alkyl group and optionally deprotecting and the resulting mixture of optical isomers is separated into the individual isomers and / or optionally compounds of formula I wherein R is a group of the formula - COORs, wherein R 5 is as defined above, and / or R 1 is other than a hydroxyl group, hydrolyzed, and / or optionally compounds of formula I wherein R is a free carboxyl group and / or R 1 is a hydroxyl group, are esterified, and / or optionally compounds of formula I wherein R is is a free carboxyl group, converted in a salt by treatment with a pharmaceutically or veterinarily acceptable base. A process according to claim 1 for the preparation of 2-oxabicyclic prostaglandins of the general formula I wherein R 1, Z 1, p and q are as defined above, R "denotes a group of the formula -COORs ¹ wherein the group -OR 'represents a carboxyl protecting group, is reacted with a compound of formula V wherein R represents a free carboxyl group or a group of the formula -COORs wherein R represents Cj- ^ an alkyl group or a group of formula ^R and / or —CON \ R b in which R _a and R _b represent, individually, hydrogen, C ₆ alkyl group or a C ₆ _ ₁₀ arytovlou group, Z 1 and Z 2, which may be the same or different, represent a hydrogen atom or an atom (halogen, Ri is hydrogen, hydroxyl, C ₁ _ ₆ alkoxylated ^| Vou, _C6 _i _{0 ares-oxy,} C ioař-C ealkioxyakupinu C ^ yacyloxyskupinu or labile ether radical, one of R2 and R 'is hydrogen, C ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ _i ₀ aryl and the other of R2 and R represents a hydroxy group, C ₆ alkoxy, _C, _ _{10 ares} C2_ _6-alkoxy or labile ether radical R 5 and R 4 are each hydrogen, C _1-6 alkyl or fluoro, X represents an oxygen atom or a sulfur atom or a group of the general formula - (CH ₂ ) _m - in which m is zero or 1, n2 is zero or an integer from 1 to 7, q is 1 or 2, p is an integer from 1 to 7, R6 is (aj hydrogen, (bj methyl group, (C cyclo-C ₃ _9alifatický radical optionally substituted with at least one C ₆ alkyl or C! _ ₆ alkoxy, (d) a saturated or unsaturated heteromonocykliciký or heterobicyclic ring containing at least one heteroatom from the group consisting of nitrogen, sulfur and oxygen and having 1 to 10 carbon atoms optionally substituted with at least one halogen atom, trifluoromethyl group, C ₆ alkyl or _C! _ ₆ alkoxy, (e) C ₆ _ ₁₀ aryl group, optionally substituted at least one halogen atom, trifluoromethyl, C ^ ₆ alkyl or Cy · ^ alkoxy, and the pharmaceutically or veterinarily acceptable salt thereof, wherein the compound of formula II wherein R, p, Z 1, q, R 1, Z 2, R 5, R 4, X, and R e are as defined above, convert to a mixture of a compound of formula I wherein R 2 is hydroxyl and R 5 is hydrogen, C 1-4 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alklnylovou group or a C ₆ _ ₁₀ arylioivou group, and compounds of formula I wherein R2 is hydrogen, C ₁ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkinyl'ovou or C ₆ _ ₁₀ arylovoiu group, and R represents hydroxyl, optionally the resulting mixture partitioned, and / or optionally converting the obtained mixture of compounds of formula I to a mixture of compounds of formula I wherein R2 is C! _ ₆ alkoxy group,. C ₆ _ _{10 ares-C 6} alkoxy group or a labile ether radical and R is hydrogen with C ₁ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkinytovou group or a C ₆ _i _and aryl, and Compound formula I wherein R 2 is hydrogen, C, _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl or C ₆ · _ ₁₀ aryl group and R represents _a C alkoxy, C ^ -mar The -C 1-6 alkoxy or labile ether group, and / or the optionally obtained mixtures are separated, and / or optionally the compounds of the formula I are deetherified, saponified, esterified and / or optionally converted into salts. 4. A process according to item 1 for the preparation of 2-oxabicyclic prostaglandins of the formula I wherein R is a free carboxyl group or a group of the formula -COORe in which Re is a C1-4 alkyl group or a group of the formula R _a / —CON \ R _b in which R _a and R _b is individually hydrogen, C ₁ _ ₆ alkyl or C ₆ aryl _i _0, Ri represents hydrogen, hydroxyl sku219S42 group, a C ₆ .. ₁ ^and alk oxy, C ₆ _ _{10 ares-oxy,} C ₆ _ _{10 ares} alikoxyskupinu-C _6, C] _ ₇ acyloxy or labile ether radical, one of R2 and R is hydrogen, C ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkinyliovou group or a C ₆ _i ₀ arylovlou group and the other of R2 and R represents hydroxyl, C ^ alkoxy, C ₆ _i ₀ ar-C ₁ _ ₆ alkoxy or labile ether radical R 5 and R 4 are each hydrogen, C _1-6 alkyl, or fluorine, X represents an oxygen atom or a sulfur atom or a group of the general formula in which m represents zero or 1, Π2 denotes zero or an integer from 1 to 7, q is 1 or 2, p is an integer from 1 to 7, R6 is (a) hydrogen, (bj methyl, (c) a cyclo-G ₃ _ ₉ allfatický residue optionally substituted with a _{C l} _ ₆ alkyl, or C _ ₆ alkoxy, (dj saturated or unsaturated heteromonocyclic or heterobicyclic ring containing at least one heteroatom from the group consisting of nitrogen, sulfur and oxygen and having 1 to 10 carbon atoms optionally substituted with at least one halogen atom, trifluoirmethylovou group, a C ₆ alkyl group, or (e) C ₆ _ ₁₀ aryliovou group optionally substituted by at least a halogen atom, a trifluoromethyl group, a C _1-6 alkyl group or a C 1-6 alkoxy group, and their pharmaceutically or veterinarily acceptable salts as well as isomers, characterized in that a compound of the formula III is dehydrohalogenated in which Z 2 is halogen, preferably chlorine , bromine or iodine, and R, p, q, R 1, R 2, R 5, R 5, R 4, X, n 2 and R e are as defined above and optionally converting a compound of formula I into another compound of formula I and / or optionally separating the isomers.