CA1183839A

CA1183839A - Bicyclic prostaglandins and process for their preparation

Info

Publication number: CA1183839A
Application number: CA000329306A
Authority: CA
Inventors: Carmelo Gandolfi; Angelo Fumagalli; Alessandro Andreoni; Carlo Passarotti; Franco Faustini; Maria M. Usardi; Roberto Ceserani
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1976-12-31
Filing date: 1979-06-08
Publication date: 1985-03-12
Also published as: CA1183840A; CA1183842A

Abstract

Abstract of the Disclosure This invention relates to a compound of formula (I) (I) wherein R is a member selected from the group consisting of (a) a free or esterified carboxy group; (b) , wherein each of the R' groups, which are the same or different, is C1-C6 alkyl or phenyl; (c) -CH2OH; (d) wherein Ra and Rb are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkanoyl and phenyl; (e) a radical ; (f) ;

Z1 is hydrogen or halogen;
p is zero or an integer of 1 to 7;
q is 1 or 2;
R1 is hydrogen3 hydroxy, C1-C6 alkoxy, ar-C1-C6-alkoxy, acyloxy;
Y is a member selected from the group consisting of -CH2CH2-, , (cis) and

Description

a~

The present invention relates to 2-oxa-bicyclic prostaglandins, to a method for their preparation and to pharmaceu-tical and veterinary compositions containing them.
The compounds of the invention are 2-oxa-bicyclic prostaglandins of formula (I) ~1 H sCH-(CH2) -R

~CH2 D G

(I) ~10 A ¦
\11 1~ I
~ ~ ~3 Rl Y - ~5- (CH2)n - ~ - X ~ (CH2)n2 R6 wherein R is a member selected from the group consisting of /OR' (a) a free or esterified carboxy group; (b) -C-OR' , wherein each OR' of the R' groups, which are the same or different, is Cl-C6 alkyl / Ra or phenyl; (c) -CH20H; (d) -CON \ , wherein Ra and Rb are independently selected from -the group consisting of hydrogen, CL-C6 alkyl, C2-C6 alkanoyl and phenyl; (e) a radical N - N
\ ¦~ ; (f) -C-N; Zl is hydrogen or halogen; p is zero or NH - N
an in-tege:r of 1 to 7; R1 is hydrogen, hydroxy, Cl-C6 alkoxy, ar-CL-C6-alkoxy, acyloxy; Y is amember seLected from the group con-g . 2C~12 , C--C-, ~ C=C \ (cis) and / C=C

83193~il (trans), wherein Z2 is hydrogen or halogen; one oE R2 and R5 is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl, and the other is hydroxy, C~-C6 alkoxy, ar-Cl-C6-alkoxy or R2 and R5, taken together, form an oxo group; each of R3 and R4, which are -the same or different, may be hydroyen, Cl-C6 alkyl or fluorine or R3 and R4, taken together with the carbon atom -to which -they are linked, form the radical - C - or the :radical / C - ; each of nl and n2, which are the same or different, is zero or an integer of 1 to 6; X is a member selected from the group consist-ing of -O-, -S- and -(CH2)m~, wherein m is zero or 1; R6 is a member selected from the group consis-ting of (a') a C3~Cg cycloaliphatic radical, unsubstituted or substituted by one or more substituents selected from the group consisting of Cl-C6 alkyl and Cl-C6 alkoxy;
(b') a saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, halo-Cl-C6-alkyl, Cl-C6 alkyl and Cl-C6 alkoxy; provided that when X is -O- or -S-, R6 is not cycloalkyl.
Also the pharmaceutically or veterinarily acceptable salts as well as the optical antipodes, i.e. -the enantiomers, the racemic mixtures of the optical antipodes, the geometric isomers and -their mixtures and the m:ix-tures of the dias-tereoisomers of the compounds of formula (I) are included in the scope oE the present invention.
:[n -the :Eormulae of -this specifica-tion the broken line tllll ) ind:ica-tes tha-t a subs-ti-tuen-t bound -to -the cyclopen-tane

- 2 -`s~

ring is in the ~--configuratiorl, i.e. below the plane of -the ring, a substituent bound to the 2-oxa-bicyelic system is in the endo-eonfiguration and a substituent bound to a chain is in the S-configuration; the heavy solid line (~) indicates that a sub-stituent bound to the cyclopentane ring is in the ~-configuration, i.e. above the plane of the ring, a substituent bound to the 2-oxa-bicyclic system is in the exo-configuration and a substituent bound to a chain is in the R-configuration; the wavy line attach-ment (~) indicates that a substituent does not possess a definite stereochemical identity, i.e. that a substituent bound to the cyclopentane ring may be both in the ~- and in the ~-configuration, a substituent bound to the 2-oxa-bicyclic system may be both in the endo- or in -the exo-configuration and a substituent bound to a chain may be both in the S- and in the R-configuration.
In the compounds of the above formula (I) the hetero-eyclie ring B is cis-fused with the cyclopentane ring A and the two bonds indieated by the dotted lines (....) are both in the ~-eonfiguration with respeet to the ring A.

The side chain ~-linked to the eyclopentane ring A is in trans-configuration with respect to the ~-fused heterocyelic ring B and eonsequently it is an exo subs-tituent with respect to the 2-oxa-bicyclie system.
The earbon a-tom of the heteroeyelie ring B bearing the ~ .'1 side ehain ~ CH-(CH2)p-R bears also an hydrogen atom.
~1 When -the side ehain ~CH-(CH2)p-R is in the endo-eon~igurat:ion with respeet to the 2-oxa-bieyelie system, then said ~r~

c ~j ~

hydrogen atom is an exo-substituen-t and its absolute configuration ~ 1 is reported as ~ while when the chain ~ CH-(CH2)p-R is in the exo-configurations, then said hydrogen atom is an endo-substituent and its absolute configuration is reported as ~.
The compounds of the invention wherein -the chain ~ ; 1 vW~CH-(CH2)p-R i.s in the exo-configuration, the hydrogen atom linked to the same carbon atom of the ring B having necessarily the ~-absolute configuration, are reported as 6~H-6,9~-oxide prostanoic acid derivatives (prostaglandin numbering), while the ~,1 10 compounds wherein the chain ~CH-(CH2)p-R is in the endo-config-uration, the hydrogen atom linked to the same carbon atom of the ring B having necessarily the ~-absolute configuration, are reported as 6~H-6,9~-oxide prostanoic acid derivatives (prostaglan-din numbering). Alternatively the 6~H-6,9~-oxide prostanoic acid derivatives are reported as (2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-alkanoic acid derivatives and the 6~H-6,9~-oxide prostanoic acid derivatives as (2'-oxa-bicyclo[3.3O0]octan-3'-endo-yl~-alkanoic acid derivatives. The 6~H-6,9~-oxide prostanoic acid derivatives have a higher chromatographic mobility (i.e. a higher Rf) and a less positive rotatory power ([~]D) -than the correspond-ing 6~H-6,9~-oxide derivatives.
All the above notations refer to the natural compounds;
the d,l-compounds are mixtures containing equimolar amounts of nat-compounds which possess the above repor-ted absolute stereo-chemistry and o~ ent--compounds which are mirror-like images of 331~

the Eormers; in the en-t-compounds the stereochemical configuration is the opposite at all the asymmetric centers with respect to the configuration of the natural compounds and -the prefix ent indicates just this.
The alkyl, alkenyl, alkynyl, alkoxy, and alkanoyloxy groups are branched or straight chain groups.
Preferably R is a free, salified or esterified carboxy group. An ar~C1-C6-alkoxy group :is preferably benzyloxy. An aryl group is preferably phenyl, ~-naphthyl or ~-naphthyl. A halo-Cl-C6-alkyl group is preferably trihalo-Cl-C6-alkyl, in particular trifluoromethyl. A Cl-C6 alkyl group is preferably methyl, ethyl or propyl. A Cl-C6 alkoxy group is preferably methoxy, ethoxy or propoxy. A C2-C6 alkenyl radical is preferably vinyl. A
C2-C6 alkynyl radical is preferably ethynyl.
When R is an esterified carboxy group it is preferably a -COORC group wherein Rc is a Cl-C12 alkyl radical, in particular methyl, ethyl, propyl or heptyl, or a C2-C12 alkenyl radical, in particulax allyl.
Preferably Zl is hydrogen.
When Zl is halogen, it is preferably chlorine, bromine or iodine.
Preferably p is an integer of 1 to 3.
When Rl is acyloxy, it is preferably C2-C12 alkanoyloxy (in par-ticular C2-C6 alkanoyloxy, e.g., acetoxy, propionyloxy) or benzoyloxy~
When Z2 is halogen, it is preferably chlorine, bromine or iodine.
Preferably R3 and R4 are independently selected from .B~g the group consisting of hydrogen, Cl-C6 alkyl and Eluorine~
Preferably nl is zero or an integer of 1 to 3; n2 is preferably an integer of 1 to 3.
When R6 is a C3-Cg cycloaliphatic radical/ it is preferably a C3-Cg cycloalkyl radical, e.g. cyclopentyl, cyclo-hexyl or cycloheptyl or a C3-Cg cycloalkenyl radical, e.g. cyclo-pentenyl, cyclohexenyl or eycloheptenyl.
When R6 is a heterocyclic ring, it may be either a heteromonocyclic ring or a heterobieyclic ring and contains at least one heteroatom selected from the group consisting of N, S
and O.
Examples of preferred heteromcnocyclic radicals are tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and 2'-tetrahydrothienyl.
Exanmples of preferred heterobicyclic radicals are 2-oxa-bieyelo[3.3.0]oetyl, 2-oxa-bieyelo[3.4.0]nonyl~ 2-thia-bieyelo-[3.3.0]oetyl, 2-thiabicyelo[3.4.0]nonyl and their aromatie analogs.
Pharmaeeutieally or veterinarily aeeeptable salts of the eompounds of formula (I) are e.g. those with pharmaeeutieally and veterinarily aeeeptable bases.
Pharmaeeutieally and veterinarily aeeeptable bases are either inorganie bases sueh as, for example, alkaline hydroxides and alkaline-earth hydroxides as well as alurninium and zine hydroxides or organie bases e.g. organie amines sueh as, for example, methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, N-methyl-N-hexylamine, deeylamine, dodecylamine, allyLam:i.ne cyelopentylamine, eyclohexylamine, benzylamine, dibenzyl-~b t ~ - 6 -amine, ~-phenyl-ethylamine, ~-phenyl-ethylamine, ethylenediamine, diethylenetriamine, morpholine, piperidine, pyrrolidine, piperazine, as well as the alkyl derivatives of a latter four bases, mono-, di- and tri-ethanolamine, ethyl-diethanolamine, N-methyl-ethanol-amine, 2-amino-1-butanol, 2-amino 2--methyl-1-propanol, N-phenyl-ethanolamine, galactamine, N methyl-glucamine, N-methyl-glucosamine, ephedrine, procaine,j:dehydroabietilamine, lysine, arginine and other ~ or ~ amino acid~s;,~:
Preferred salts of the invention are those of the com-pounds of forrnula (I) wherein R is -COORd wherein Rd is a pharm-aceutically or veterinarily acceptable cation deriving from one of the above mentioned bases.
Particularly preferred compounds of -the invention are 6~H-6,9~-oxide compounds of formula (I) wherein R is a free carboxy group and R6 is C5-C7 cycloalkyl.
The prefixes nor, dinor, trinor, tetranor- etc., are used to identify the compounds of formula (I) wherein the side chain bound to the cyclopentane ring A is one, two, three, four, etc. carbon atoms shorter than the analogous chain in the natural prostaglandins.
Specific examples of preferred compounds of the invention are the following:
13t-6~H-6,9~ oxide-11~,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl--20,19,18-trinor-prost-13-enoic acid and the single 16(S)- and 16(R)-fluoro isomer;
13t--6~1--6,9~-ox.ide-11~,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-prosk-13-enoic acid;
13-6~-6,9~-oxide-11~,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-~1 ''`' ALJt 7 prost-13-ynoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-17-(2'-tetrahydrofuryl)-20, 19,18-trinor-prost-13-enoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-17-(2'-tetrahydrothienyl)-20,19,18 -trinor-prost ~3-enoic acld;
as well as the 5-bromo, thë` 5 1odo, the 5-chloro analogs of all the 6~H-6,9~-oxide derivatives above listed, as well as the 15R-epimers, the 15-oxo-derivatives and the 6~H-diastereo-isomers of all the compounds mentioned above.
The compounds of the inven-tion are prepared by a process comprising:
(a) halocyclizing a compound of formula (II) O~ CH2-D-(CH2)p-R

(II) ~ ~ ~ R~2 ~3 R'l Y - C - (CH2)n - ~ - X ~ (CH2)n2 6 '5 R4 wherein p, Y, nl, n2, R3, R4, X and R6 are as defined above, D

is cis- or trans- -CH=CH-, R" is (a") a free or esterified carboxy /OR' group; (b") a group -C-OR' , wherein each of the R' groups is OR' as defined above (c") the group -CH2-R7, wherein R7 is hydroxy or a ~nown protecting group bound to the -CH2- group by an /Ra ethereal oxygen atom; (d") -CON ~ wherein Ra and Rb are as 't ~

N N
defined above; (e"~ a radicaLi of~f~r.~la -C ¦¦ ; ( f~) -C-N;
NH - N
R'l is hydroyen, hydroxy, C1-C6 alkoxy, ar-C1-C6-alkoxy, acyloxy or a known protecting group bound to the ring by an ethereal oxygen atom; one of R'2 and R'5 is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and the other is hydroxy, Cl-C6 alkoxy, ar~-Cl-C6-alkoxy or a known protecting group bound -to the chain by an ethereal oxygen atom, or R'2 and R'5, taken toge-ther, form an oxo group, so obtaining, after the removal of the known protecting groups, if present, a compound of formula (I) wherein Zl is halogen and, if necessary, deetherifying and/or, if desired, dehalogenating the obtained compound to give a compound of formula (I) wherein Zl is hydrogen; or (b) reducing a compound of formula (III) H ~CH-(CH2)p~R
~, ~ B c r ~t (III) ~ 3 Rl Y - C ~ (CH2)n ~ C~ - X (CH2)n2 6 R5 R~

wherein Q is halogen or a group ~ Hg( )Z( ), wherein Z( ) is 0~1( ) or the anionic residue o:E an acid, R, p, Rl, Y, R2, R5, R3, R~l, nL, n2, ~ and R6 are as defined above, so obtaining a compound _ g_ ~$113~
...,. ~ . . , of formula (I) wherein Zl is hydrogen; and, if desired, reducing a compound of formula (I) wherein R2 and R5, taken together, form an oxo group and Y is -CH=CZ2- wherein Z2 is as defined above, to give a compound of for~mula.(I) wherein one of R2 and R5 is hydrogen and the other.is hydro~y and Y is -CH=CZ2-, wherein Z2 is as defined above, or, if desired, converting a compound of formula (I) wherein R2 and R5, taken together, form an oxo group and Y is -CH=CZ2- wherein Z2 is as defined above, into a compound of formula (I) wheréin one of R2 and R5 is hydroxy and the other is Cl-C6 alkyl, C2-C6 alkenyl, C2~C6 alkynyl or aryl and, if desired, etherifying a compound of formula (I) wherein one of R2 and R5 is hydroxy and the other is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and Y is -CH=CZ2- wherein Z2 is as defined above, to give a compound of formula (I) wherein one of R2 and R5 is Cl-C6 alkoxy or ar-Cl-C6-alkoxy and the o-ther is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and Y is -CH=CZ2- wherein Z2 is as defined above, and/or, if desired, hydrogenating a compound of formula (I) wherein Y is -CH=CZ2-wherein Z2 is hydrogen, to give a compound of formula (I) wherein Y is -CH2CEI2- or, if desired, dehydrohalogenating a compound of formula (I) wherein Zl is hydrogen and Y is -CH=CZ2- wherein Z2 is halogen, ~,q ~
,~ !i - 1 0 ~,~,.8 ~e,~ , _ .
to give a compound of formula ~I~ wherein Y is -C~C- and Zl is hydrogen or~
if desired, hydrogenating a compound of formula (I) wherein R2 and R5~ taken together, form an oxo group and Y is -CH=CZ2- wherein Z2 is hydrogen~ to give a compound of formula ~I) wherein R2 and R5, taken together, form an oxo group and Y is -CH2Cll2- or, i desired, dehydrohalogenating a compound of formula ~I) wherein Zl is hydrogen, R2 and R~, taken together, form an oxo group, and Y is -CH=CZ2- wherein Z2 is halogen, to give a compound of formula (I~ wherein Zl is hydrogen, R2 and R5, taken together, form an oxo group and Y is -C-C- and, if desired, reducing a compound of formula ~I) wherein R2 and R5, taken together, form an oxo group, to give a compound of formula ~I) wherein one of R2 and R5 is hydrogen and the other is hydroxy, or, if desired, converting a compound of formula ~I) wherein R2 and R5, taken toge-ther, form an oxo group, into a compound of formula ~I) wherein one of R2 and R5 is hydroxy and ~he other is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and, if desired, etherifying a compound of formula ~I) wherein one of R2 and R5 is hydroxy and the other is hydrogen, Cl-C6 alkyl, C2-C6 alXenyl, C2-C6 alkynyl or ary~l, to give a compound of formula ~I) wherein one of R2 and R5 is Cl-C6 alkoxy or ar-Cl-C6~alkoxy and the other is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C -C alkynyl or aryl;
and/or, if desired, converting a compound of formula ~I) into another compound o$ ~ormula (I) and/or, i~ desired, salifying a compound of formula ~I) and/orS
i$ desired, obtaining a $ree compound of formula (I) from a salt thereof and~or, i$ desired, separating a mixture of isomers into the single isomers.
In the optional steps o$ the above processes when only one or a few substituents are specifically mentioned for a compound, it is understood that the other substituents have all the meanings previously indicated for formu-la ~

r~ ~

3~

The knohn protecting groups, i.e., ether groups, are convertible to hydroxy groups under mild reaction conditions, e.g., acid hydrolysis.
Examples are acetal ethers, enol ethers and silyl ethers.
The preferred groups are ~CH3)3-SiO- , ~ OAlk ~ O- , O ~ , ~ Si-O-wherein W is -O- or -CH~- and Alk is a lower alkyl group.
When in the compound of formula ~III) Q represents a group ~Hg~ )Z~ ), wherein zt ) is the anionic residue of an acid, Z( ) is preferab-ly selected ~rom the group consisting of Cl( ), Br( ), I( ), Rg-COO~ ), wherein R8 is an optionally halo-substituted Cl-C12 alkyl group (preferably Cl-C6 alkyl or trifluoromethyl) and Rg~ COO( ), wherein R9 is e.g., hydrogen, Cl-C6 alkyl, halogen, e.g., bromine, or trifluoromethyl.
Preferably Z~ ) is Cl~ ), Br~ ), CH3COO( ), ~F3COO( ) or ~ COO~~), The halocycli~ation of a compound o~ ~ormula (II) may be performed by reaction with either a stoichiometric amount or a small excess of a halogen-ating agent in an inert solvent, in either the presence or in absence o a base.
PreEer~ed halogenating agents, are, e.g., iodine, bromine~ chlorine, ~3 ~

3i3~9`

bromodioxane, bromopyridine, Br2.pyridine.HBr, KI3, pyrrolidone-hydrotribro-mide, an N-haloamide such as N-chloro-succinimide, N-bromo-succinimide, N-iodo-succinimide, a cupric halide such as CuC12 or CuBr2, a mixed halide such as ICI or IBr, as well as a mixture of an alkaline chloride wi~h an alkaline chlorate, a mixture of an alkaline hromide with an alkaline bromate or a mix-ture of an alkaline iodide with an alkaline bromate.
Suitable solvents are, for example, halogenated hydrocarbons such as CHC13, CCl~, CH2C12; aliphatic hydrocarbons such as n-hexane, n-heptane, cyc-loaliphatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, pyridine, cyclic or linear ethers, e.g., dioxane, tetrahydro-furan, diethylether, climethoxyethane; as well as mixtures thereof.
Preferred solvents are halogenated hydrocarbons, e.g. CH2C12, since both the compound of formula ~II) and the halogenating agent are usually solu-hle in these solvents.
A stoichiometric amount of a base is necessary when a hydrohalic acid is formed during the halocyclization reaction.
Such a base may be an inorganic base, e.g., an alkaline or an alkaline-earth oxide, carbonate or bicarbonate, e.g., CaO, CaCO3 and K2CO3, NaHCO3, Na2CO3; an organic base such as a tertiary amine, e.g., triethylamine;
or an aromatic base, e.g., pyridine or an alkyl-substituted pyridine; or an anionic ion-exchange resin.
The halocyclization reaction is preferably carried out at tempera-tures ranging from about -70C to about 100C; preferably the reaction is performed at room temperature.
The reaction times range from few minutes to several days, but usu-ally do not exceed two hours and often a few minutes are sufficient to com-plete the reaction.
~Yhen other unsaturated bonds are present in the compound of formula ~CI) hesides the double bond contained in the substituent D, those ~msaturatPd -bonds may add halogen during the halocyclization reaction.
The added halogen may be easily removed to reobtain -the original unsaturations, by trea-ting the reaction product with an alkaline or alkaline-earth iodide in a suitable solvent such as, eOg., acetone at temperatures ranging from room temperature to reflux temperature but preferably at room temperature. Reac-tion time may range from about 2 to 3 hours to about 2 to 3 days.
The removal of the known protecting groups bound to the ring or to the chain by an ethereal oxygen atom is, whenever required, performed under conditions of mild acid hydrolysis, for example with a mono- or poly-carboxylic acid such as formic, acetic, oxalic, citric and tartaric acid, and in a solvent, which may be water, acetone, tetrahydrofuran, dimethoxyethane or a lower aliphatic alcohol, or with a sulphonic acid, e.g., p-toluenesul-phonic acid in a solvent such as a lower aliphatic alcohol, dry methanol or dry ethanol, for example, or with a polystyrene-sulphonic resin.
For example, 0.1 to 0~25 N poly-carboxylic acid (e.g., oxalic or citric acid) is used in the presence of a convenient low-boiling co-solvent which is miscible with water and which can be easilyremoved ln vacuo at the end of the reaction.
All the cyclization reactions described in this specifi-cation such as e.g. the hereabove described halocyclization of a compound of formula (II) -to give a compound of formula (I) where-in Zl is halogen and the herebelow described cyclization of a com-pound oE formula (II) to give a compound of formula (III) wherein Q is .~Hg( )Z( ) a~e i.dentical reactions as to -their mechanism and the number of the isomers contained in -the reaction mixture is the same for all the above cyclizations. Thus ~or example the above halocyclization reaction of a compound of formula (II) can give to a mixture of four components, i.e. compounds of formula (I) wherein Zl is halogen, consisting in a couple of diastereo-isomers having the side chain v~ ~CH-(CH2)p-R in the exo-configura-tion and differing each other for the S or R configuration of thehalogen Zl and a couple of diastereoisomers having the side chain V~ H-(CH2)p~R in the endo-configuration and differing each o-ther for the S or R configuration of the halogen Zl While the chromatographic mobility (Rf) of the endo-isomer is clearly different from the chromatographic mobility oE
the exo-isomer, the difference of Rf between two endo- (or exo-) isomers differing each other only for the S or R configuration of the Zl substituent, is very small.
The couple of diastereoisomers wherein the chain CH-(CH2)p-R is in the exo-configuration may be separated from Zl the couple of diastereoisomers wherein said chain is in the endo-configuration by fractional crystallization e.g. from diethylether, but preferably by thin layer preparative chromatography, by column chromatography or by high speed liquid chromatography.
The separation by thin layer preparative chromatography or by column chromatography is preferably carried out on a support oE silica gel or magnesium silicate with methylene chloride, di-ethylether, lsopropylether, ethylacetate, benzene, me-thyl acetate, cyclohexane or their mixtures as elution so]ven-ts.

.~ - 15 -The reductive dehalogenation of a compound of formula (I) wherein Zl is halogen, to give a compound of formula (I) wherein Zl is hydrogen, is performed by reduction, e.g., with chromous acetate or a hydride such as tri(n-butyl)tin hydricle, or by catalytic hydrogenation.
When it is desired -to obtain a compound of formula (I) wherein Y is -C~C- or CH=CZ2- wherein Z2 is as defined above, the dehalogenation is carried out only by reduction, e.g. with tri(n-butyl)tin hydride or chromous .. 1~

acetate.
W~en it is desired to obtain a compound of formula (I) wherein R2 and R5 ta~en together form an oxo group, by the dehalogenation of the compound of formula (I) wherein Zl is halogen, the :reaction time should not exceed half an hour.
When the reductive dehalogena-ion is carried out with chromous ace-tate, this reagent is added, with stirring, to a cooled solution of the com-pound of formula ~I) wherein Zl is halogen, in a mixture of ethanol and aque-ous sodium or potassium hydroxide under an atmosphere of nitrogen. The re-action mixture is then stirred one to three days at room temperature, accord-ing to the method described in J. Am. Chem. Soc. 76, 5499 (1954).
~hen the dehalogenation is carried out with tri(n-butyl)tin hydride, about 1.2 equivalents of the reducing agent are used for each equivalent of t~e compound of formula ~I) wherein Zl is halogen. Suitable solvents for the reaction are aromatic hydrocarbons such as benzene or toluene and the tempera-tures preferably are between room temperature and about 70 C.
Preferably the reaction is carried out at about 55C in benzene and lasts about 12 hours.
The catalytic hydrogenation of a compound of formula ~I) wherein Z
is halogen to give a compound of formula ~I) wherein Zl is hydrogen and Y is -CH2CH2- may be performed either at room temperature or by heating this com-pound, e.g., at 30 - 60C either at atmospheric pressure or under pressure, e.g., at 1.1 - 2 atm. in a solvent such as, e.g., a lower aliphatic alcohol, tetrahydrofuran, dioxane, benzene, toluene in the presence of a catalyst such as palladium or platinum on charcoal or CaC03 and optionally in the presence of an ammonium salt, e g., ammonium acetate or propionate.
The reductive dehalogenation converts a compo~md of formula ~I) wherein Zl is halogen into a compound of formula ~I) wherein Zl is hydrogen - ~,87/

`\

and thereore during the dehalogenation the carbon atom carrying the Zl sub-stituent loses its asymmetry.
The number of the possible diastereoisomers consequently contained in the dehalogenation reaction mixture is lower than the number of diastereo-isomers contained in the halocyclization reaction mixture.
When the reductive dehalogenation is carried out directly on the mixture of four diastereoisomers obtained from the halocyclization process J
a mixture of two only diastereoisomers of formula ~I) wherein Zl is hydrogen is obtainad, differing each other for the exo- or endo-configuration of the side chain ~CH2-(CH2)p-R.
~ hen the reductive dehalogenation is carried out on a single couple of diastereoisomers of formula ~I) having the side chain ~CH-(CH2) -R, wherein Zl is halogen, in the exo- or in the endo-configuration and differing each other for the S or R configuration of Zl~ then only one isomer of formu-la (I) wherein Zl is hydrogen is obtained wherein the side chain W--CH2-~CH2) -R is in the exo- or in the endo-configuration.
If a mixture of the above diastereoisomers is obtained the single diastereoisomers may be easily separated by fractional crystalli~ation or by column chromatography as described above for the separation of the diastereo-isomers wherein Zl is halogen.
The reduction of the compound of formula ~III) may be carried outby treatment with mixed hydrides such as alkaline, e.g., sodium, potassium or lithium, borohydrides, with alkaline-earth, e.g., calcium or magnesium, boro-hydrides in an inert solvent, preferably a solvent miscible ~ith water, such as tetrahydrofuran, dimethoxyethane or lower aliphatic alcohols, e.g. methanol or ethanol; or with tri(n-butyl)tin hydride in benzene or toluene, preferably benzen0; o~ also by treatment with hydrazine hydrate in a lower aliphatic ~:3 ~

alcohol, e.g., methanol or ethanol as solvent, at temperatures varying from room temperature to the reflux temperature of the solvent used.
When it is desired to obtain compounds of formula (I) wherein Zl is hydrogen and R2 and R5 taken together form an oxo group, the reduction of the compound of formula (III) is preferably carried out with tri(n-butyl)tin hydride for a short reaction time, preferably a time varying from about 5 minutes to about half an hour.
During the above reduction of a compound of formula (III) the carbon atom carrying the Q substituent loses its asymmetry and therefore the number of the possible diastereoisomers contained in the reaction mixture at the end of the reduction pro-cess is half the number of the diastereoisomers contained in the starting material, analogously to what above reported with regards to dehalogenation of a compound of formula (I) wherein Zl is halogen.
The compound of formula (I) wherein Y is trans-CH=CZ2-wherein Z2 is as defined above, may be separated from the mixture by crystallization with a suitable solvent, while the compound of formula (I) wherein Y is cis-CH=CZ2- wherein Z2 is as defined above, may be obtained by concentration of the mother liquor and subsequent chromatographic separation of the residue, either by column or preparative TLC chromatography using silica gel or mag-nesium silicate as support and e.g. methylene chloride, diethyl-ether, isopropylether, ethylacetate, benzene, cyclohexane or their mixtures as elution solvents.
The removal of the protecting groups, if present, may - 19 _ 1.. ~1 be performed by mild acid hydrolysis as described above for the compounds obtained by the halocyclization and the reduction pro-cesses.
~ ither the optional reduction of a compound of formula (I) wherein R2 and R5, taken together form an oxo group, and Y
is -CH=CZ2-, wherein Z2 is as defined above, to give a compound of formula (I) wherein Y is -CH=CZ2-, wherein 22 is as defined above and wherei.n one of R2 and R5 is hydrogen and the other is hydroxy or the optional conversion of a compound of formula (I) wherein R2 and R5, taken together, form an oxo group and Y is -CH=CZ2- wherein Z2 is as defined above, into a compound of formula (I) wherein Y is ~''''`) -C~=CZ2-, wherein Z2 is as defined above, and wherein one of R2 and R5 is hydroxy and the other is Cl-C6 alkyl, C2-C6 alkenyl, C2--C6 alkynyl or aryl must be regarded as different applications of one only reaction which is a 1.2 polar addition to the carbonyl group.
The optional reductlon of an obtained compound of formula ~I) where-in R2 and R5 taken together form an oxo group, and Y is -CH=CZ2-, wheEein Z2 is as defined above, to give ~ compound of formula (I) wherein Y is -CH=CZ2-, wherein Z2 is as defined above, and wherein one of R2 and R5 is hydrogen and the other is hydroxy, is preferably carried ou~ with alkaline or alkaline-earth metal borohydrides, preferably sodium, lithium, calcium, magnesium or zinc borohydride, using ~rom 0.5 to 6 moles of the reducing agent for each mole of the compound of formula (I). The reduction may be performed either in aqueous or anhydrous inert solvents such as linear or cyclic ethers, e.g., ethyl ether, tetrahydrofuran, dimethoxyethane, dioxane or aliphatic or aromatic hydrocarbons, e.g., n-heptane or benzene, or halogenated hydrocarbons, e.g.
methylene dichloride, or hydroxylated solvents, e.g., ethyl, methyl or iso-propyl alcohol, or mixturcs of these solvents.
The reac~ion temperature may vary between approximately -40C and the boiling point of the solvent used, but the preferred temperature ranges from about ~20C to about 25C.
OH
This reduction leads to a mixture of the two epimeric S ~-C-~ ) ~ OH
and R ~-C-" ) alcohols from which the single epimers can be separated, if desired, by ~ractional cr~rstallization, e.g. with diethylether, n-hexane, n-heptane, cyclohexane but preferably by chromatography either on silica gel or magnesium silicate columns or preparative TLC chromatography with, for example, silica gel, eluting, e.g., ~ith CH2C12, ethyl ether, isopropyl ether, ethyl acetate, methyl acetate, benzene, cyclohexane or mix-tures of these, or by high specd liquid chromatography.

The optional conversion of a compound of formula (I) wherein R2 and R5 taken together form an oxo group and Y is -CH=CZ~-, wherein Z2 is as de--fined above, into a compo~ld of formula ~I) wherein one of R2 and R5 is hy-droxy and the other is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and Y is -CH=CZ2- wherein Z2 is as defined above, may be carried out by treatment with a Grignard reagent of formula R"'-Mgllal, wherein Hal is halogen, prefer-ably bromine or iodine and R" ' is Cl-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl or aryl, preferably methyl, vinyl, ethynyl, phenyl.
The Grignard reaction is carried out with 1.05 to 2 moles of the magnesium derivative for each mole of ketone, operating in anhydrous solvents which may be linear or cyclic ethers, e.g., ethyl ether, tetrahydrofuran, di-oxane, dimethoxyathane or aliphatic or aromatic hydrocarbons, e.g., n-heptane, n-hexane, benzene, toluene, at temperatures varying from approximately -70C
to the boiling point of the solvent used. The preferred temperatures range between -60 C and 10 C.
The optional etherification of a compound of formula ~I) wherein Y
is -CH=CZ2-, wherein Z2 is as defined above, and one of R2 and R5 is hydroxy and the other is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl to give a compound of formula ~I) wherein Y is -CH=CZ2-, wherein Z2 is as de-fined above, and one of R2 and R5 is Cl-C6 alkoxy or aralkoxy and the other is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl, may be carried out, for example, by reaction with an optionally aryl-substituted diazoalkane in the presence of a catalyst such as fluoboric acidor borontri1uoride and in an organic solvent such as dichloromethane or by reaction of the free or sali-fied hydroxy group with an a]kyl or aralkyl halide in presence of a base such as silver oxide and in a solvent such as dlmethylsulphoxide or dimethylform-amide.
The optional hydrogenation of a compound of formula (I) wherein Y is -Cl[=CZ2-, wherein Z2 is hydrogen, to give a compound of formula (I) wherein Y

..~

~3~

is -CH2-CH2- is carried out, e.g., catalytically, preferably in an alcoholic solvent, in the presence of platinum or palladium on charcoal as catalyst at temperatures varying from about -40C to the reflux temperature of the solvent.
When it is desired to obtain co~pounds of formula (I) wherein Zl is halogen and Y is CH2-CH2- the hydrogenation is preferably carried out at tem-peratures ranging from about -40C to about -20C.
The optional dehydrohalogenation of a compound of formula (I) where-in Zl is hydrogen, and Y is -CH=CZ2-, whercin Z2 is halogen, so as to obtain the corresponding compounds of formula (I) wherein Zl is hydrogen and Y is -C-C-J may be carried out using a dehydrohalogenatiilg agent preferably selected from the group consisting of a dimethylsulfinylcarbanion of formula CH3SOCH2( ), diazabicycloundecene, diazabicyclononene, the amide or the alkoxide of an alkaline metal. From 1 to 5, and preferably from 1.5 to 1.8, molar equivalents of the basic dehydrohalogenating agent may be employed for each mole of the compound of formula (I) wherein Y is -CH=CZ2-, wherein Z2 is halogen.
This dehydrohalogenation process is preferably carried out in the absence of atmospheric oxygen, in an inert solvent such as dimethylsulphox~de, dimethylformamide, hexamethylphosphoramide; a linear or cyclic ether, e.g., dimethoxyethane, tetrahydrofuran, dioxane; an aromatic hydrocarbon, e.g., benzeneJ toluene; or liquid ammonia or a mixture of these solvents.
The reaction temperature may vary between the liquefaction point of the ammonia and approximately 100C, but the preferred temperature is room temperature.
Depending on the solvent, the reaction temperature and the molar ratio used between the reagent and the compound, the reaction time may vary from a ew minutes to several hours.
Thc optional reduction of a compound oE formula (I) wherein R2 and R5 taken together forrn an oxo group and Y is -CH2-CH2- or -C_C- to give a colllpound Oe formula (I) wherein one of R2 and R5 is hydrogen and the other is ~L8~

hydroxy and Y is -C112-C~12- or -C-C- may be carried out as described above for the analogous reduction of a compound of formula (I) wherein R2 and R5 taken ~ogether form an oxo group and Y is -CH-CZ2-, wherein Z2 is as defined above.
The optional conversion of a compound of formula (I) wherein R2 and R5 taken together form an oxo group and Y is -CH2-CH2 or -C-C- into a compound of formula (I) wherein one of R2 and R5 is hydroxy and the other is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl may be effected under the same reaction conditions described above for th~e analogous conversion of the com-poun~s of formula (I) wherein Y is -CH=CZ2-, wherein Z2 is as defined above.
Also the optional etherification of a compound of formula ~I) where-in one of R2 and R5 is hydroxy and the other is hydrogen or Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and Y is -CH2-CH2- or -C_C- may be carried out as described above for the etherification of a compound of formula (I) wherein one of R2 and R5 is hydroxy and the other is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, Cl-C6 alkynyl or aryl and Y is -CH=CZ2-, wherein Z2 is as defined above.
The optional conversion of a compound of formula (I) into another compound of formula (I) as well as the salification of a compound of formula ~I) J the preparation of a ree compound from a salt and the separation of ~he isomers from a mixture may be carried out by known methods.
Thus, for example, a compound of formula (I) wherein one of R2 and R5 is hydrogen and the other is hydroxy may be converted into a compound of formula (I) wherein R2 and R5 taken together form an oxo group by oxidation.
The oxidation mc~ be carried out by treatment with 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 varying between several hours and one or more days.
~lternat:iveLy, the oxidation may be carried out by reaction with a 1.1 - 1.2 molar equivalent of dichlorodicyanobenzoquinone (DDQ) in an inert solvellt such as dioxane, tetrahydrofuran, benzene or a mixture of these at 1,~ o?~

temperatures ranging from about 40C to the boiling point of the solvent.
A compound of formula (I) wherein R i5 a free carboxy group may be converted into a compound of formula (I) wherein R is an esterified carboxy group, e.g., a Cl-C12 carbalkoxy group) by known methods, e.g., by reaction with the appro-priate alcohol, e.g., a Cl-C12 alipha~ic alcohol, in the presence of an acid catalyst, e.g., p-toluenesulphonic acid and also by treatment with a diazo-alkane.
The optional conversion of a compound of formula (I) wherein Rl is hydroxy into a compound of formula (I) whe-rein Rl is acyloxy~ if desired, may be performed in a conventional manner, e.g., by treatment with an anhydride or a halide, such as a chloride of the appropriate carboxylic acid in the pres-ence of a base.
When one o~ R2 and R5 is hydroxy, this hydroxy group may be protect-ed before the acylation by one of the known protecting group mentioned above.
The optional conversion of a compound of formula (I) wherein R is an esteriEied carboxy group into a compound of formula (I) wherein R is a free carboxy group, if desired, may be carried out by the usual methods of saponi-fication, e.g., by treatment with an alkaline or alkaline-earth hydroxide in aqueous or alcoholic aqueous solution followed by acidification.
In a compound of formula (I) wherein R is an esterified carboxy and Rl is acyloxy, the optional saponification may be carried out selectively with respect to the esterified carboxy, if desired, by transesterification, i.e., by reacting it in the same alcohol which esterifies the carboxy groups and in the presence of a base such as an alkaline or alkaline-earth alkoxide or K2C03.
The optional conversion of a compound of formula (I) wherein Rl is hydroxy into a compow~d o formula (I) wherein Rl is Cl-C6 alkoxy or aralkoxy, iE dosired, may be carried out by the usual methods of the etherification, for cxmnple as described above for the etherification of a compound of formula ~I) wherein one o R2 and R5 is hydroxy ! .L~

33~

When it is desired to etherify only one of several hydroxyl func-tions present it is use~ul to protect before the etherification the hydroxy groups which it is desired to not etheriy, e.g., with the known protecting groups above mentioned, then removing these at the end of the etherification by the procedures already described above.
The optional conversion of a compound of formula ~I) wherein R is a free or esterified carboxygroup into a compound of formula (I) wherein R is -CH2-OH, if desired, may be carried out, e.g., by reducing the ester with LiAlH4 in ethyl ether or tetrahydrofuran at reflux temperature.
The optional conversion of a compound of formula (I) wherein R is a free carboxy group into a compound of formula (I) wherein R is -CO-N ~Ra , wherein Ra and Rb are as defined above, may be performed by treatment with an amine of formula NHRaRb in the presence of a condensing agent, e.g., a carbodi-imide such as dicyclohexylcarbodiimide, and the optional conversion of a com-pound of formula (I) wherein R is an esterified carboxy into a compound of formula (I) wherein R is -CON~ Ra may be effected by treatment with an amine of formula NHRaRb in a suitable organic solvent at reflux temperature for - 3 hours.
The optional conversion of a compound of formula (I) wherein R is a free carboxy group into a compound of formula (I) wherein R is a radical N - N
-C~ 11 , may be carried out by converting the carboxy group into the cor-NH_ N
responding halide, preferably chloride, e.g., by reaction with thionyl chlo-ride or oxaly~l chloride in dioxane or dichloroethane at reflux temperature, then reacting the halide, e.g., with ammoniaJ to give the amide, dehydrating the amide to nitrileJ e.g. J with p-toluenesulphonylchloride in pyridine at ~ppro~imately 90C ~ 100CJ and ~inally reacting the nitrile with sodium o~

azide and ammonium chloride in dimethylformamide at a temperature varying between the room temperature and 100C. But preferably the hereabove re-por~ed conversions of the carboxy group into -CN or -C~ ~¦ are performed ~NH -N
on the starting materials i.e. for example on the compounds of formula and (VI).
The optional salification of a compound of formula ~I) may be per-formed in a conventional manner.
Also the optional separation of the optically active compounds from a racemic mixture as well as the optional separation of the diastereoisomers or of the geometrical isomers from their mixtures may be effected by conven-tional methods.
The compounds of formula (II) are already known compounds and may be prepared, e.g., as described by E.J. Corey et al, Ann. of New York Acad.
of Sciences, 180, 24 (1971), by J. Fried et al, J. Med. Chem. 16, 429 (1973), G.L. Bundy et al, Amer. Chem. Soc. 94, 2124 (1972), by Gandolfi et al, Il Far-mdoc Ed. Sc. 2 , 1125 (1972), in the United States Patent Number 3,935,254, Derwent Farmdoc 20717 X, in the German Offenlegungsschrift Number 26 11 788 (Derwent Farmdoc 61615X), in the German Offenlegungsschrift Number 26 10 503 ~Derwent Farmdoc 59715X), in the German Offenlegungsschrift 2Q Number 26 27 ~22 (Derwent Farmdoc 85028X), in the United States Patent Number 3,706,789, in the United States Patent Number 3,728,382, in the United States Patent Number 3,903,131, in the United States Patent Number 3,962,293, in the llnited States Patent Number 3,969,380, Derwent Farmdoc 73279U, Derwent Farmdoc 31279T, in the Unite~ States Patent Number 3,890,372, in the United States Number 3,636,120, in the United States Patent Number 3,883,513, in the United States Patent No. 3,932,389, in the United States Patent Number 3,932,479, Derwent ~armdoc 195941~, Derwent Farmdoc 54179U and in the British Patent Num-~er 1,483,880.

~8~

The compound of formula (III) wherein Q is halogen may be obtained by the same reaction described above for the synthesis of the compound of formula (I) wherein Zl is halogen.
The compound of formula (III) wherein Q is a group ~ v~Hg( )Z( ) wherein Z( ) is as defined above may be prepared by cyclizing a compound of formula (II) in the presence of a source of Hg( ) ions.
Suitable sources of Hg( ) ions may be, e.g., either compounds of formula Hg(z)2 or compounds of formula Hg(OH)Z.
The above cyclization may be performed, e.g., using 1.01 to 1.5, preferably 1.2, equivalents of the mercuric compound for each mole of the compound of formula (II), in an organic solvent miscible with water, e.g., tetrahydrofuran, methanol, ethanol or in a mixture of the organic solvent and water.
The reaction temperature may vary between ~C and the boiling point of the reaction mixture and the reaction time ranges from about 5 minutes to about 2 hours. The cyclization gives a mixture of four diastereoisomers of formula (III) differing from each other for the configuration (endo or exo) of the side chain linked to the heterocyclic ring B or for the configuration (S or R) of the Q substituent.
The separation of the diastereoisomers from their mix-ture, which may be carried out according to known methods, e.g., those already described above, may be efEected at -this point or, iE deslred, aEter the reduction of the compound of formula (III).
The compounds of the invention can be used, in general, Eor the same therapeuticindications as the natural prostaglandins ;n either h~man or veterinary medicine.

In particular, those having an acetylene bond in the 13,14-position instead of an ethylene and those with mono and di-substituents such as methyl and fluorine groups have the advantages of superior resistance to degradation by the 15-PG-dehydrogenase enzymes, which quickly inactivate natural compounds, and, of a more selective therapeutic action, as indicated below.
In order to obtain a preliminary biological profile, i.e., to assess whether the compounds of the invention possess PG-like or thromboxane (TXA2)- like or PGX-like activity, they were at first tested by a superfusion cascade technique by the method of Piper and Vane, Nature 2~3, 29 (1969).
In order to increase the sensitivity of the bioassay, a mixture of antagonists [Gilmore et al. Nature 218, 1135 (1968)]
is added to the Krebs-Henseleit and indomethacin (4 ~g/ml) is also added to prevent the endogenous biosynthesis of prostaglandins~

..~...~p l~, - 29 -Contraction of rat colon (RC), rat stomach strip (RSS) and bovine coronary artery ~BCA)~ and relaxation of rabbit mesentery artery ~RbMA) are assumed to represent prostaglandin-like activity. TXA2-like activity is in-dicated when RbMA is contracted and must be confirmed by in vitro platelet pro-aggregation activity, since PGF2 -like compounds also contract ~bMA, as opposed to PGE. Finally, PGX-like activity is indicated by the relaxation of BCA, and is confirmed by in vitro platelet anti-aggrega~ion activity.
Synthe~ic PGE2 and both the biosynthetic TXA2 ,md PGX are utilized as standard compolmds.
They are active at a range of concentrations from 1 - 5 ~g/ml.
The compounds of the invention were dissolved in a few drops of sthanol just before testing; the s~ock solution was prepared in 0.1 M tris-buffer, pH 9.0, (1 mg/ml) and diluted with Krebs-Henseleit to the required concentration.
The compound 13-trans-11~,15S-dihydroxy-6~H-6,9~-oxide-prostenoic acid was taken as the parent compound and is called 6~H-6,9~-oxide; the di-astereoisomer 13-trans~ ,15S-dihydroxy-6aH-6,9~-oxide-prostenoic acid is then referred to as 6~H-6,9~-oxide. The chemical names of the other tested compounds are also referred to those of the parent compounds. The compounds ~ere tested at concentrations up to 100 mg/ml.
The results obtained showed that, in general, the 6~H-diastereo-isomers, e.g., the compounds 6~H-6,9a-oxide, dl-6~H-5-bromo-6,9~-oxide, 6~H-6,9~-oxide-16-_-CF3-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-_-chloro-phenoxy-~-tetranor possess BCA-relaxing activity and therefore have PGX-like activity.
Among the 6~H-derivatives, only the compound dl-6~11-6,9~-oxide-16-~, 3~D

methyl-16-butoxy-~-tetranor showed a BCA-contracting activity. The 6~H-derivatives, e.g. the compound 6~H-6,9~-oxide, dl-6~H-5-~romo-6,9~-oxide, dl-6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor, 6~H-6,9~-oxide-16-m-CF3-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-_-chloro-phenoxy-~-tetranor also showed BCA-contracting activity.
In general, the exo-configuration is associated with BCA contrac-tion.
Furthermore, the compounds of the invention have hypotensive activi-ty in mammals as does the natural compound PGX. However, as compared to PGX, they have the great advantage of a higher chemical stability and can be used in pharmaceutical formulations.
The hypotensive activity was demonstrated ~y the limb perfusion test.
During the perfusion of the rat's left leg, through the left femoral artery, with a constant perfusion pressure, both the 6~H- and 6~H-6,9~-oxide compounds caused a lowering of the values of the mean perfusion pressure at all the doses, over the range from 0.05 - 1 ~g (to -42,5% for 6~H and -32%
for 6~H).
Moreover, the systemic pressure both systolic and diastolic, was depressed from 0.05 ~g/kg up to 5 ~g/kg ~about -45%).
Because of their hypotensive and vasodilatory activity, the compounds of the invention are useful for treatment of cases of gangrene of the lower limbs. For this therapeutic use they have been found to be more active than PGEl and PGE2. They are also useful in disturbances of the peripheral vas-culature and, therefore in the prevention and treatment of diseases such as phlebitis, hepato-renal syndrome, ductus arteriosus, non-obstructive mesenteric ischemia, arteritis and ischemic ulcerations of the leg.

~3 3~

~3~

Among the compounds of the invention, in particular, the 6~H-deriva-tives also have a high anti-aggregating activity.
Among the 6~H compounds, the more important ones are, in order of increasing potency, compounds dl-6~H-5-bromo-6,9c~-oxide, 6~H~6,9c~-oxide-16-m-CF3-phenoxy-~-tetranor, dl-6~H-6,9c~-oxide, and 6~H-6,9~-oxide.
Using platelet-rich plasma (PRP) from healthy human donors who had not taken any drugs for at least one week, and monitoring platelet aggregation by continuous recording of light transmission in a Born aggregometer [Born G. V. R., Nature (London~ 194, 927 (1962)] there is evidence that the compounds 6~H-6,9a-oxide, dl-6~H-5-bromo-6,9~-oxide, 6~H-6,9c~-oxide-16-_-CF3-phenoxy-~-tetranor and 6~H-6,9c~-oxide-16-m-chloro-phenoxy-~-tetranor ~imic the biosyn-thetic PGX in its platelet-antiaggregating properties.
The compounds investigated were incubated for 2-3 minutes at 37C
in the PRP prior to the addition of the aggregating agents, arachidonic acid (0.4 mM), ADP ~10 ~M), collagen ~38 ~M) or adrenaline (15 ~M). The potency ratio for the compound is, e.g., 1:10 for arachidonic acid-induced aggregation and 1:100 for ADP-induced aggregation, as compared with biosynthetic PGX.
A very interesting increase in the an~i-aggregating potency follows 20-methyl su~stitution in both the 6~H- and 6c~H-6,9c~-oxide parent compounds.
2~ Similarly, 6~H-5-bromo-20-methyl~ 6~H-5,14-dibromo, 6~H-13,14-dide-hydro-20-methyl and inally 6~H-5-bromo-13,14-didehydro compounds and their 6~H 5 iodo (but not 6c~H-5-iodo isomers) are very ac~ive compounds as anti-aggregating agents.
The compounds of the invention are, therefore, particularly useful in mammals for inhibiting platelet aggregation, for preventing and inhibiting thrombus formation and for decreasing the adhesiveness of platelets.
Therefore, they are useful in treatment and prevention of thromboses ~nd myocarclial infarct, in treatment of atherosclerosis, and in general in all ~c~

~3~

syndromes etiologically based on or associated with lipid imbalance or hyper-lipidemia, as well as in treatment of geriatric patients for prevention of cerebral ischemic episodes, and in long-term treatment after myocardial in farct.
When the compounds of the invention are given as anti-aggregating agents, the routes of administration are the usual ones, oral, intravenous, subcutaneous, intramuscular. In emergency situations, the preferred route is intravenous, with doses that can vary from 0.005 to about 10 mg/kg/day. The exact dose will depend on the condition of the patient, his weight, his age and the route of administration.
The compounds of the invention were also studied for their uterine contractile activity, both in vitro and in vivo, against PGF2 as standard.
For example, in vitro, on the uterus of the estrogenized rat, com-pounds 6~H-6,9~-oxide-16-_-chloro-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-m--C~3-phenoxy-~-tetranor, were 1.3 and 3.1 times as active as PGF . In the 2~
in vivo assay, measuring the ntrauterine pressure o~ the ovariectomized rab-bit, the same compounds were~ and 8.25 times as active as PGF2 (see the following Table).

; _ in vitro _ v _ _ .
Uterus Ileum PGF2a _~ . .,_____ 6~H-6,9~-oxide-16-m-1.3 0.05 5.9 chloro-phenoxy-~-tetranor 6~H-6,9~ oxlde-16-m-¦ 3.1 0.1 8.25 C~3-phenoxy-~-tetra- .

~3 ~

33~

Tha ~able shows that the compounds have greater activit~ on the uterus than on the gastrointestinal tract.
These compounds, which are useful for induction of labor, for ex-pulsion of dead fetuses from the pregnant female, in either human or veteri-nary medicine, are without the undesirable side effects of the natural prosta-glandins, such as vomiting and diarrhea.
For this purpose the compolmds of the invention can be given by in-~ravenous infusion, at a dose of about 0.01 ~g/kg/minute ~mtil the end of labor. At ~he same dosage, the compounds of the invention dilate the uterine cervix, facilitating therapeutic abortion and, in that situation are given preferably in the form of vaginal tablets or suppositories.
The compounds of the invention, in particular the compound dl-6~H-6,9~-oxide-16-m-chloro-phenoxy-o-tetranor also have luteolytic activity and are therefore of use for control of fertility.
The 6~H-6,9~-oxide and their 6~H-isomers were also investigated for their action on the gastrointestinal tract, in order to know: ~a) cytoprotec-tive activit~ against lesions induced by non-steroid anti-inflammatory drugs;
~b) ability to prevent the ulcers induced by the method of Togagi-Okabe ~CJapan J. Pharmac. vol. 18, 9 (1968)] and (c) antisecretory activity, accord-ing to Shay et al Gastroenter. 26, 906 (lg54).
~he cytoprotective ability is a common feature of all the compounds.
For example, given subcutaneously, the 6~H-6,9~-oxide is slightly more active (1.5 - 2 times) than the standard PGE2 as a gastric antisecretory agent.
In general, the cytoprotective activity of the 6~H compounds is doubled when an acet~lene bond is present in the 13,1~-position; it is quad-rupled when a 16-alk~l group, usually a methyl, is positioned in the 16(S)-coniguration.
~s an ulceT~-preventing substance, the parent 6~H-6,9~-oxide analog 3 ~
3 - .37 -q~8~
.. . . .
is at least equipotent with PGE2 and the following substitutions, 13,14-acetylene bond; 16S, or R methyl; 16S, or R fluoro, highly increase ~up to 30 times) the potency ratio.
Furthermore, a significant oral antisecretory activity appears when a methyl group is in the C-15-position of the parent 6~H-6,9~-oxide or in the 16,16-dimethyl compounds, such as the 6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor derivative.
For this purpose the compounds are preferably given by intravenous in~ection or infusion, subcutaneously or intramuscularly. For intravenous infusion, the doses vary from about 0.1 ~g to about 500 ~g/kg body weight/
minute. The total daily dose, either by injection or by infusion, is of the order of 0.1 to 20 mg/kg, the exact dose depending on the age, weight and condition of the patient or of the animal being treated and on the route of administration.
In addition, the compounds are also useful for treatment of obstruc-tive pulmonary diseases such as bronchial asthma, since they have considerable bronchodilatory activity.
For treatment of the obstructive pulmonary disorders, for example bronchial asthma, the compounds of the invention can be given by different ~0 routes: orally in the form of tablets, capsules, coated tablets or in liquid form as drops or syrups; rectally in suppositories3 intravenously, intramuscu-larly or subcutaneously; by inhalation, as aerosols or solutions for the ne-bulizer; by insufflation, in powdered form.
Doses of the order of 0.01 - ~ mg/kg can be given from 1 to ~ times a day, with the exact dose dependlng on the age, weight, and condition of the patient and on the route of administration.
r:or use ac; an antiasthmatic, the compounds of the invention can be combined with other antiasthmatic agents, such as sympathicomimetic drugs 3S'-r like isoproterenol, ephedrine, etc., xanthine derivatives, such as theophyl-line and aminophylline, or corticosteroids.
The dosages when used as hypotensive and vasodilatory agents are about the same as those used for the anti-aggregating effects.
As previously stated, the compounds of the invention can be given, either to humans or animals in a variety of dosage forms, e.g., orally in the form of tablets, capsules or liquids; rectally, in the form of suppositories, parenterally, subcutaneously or intramuscularly, with intravenous administra-tion being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; in the form of sterila implants for prolonged action; or intravaginally in the form, e.g., of bougies.
The pharmaceutical or veterinary compositions containing the com-pounds of the invention may be prepared in conventional ways and contain con-ventional carriers and/or diluents.
For example, for intraveous injection or infusion, sterile aqueous isotonic solutions are preferred. For subcutaneous or intramuscular injec-tion, sterile solutions or suspensions in aqueous or non-aqueous media may be used; for tissue implants, a sterile tablet or silicone rubber capsule contain-ing or impregnated with the compound is used.
Conventional carriers or diluents are, for example, water, gelatine, lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium or magnesium stearate, glycol, starch, gum arabic, tragacanth gum, alginic acid or alginates, lecithin, polysorbate, vegetable oils, etc.
For administration by nebulizer, a suspension or a solution of the compound o~ the invention, preferably in the form of a salt, such as the sodi-um salt in water, can be usecl. Alternatively, the pharmaceutical preparation can be in the form of a suspension o~; of a solution of the compound of the invention in one o t~e usual liquefied propellants, such as dichlorodifluoro-3~

. ~ ..

` -.
methane or dichlorotetrafluoroethane, administered from a pressur-ized container such as an aerosol bomb. When the compound is no-t soluble in the propellant it may be necessary to add a co-solvent, such as ethanol, dipropylene glycol and/or a surfactant to the pharmaceutical formulation.
The invention is illustrated by the following examples, wherein the abbreviations "THF", "DME", "DMSO", "THP", "Et2O"
refer to tetrahydrofuran, dimethoxyethane, dimethylsulphoxide, tetrahydropyranyl, and ethyl ether, respectively.
The following examples illustrate the preparation of compounds of the invention, the preparation ofcompounds which are the subject of related applications 294,195; 329,309; 366,521 and 394,875 and the preparation of intermediate compounds but do not limit the present invention.
Example 1 To a solution of 1.0 g of dl-5~-hydroxymethyl-2~,4~-dihydroxy-cyclopentan-l~-acetic acid--~-lactone-4-p-phenylbenzoate in 8 ml of benzene/DMSO (75/25) is added wi-th stirring 0.89 g of dicyclohexylcarbodiimide. At room temperature, 1.42 ml of a solu-tion of pyridinium trifluoroacetate is added (prepared from 1 mlof trifluoroacetic acid and 2 ml of pyridine brought to 25 ml with 75/25 benzene/DMSO). After 3 hours 19 ml of benzene is added and the mixture is treated dropwise with an oxalic acid dihydrate solution, 0.3 g in 3.8 ml of water. After approximately 15 minutes of stirring, the mixture is fi]tered, and the organic phase is washed wi-th water until neutral, concentrated to 2 ml, and then cliluted wi-th 5 ml of isopropyl ether. The product is isola-ted by filtration and crystallized Erom isopropyl ether to give 0.8 g of dl-5~-formyl-2~,4~-dihydroxy-cyclopentan-1~-acetic acid-~-lactone-4-p-phenylbenzoate, m.p. = 129 - 131C. A solution of 800 mg of this in 2.8 ml of anhydrous methanol is treated with 0.62 ml of methyl orthoformate and 18 mg of p-toluenesulfonic acicl monohydra-te. After 1 hour, 0.01 ml of pyridine is added and the solution is evaporated to dryness. The residue is dissolved in ethyl acetate; it is washed with l.On NaOH and then saturated ~, ,q~

NaCl until neutral. The solvent is removed at reduced pressure and the resi-due is crystallized from methanol to give 800 mg of dl-S~-dimethoxymethyl-2~,

4~-dihydroxy-cyclopentan-1~-acetic acid-y-Lactone-4-_-phenylbenzoate, m. p. =
108 - 110C.
60 mg of K2C03 is added to a solution of this in 5.6 ml of anhydrous methanol. After 4 hours of stirring at room temperature, the solution is filtered; it is then reduced to small volume and acidified with a saturated NaH2PO4 solution. The methanol is removed and the residue taken up in ethyl acetate. This is washed with saturated NaCl until neutral, is dried over an-hydrous Na2S04, is filtered, and evaporated under reduced pressure to give 480 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-1~-acetic acid-y-lactone.
A solution of this in 4 ml of CH2C12 is treated with 0.32 ml of 2,3-dihydropyran and 4.8 mg of _-toluenesulfonic acid. After 4 hours at room temperature, pyridine is added and the solution is evaporated at reduced pres-sure. The crude reaction product is filtered on S g of silica gel, with cyc-lohexane:ethylether ~50:50) as eluent, to give 380 mg of dl-5~-dimethoxymethyl 2~,4~-dihydroxy-cyclopentan-1~-acetic acid-y-lactone-4-tetrahydropyranyl ether.
Starting from a 4-ester of 5~-dimethoxymethyl-2~,4a-dihydroxy-cyclopentan~
acetic acid-y-lactone ~for example: 4-_-phenylbenzoate, m. p. 128 - 130C, ~]D = -85) or from a 4-ester of 5~-hydroxyme~hyl-2~,4~-dihydroxy-cyclopentan-l~-acetic-y-lactone ~for example: the 4-~-phenylbenzoate, m. p. = 127 - 129C, L~] = ~84.5), the same procedure was used to prepare the following compounds:

5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-lr-acetic acid-y-lactone-4-tetrahydropyranyl ether and 5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-l~-acetic acid-r-lactone-4-tetrahydropyranyl ether. If 1,4-diox-2-ene is used lnstead of 2,3-dihydropyran, the corresponding 4-dioxanyl ether derivatives are obtained.

t ~ ~

Example 2 A solution of 216 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-tan-l~-acetic acid-~-lactone [~]D = -16 [~]365= -48 (C = 1.0 CHC13) in 1.6 ml of dimethylformamide is treated with 0.3 ml of triethylamine followed by 291 mg of dimethyl-tert-butylchlorosilane. After one hour, the mixture is diluted with 8.3 ml of water and extracted with hexane. The organic phase is washed ~ith ~ater and dried over Na2SO4 to give 310 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-acetic acid-y-lactone-4-dimethyl-tert-butylsilyl ether.
Example 3 To a solution of dl-5~-hydroxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-p-phenylbenzoate ~1 g) in 8 ml of benzene:DMSO
C75:25) is added 0.86 g of dicyclohexylcarbodiimide followed by 1.37 ml of a freshly prepared pyridinium trifluoroacetate ~see example 1). After three hours, 18 ml of benzene is added; a solution of 0.29 g of oxalic acid dihydrate in 3.7 ml of ~ater is then added dropwise. After 15 minutes of stirring, the dicyclohexylurea is removed by filtration and the organic phase is washed with water until neutral. This is then reduced to volume to approximately 2 ml and isopropyl ether is added. One obtains 0.793 g of dl-5~-formyl-2~,4~-dihydroxy cyclopentan-l~-propionic acid-~-lactone-4-~-phenylbenzoate.
A solution of 780 mg of this in 2.7 ml of anhydrous methanol is treated with 0.59 ml of methylorthoformate and 17.3 mg of p-toluenesulfonic acid. After approximately one hour, 0.01 ml of pyridine is added and the solu-tion is evaporated to dryness. The residue is taken up in ethyl acetate; the organic phase is washed with lN NaOH and then saturated NaCl until neutral.
r:vaporation to dryness gives 769 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-l~-propionic acid-~-lactone-4-_-phenylbenzoate. This is then dis-solved in 5.4 ml of anhydrous methanol and 75 mg of ~2CO3 is added. After ~0 ,~ _ four hours of stirring at room temperature and filtra*ion, the solution is reduced in volume and acidified with a saturated solution of Nal-l2P04. The methanol is evaporated and the aqueous phase treated with ethyl acetate; the organic phase is then washed with a saturated NaCl solution until neutral, dried over Na2S04, and evaporated under vacuum to give crude dl-5~-dimethoxy-methyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone. A solution of this in 4 ml of CH2C12 is treated with 0.3 ml of 2,3-dihydropyran and 4.5 mg of ~-toluenesulfonic acid. After four hours at room temperature, 0.01 ml of pyridine is added and the solution is evaporated to dryness. The reaction product is purified on silica gel with cyclohexane: ethyl ether (50:50) as eluent to give 480 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-tetrahydropyranyl e*her.
From a 4-ester of 5~-hydroxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid~-lactone and from a 4-ester of 5~-hydroxymethyl-2~,4~-dihy-droxycyclopentan-l~-propanoic acid-~-lactone ~for example, the 4-p-phenylbenzo-ate), using the same procedure, the following compounds were obtained:
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-tetrahydropyranyl ether;
5~-dimethoxymethyl-2~94~-dihydroxycyclopentan-l~-propanoic acid-~-lactone-4-tetrahydropyranyl ether.
If 1,4-diox-2-ene is used instead of 2,3-dihydropyran, the corresponding 4-dioxanyl ether derivatives are obtained.
Example 4 A solution of 1 g of 5~-formyl-2~-hydroxycyclopentan-1~-acetic acid-~-lactone in 6.5 ml of anhydrous methanol is treated with 1.74 ml of methylorthoeormate and 52 mg of p-toluenesulfonic acid. After approximately one hour, 0.0~ ml of pyridine is added and the solution is evaporated to dry-ness. The residue is taken up in ethyl acetate,and then washed with lN NaOH
~L~
-- .~5 --3~

and then saturated NaCl until neutral. Evaporation under ~acuum gives I g of 5~-dimethoxymethyl-2~-hydroxycyclopentan-1~-acetic acid-y-lactone, [~] = -16.
The same procedure gave 5~-dimethoxymethyl-2~-hydroxycyclopentan-l~-propionic acid-~ lactone and its dl derivatives from 5~-formyl-2~-hydroxy-cyclopentan-l~-propionic acid-~-lactone.
~xample 5 To a solution of 960 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-l~-acetic acid-y-lactone-4-tetrahydropyranyl ether in 16 ml of toluene, cooled to -70C, is added 8.5 ml of a 0.5N toluene solution of di-iso-butylaluminum hydride, over a 30 minute period. After a further 30 minutes of stirring at -70C, 10 ml of a 2M toluene solution of iso-propanol is added drop~Yise. The solution is warmed to 0C and treated with 3 ml of a 30% solu-tion of NaH2P04. After 1 hour of stirring, 12 g of anhydrous Na2SO4 is added.
Filtration and evaporation of solvent gives 900 mg of dl-5~-dimethoxymethyl-2a,4~-dihydroxycyclopentan-1~-ethanal -r -lactol-4-tetrahydropyranyl ether.
~xample 6 Following the procedure o example 5, a solution of 400 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~ acetic acid-y-lactone-4-dimethyl-tert-butylsilyl ether in 11 ml of toluene, cooled to -70C, is treated drop-wise with 5~9 ml of a 0.5N toluene solution of di-iso-butylaluminum hydride to give 0.43 g of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-ethanal-y- lactol-4-dimethyl-tert-butylsilyl ether.
Example 7 Under a nitrogen atmosphere, a solution of 62~ mg of 5~-dimethoxy-methyl-2~,4~-dihydroxycyclopentan-1~-propanolc acid-~-lactone-4-tetrahydro-pyranyl ether in 11 ml of toluene, cooled to -70C, is treated dropwise with 5.9 ml of a 0.5M toluene solution of di-iso-butylaluminum hydride. After 30 minutes at -70C, 10.9 ml of a 2M toluene solution of isopropanol is added ~ _ ''1-~
...~

3~

dropwise. The temperature is allowed to rise to 0C and 2 ml of 30% NaH2P04 is added. A$ter one howr of stirring, 8.3 g of anhydrous Na2S0~ is added and the mixture is filtered. E~aporation of the organic phase under vacuum gives 620 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanal-~-lactol-4-tetrahydropyranyl ether.
Example 8 Using one of the procedures outlined in examples 5, 6 and 7, a 4-acetal ~4-tetrahydropyranyl ether; ~-dioxanyl ether~ and a 4-dimethylbutyl-silyl ether of the following compounds are prepared:
5~-dimethoxymethyl-2~ -dihydroxycyclopentan-1~-ethanal-~-lactol, in its dl and optically active form (or nat-);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-ethanal-~-lactol (or ent-form);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanal-~-lactol, in its dl and optically active form (or nat-);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanal-~-lactol (or ent-form).
Example 9 0.29 ml of absolute ethanol in 3.5 ml of toluene is added dropwise to a solution of 5 x 10 3 mol of sodium ~2-methoxyethoxy)aluminum hydride ~1.4 ml of a 70% benzene solution diluted with 5 ml of toluene) cooled to 0 C.
8.2 ml of the alanate solution so prepared is addedJ at -30C, to 0.98 g of dl-5~-benzyloxymethyl-2~-hydroxycyclopentan-1~-propionic acid-~-lactone in 22 ml of toluene. After 45 minutes, excess reagent is quenched with 6 ml of a 0.5 M toluene solution of isopropanol. The mixture is warmed to 0C, 4 ml of 30% Na~l2P04 is added, and the resulting mixture is stirred for 2 hours. The inorganic salts are removed by filtration and the solution is evaporated to dryness to give 0.94 g of dl-5~-benzyloxymethyl-2~-hydroxycyclopentan-lu-propanal-~-lactol.
~1 .

~3~3~i Using the procedure reported above, or one of those from examples 4 to 7, the following compounds were prepared from their corresponding y-lac-tones:
5~-benzyloxymethyl-2~-hydroxycyclopentan~ ethanal-~-lactol;
5~-benzyloxyme~hyl-2~-hydroxycyclopentan-1~-propanal-~-lactol;
5~-dimethoxymethyl-2~-hydroxycyclopentan-1~-ethanal-r-lactol;
5~-dimethoxymethyl-2~-hydroxycyclopentan-1~-propanal-~-lactol.
Example 10 With stirring and external cooling to maintain a reaction tempera-ture of 20 - 22C, a solution of 1.05 g of potassium tert-butylate in 10 ml of DMSO is added dropwise to a solution of 1.8 g of 4-carboxybutyl-triphenyl-phosphonium bromide and 0.38 g of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-tan~ ethanal-y-lac~ol-4-tetrahydropyranyl ether. After the addition, the mixture is held at room temperature for 1 hour and then diluted with 16 ml of ice/~ater. The aqueous phase is extracted with ether ~5 x 8 ml) and ether:
benzene (70:30, 5 x 6 ml), the organic layers, after re-extraction with 0.5M
NaOH ~? x lo ml), are discarded. The combined alkaline aqueous phase is acid-ified to pH 4.8 with 30% NaH2PO4 and then extracted with ethyl ether:pentane ~1:1, 5 x 15 ml); from the combined organic phases, after drying over Na2SO4 and solvent removal, one obtains 0.45 g of 5-_is-7-~2'~,4'~-dihydroxy-5'~-dimethoxymethylcyclopentan.l'~-yl)-hept-5-enoic acid~4'-tetrahydropyranyl ether. This in turn is converted to the corresponding methyl ester upon treat-ment ~Yith diazomethane in ether. An analytic sample is prepared by adsorbing 1~0 mg of the crude product on 1 g of silica gel and eluting with benzene:

ethyl ether ~85:15). N.M.R.: _C=C 5.46 p.p.m. multiplet.
H ~1 Example_ In an anhydrous nitrogen atmosphere, a suspension of 0.39 g of a 75% oil dispersion of NaH in DMS0 ~13.5 ml) is heated to 60 - 65C for 3 1/2 hours; ater coolin~ to room temperature and while maintaining the reaction mixture at 20 -- 22C, the following are added, in order: 2.6~ g of 3-carboxy-propyltriphenylphosphonium bromide in 6 ml of DMSO and 0.6 g of 5~-dimethoxy-methyl-2~,4~-dihydroxycyclopentan-1~-propanal-~-lactol-4-tetrahydropyranyl ether in 3 ml of DMSO. The mixture is stirred for 3 hours, and then diluted with 35 ml of water. The aqueous phase is extracted with ethyl ether (5 x 12 ml) and ethyl ether:benzene ~70:30, 7 x 12 ml); the combined organic extract, after re-extraction with 0.5N NaOH ~2 x 15 ml), is discarded. The combined alkaline aqueous extract is acidified to pH 4.3 with 30% aqueous Na~l2PO4 and extracted with ethyl ether:pentane (1:1) to give, after washing until neutral, drying over Na2SO4, and removal of the solvent, 0.71 g of 4-cis-7-(2'~,4'a-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic acid. Treatment with diazomethane affords the corresponding methyl ester.
Example 12 The methyl esters of the following acids were prepared from lactols made according to the procedures in examples 4 to 8 by treatment with a Wittig reagent (prepared from 4-carboxybutyl-triphenylphosphonium bromide or 3-car-boxypropyltriphenylphosphonium bromide) and successive esterification with diazomethane, in their optically active or dl forms:
4-cis-7-(2'~-hydroxy-5'~benzyloxymethylcyclopent-1'~-yl)-hept-4-enoic;
4 -Ci S - 7-(2'~-hydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic;
5-cis-7-~2'~-hydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-enoic;
5-cis-7-(2'u-hydroxy-5'~-benzyloxymethyl-cyclopent~ -yl)-hept-5-enoic;
5-cis-7-~2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-enoic and its 4'-dioxanyl, tetrahydropyranil and dimethyl-tert-butylsilyl)-ethers;
4-cls-7-~2'~,4'o~-dihydroxy-5'~-dimethoxymethyl-cyclopent-l'cl-yl)-hept-4-enoic cmd its 4'-(dioxanyl" tetrahydropyranyl and dimethyl-tert-butylsilyl)-ethers;
~f5 11-'~ f~
.~

3~

4-cis-6-~2'a,4'a-dihydroxy-5'~-dimethoxymethyl-cyclopent-l'a-yl)-hex-4-enoic and its 4'-~tetrahydropyranylether;
5-cis-8-~2'a,4'a-dihydroxy-5'~-dimethoxymethyl-cyclopent-l'a~yl)oct-5-enoic and its 4'-tetrahydropyranylether.
Example 13 ~ solution of 1.06 g of the methyl ester of 5-cis-7-(2'~,4'a-dihy-droxy-5'~-dimethoxymethyl-cyclopent-l'a-yl)-hept-5-enoic acid-4'-tetrahydro-pyranyl ether in 5 ml of methanol is added to 0.84 g of mercuric acetate in methanol. After 30 minutes at room temperature, a solution of 250 mg of sodi-um ~orohydride in 2 ml of water is added with stirring and external cooling.
After 20 minutes of stirring, the mixture is acidified to pH 6.5 with aqueous monosodium phosphate, the methanol is removed under vacuum, and the residue is taken up in water/ethyl ether. The organic phase, upon removal of the solvent, affords 1.02 g of 5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-6icyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether.
Example 14 A solution of 1.59 g of 4-cls-7-~2'~,4'a-dihydroxy-5'~-dimethoxy-methyl-cyclopent-l'a-yl)-hept-4-enoic methyl ester-4'-tetrahydropyranyl ether in 6 ml of THF is added ~o a solution of 1.26 g of mercuric acetate in 4 ml of water diluted with 4 ml of THF. The mixture is stirred for 1 1/2 hours until precipitation is complete. 180 mg of sodium borohydride ~in 2.5 ml of water) is then added and the resulting mixture is stirred for 30 minutes. The solution is decanted from the precipitate, which is then washed with THF. The aqueous/organlc decanted solut:i.on is concentrated under reduced pressure and the ~esidue extracted with ethyl acetate. The combined organic extract, after washing with water ulltil neutral, affords upon removal of the solvent 0.98 g of (~-~7~-exo-di.methoxymethyl-8'-endo-'hydroxy-2'_oxa.~bicyclo~3.4.0~nonan-3~-yl) butanoic acid methyl ester-8'-tetrahydropyranyl ether.
'f~
'1 3 ~

, ~3~

Exam~le 15 ~, .
Starting from the esters prepared as described in examples 9 to 11, by reaction with a mercuric salt and subsequent reductive demercuration as described in the procedures in examples 13 and 14, the following bicyclic deriva~ives are obtained:
5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0~octan-3'~-yl)-pentanoic acid methyl ester;
4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester;
4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclor3.4.0~nonan-3'~-yl)-butanoic acid methyl ester;
a 7'-acetal ether (tetrahydropyranyl ether, dioxanyl ether), and a 7'-dimethyl-tert-butylsilyl ether of 5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.03Octan-3'~-yl)-pentanoic acid methyl ester;
an 8'-acetal ether (tetrahydropyranyl ether, dioxanyl ether) and an 8'-dimethyl-tert-butylsilyl ether of 4-~7'-exo-dimethyoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester.
4-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-butanoic acid methyl ester-7'-tetrahydropyranyl ether;
5-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.~]nonan-3'~-yl)-pentanoic acid methyl ester-8'-tetrahydropyranyl ether.
All these compounds are obtained in the d,l-, nat-- and ent-forms.
Example 16 A solution of 0.48 g of bromine in 5 ml of methylene chloride is added dropwise, with stirring, to a solution of 0.27 g of pyridine and 1.2 g of S-cis-7-(2'~ dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid methyl ester-4'-tetrahydropyranyl ether in 6 ml of methylene chlo-ride, cooled to 0C. Stirring is continued for ten minutes following the ad-dition. The organic phase is washed with 5 ml of a pH 7 buffer solution 10%
in sodiurn thio sulfate and then with water until neutral. After drying over Na2S04, removal of the solvent affords 1.38 g of 5-bromo-5-~6'-exo-dimethoxy-methyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether.
Example 17 1.24 g of N-iodosuccinimide is added to a solution of 2 g of 5-cis-7-(2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid methyl ester-4'-tetrahydropyranyl eth~r in 15 ml of carbon tetrachloride. The mixture is stirred for 3 hours and 30 ml of eth~l ether is added. The organic phase is ~ashed with lN Na2S203 and then with water until neutral. Removal of the solvent affords 2.48 g of 5-iodo-5'-~6'-exo-dimethoxymethyl-7'-endo-hy-droxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetra-hydropyranyl ether.
Example 18 422 mg of N-bromosuccinimide is added with stirring to a solution of 0.78 g of 4-cis-7-(2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic acid methyl ester-4-tetrahydropyranyl ether in 11 ml of CC14.
After four hours of stirringJ ethyl ether is added; the solution is then washed with water, lN Na2S203, and water until neutral. Evaporation to dry-ness gives 0.98 g of 4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyra-nyl ether.
Example 19 To a suspen~ion of 0.25 g of dry CaC03 in a solution of 346 mg of 5-cis-7-~2~-hydroxy-5'~-benzyloxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid i :~L~

methyl ester in 10 ml of CC14 cooled to 0 - 5C is added with stirring a solu-tion of 75 mg of chlorine in 3 ml of CC14. After stirring for ~ hours, the inorganic salts are removed by filtration. The solution is washed with a 7%
aqueous solution of KI and Na2S2O3 and then with water until neutral. The residue upon evaporation to dryness is adsorbed on silica gel and eluted with cyclohexane:ethyl ether (80:20) to give 0.27 g of 5-chloro-5-(6'-exo-benzyl-oxymethyl-2'-oxa~bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester.

A solution of 0.39 g of 5-cis-7-(2'~,4'~-dihydroxy-5'3-dimethoxy-methyl-cyclopent-1'~-yl)-hept-5-enoic acid methyl ester-4'-dioxanyl ether and 98 mg of pyridine in 10 ml of dichloromethane is cooled to -40C. A solution of 81 mg of chlorine in 6 ml of CH2C12 is then added over a period of 30 min-utes. After 10 minutes of stirring, the mixture is heated to room temperature.
The organic phase is washed with a 7% solution of KI and Na2S2O3 and then with water until neutral. Removal of the solvent affords 0.39 g of 5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3 "-yl)-pentan-oic acid methyl ester-4'-dioxanyl ether.
Example 21 280 mg of iodine in CC14 is added to a solution of 0.39 g of 4-cis-7-(2'c~,4'~-dihydroxy-5~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic acid methyl ester-4'-tetrahydropyranyl ether and 82 mg of pyridine in 10 ml of CC14. Stirring is continucd until the color disappears; 30 ml of ethyl ether is then added. The organic phase is washed with water, then a solution 7%
ln KI and Na2S2O3, and then water until neutral. Removal of thc solvent af-fords 0.48 g of 4-iodo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-b~cyclo[3.4.0~nonan-3'Z-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether.

~3 -~_ ....

~3~i33~1 Example 22 To a solution of 0.34 g of 5-cis-7-~2'~-hydro~y-5'~-ben~yloxymethyl-cyclopent-l'~-yl)-hept-5-enoic acid methyl ester in 6 ml of methanol is added with stirring a solution of 0.325 g of mercuric acetate in water:methanol (1:9,6 ml). The mixture is stirred for 15 minutes, reduced to 3 ml under vacuum, and then added to S ml of a saturated solution of NaCl in water. The precipitate is then extracted with methylene chloride. The organic phase is ~ashed with water and evaporated to dryness to give 0 52 g of crude 5-chloro-mercurio-5-~6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl~-pentanoic acid methyl ester. A solution of this in methylene chloride ~10 ml) is treat-ed wi*h 80 mg of pyridine in 2 ml of CH2C12 and then dropwise with stirring with a solution of 150 mg of Br2 in CH2C12. After 20 minutes of stirring at room temperature, the organic phase is washed with water, then 7% Ki and Na2S2O3, and water until neutral. Evaporation to dryness gives 0.34 g of 5-bromo-5-~6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3')-yl)-pentanoic acid methyl ester.
Mass spectrum M 424,426 m/e M -HBr 344 m/e M -CHBr ~CH2)3C02~CH3 = 231 m/e.
Example 23 10.5 mg o ~-toluenesulfonic acid monohydrate is added to a solution of 0.26 g of 5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo ~3.3.0Joctan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether and the resulting mixture is left at room temperature for 30 minutes. 10 mg of pyridine is then added and the solution is evaporated to dryness. The residue is taken up in ethyl ether/water. After drying over Na2S04, the organic phase gives upon xolvent evaporation 0.23 g of crude 5-iodo-5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acicl methyl ester. Separation by chromatography on silica gel with methylcne chloride: ethyl ether ~75:25) as eluent affords 84 mg of 5-iodo-5-. ~....

5~1 (6'-exo-dimethoY~ymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-pentanoic acid methyl ester and 55 mg of the 3'-exo isomer.
Referring the spectroMetric data, the prostaglandin numbering will be used;
thus the above diastereoisomers can be named as follows: the endo diastereo--~^o~o ~ r isomer: ~ ~H-6,9~-oxide~ -hydroxy-12~-dimethoxy ~ormylacetal-~20 ~ 13)te~-~f - io C/~
~a~4r-prostanoic acid methyl ester and the exo diastere~ somer1r6~H-6,9~-oxide-~ e~ ~ r ll~-hydroxy-12~-dimet]loxy-~ormylace~al-~(20 ~ 13)te~a~e~-prostanoic acid methyl ester.
Analytical data:
endo diastereoisomer: TLC more polar-or.e spot Mass spectrum ~m/e; % intensity fragment): 442 0.002 M ; 412 4 M -CH2O, ~ OCH
315/314 3 M -iodine/Hl 283 11 315-CH30H, 75 100 CH oCH3 N.M.R. ~solvent CDC13, TMS internal standard) p.p.m.:
~OCH
3.49 and 3.52 s, 3H/3H, CH ocH3 ; 3.64 s, 3H, CO2CH3;
,,OCH3 4.00 m, 3H ~protons at C5, Cg, Cll); 4-29 d, lH~ -CH OCH
4.60 m, lH, 6~H
C-MR ~at 20MH~ in C6D6 solution TMS int. standard) p.p.m.
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, 51Ø
exo diastereoisomer: TLC less polar-one spot Mass spectrum: 442 0.01 M , 366 3 M CH2CH~OCH3)2, 31S 4 M -1; 283 10 M -l-C}130H; 75 100 CH~OCH3)2 ,,OCH3 N.M.R.: p.p.m. 3.34 and 3.37 3H/3H s CH OCH ; 3-5 and 4-1 m lH and 2}1 protons at C5, C9, Cll uncertain assignment, ~OCH
3.65, s 3~1, CO2CH3; 4.21, dlH, CH OCH ; 4.35 m, 1~1,6 ~/

3~

13CMR: p.p.m. 173.0, 37.0, 33.1, 25.5J 40.1, 84.4, 39.7, 57.2, 83.7, 40.5, 75.9, 44.0~ 107.3, 5~.0, 53.8, 51.1.
Example 24 A solution of 980 mg of ~-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-~icyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether in 6 ml of anhydrous methanol is treated at room temperature for 30 minutes with 48 mg of _-toluenesulfonic acid. 2% aqueous NaHCO3 is added and the mixture is extracted with ethyl ether. From the organic phase, after washing until neutral and evaporation of the solvent, one obtains 0.68 g of a crude product which after purification on silica gel with methylene chloride: ethyl ether (80:20) as eluent affords 0.30 g of 4-bromo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-exo-yl)-butanoic acid methyl ester and 0.29 g of the 3'-endo isomer.
Example 25 Starting from acids prepared according to the procedure of example 11 and performing their halocycli~ation as described in one of the examples 16 to 22, the following haiobicyclic compounds are prepared:
5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester~7'-tetrahydropyranyl ether ~and 7'-di-oxanyl ether and 7'-dimethylbutylsilyl ether);
4-chloro-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether ~and 8'-di-oxanyl and 8'-dimethylbutylsilyl ethers);
5-chloro-5-~6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3';-yl)-pen-tanoic acid methyl ester;
S-chloro-5-~6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acid methyl ester;
4-chloro-4 ~7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-æ

~utano:ic acid methyl es~er;
4-chloro-4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester;
5-bromo-5-(6'-exo-dim0thoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether ~and 7'-di-oxanyl and 7'-dimethylbutylsilyl ethers);
4-bromo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0[nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and 8'-dioxanyl and ~'-dimethylbutylsilyl ethers);

5-bromo-5-~6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
5-bromo-5-(6'-exo-benzyloxymethyl-21-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
4-bromo-4-~7'-exo-dimethoxymethyl-2i-oxa-bicyclo[3.4.0]nonan-3'~,-yl)-butanoic acid methyl ester;
4-bromo-4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0~nonan-3'~-yl)-butanoic acid-methyl ester;
5-iodo-5-(6'-exo-dimethoxyme~hyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-~etrahydropyranyl ether ~and 7'-di-oxanyl and 7'-di~ethylbutylsilyl esters);
4-iodo-4-t7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo~3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether ~and 8'-di-oxanyl and 8'-dimethylbutylsilyl ethers);
5-iodo-5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
5-iodo-5-~6'-exo~benæyloxymethyl-2'-oxa-bicyclo[3.3.0]octan3'~-yl)-pentanoic acicl methyl ester;
4-ioclo-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic ~31~3~

acid methyl ester;
4-iodo-4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3~4.03nonan-3'~-yl)-butanoic acid methyl ester~
Example 26 Selective de-acetalization or de-silylization of the ethers de-scribed in example 25, according to the p-rocedure in examples 23 and 24 af-fords the 3'~-oxiran-hydroxide-~ormyl acetal derivatives, which give the following upon separation of isomers:
5-chloro-5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan--3'~-yl)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endo isomers;
4-chloro-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester, and its individual 3'exo and 3'-endo isomers;
5-bromo-5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy 2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentaroic acid methyl ester, and its individual 3'-exo and 3'-endo isomers;
endo isomer: TIC on SiO2 more polar one spot N.M.R.: (CDC13) p.p.m. 3.4 d,6H, CH oCH3 ; 3.65, s~3H CO2CH3 " OCH3 4.00 m,4H ~protons at C4, C5, Cg, Cll); 4-17 d,l, CH OCH
4.5 m, lH, 6~H
CMR: 173,0, 35.0, 33.3. 23.6, 59.4, 80.6, 36.4, 55.6, ~3.3, 41.6, 74.3, 44.5, 108.0, 54.4, 54~2, 51.1 exo isomer: TLC on SiO2 less polar isomer one spot N.M.R.: (CDC13) p.p.m.: 3.37 d,6H ~CH oC113 ; 3.66 s,3H,CO2CH3 ~ OCH
4.00 m,4H, protons at C4, C5, C9, Cll; 4-2 d,l, -C_ oCH3 4.32 m,lH, 6~H
, ~ 4 : ~ , -- 5~--8~

CMR: 173.0, 35.5, 33.3, 23.6, 57.7, 84.2, 38.2, 57.9, 83.6, 40.5, 76.0, ~3.9, 107.2, 53.8, 53.8, 51Ø
4-bromo-4-(7'-e~o-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester and its individual isomers, 3'-exo and 3'-endo;
5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0~octan--3'~-yl)-pentanoic acid methyl ester and its individual 3'-exo and 3'-endo isomers;
4-iodo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester and its individual 3'-exo and 3'-endo isomers.
Example 27 With stirring under nitrogen, a benzene solution (30 ml) of 2.8 g of 5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether is treated with a solution of 2.~ g of tributyltin hydride in 8 ml o benzene. The mixture is held at 55C for 8 hours and then overnight at room temperature. The ben-zene layer is washed with 2 x 10 ml of a 5% NaHC03 solution and then with water until neutral. The residue upon solvent evaporation is adsorbed on 10 g of silica gel and eluted with benzene and benzene:ethyl ether ~85:15) to give 1.94 g of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]
octan-3'~-yl)-pentanoic acid methyl ester-7'-te-trahydropyranyl ether.
Example 28 60 mg of ~-toluenesulfonic acid is added to a solution of 1.98 g of 5-~6'-exo-dimethox~nethyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether in 10 ml of anhydrous methanol. ~eter 30 minutes at room temperature, this is added to 20 ml of 20% aqueous Na~lC0~. The mixture is extracted with ethyl ether; the combined 1~L8~3~1 ether extract, after drying over Na2SO4, is evaporated to dryness. The resi-due is adsorbed on 100 g of silica gel and eluted with methylene chloride:
ethyl ether (94:6) to give 0.64 g of 5-(6'-exo-dimethoxyme~hyl-7'-ando-hydroxy-2~-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester, 0.52 g of the 3'-endo isomer and 0.12 g o:E the 3' -yl.
N.M.R. (CDC13) endo isomer 4.6 p.p.m. m,lH 6~H, T.L.C. more polar;
exo isomer 4.3 p.p.m. m,l}l 6~H, T.L.C. less polar.
0.32 g of the 3'-endo isomer is dissolved in pyridine (0.8 ml) and treated for 8 hours at room temperature with 0.3 ml of acetic anhydride. The mixture is then poured into ice/water, and, af~er acidifying to pH 4.2, is extracted with ethyl ether. The combined extract, after washing until neutral, is evaporated to give 0.315 g of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester-7'-acetate.
Example 29 A solution of 1.32 g of 4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0Jnonan-3'~-yl)-butanoic acid methyl ester-8'-tert-butyl-methylsilyl ether in 10 ml of anhydrous methanol is treated with 55 mg of _-toluenesul~onic acid for 2 hours at room temperature. 0.1 ml of pyridine is added, the solvent is removed under vacuum, and the residue is taken up in water/ethyl ether. The organic phase gives, upon removal of the solvent, 1.1 g of the crude 8'-hydroxy-3'~-yl derivative. Chromatography of this on silica gel with ben~ene:ethyl ether (80:20) as eluent separates this into 4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo~3.4.0]nonan-3'-endo-yl)-bu-tanoic acid methyl ester ~0.42 g) and the 3'-exo-yl isomer (0.34 g).
~:xa]nple 30 Using the p~ocedure in examples 28 and 29, methanolysis of the ~thcrs (acetal or silyl) described in example 15 gives the corresponding free alcohols.
. .~. -~

-~1~38~
Example 31 Upon acetylation with pyridine (0.6 ml) and acetic anhydride (0.3 ml) 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 gives 0.21 g of the cor-responding 7'-acetoxy derivative.
N.M.R. (CDC13) p.p.m.: 2.03 s,3H OCOCH3; 3.36 - 3.40 s,s 3H/3H

/OCH
CH 3; 3.66 s 3H CO CH3 ; 4.00 m 2H protons at - OCH - --3 , " OCII
C5, C9; 4.27 d lH CH ; 4.6 m lH 6~H 5.0 m lH
proton at Cll 3 [The spectrometric data for the 6~H isomer acetate are respectively the fol-lowing 2.03; 3.34 - 338, 3.66 s+m 4H CO2CH3 and one of C5, Cg protons 4.1 m lH
other of C5, C9 protons 4.2, 4.4 m lH 6~H, 5.1]. A solution of the 5-iodo-3'-endo-acetate in benzene (5 ml) is treated with 0.4 g of tributyltin hydride for 10 hours at 50 C. After the benzene phase is washed with 5% NaHCO3 and water evaporation of the solvent and purification on silica gel (10 g) with a ben-zene:ethyl ether (80:20) eluent afford 0.105 g of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-pentanoic acid methyl ester -7'-acetate, identical in all respects with a sample prepared by the procedure in example 28.
Example 32 Using the procedure of examples 27 and 31, the reduction with tri-butyltin hydride of one of the halo-derivatives synthesized in examples 16-26 gives the corresponding derivative in whic}l halogen is replaced by hydrogen.
These are identical in every way with the compounds prepared according to the procedures of examples 15, 28, 29 and 30.
~xample 33 S.~l mg o hydroquinone and a solution of 1.63 g of oxalic acid in ~8 ml o~ ~ater are added to a solution of ~ g of 5-(6'-exo-dimethoxymethyl-j~

~L8~1!33$1 7'-endo-hydroxy-2'-oxa-bicycloL3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 180 ml of acetone. Af~er 12 hours at 40C, the acetone is removed at reduced pressure and the mixture is extracted with ethyl acetate ~3 x 25 ml). The com~ined organic extract is washed until neutral with a 10% ammonium sulfate solution and dried over Na2S04. Removal of the solvent affords 3.21 g of 5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acid methyl ester. The 6'-exo-formyl-3'-endo and the 6'-exo-formyl-3'-exo derivatives are prepared from the corresponding individual isomers.
Example 34 10 Using the procedure of example 33) starting from the corresponding bicyclo[3.3.0]octan-6'-exo-dimethoxymethyl and bicyc lo L 3.4.0]nonan-7'-exo-dimethoxymethyl derivatives, the following compounds are prepared, either as individual 3'-exo and 3'-endo or 3'~ isomers:
5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl es~er;
4-~7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pelltanoic acid methyl ester;

4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic 2Q acid methyl ester;

5-chloro-5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-chloro-4-~7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-chloro-5-~6'-exo-ormyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-chloro-4-~7'-exo-tormyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-~utanoic acid methyl ester;

~3 ~

-3~8~

5-bromo-5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-bromo-4-(7'-exo-formyl-27-oxa-bicyclo~3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-bromo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.Q]octan-3'-yl)-pentanoic acid methyl ester;
4-bromo-4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;

5-iodo-5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-iodo-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-iodo-5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-iodo-4-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-acetate;
5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl-2Q pentanoic acid methyl ester-7'-acetate;
5-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0~nonan-3'-yl)-pentanoic acid methyl ester;
4-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-butanoic acid methy~l ester.
Example 35 To a solutLon of 1.2 g o~ 5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo ~3.3.0]octan~3~-yl)-pcntanoic acid methyl ester in methanol:methyl acetate (L0 ml:10 ml) is added 2 ml of a O;lN methanol solution of HCl. After 0.15 g 5~

of PtO2 is added, the mixture is hydrogenated at ambient temperature and pres-sure until 1 molar equivalent of hydrogen is abosrbed. After the removal of the gas under vacuum and washing with nitrogen, the suspension is filtered, neutralized, and evaporated to dryness. The residue is taken up in water/
ethyl acetate, and the organic phase yields 0.84 g of 5-(6'-exo-hydroxymethyl-2t-oxa-~icyclo[3.3.o]octan-3l~-yl)-pentanoic acid methyl ester. This is then oxidized to the 6'-exo-formyl derivative by the procedure in example 1, using dicyclohexylcarbodiimide in DMSO:benzene ~25:75).
Example 36 To a solution of 18.1 g of 5~-tetrahydropyranyloxymethyl-2~,4~-dihydroxy-cyclopent-lti-acetic acid-y-lactone-4-tetrahydropyranyl ether in 150 ml of toluene cooled to -70C is added in 30 minutes ]28 ml of a 5M solution of di-iso-butylaluminum hydride (1.2M/M). After 30 minutes at -70 C, 128 ml of a 2M toluene solution of lsopropanol is added and the solution is brought to 0C. Then 10 ml of a saturated aqueous solution of NaH2P04 is added and the mixture is stirred for four hours. Following the addition of 10 g of anhydrous Na2SO4 and 10 g of fil~ering earth, the solution is filtered and evaporated to dryness to give 18.1 g of 5~-tetrahydropyranyloxymethyl-2~,4a-dihydroxy-cyclopent-lt~-ethanal-y-lactol-4-tetrahydropyranyl ether. A solution o~ this in 24 ml of anhydrous DMS0 is added dropwise to a solution of the ylide prepared as follows: 9.6 g of 80% sodium hydride in 300 ml of DMSO is heated for four hours at 60C. Then after the mixture is brought to 18 - 20C, 67 g o 4-car~oxybut~ltriphenyl phosphonium bromide dissolved in 80 ml of an-hydrous DMSO is added while maintaining a temperature of 20 - 22C to generate a bright red color. After four hours of stirring, 600 ml of water is added and the mixture Ls extracted with ethyl ether:benzene ~70:30) to remove the triphenylphosphine oxide. The benzene organic phase is re-extracted with ~.

. . ~ . .

0.lN NaOH and then with water until neutral; it is then discarded. The alkaline aqueous phase is acidified to pll 5 - 4.8 and then extracted with ethyl ether:pentane ~1:1) to give 21.6 g of 5-cis-7-~2'~,4'~-dihydroxy-5'~-tetrahydropyranyloxymethyl-cyclopent-l~-yl)-hept-S-enoic acid-4'-~etrahydro-pyranyl ether, which may be converted to its methyl ester by treatment with diazomethane in ether. 7.72 g of this ester in 28 ml of tetrahydrofuran is added dropwise to a yellow-brown suspension formed by adding 28 ml of THF to a solution of 6.13 g of mercuric acetate in 28 ml of water. After the mixture is stirred ~or 20 minutes at room temperature, it is coo]ed in an ice:water btath and 810 mg of NaBH4 in 14 ml of water is added drt~ise. Elemental mercury precipitates out, che suspension is decanted, the tetrahydrofuran is evaporated at reduced pressure and the residue is extracted with ethyl ether. Removal of the solvent affords 7.5 g of 5-~6'-exo-tetrahydropyranyloxymethyl-7'-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3",-yl)-pentanoic acid methyl ester-7'-tetrahydro-pyranyl ether; 0.42 g of _-toluenesulfonic acid is then added to a solution of this in 30 ml of methanol. After 2 hours at room temperature, the solution is concentrated under vacuum and water is added. After extraction with ether and chromatography on silica gel with ethyl ether as eluent, one obtains 2.4 g of 5-(6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-2Q pentanoic acid methyl ester and 2.6 g of the 3'-endo isomer.
Example 37 2.5 g of N-iodosuccinimide is added to a solution of 4.26 g of 5-cis-7-~2'~,4'u-dihydroxy-5'~-tetrahydropyranyloxymetllyl-cyclopent-1'~-yl)-hept-5-enoic acid-4'-tetrahydropyranyl ether in CH2C12:CC14 ~10 ml:10 ml) and the resultlng mixture is stirred for four hours. 30 ml of anhydrous methanol containing 130 mg of ~-toluenesulfonic acid is added and stirring is continued eor allother 2 hours. 0.2 ml of pyridine is added, the mixture is reduced to small volume, and the residue is taken up in water/ethyl acetate. Af~er washillg with Na2S2O3 and then water until neutral, the organic phase is evap-~;

orated to dryness to give a residue that is adsorbed on silica gel and eluted with ethyl ether to give 2.2 g of 5-iodo-5-~6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester and 1.85 g of the 3'-endo isomer.
~xample _ Following the procedure of example 37, but using the methyl ester inst0ad of the acid and N-bromoacetamide instead of N-iodosuccinimide, the 5-bromo-5-(6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester is prepared. Silica gel chromatography allows the separation into the 3'-cxo and 3'-endo isomers.
Example 39 A solution of 0.86 g of pyridine and 2.2 g of 5-cis-7-(2'~,4'~-di-hydroxy~5'~-tetrahydropyranyloxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid methyl ester-4'-tetrahydropyranyl ether in dichloromethane (20 ml) is cooled to -30C and 0.38 g of chlorine in 10 ml of CC14:CH2C12 ~1:1) is addedO The mixture is stirred for 2 hours, warmed to room temperature, and washed with 2N H2S04 and then water until neutral. After evaporation of the solvent, the residue is dissolved in methanol ~10 ml) and treated with 0.1 g of _-toluene-sulfonic acid. The solution is then concentrated, diluted with water, and extracted with ethyl acetate. Removal o the solvent and purification of the residue on silica gel afford 0.6 g of 5~chloro-5-~6'-exo-hydroxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid and 0.71 g of the 3'-endo isomer.
~xample 40 To a solution of 0.356 g o 5-iodo-5-~6'-exo-hydroxymethyl-7'-endo-hydroxy-2'-oxa bicyclo[3.3.0~octan-3'-exo-yl)-pentanoic acid methyl ester in 4.8 ml oE benzene:~MS0 ~75:25) are added, in order, 0.28 g of dicyclohexyl-carbodiimide and 0.4 ml of a pyridinium trlfluoroacetate solution ~see example ~ ~

~ ~39~

1). Ater 3 hours of stirring, 8 ml of benzene and then aqueous oxalic acid ~94 mg in 1.2 ml) are added. The precipitate is removed by filtration and the benzene solution is washed with water until neutral. Removal of the sol-vent affords 0.32 g of 5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester.
Example 41 Upon oxidation of the 6'-exo-hydroxymethyl-7'-endo-hydroxy deriva-tives prepared according to examples 36 - 39, following the procedure of ex-ample 40, the corresponding 6'-exo-formyl derivatives are prepared.
Example 42 A solution of 3.4 g of (2-oxo-heptyl)dimethoxyphosphonate in 50 ml of dimethoxyethane i5 added dropwise to a suspension of 0.45 g of 80% NaH
(mineral oil dispersion). After stirring for 1 hour, a solution of 2.7 g of 5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 40 ml o~ dimethoxyethane is added. In 10 minutes this is diluted with 50 ml of a 30% aqueous solution of monobasic sodium phosphate.
The organic phase is separated, the aqueous phase is re-extracted, and the combined organic extract is evaporated. Purification of the crude product on 50 g of silica gel ~cyclohexane:ethyl ether, 50:50) gives l.lg of 5-[6'-exo-~3"-oxo-oct-1"-trans-en-1"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl~-pentanoic acid methyl ester or 13t-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-prost-13--enoic acid methyl ester and 0.98 g of 5-[6'-exo-(3"-oxo-oct-1"-trans-en~ yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl]-pen-tanoic acid methyl ester or 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, plus 0.9 g of a 1:1 mixture of the two isomers ~3'-exo and 3'-endo~ or 6~H and 6~H). This last mixture is separated into its t~o isomeric components b~ thin layer chromatography with ethyl ether. They show the Eollowing absorptions, respectively:
~3 ~ Mex~l = 230 m~, = 13,070; ~ MnaXll ~ 228 m~ = 12,~00.

N-M-R- ~CDC13) 0.9 t 3H C20-CH3, 3.68 s 3H CO2CH3, 6.16 d lH vinylic proton at Cl~ (JH14-H15

6.71 q lH vinylic proton at C13 ~ H13 z B~ the same proced~re, from the corresponding 5-H and 5-halo com-pounds, the following prostenoic acid derivatives are prepared:
13t-6aH-6(g~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a~-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a)-oxide-5-iodo-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a)-oxide-5-chloro-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a)-oxide-5-bromo-lla-hydroxy-15-oxo-pros~-13-enolc acid methyl ester, N.M.R. ~ 3.67 s 3H C02CH3, 3.95 m 4H C5, Cg, Cll protons and Hx/Hy proton at C4; 4.3 m lH 6aH; 6.15 d lH C14 proton; 6.63 q lH C13 proton;
13t-6aH-6(9a)-oxide-5-iodo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, N-.M.R. 0.9 s 3H C20CH3, 3.53 m lH pro~on at C5, 3.6 s 3H CO2CH3 3.9 m H
proton at C4, ~.1 m 2H proton at C9, Cll; 4.4.m lH 6aH; 6.2 d lH proton at Cl~ 6.75 q lH proton at C13;
13t-6~H-6~9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9a)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9a)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6~ 6(9a)-oxide-Ci-iodo-15 oxo-prost-13-enoic acid methyl ester;
13t-6~H-6~9a)~oxide-C;-chloro-lla-hydroxy-15-oxo-prost-13-enoic acid methyl e~ter;
~t~1~3' -~

13t-6~1l-6(9~)-oxide-5-bromo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, N.M.R.: 3.65 s 3H C02CH3; 4.00 m 3H proton at C5, C9, Cll, 4.6 m lH 6~H;
6.2 d lH proton at C14; 6.64 q lH proton at C13;
13t-6~H-6~9~)-oxide-5-iodo-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
N.M.R. 3.66 s 3H C02CH3, 3.96 m 3H protons at Cg, Cll and C5, 4.6 m lH 6~H, 6.21 d lH proton at C14 6.75 q lH proton at C13.
~ le 43 A solution of 2.16 g of (2-oxo-octyl)dimethylphosphonate in 20 ml of benzene is added dropwise to a suspension of 292 mg of NaH ~75% mineral oil dispersion) in 30 ml of benzene. After 30 minutes of stirring, a solu-tion of 2~6 g of 4-bromo-4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.
O]nonan-3'~-yl)-butanoic acid methyl ester in 20 ml of benzene is added drop by drop. Stirring is continued for another 30 minutes, and 24 ml of a 30%
aqueous solution of NaH2PO4 is added. The organic phase is separated, and the aqueous phase is re-extracted tYith benzere. The organic layers are com-bined and evaporated to dryness. The residue is purified on silica gel (50 g) Nith CH2C12:ethyl ether ~120:40) as eluent to give 0.52 g of 4-bromo-4-[7'-exo-~3"-oxo-oct-1"-trans-1"-enyl)-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-endo-yl]-butanoic acid methyl ester or 13-trans-4-bromo-5~H-5~9~)-oxide-ll~-hydroxy-15-oxo-prost-13-enoic acid methyl ester and 1.45 g of 4-bromo-4-~7'-exo-~3"-oxo-oct-1"-trans-1"-enyl)-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]
nonan-3'-exo-yl]-butanoic acid methyl ester or 13-trans-4-bromo-5~H-5~9~)-axide~ -hydroxy-15-oxo-prost-13-enoic acid methyl ester. Methanolic solu-tions Oe these ttYo compounds absorb in the UV at A n~ax ~ 230 m~, - 10,640, and A MmaxH = 229 m~, = 11,600, respectively.
`'1-'"~
.. i.~ _~

The same procedure, starting from the 4-}l and 4-halo bicyclo deriva-tives, gives the following prostenoic acids:
13-trans-5~H-5(9a)-oxide 15-oxo-prost-13-enoic acid methyl ester;
13-trans-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5(9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-hromo-5~H-5~9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-bromo-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-_rans-5aH-5(9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-5aH-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5aH-5~9a)-oxide-15-oxo-prost-13-enolc acid methyl ester.
13-trans-4-chloro-5aH-5(9~)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-bromo-5aH-5(9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4~bromo-5aH-5(9a)-oxide-lla-hydroxy-15-oxo-pros~-13-enoic acid methyl ester;
13-trans-4-iodo-5aH-5~9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5aH-5(9a~-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester.
F.xample 44 By the procedure o example 42~ the reaction o~ 620 mg of (2-oxo-3-methyl-4-llutox~butyl) phosphonate with 74 mg of NaH (75%) and 0,43 g o~ 5_~
exo-:~ormyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0~octan-3''-yl)-pentanoic acid 1' ~ ~~

3~

methyl ester in dimethoxyethane gives, after chromatography on silica gel (25 g) with 1:1 ethyl ether:hexane as eluentJ 0.15 g of 13t-6~H-6~9~)-oxide-ll~-hydroxy-15-oxo-16-methyl-16-butoxy-18~19,20-trinor-prost-13-enoic acid methyl ester ~ = 238 m~, ~ = 14,500) and 300 mg of the 6~H-isomer ~-~ max = 237 m~, ~ = 12,280)-Mass spectrum: m/e 410 M , m/e 392 M -H20;
m/e 379 M -OCH3; m/e 295 M -115, m/e 115 ~0-C4H9 -The two isomers present similar spectra with minimal differences at levelof secondary fragmentation.
Using the same procedure the 5-chloro, 5-bromo and 5-iodo 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester.
Example 45 By the procedure of example 44, from 4-~7'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester and the 4-iodo bicyclic derivative the following are obtained:
13t-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5~9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5~1-5~9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5~9~)-oxide~ -hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester.
Example 4~
To a suspension of 45 mg of 80~ Nall in 10 ml of benzene is added a solution of 375 mg of ~2-oxo-3,3-dimethyl-heptyl)-dimethylphosphonate in 10 ml o~ benzene, followed 30 minutes later by a solution of 0.305 g of 5-iodo-5-(6'-exo-formyl-21-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl es~er. After stirring for 45 minutes, the mixture is diluted with 10% aqueous NaH2P04. The organic phase is washed until neutral, dried and concentrated to small volume. Adsorption on silica gel and elution with cyclohexane:ethyl ether ~90:10) give 0.12 g of 13t-5-iodo-6~,H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester and 0.095 g of 13t-5-iodo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-13-enoic acid methyl ester.
Example 47 By substituting in the procedure of example 46 the formyl derivatives prepared according to example 34, the following 16,16-dimethyl derivatives are prepared:
13t-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9u)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid ~nethyl ester;
13t-5~H-5(9~)-oxide-llu-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-chloro-6~H-6(9u)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-chloro-6~H-6(9c~)-axide-llc~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-chloro-5~H-5(9u)-oxide-15-oxo-16/16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-chloro^5~H-5(9u)-oxide-llu-hydroxy-15-oxo-16,16-dimethyl-prost-13-enolc acicl methyl est:er;
13t-5-bromo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13 enoic acid methyl s~

ester;
13t-5-~romo-6~H-6~9~)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5~9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H~6~9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6aH-6(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6aH-6~9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9a)-oxide-15-oxo -16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5aH-5(9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-chloro-6aH-6(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-chloro-6aH-6~9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-chloro-5a~l-5(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t~_chlorc)-5all_5(,9a)-Qxide~lla_hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-bromo-6~H-6~9~)-oxide-15-oxo-16,16-dime~hyl-prost-13-enoic acid methyl ester;
13t-5-bromo-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-~romo-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6cLH-6(9~)-oxide-llcL-hydroxy-15-oxo-16,16-dimethrl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9~)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
Example 48 To a suspension of 178 mg of Nall (75% mineral oil dispersion) in 15 ml of benzene is added dropwise a solution of 1.55 g of [2-oxo-3(S,R)-fluoro-4-cyclohexyl-butyl]-dimethylphosphonate in 10 ml of anhydrous benzene.
After 30 minutes of stirring, a solution of 1 g of 5-(6'-exo-formyl-7'-endo-hy~roxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester is added and stirring is continued for another hour. The mixture is neutralized with 30% aqueous Na~l2PO~ and the organic phase is separated, concentrated ~md adsorbed on silica gel. Elution with CH2C12:Et20 (90:10) gives, 0.62 g of 13t~6~ 6(9~)-oxide-11~-hydroxy-15-oxo-16(S,R)~Eluoro-17-cyclohexyl-18,19~20-trinor-~rost~13-enoic acid methyl ester ~-3 ~3~33~

MeOH = 238 m~, E = 12~765) and 0.31 g of the 6~H isomer ~ = 238 m~, ~ = 9,~70)-The N.M.R. data for the former compound are the following (CDC13) p.p.m.
3.64 s 3H C02CH3, 3.8 m lH Cg proton, 4.03 q lH proton at Cll, 4.3 m lH S~H, 5.00 and 5.55 t,t 1/2 H~ 1/2 H proton at C16 3~1P 55 Hz, 6.54 q lH proton at C14 6. q p 13 H14-H12 ' H13-H12 ' H13-H14 Treating this compound with pyridine and acetic anhydride it is converted into the ll-acetoxy derivative, for which N.M.R. data are: ~CHC13) p.p.m. 2002 s 3H OCOCH3, 3.64 s 3H C02CH3, 3.8 proton at Cg, 4.25 m lH 6~H; 4.66, 5.22 t-t- 1~2 H, 1/2 H proton at C16; 4.97 q lH pro~on at Cll; 6.51 proton at C14, 6.90 proton at C13;
For the diastereoisomeric hydroxy ketones the mass spectrum shows the follow-ing masses:
M 424 m/e and then M -H20, M -HF, M -~130H/CH20 M -CH2=CHOH (basis ion) M -115 M -44-59 and M -~CHF-CH2-C~Hll).
In mass spectrum of exo-diastereoisomer the following masses are predominant:
M -CH30H and M -44-28; in that of endo-diastereoisomer the predominant ones are M -CH30 and M+-44-18.
From the 5-bromo derivative, 13t-5-bromo-6~H-6(9a)-oxide-11~-hydroxy-15-oxo-16(5,R)-fluoro-17-cyclohexyl-18,1g,20-trinor-prost-13-enoic acid methyl ester is prepared.
Example 49 Subs,tituting in the procedure of example 48 a phosphonate chosen from (2-oxo-4-cyclohexyl-butyl)-dimethylphosphonate and (2-oxo-4-phenyl-butyl)-dimethylphosphonate~ the ~ollowing we~e prepared:

~' ~13~

13t-6~H-6(9~)-oxide-11~-hydrox~-15-oxo-17-c~clohexyl-18,19,20-trinor-prost-13-enoic acid meth~l ester, 13t-6~H-6(9~)-oxi~e-11~-h~droxy-15-oxo-17-phen~1-18,19,20-trinor-prost-13-enoic acid methyl ester and their 6~H isomers.
Example 50 To a suspension of 178 mg of NaH (75% mineral oil dispersion) in anhydrous tetrahydrofuran at 0C is added dropwise ~ith stirring a solution of 1.63 g of 2-oxo-3-~m-chlorophenoxy)-propyl-dimethylphosphonate in 10 ml of anhydrousTHF. After 30 minutes of stirring, a solution of 1 g of 5-(6'-exo-formyl-7'-endo-2'-oxa-blcyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester is added and stirring is continued for another hour. The mixture is acidlfied wi~h aqueous NaH2PO4J the organic phase is separated, and the aque-ous phase is re-extracted with~benzene. From the combined organic ex~ract, after chromatography on silica gel with CH2C12:Et2O (95:5) as eluent, one obtains of 0.43 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16-m-chloro-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid meth~l ester ~ MeOH = 227 m~, c = i6,800) and 0.11 g of the 6~H isomer (~max = 224 m~, F = 16,900)-Both the diastereoisomers show the mass peak m/e 436 according to C23H29C106. This ion is invoived in the ~ollowing fragmentation:
M -H2O, M -OCH3/CH3OH, M -44~ M -~O-C6H4Cl), M -H2O-(O-C6H4Cl) and M -~CH2)4-CO2CH3, so furthermore confirming the proposed structure.
The following differences are between the ~wo diastereoisomers: the exo 6~H
isomer shows a peak at hl -32 and a little intense peak at M -44 on the other hand the endo 6~H isomer shows a peak at M -31 and an intense peak M -44.
Example 51 The substitution of a phosphonate chosen from 2-oxo-3-(m-trlfluoro-- ~7~

,i , '' ~ ~ ................................................................. ...

methylphenoxy)-propyl-dimethylphosphonate and 2-oxo-3-(~-fluorophenoxy)-propyl-dimethylphosphonate in the procedure of example 50 leads to the follow-ing compounds, respectively:
13t-6~H-6~9~)-oxide~ hydroxy-15-oxo-16-m-trifluoromethylphenoxy-17,18, 19,20-tetranor-prost-13-enoic acid methyl ester, 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16-_-fluorophenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester, and their 6~H isomers.
The mass spectra of all the compounds agree with the proposed structure for example showing the mass peak M -115; an interesting difference between the endo- and exo- trifluoromethyl analogous is that the mass peaks M -CH30H and M -CF3-C6H4-OH are in the exo-isomer and the mass peak M -CH30 and M -C~3-C6H4-O
are in the endo-isomer.
Example 5?
The substitution of ~2-oxo-3S-methyl-butyl)-dimethylphosphonate for the phosphonate in the procedure of example 48 gave 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16S-methyl-prost-l3-enoic acid methyl ester and its 6~H isomer.
To a solution o-f 2.2 g of the 6~H isomer in 2.6 ml of pyridine, cooled to 0C, is added 1.05 ml of acetic anhydride. The solution is held at 0C overnight and then added to an excess of cold 0.05N sulfuric acid. Extraction with ethyl ether and evaporation to dryness give 2.3 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16S-methyl-prost-13-enoic acid methyl ester-ll-acetate MeOH = 229 m~, = 12,050)-875 mg of bromine in glacial acetic acid is added dropwise to a solution of the latter compound in 10 ml of glacial acetic acid, until a llght orange color appears. 1.52 g of anhydrous potassium carbonate is then added and the resulting mixture is held at 80C for 4 - 5 hours to comple~e the precipitation oE potassium bromide. E~cessacetic acid is removed ~mder 73~
~:3 ~

vacuum, water is added, and the pH is brought to pH 6.8 with alkaline hydrate.
This is then extracted with ethyl ether and the organic phase is reduced in volume. Adsorption on silica gel and elution with methylene chloride:ethyl ether ~70:30) gives 2.01 g of 13t-6~H-6(9~)-oxide-ll~-hydroxy-14-bromo-15-oxo 15S-methyl-prost-13-enoic acid methyl ester-ll-acetate, max = 249 m~, = 11,450.
The 6~H isomer is similarly prepared.
Example 53 A solution of 2.06 g of ~2-oxo-3S-methylheptyl)-dimethylphosphonate in 20 ml of dimethoxyethane is added dropwise to a suspension of 0.265 g of NaH (80% mineral oil dispersion) in DME (10 ml). After stirring for 30 mi-nutes, 1.6 g of N-bromosuccinimide is added and vigorous stirring is continued for 10 minutes. 1.35 g of 5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 5 ml of dimethoxyethane is then added. The mixture is stirred for 1 hour and 20 ml of 30% NaH2P04 is added. After the usual work-up, crude 14-bromo-enone is obtained.
Separation on silica gel with methylene chloride:ethyl ether ~85:15) gives 0.9 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoic acid methyl ester and 0.92 g of the 6~H isomer. Upon treatment wi~h 0.4 ml of pyridine and 0.2 ml of acetic anhydride, 0.2 g of the 6~H isomer gives 0.205 g of the ll-acetoxy derivative~ identical in all respects with that made by the procedure of example 52.
Example 54 A 501ution o$ 0.43 g of ~2-oxo-octyl)-dimethylphosphonate in 10 ml of ~enzene is added dropwise to a suspension of 54 mg of NaH ~80% mineral oil di~persion) in 5 ml of benzene. After 1 hour, when the evolution of H2 has ccnsed, 0.32 g Oe n-bromosuccinimide is added all at once. To the carbanion thus prepared, Oe (l-~romo-2-oxo-octyl)-dimethylphosphonate is added a solution '~3 ,~' ~33~
" ~ .
of 270 mg of 5~6'-exo-formyl-7' endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 8 ml of benzene. After 30 minutes, the reaction is ~enched by the addition of 20 n~ of a 10% solution of N~12P04.
The organic phase, after being washed until neutral, gives 0.31 g of 13t-6~H-6(9)-oxide-11-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester; this is then separated into the 6aH and 6~H isomers.
Example 55 Upon substitution of the ~2-oxo-octyl)-dimethylphosphonate in the procedure of example 54 with ~2-oxo-4-cyclohexyl-butyl)-dimethylphosphonate and (2-oxo-4-phenyl-butyl)-dimethylphosphonate, the following compounds were prepared:
13t-6~H-6(9a)-oxide-11-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-6~H-6(9a~-oxide-lla-hydroxy 14-bromo-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoic acid methyl ester.
Example 56 By substituting the formyl derivatives in examples 53, 54 and 55 with 5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester, 4-iodo-4-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester, and the correspond-ing 4-H derivative, the following compounds were prepared:
13t-s-iodo-6~H-6(9a)-oxide-lla-hydroxy-l4-bromo-l5-oxo-l6s-methyl-prost-l3 enoic acid methyl ester;
13t-4-iodo-5~H-5(9a)-oxide-ll-hydroxy-l4-bromo-l5-oxo-l6s-methyl-prost-l3 enoic acid methyl ester;
13t-5~l~5(9a~oxide-11~-hyd~oxy~14~bromo 15-oxo-16S-methyl-pTost^13-enoic acid methyl ester;

~ ~ ~ 7~

~ ~3g~

13t-5-iodo-6~H-6(9~)-oxide-11~-hydroxy~14-bromo-15-oxo-20-methyl-pros~-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9a)-oxide-11~-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide~ -hydroxy-14-bromo 15-oxo-20-methyl~prost-13-enoic acid methyl ester;
13t-5-iodo-6BH-6~9~)-oxide-11~-hydroxy-14-bromo~15-oxo-17-cyclohexyl-18,19, 20-trinor-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide-lla-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5-io~o-6~H-6(9~)-oxide-11~-hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5~H-5(9a)-oxide-lla-hydroxy-14-bromo-15-oxo-17-phenyl-18319,20-trinor-prost-13-enoic acid methyl ester.
Example 57 A solution of 0.61 g of 2-oxo-octyl-triphenylphosphonium bromide in 6 ml of DMSO is added to a solution of 0.15 g of po~assium t-butylate in 3 ml of DMSO while keeping the reaction temperature at 16 - 19C. 0.27 g of 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 is then added. After 30 minutes o~ stirring, an equal volume of water is added and the mixture is extracted with ethyl e*her. The combined organic extract is washed until neutral and the solvent is evaporated. Chromatography on silica gel (cyclo-hexane:ethyl ether, 40:60) gives 0.21 g of 13t-6~H-6~9~)-oxide-ll~-hydroxy-15-oxo-20-methyl-prost-13-enoic acid methyl ester.

t~
,, ~, . ., Subsequent preparative thin layer chromatography (SiO2-Et20) allows separation of the 6aH and 6~H isomers.
Example 58 A solution of d,l-13t-6aH-6~9a~-oxide-lla-hydroxy-15-oxo-13-enoic acid methyl ester (exo-isomer at greatest Rf), (0.9 g), in dry ethyl ether (30 ml) is dripped on to a stirred 0.1 M solution of Zn(BH4)2 in dry ethyl ether (30 ml), over 15 minutes. After 2 hours, the excess reagent is decomposed by cautious addition of saturated NaCl solutlon and aqueous 2N sulfuric acid.
The organic layer is separated, washed to neutral and evaporated to dryness affording a residue which is adsorbed on silica gel, eluted with ethyl ether to yield 0.38 g of 13t-6aH-6(9a)-oxide-lla,15R-dihydroxy-prostenoic acid me~hyl ester, as an oil, and 0.42 g of d,l-13t-6aH-6(9a)-oxide-lla,15S-di-hydroxy-prostenoic acid m0thyl ester, m.p. 69 - 71 C (mass spectrum m/e 350 M -18, 319 M -18 -CH30; 318 M -18-CH3OH~. A solution in methanol (4 ml) of this ester is treated with 60 mg of li~hium hydroxide and water (0.8 ml) for 8 hours at room temperature. The methanol is removed in vacuum, ~he residue is diluted with water and extracted with ethyl ether to remove neutral impurities. The alkaline phase is treated with aqueous saturated NaH2PO4 solution until to pH 5 and then extracted with ethyl ether. The later organic phases are collected to yield after evaporation o the solvents the free acid d,l-13t-6all-6(9a)-oxide-lla,15S-dihydroxy-prostenoic acid, m.p.
105 - 106C. The 15R-hydroxy compound is a non-crystalli~able oil.
In the same way using nat-keto compound in the reduction reaction with Zn(BH4)2 we obtained besides the 15-epi alcohol, the nat-13t-6aH-6~9a)-oxide-lla,15S-dihydroxy-prostenoic acid methyl ester, m.p. 71 - 72C [a]D =
+ 10.2 , [a]365o - * 32.2 (CHC13) and after saponification the free acid m.p. 101 - 102C [a]l~ = + 6.34, [a]365o = + 33.2 ~CHC13).

B~:
Starting from the endo-diastereoisomers ~more polar compounds), the following esters were obtained:
13t-6~H-6~9~)-oxide~ ,15R-dihydroxy-prostenoic acid methyl ester ~d,l, nat-, ent- oils);
13t-6~H-6~9~)-oxide-lla,15S-dihydroxy-prostenoic acid methyl ester ~d, 1, nat-, [~]D = + 24-5 , [~]365 = ~ 52-9 ~CHC13) oil; ent- [~]D = -22 , oil), and after saponification the following free acids:
13t-6eH-6~9~)-oxide-11~,15R-dihydroxy-prostenoic acid ~d,l, nat-, ent- oils);
13t-6~H-6~9~)-oxide-11~315S-dihydroxy-prostenoic acid ~d,l oil, nat-, m.p.
78 - 80 C [~]D = + 32-5 ~ [~3365O = + 11-6 ~EtOH), ent- m-p- 78 - 79 C, [~]D = ~ 31 ~EtOH)).
Example 59 With the temperature of the reaction mixture kept at around -5 to -8CJ a solutlon of 159 mg of NaBH4 in 7 ml of propan-2-ol, is gradually added to a solution of 0.332 g of anhydrous CaC12 in propan-2-ol ~ ml); then, under stirring, a solution of 0.38 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16(S,R~-fluoro-17-cyclohexyl-18,19J20-trinor-prost-13-enoic acid methyl ester in 3 ml of propan-2 ol is added to the above prepared Ca~BH4)2 in a period of 40 minutes. The reaction mixture is kept under stirring at a temperature ranging at ~ 5C, then the excess reagent is destroyed by addition of 5 ml of acetone and 2 ml of water. The solvent is evaporated under vacuum and the residue is partitioned among water, O.lN H2SO4 and ethyl acetate. The organic extracts are collected, washed until neutral and after evaporation of solvent the residue chromatographed on silica gel ~30 g) using CH2Cl2-ethyl ether 70:30 as eluent. The eluate yields 0.21 g of 13t-6~H-6~9~)-oxide-11~,15R-dihydroxy-16~S,R)~luo~o-17-cyclohexyl -1 8, 1 9, 20-trinor-prost-13-enoic acid methyl ester, and 0.l4 g oE the 15S-epimer, m.p. 83C - 84C ~from ethyl ether).

3 ~ ~

In the same way, reductlon of the 6~H-isomer ~220 mg) yields 0.1 g of 13t-6~H-6~9~)-oxlde-11~,15R-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19, 20-trinor-prost-13-enoic acid methyl ester, m.p. 63 - 6~ C (from isopropylic ether), and 60 mg of 15S-alcohol.
Example 60 A solution of 0.15 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-15-keto-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester in methanol ~5 ml) is cooled at -5 . - 10C and reduced by addition of a solution of NaBH4 ~30 mg) in water (0.5 ml).
The reaction mixture is neutralized by addition of 15% aqueous NaH2PO~ solution after 15 minutes and then evaporated in vacuum. The aqueous residue is extracted with ethyl ether to yield a crude mixture of epimeric 15R,15S-alcohols. Chromatographic separation on silica gel ~CH2C12-ethyl ether 70:30 as eluent) affords respectively 13t-6~H-6~9~)-oxide~ ,15R-di-hydroxy-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester ~45 mg) and 15S-hydroxy-epimer ~62 mg).
Example 61 By reduction of 13t-5~1-5~9~)-oxide~ -hydroxy-15-keto-16-methyl-16-butoxy-18J19,20-trinor-prostenoic acid methyl ester, under the same trial conditions as in the procedure of example 60 followed by chromatographic separation of the epimeric alcohols ~300 mg) on silica gel ~12 g) with methylene chloride-ethyl ether 75:25 eluent, we respectively obtained 100 mg of 13t-5NH-5~9~)-oxide-11~-15R-dihydroxy-15-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester, and 110 mg of 15S-epimer. These are then saponified to yLeld the corresponding free acids.
Exa~nple 62 DrapwisG, ~o a stirred 0.12 M solution o~ zincborohydride in ethyl cther ~8 ml) a solut:Lon of 0.135 g of 13t-5-bromo-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-prostenoic acid methyl ester in 2 ml of anhydrous Et2O is added. The mixture is stirred for 2 hours and th~ excess reagent is decomposed with water--2N H2SO4. The organic phase is separated, washed to neutral and evaporated to dryness. After TLC on silica gel with ethyl ether-ethyl acetate 90:10, 38 mg of 13t-5-bromo-6~H-6~9~)-oxide-11~,15R-dihydroxy-prostenoic acid methyl ester and 46 mg of 15S-epimer were obtained.
Example 63 Starting from 13t-5,14-dibromo-6~H-6~9~)-oxide-lla-hydroxy-15-oxo-prostenoic acid methyl ester ~0.2 g) and using a mixture of CH2C12-ethyl ether 60:40, during the chromatographic separation on silica gel, we obtained 0.056 g of 13t-5~14-dibromo-6~H-6~9~)-oxide-11~,15R-dihydroxy-prostenoic acid methyl ester and 0.098 g of 15S-isomer.
A solution of this product in methanol is then hydrolized with aqueous LiOH to yield 72 mg of 13t-5,14-dibromo-6~H-6~9~)-oxide~ ,15S-dihydroxy-prostenoic acid.
Example 64 Using, in the procedure of example 60, isopropanol as solvent and NaBH4 ~45 mg), the reduction of 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16-~m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester ~0.47 g) yields 0.20 g of 13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-16-~m-tri-fluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester, [~]D = ~ 33.3 ~MeOH) and 0.15 g of 15R-epimer. The 6~H-15S-alcohol epimer is an oil with [~]D ~ ~ 12 ~MeOH).
Example 65 A solution in dry ethyl ether ~20 ml) of 13t-16S-methyl-6~H-6~9~)-oxide~ -hydroxy-15-oxo-prost-13-enoic acid methyl ester ~0.002 M, 0.72 g) ls added to a stirred etheral solution of ~inc borohydride ~0.01 M, 100 ml).
'[`he excess reagent is destroyed, after 30 - 45 minutes, by addition of 2N-~ &o ~3 513~

sulphuric acid ln NaCl saturated a4ueous solution. The organic phase is washed until neutral and evaporated to dryness. The residue is chromatog-raphed on silica gel ~25 g) using methylene-chloride:ethyl ether (80:20) as eluent affording ~7.5.10 4 M, 0.27 g) of the 15R-hydroxy-isomer and ~l.l.lO 4 M; 0.38 g) of the 15S-alcohol: 13t-16S-methyl-6~1-6~9~)-oxide-11~, 15S-dihydroxy-prost-13-enoic acid methyl ester. ~sing this procedure, the follo~ing methyl esters ~ere obtained:
13t-6~H-6~9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6~9~)-oxide-16,16-dimethyl~ ,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-20-methyl-11~,15S-dihydroxy-prost-13-enoic acid, m.p.

57 - 59 C [~]D = ~14 ~ [~]365 = +47 (CHC13);
13t-6~H-6~9~-oxide-20S-methyl-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
38 - 39 C, [~]D = +21-7 ~ [~]365 = ~77 (CHCl3);
13t-5-bromo-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-11~,15S-dihydroxy-20-methyl-prost-13-enoic acid, ~]D = + 38 ;
13t-5-iodo-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H 6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6~9~)-oxide-llN,15S-dihydroxy-20-methyl-prost-13-enoic acid, [~]D ~ ~ 23 ~ [~]365 = -~ 78 (CHC13);
l3t-5-chloro-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
'ID ~

13t-5~ll-5~9~)-oxide-16S-methyl-11~,15s-dihydroxy-prost-13-enoic acid;
13t-5~11-5~9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-4-bromo-5~1-1-5(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t~4-bromo-5~H-5(9~)-oxide-16R-meth~1-11~,15S-dihydroxy-prost-13-enoic acid;
13t-4-bromo-5~H-5(9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-4-iodo-5~H-5(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-4-chloro-5~H-5(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-16S-me~hyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6~9~)-oxide-20-methyl-ll~,lSS-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-15~S,R)-20-dimethyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic acid, 13t-5~H-5(9~)-oxide-16S-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-5(9~)-oxide-16R-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-5~9a)-oxide-20-methyl~ ,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-5~9c~)-oxide-16(S,R)-20-metllyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5-bromo-6~l-l-6~9~)-oxide-16S-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic ncicl;
13t-S-bromo-6~ 6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-14-bromo-prost-13-3:3 ~

enoic acid;13t-5-bromo-6~ 6~9~-oxide-20-methyl-11~,15S-dihydroxy-14-bromo-pros~-13-enoic acid;
13t-5-bromo-6~H-6~9~)-oxide-16~S,R)-20-dimethyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H-5~9~)-oxide-16S-methyl~ ,15S-dihydroxy-14-bromo-prost-13-enoic acid;

13t-4-bromo-5~H-5~9~)-oxide-16R-methyl-llcY,15S-dihydroxy-l~-bromo-prost-13-enoic acid;
13t-4-bromo-5~H-5~9~)-oxide-20-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H- 5~9~)-oxide-16~S,R)-20-dimethyl-llcY,15S-dihydroxy-14-bromo-prost-13-enoic acid;
together with their 15R-epimeric alcohols, when the corresponding 15-keto compounds are submitted to reduction followed by chromatographic separation.
Starting from 6aH and 5cYH dias~ereoisomeric 15-keto compounds we prepare the corresponding 15S- and 15R-alcohols. All these compounds are then saponified to yield the corresponding free acids.
Example 66 A solution of 13t-5-iodo-6~H-6~9~)-oxide-16R-methyl-15-oxo-prost-13-enoic acid methyl ester ~0.32 g) in ethyl ether ~8 ml) is added to a stirred solution of ~inc borohydride in ethyl ether ~25 ml). After 30 minutes, the excess reagent was destroyed by adclition of a saturated solution of NaCl and N ~12S04. After the usuaL work up the organic phase is separated and the crude residue is chromatographed on SiO2 ~eluent ~C112C12-ethyl ether) to yield 0.16 g of 13t-5-iodo-6~1-6~9cY)-oxide-16R-methyl-15S-hydroxy-prost-13-enoic-ncicl mothyL ester and 0.095 g of 15R-epimer. Using this procedure the follow-ing methyl esters were obtained:
~3 ''I' . ~. .

13t-6~H-6(9a)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-6~H-6~9a)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-6~H-6~9~)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5~H-5(9a)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-5~H-5~9a)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5~H-5(9~)-oxide-15S-hydroxy-16,16-dimethyl-pros~-13-enoic acid;
13t-5-bromo-6~H-6~9~)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9a)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-15S-hydroxy-16J16-dimethyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9~)-oxide-15S-hydroxy-20-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9~)-oxide-15S-hydroxy-16S,20-dimethyl-prost-13-enoic acid, together with their 15R-epimeric alcohols, when the corresponding 15-keto compounds are submitted to reduction followed by chromatographic separation.
Starting from 6aH and 5aH diastereoisomeric 15-keto compounds we prepare the corresponding 15S- and 15R-alcohols.
Example 67 The following 15S-hydroxy-9~-oxide prostanoic acids methyl esters together with their 15R-epimeric alcohols are obtained after reduction of the corresponding 15-keto compounds using one of the procedures described in examples 58 to 66;
13t-6~H-6~9a)-oxide-11~,15S-dihydroxy-13-prostanoic acid;
13t-14-bromo-6~H-6~9a)-oxide-11~,15S-dihydroxy-13-prostenoic acid;
13t-14-chloro-6~H-6~9a)-oxide-11~,15S-dihydroxy-13-prGstenoic acid;
13t-5,14-dibromo-6~H-6~9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-6~1-6~9~)-oxide-11~,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla~15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-5,14-dibromo-6~H-6~9a)-oxide-11~,15S-dihydroxy-20-methyl-13-prostenoic acid;

i3~
il J~ , tj 13t-5-iodo~6~H-6(9)-oxide-lla,15S-dihydroxy~20-methyl-13-prostenoic acid;
13t-5-iodo-14-bro -6~1-6(9~)-oxide-11 ~15S-dihydroxy-20-methyl-13-prostenoic ~cid;
13t-14-bTomo-6~H-6(9c~)-oxide-11~,15S-dihyd.roxy-16(S,R~-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5,14-dibromo-6~H-6(9a~-oxide~ ,15S-dihydroxy-16(S,R)-1uoro-17-cyclo-hexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-11~,15S-dihydToxy-16~S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-6BH-6(9)-oxide-llc~,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-trinor-pr~st-13-enoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-6~H-6~9a)-oxide-llc~,15S-dihyd~oxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoic acid;
13t-14-bromo-6~H-6(9~)-oxide-llaglSS-dihydroxy-16(S,R)-fluoro-17-phenyl-18, 19,20-trinor-prostY13-enoic acid;
13t-6BH-6~9~)-oxide-lla,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-pros~-13-enoic acid;
13t-6~H-6(9a)~oxide-ll,lSS-dihydroxy-17-cyclohexyl-1~,19,20-trinor-prost-13-enoic acid;
13t-14-bromo-6~H-6(9a)~oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5,14-dibromo-6~H-6~9a)-oxide-lla,15S~dihydroxy-17-cyclohexyl-18,19,20-trinor px~st~13~enoic acicl;

~,, 13t-5-bromo-6~_6(9a)-oxide-11~,15S_dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5-chloro-6~H-6(9a) -oxide-lla,15S-dihydroxy-17-cyclohexyl-1~,19 ,20-trinor-prost-13-enoic acid;
13t~5-iodo-6~H~^6(9a)-oxide-lla,15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinor~prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-methyl-16-amyloxy-18,19,20-lQ trinor-prost-13-enoic acid;
13t-5-iodo-6~H_6(9a)-oxide-lla,15S-dihydroxy-17-cycloheptyl-18,19~20-trinor-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-lla,15S-dihydroxy-16~(p-fluoro)-phenoxy-17,18,19,20-tetranor-13~prostenoic acid;
13t-6BH-6(ga)-oxide-lla~l5s-dihydroxy-l6-phenoxy-l7~ls~l9~2o-tetranor 13-prostenoic acid;
13t-6~H-6(9a)~oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-6~H-6(9a)-oxide-llaJl5s^dihydroxy-l6-~m-chloro)-phenoxy-l7~l8~l9~2 tetranor-13-prostenoic acid;
13t-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18, 19,20-tetranor-13-prostenoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18, 19,20-tetranor-13-prostenoic acid;
13t 14~br~ 6~1~6C~a~oxide~l].a,15S~dihydToxy~16-phenoxy~17,18,19,20-tetranor-13-prostenoi.c acid;
13t-14-bromo-6~{~6(9a)-oxide~llaJ15S-dihydroxy-16-(m-chloro)-phenoxy-17,18 19l20~tetranor-13~prostenoic acid;

~7 ~ ~

13t-14-bromo 6~H_~C9a) oxide-lla,15S-dihydroxy-16~(m-trifluoromethyl~-phenoxy-17,18,19,20-tetranor 13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19, 20-tetranor~13-prostenoic acid;
13t-5-iodo-6~H-6~9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranoT-13-prostenoic acid;
13t-5-iodo-6~H~6(9a)-oxide-lla,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18,19, 2Q-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-5~H-5~9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-pros*enoic acid;
13t-14-chloro-5~H-5~9a)-oxide-11,15S-dihydroxy-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-5RH-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-pros~noic acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,155~dihydroxy-20-methyl-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-4-iodo-5~H-5(9a3-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-4-iodo-14-bromo-5BH-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-pros~-13-enoic acid;
13t~4,14 dibromo~5~H~5~9)-oxide-lla,15S-dihydroxy-16~S,R)-fluoro-17-cyclo-hexyl~l8,1~,2Q~trino:r~prost~13~enoic acid;
13t-4-bromo-5BH-5(9a)-oxide-lla,15S-dihydroxy-16~S,R)-fluoro-17-cyclohexyl-18J 19 ~ 20-trinor_prost-13_enoic acid;
13t-SBH 5(9a)-oxide-lla,15S-dihydroxy-16~5,R)-fluoro-17-phenyl-18,19,20-trinor-pros~-13-enoic acid;
13t-14-bromo-5~H-5~9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro~17-phenyl-18,19,20-trinor-prost 13-enoic acid;
13t-5~H-5~9a)-oxide--lla,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-prost-13-enoic acid;
13t-5BH-5~9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
lQ 13t-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-4,14-dibro -5~H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5~1-5(9a)-oxide-11~,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9~)-oxide-11,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor_ 13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19320-tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16(m-chloro)-phenoxy-17,18,19, 20-tetranor-13~prostenoic acid;
13t-4^iodo-5 ~1-5~9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoic acid.
In similar way, we prepare the diastereoisomeric ~I-9a-oxide-lSS-and o~-9a-oxide-lSR-alcohols when we use aH-9a-oxide-15-keto diastereoisomer a~ startin~ material~
All these esters are then saponified to obtain the free acids.

, &` ~
~, ~

Example 68 0.46 g o~ 13t-5~H-5(9~)-oxide-16S-methyl-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester are treated with pyridine (2 ml) and acetic an-hydride (1 ml). After 6 hours at room temperature the mixture is diluted with brine, acidified ~o pH 4.5 - 4.8 and extracted with ethyl ether. The combined organic phases are then evaporated to dryness yielding 0.48 g of ll-acetoxy-derivative ~ mex~ = 229 m~, e = 11.058). A solution of this compound in ethyl ether is then added dropwise to a solution of Zn~BH4)2 in ethyl ether.
After 30 minutes the excess reagent is decom~osed with a N solution of H2SO4 and after the usual work -up, 0.47 g of 13t-5~H-5(9~)-oxide-16S-methyl-ll~, 15~S,R)-dihydroxy-13-prostenoic acid methyl ester ll-acetate are obtained.
A solution of this mixture in CH2C12 ~5 ml) cooled to about -5C, -10C, is treated with a solution of BF3 etherate ~1.2 x 10 4 M) in CH2C12 and then with a 5% solution of diazomethane in CH2C12 until a persistent yellow coloration.
The reaction mixture is evaporated to half volume under vacuum, washed with a 5% aqueous Na~lC03 solution and water to neutral, and evaporated *o dryness to yield 0.47 g of 13t-5~H-5~9~)-oxide-16S-methyl-ll~-hydroxy-15(S~R)-methoxy-prost-13-enoic acid-ll-acetate which is separated in the individual isomers by chromatography on SiO2 using benzene-ethyl ether (85:15) as eluent. On the other hand, 0.21 g of the mixture of 15(S,R)-methoxy-derivatives is dissolved in dry methanol ~4 ml) and selectively deacetilated by treatment with 20 mg of K2CO3 for 4 hours at room temperature. After neutralization by dilution ~ith aqueous Nc~12PO4, the methanol evaporated under vacuum and the residue is extracted ~ith ethyl ether ~2 x 5) ethyl acetate ~2 x 6 ml). The combined organic phases are evaporated to dryness to yield 180 mg of the crude 13t-5~ll-5(9~)-oxide-16S-methyl-ll~-hydroxy-15~S,R)-methoxy-prostenoic acid methyl ester, wh:ich is then readil~ separated by means o~ a silica gel column chroma-tograph~ using C~12C12-ethyl ether 80:20 as eluent to yield the two pure ~38~
, . .... .
lsomers: 15S-methoxy and 15R-methoxy. Using the same procedure the following methyl esters were obtained:
13t-6~H-6~9a)-oxide-16S-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~1-6(9a)-oxide-16R-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~H-6~9~)-oxide-20-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-20-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~l-6(9a)-oxide-11~-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-16S-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic acid, and their epimeric 15R-methoxy compounds are obtained starting from the cor-responding ll-acetoxy-15-keto compounds.
Using in this procedure the aH-diastereoisomer instead of the ~H, the corresponding aH-15-methoxy compounds are also obtained.
The same procedure can be also utilized for any 15-keto compound, previously described and analogously an other diazo alkane can be used inside o$ diazomethane.
Example 69 To a solution of 0.26 g of 13t-6~H-6~9a)-oxide-15(S,R)-hydroxy-16S-methyl-prost-13-enoic acid methyl ester in methylene chloride, treated with 0.3 ml of a solution of BF3 etherate in methylene chloride, cooled at -10 . -8C, a solution of diazoethane in methylene chloride is added until a persistent yello~ coloration is formed. The solvent is evaporated under vacuum and the residue chromatographed on silica gel using ethyl ether-methylene chloride 10:90 as eluent to yield 0.115 g of 13t-6~H-6(9a)-oxide-15S~ethoxy-16S-meth~:L-prostenoic acid methylester, and 0.1 g of 15R-ethoxy :LSOnler .
When a mixture o:F 15S,15R~alcohols, for example 13t-6~H-6(9a)-oxide-~.

~33~3~

11~,15~S,R)~dihydroxy-16S-methyl-prostenoic acid, containing a free 11-hydroxy group is submitted to the procedure of the examples 68 and 69, the simultaneous alkoxylation of the ll-alcoholic function also occurs yielding with diazomethane for example a~ter chromatographic separation the 13t-6~H-6~9~)-oxide~ ,15S-dimethoxy-16S-methyl-prostenoic acid methyl ester beside the 15R-epimeric derivative.
In a similar way the following ]5S-alkox~ prostenoic derivatives were obtained:
13t-5~H-5(9~)-oxide-11~,15S-dimethoxy-prostenoic acid;
13t-6~H-6(9a)-oxide-11~,15S-dimethoxy-prostenoic acid;
13t-6~H-6(9~)-oxide-5-bromo-11~,15S-dimethoxy-prostenoic acid;
13t-6~H-6(9~)-oxide-5-iodo-11~,15S-dimethoxy-prostenoic acid;
13t-5~H-5(9~)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6(9~)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6~9~)-oxide-15S-methoxy-16R-methyl-prostenoic acid;
13t-6~H-6(9~)-oxide-15S-methoxy-16-methyl-16-butoxy-18,19,20-trinor-prostanoic acid, and their 15R epimers are obtained and when they are saponiied with LiOH in methanol the free acids are prepared. The same procedure can be used to ob-tain diastereoisomeric ~H-9~-oxide derivatives.
~xample 70 2 To a stirred solution of 1.33 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid meth~l ester-ll-acetate in 6 ml of toluene and 54 ml of benzene, cooled at ~4C, a solution of 1.67 g of methylmagnesium iodide in eth~l ether is adcled. After 20 minutes, the excess reagent is decomposed with an iced 20% solution of ammonium chloride in water. After dilution with one volumc Oe ethyl ether the organic phase is washed with water, sodium bi-carbonate and water~ dried over magnesium sulphate, treated with 0.1 ml of q~

~331~

pyridine and evaporated to dryness to yield 1.2 g of 13t-6~1-6(9~)-oxide-11~, 15(S,R)-dihydroxy-15-methyl-prostenoic acid-methylester-ll-acetate, vf which 0.2 g are separated into the pure component by thin layer chromatography on silica gel, with benzene-ether 60:40 eluent. 1 g of the mixture of th0 two alcohols is dissolved in anhydrous methanol ~20 ml) and stirred for 4 hours with 0.25 g of K2C03. The mixture is evaporated to dryness, the residue is par~itioned between ethyl ether and aqueous 15% NaH2P04. The organic phase is evaporated in vacuum and the residue is absorbed on silica gel (200 g).
~ Elution with ethyl ether-isopropylic ether 80:20 affords 0.20 g of 13t-6~H ~lC
6~9c~)-oxide~ ,15R-dihydroxy-15-methyl-prost-13-enoic acid methyl esterl and 0.36 g of 15S-epimer. 0.16 g of this compound are dissolved in 12 ml of methanol and treated with 0.8 ml of water and 0.2 g of K2C03. After 5 hours at room temperature the methanol is evaporated under vacuum, the residue is treated with 20% NaH2P04 and ethyl acetate. The organic phase yields 0.1~ g of 13t-6ctH-6(9~)-oxide-11~,15S-dihydroxy-15-methyl-prost-13-enoic acid. The corresponding 6~11-isomers are prepared in the same way.
Example 71 To 1.79 g of 13t-5~H-5(9a)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester-ll-acetate in 20 ml of anhydrous tetrahydrofurane, 50 ml of 0.3 M ethynylmagnesium bromide in anhydrous tetrahydrofurane is added.
Keep shaking for one hour, eliminate the excess reagent by treating with a saturated NH4Cl solution, concentrate the organic phase under vacuum, and take up with ethyl ether to yield 1.62 g o 13t-5~H-5(9~)-oxide-11~,15(S,R)-dihydroxy-15-ethynyl-prost-13-enoic acid methyl ester-ll-acetate, which is d~ssolved in anhydrous methanol and treated with 250 mg of anhydrous potassium carbonate for 3 hours under shaking. Evaporated under vacuum and dilute with 20~ aclueous Nc~12PO4 and ethyl ether. A$ter evaporating the solvent, the organic phase yields 1.41 g o~ 13t-5~H-5~9~)-oxide-11~,15(S,R)-dihydroxy-15-_ ~ , ethynyl-prostanoic acid methyl ester, which is separated into the two pure 15S-hydroxy and 15R-hydroxy epimer by silica gel chromatography with benzene-ethyl ether 1:1 as eluent, and after saponification of the 15S-hydroxy epimer with K2CO3 in methanol, there is yield of the 13t-5~H-5(9~)-oxide-11~,15S-dihydroxy-15-ethynyl-prostenoic acid.
Example 72 To a solution in tetrahydrofuran anhydrous (25 ml) of 1.41 g of 13t-5-bromo-6~H-6~9a)-oxide-15-oxo-prost-13-enoic acid methyl ester, a 0.5 M
solution of magnesium vinyl bromide in tetrahydrofurane (25 ml) is added at 0 - 5 C and let stand for 4 hours at room temperature. Decompose the excess reagent with a saturated solution of ammonium chloride, distil the tetrahydro-furane under vacuum and take up with ethyl ether. The organic phase is ad-sorbed on silica gel and eluted with methylene chloride-ethyl ether to yield 0.41 g of 13t-S-bromo-6~H-6~9~)-oxide-15R-hydroxy-15-vinyl-prostenoic acid methyl ester, and 0.62 g of 15S-isomer, which after saponification with LiOH
in methanol yields 0.49 g of pure 13t-5-bromo-6~H-6~9~)-oxide-15S-hydroxy-15-vinyl-prostenoic acid.
Example 73 A solution o 0.98 g of 13t-5-bromo-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-20-methyl-prostenoic acid methyl ester-ll-acetate in 30 ml of benzene-toluene ~85:15) is cooled at 3 - 4C and to this a solution of 0.92 g of phenylmagnesium bromide in ethyl ether-benzene 1:1 is added. Let stand for 5 hours at room temperature, then decompose the excess reagent with an iced solution of 15% NH4Cl, wash the organic phase repeatedly with water to neutral then evaporate. The crude 15-phenyl-15~S,R)-hydroxy derivative is dissolved in anhydrous methanol to which 0.25 g. of K2CO3 is added, kept shaking for 2 hours. Evaporate to dryness, dilute with aqueous 20% NaH2PO4 and ethyl ether, and Erom the organic phase after evaporation of the solvent, there is a yield of 0.81 g o~ 13t-5-bromo-6~H-6~9~)-oxide~ ,15(S,R)-dihydroxy-15-phenyl-20-methyl-prostenoic acid methyl ester, which after separation on silica gel with ethyl ether elution y:ields the individual 15S and 15R isomers.
Example 74 -By reaction of the corresponding 15-oxo-derivative with a reagent selected from the group of an halogenide of methyl magnesium, vinyl magnesium, ethynyl magnesium and phenyl magnesium, working to one of the procedures given in example 70 to 73, the following methylesters were prepared:
13t-6~H-6(9~)-oxide-15S-hydroxy-15-methyl-prostenoic acid;
13t-6~H-6(9a)-oxide-15S-hydroxy-15,20-dimethyl-prostenoic acid;
13t-6~H-6(9u)-oxide-15S-hydroxy-15-ethyl-prostenoic acid;
13t-6~H-6(9~)-oxide-15S-hydroxy-15-ethynyl-prostenoic acid;
13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid;
13t-6~H-6(9~-oxide-11~,15S-dihydroxy-15-ethyl-prostenoic acid;
13t-6~H-6~9~)-oxide~ 15S-dihydroxy-15-vinyl-prostenoic acid;
13t-6~H-6~9~)-oxide-11~,15S-di.hydroxy-15-ethynyl-prostenoic acid;
13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-15,20-dimethyl-prostenoic acid;
13t-5-bromo-6~H-6~9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic zcid;
13t-5-bromo-6~H-6~9~)-oxide-11~,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-5-bromo-6~H-6 t9G) -oxide-11~,15S-dihydroxy-15-ethynyl-prostenoic acid;
13t-5-bromo-6~H-6~9)-oxide-11~,15S-dihydroxy-15-ethyl-prostenoic acid;
13t-5-bromo-6~H-6~9a)-oxide-11~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-4-bromo-5~H-5~9~-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid;

13t-4-bromo-5~H-5~9~)-oxide-11~,15S-dihydroxy-15,20-dimethyl-prostenoic acid;
13t-4-brolno 5~ 5~9~)-oxide-11~,15S-dihydroxy-15-ethynyl-prosteno:ic acid;
13t-5~l-5t9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid;
13t-5~1-5~9a)-oxide-11~,15S-dihydroxy-15,20-dimethyl-prostenoic acid;
"~`3 ~' ~l~a~

13t-5~1-5(9a)-oxide-lla,15S-dihydroxy-15-phenyl-pros~enoic acid;
13t-5~H-5~9~)-oxide-11~,15S-dihydroxy-15-ethynyl-prostenoic acid;
13t-5~H-5(9~)-oxide-lla,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-5~H-5~9a)-oxide-lla,15S-dihydroxy-15-methyl-prostenoic acid, and their 15R-hydroxy epimers.
Analogously starting from the a~-(9~)-oxide-15-keto-compounds we obtained the corresponding ~I-~9a)-oxide-15-substituted alcohols.
Example 75 To a solution of 0.5 g of 13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-14-bromo-16S-methyl-prostenoic acid-methyl ester-ll-acetate in 2 ml of di-methylformamide, dimethyl-t-butyl silane chloride (0.21 g) and triethylamine (0.16 g) are added. Keep shaking for 2 hours, then dilute with 4 volumes of water and extract with ethyl ether. The organic phase, after the usual washings, evaporation of the solvent, and filtration through silica gel with cyclohexane-ethyl ether 90:10 eluent, yields 0.57 g of 13t-6~H-6(9a)-oxide 11~,15S-dihydroxy-14-bromo-16S-methyl-prostenoic acid methyl ester-ll-acetate-15-dimethyl-t.butylsilylether, from which, by transesterification in anhydrous methanol and 0.5 molar equivalents of K2CO3, the corresponding ll-hydroxy-derivative is yielded.
Example 76 To 0.52 g of 13t-5,14-dibromo-6 ~1-6(9a)-oxide-11~,15S-dihydroxy-prostenoic acid methyl ester in 10 ml of dichloromethane, 2,3-dihydro-pyrane (0.27 g) and p-toluensulphonic acid (4 mg) are added. Keep at room tempera-ture for 3 hours, then wash with a 5% solution of KtlC03 and water to neutral, and evaporate to dryness. Filter through silica gel with cyclohexane-ethyl othel 90:10 as e~uent, which yields 0.59 g of 13t-5,14-dibromo-6~H-6(9a)-oxide-lla,15S dihydroxy~prostenoic acid methyl ester-11,15-his-tetrahydropyranyl-e~her.

~3 ~

~8~

Exam~le 77 The 14-bromo-alcohols yielded by the foregoing examples, when treat-ed with dimethyl-t.butylchlorosilane in dimethylformamide while, working to the procedures as in example 75,or with an acetalic ether such as 2,3-dihydro-pyrane-1,4-diox-2-ene, l-ethoxy-ethylene, and working to the procedure of example 76, are then converted into ~he co-rresponding silyloxy or the corres-ponding acetalic ethers.
Exam~le 78 Under an atmosphere of inert gas, to a stirred solution of 0.46 g of 13t-14-bromo-6~H-6(9~)-oxide-15S-methoxy-16S-methyl-prost-13-enoic acid methyl ester in anhydrous dimethylsulfoxide ~5 ml), potassium tert-butylate ~0.15 g) is added and the stirring is continued for 30 minutes. The reaction mixture is diluted with 2 volumes of water and stirred for 15 minutes, then extracted with ethyl ether. The organic phases are re-extracted with 2 x 5 ml of 0.2N NaOH and then with water u~til neutral and evaporated to dryness to give 30 mg of 6~H-6~9~)-oxide-15S-methoxy-16S-methyl-prost-13-ynoic acid methyl ester. The combined aqueous phase are acidified to pH 5.1 and extracted with ethyl ether. After evaporation of the solvent, 0.28 g of 6~H-6(9~)-oxide-15S-methoxy-16S-methyl-prost-13-ynoic acid is obtained.
Example 79 Under an atmosphere of inert gas, with stirring and rigorous ex-clusion of humidity, 0.84 g of trimethylsilylimidazole is added to an anhydrous dimethylsul~oxide solution of 0.445 g oE 13t-5~H-5~9~)-oxide-14-bromo-16R-meth~l-prost-13-enoic acid. Stirring is continued for 30 minutes and then a solution of 0.19 g of K-tert-butylate is added. After 30 minutes stirring, the mixture ls diluted with 3 volumes of water and stirred Eor 2 more hours.
Aeter acidl~ication to ptl 5.2, it is extracted wlth ethyl ether:hexane 80:20 nnd t}le organi.c extracts are dried and evaporated to dryness to give 0.31 g 3i~

of 5aH-5(9~)-oxide-16R-methyl-prost-13-ynoic acid.
Example 80 To a solu~ion of sodium methylsulfinylcarbanion, obtained by heating at 60 C for 3 hours and 30 minutes a suspension of 50 mg of 80% NaH in 8 ml of anhydrous dimethylsulfoxide, a solution of 13t-6~H-6~9~)-oxide~ ,15S-dimethoxy-14-bromo-16~S,R)-fluoro-20-methyl-prost-13~enoic acid methyl ester ~0.~6 g~ in 5 ml of dimethyl sulfoxide is added with stirring under an at-mosphere of inert gas, at a temperature of 18 - 20C. After 40 minutes of stirring an excess of 25% NaH2P04 is poured in and the mixture extracted with ethyl ether to give 0.51 g of 6~H-6~9~)-oxide-11~,15S-dimethoxy-16(S,R)-fluoro-20-methyl-prost-13-ynoic acid methyl ester.
Example 81 To a solution of 80 mg of sodium amide in 10 ml of dimethyl-sulfoxide a solution of 13t-14-bromo-5~H-5(9~)-oxide-11~,15S-dihydroxy-16-m-trifluoromethylphenox~-l7~l8~l9~2o-tetranor-prost-l3-enoic acid-11,15-bis-tetrahydropyran~l-ether (0.65 g) in 5 ml of dimethylsulfoxide is added.
It is stirred for 2 hours and then diluted with water and extracted with ethyl ether. The ether extracts, after re-extraction with alkali are dis-carded. The aqueous alkaline extracts are acidified ~o pH 4.5 and extracted ~ith ethyl ether to give 0.54 g of 5~H-5(9~)-oxide-11~,15S-dihydroxy-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-ynoic acid-11,15-bis-tetrahydropyranyl ether. A solution of this compound (0.23 g) in anhydrous ethanol ~5 ml) and 2,2-diethoxypropane (3 ml) is treated with 20 mg of p-toluenesulfonic acid. After 5~hours at room temperature it is neutralized with aqueous NaHC03, evaporated under vacuum and the residue partitioned hetween ~ater and ethyl ether. The org.mic phase is evaporated and after p~ssing the residue through silica gel 0.1 g oE 5~H-5~9~)-oxide-11~,15S-clihydroxy~-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-ynoic ~'~ _ ~' acid ethyl ester is obtained. Deacetalization carried out on another 0.2 g of product dissolved in 5 ml of acetone and treated with 3.5 ml of 0.2N oxalic acid for 8 hours at 40C, after e~aporation of the acetone under vacuumJ ex-traction of the aqueous phase with ethyl ether and chromatography on silica gel with ethyl ether:ethyl acetate 95:5 the free acid (95 mg) is obtained.
In the same way, starting from 13t-14-chloro-6~H-6(9~ -oxide-lla, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid-11,15-bis-dioxanylether the 6aH-6(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-ynoic acid is obtained~
Example 8?
To a solution of 0.48 g of~l3t-14-bromo-6~H-6(9a)-oxide-11~,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester in 3 ml of anhydrous dimethylsulfoxide is added after 30 minutes a solu-tion of 1,5-diazabicyclo[5.4.0]undec-5-ene (0.25 g) in 2 ml of anhydrous di-methylformamide and the reaction mixture maintained for 6 hours at 65 C. It is diluted with water acidified to pH 4.5, extracted with ethyl ether. From the organic phase, after evaporation of the solvent and purification on silica gel ~eluted with benzene-ethyl ether 80:20), 6~H-6(9a)-oxide-lla,15S-dihydroxy-16-cycloheYyloxy-17,18,19,20-tetranor-prost-13-ynoic acid methyl ester ~0.29 2a g) is obtained~
Example 83 -Using one of the procedures described in examples 78 to 82 and starting from ~he corresponding 13t-14-halo-prost-13-enoic acids, the follow-ing prost-13-ynoic acids are prepared: .
6~ll-6t9a)-oxide-lla,15S-dihydroxy-prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,15R-dihydroxy-prost-13-ynoic acid;
6~}1-6t9a)-oxide-15-methoxy-prost-13-ynoic acid;
6~l-6~9a)-oxide-lla,15S-dihydroxy-l6S-methyl-prost-13-ynoic acid;
~,.

~3i~3~

6~H-6~9a)-oxide-11~,15S-dihydroxy-16S,20-dimethyl-prost-13-ynoic acid;
6~H-6(9a)-oxide-11~,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
6~H-6~9a)-oxide~ ,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;
6~H-6(9a)-oxide-11~,15S-dihydroxy-16,16-difluoro-prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,15S-dihydroxy-20-methyl-prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,155-dihydroxy-16-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,l~S-dihydroxy-16-p-fluorophenoxy-17,18,19,20-tetranor-prost-13-ynoic acid, 6~H-6~9a)-oxide-11~,15S-dihydroxy-17-phenyl-18,19,20-trinor-prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-16S-methyl-prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-16S,20-dimethyl~prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
5~H-5(9a)-oxide-lla,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-20-methyl-prost-13-ynoic acid.
Starting from aH-~9a)-oxide compounds and using the same procedure, the epimeric aH-(9a~-oxide-13-ynoic compounds are prepared.
Example 84 A solution of 0.35 g o~ mercuric acetate in mèthanol is added at room temperature, ~ith stirring, to a solution o~ 0.54 g of 5c,13t--9~ ,15S-trihydroxy-prostadienoic acid methyl ester-11,15-bis-TIIP-ether (PGF2 -bis-TilP-ether-methyl ester). After stirring for 15 minutes, 50 mg of sodium ~orohydride is added in small portions, the elemental mercury generated is removed by filtration and the methanol is evaporated under vacuum. The resi-due is partitioned between dichloromethane/water; the organic phase, after Oq ~l8315 3~

washing with sodi~1m bicarbonate and water until neutral, is evaporated to give 0.51 g of crude 13t~ ,15S-dihydroxy-6~H-6(9~)-oxide-prostenoic acid methyl ester-11,15-bis-THP-ether. A solution of this in 10 ml of acetone added to 8 ml of 0.2N oxalic acid is heated to 40 - 45C for 6 hours. After the removal of the acetone under vacuum, the aqueous suspension is extracted with ethyl acetate ~3 x 15 ml). The organic phase is washed until neutral and evaporated to dryness. The residue ~approximately 0.45 g) is adsorbed on silica gel ~50 g) and eluted with ethyl ether collecting fractions of 20 ml.
From fractions 11 to 50, 13t-11~,15S-dihydroxy-6~H-6(9~)-oxide-prostenoic acid methyl ester ~0.11 g; m.p. 67 - 6gC) is obtained. I'hen, after a mixture of diastereoisomers as 5 - 10% of ethyl acetate is added to ethyl ether, 13t-lla,15S-dihydroxy-6~H-6(9~)-oxide-prostenoic acid methyl ester (0.16 g;
~]D = + 19.62 (CHC13)) is collected.
A sample of the later compound, after crystallization, shows m.p.

40 - ~1 C, [~]D = +25-2 ~ [~]365 = +83.8 ~C~IC13).
The crude free acid has [~]D = +18.3 (EtOH).
A sample is crystallized from pentane-ethyl ether affording pure crystalline 13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
80 - 81 C, [~]D = +32.5 ~ [~]365 = +11`1.6 (EtOH). The mass spectrum of the compound shows the following peaks (m/e, intensity, structure):
336 7% [M-H2O] , 318 3% [M-2H2O] ; 292 100% [M-H2O-~] ;
264 30% [M-H2O-CH2CHCO2H] ; 235 ~% [M-H2O-(C~I2)~CO2H].
The mass spectrum of the 6~H-diastereoisomer is substantially similar .
Example 85 A solution Oe o.ls g of 5c,13t-9~ ,15S-trihydroxy-15-methyl-PGF2~methyl cster in 2.5 ml of THF is added to 0.3 g of mercuric acetate in l.5 ml water/3.0 ml THF. After 30 minutes of stirring, 60 mg of sodium 131~3~

borohydride in 1.2 ml of water is added to the deep yellow suspension~ After the mercury is separated, the THF is removed under vacuwn and the aqueous sus-pension is extracted repeatedly with ethyl acetate. The organic phase, when washed until neutral and evaporated to dryness, yields 0.16 g of product which is purifiecl by thin layer chromatography to give 0.04 g of 13t~ ,15S-di-hydroxy-6t~H-6~9~)-oxide-15-methyl-PGF2 -methyl ester, [~]D = ~6.2 (CHC13) and 0.034 g of the 6~H-6(9~)-oxide-isomer, [~]D = ~19.62 (CHC13).
Example 86 0.43 g of 5c,13t-9~,15S-dihydroxy-16R-methyl-prostadienoic acid methyl ester-15-dioxanyl ether in methanol (2.5 ml) is reacted with a solution of 0.38 g of mercuric bromide in methanol. The reaction mixture is held at room temperature for 15 minutes and overnight at 0C. The crystalline pre-cipitate which forms is isolated by filtration to give 0.36 g of 13t-15~-hydroxy-16R-methyl-6~H-6(9~)-oxide-5-bromomercuric prostenoic acid methyl ester, from which the mercury is removed upon treatment with sodium borohydride to give 0.12 g of 13t-15S-hydroxy-16R-methyl-6~H-6(9~)-oxide-prostenoic acid methyl ester. Column chromatography on silica gel affects the separation into the 6~H-6(9~)-oxide and 6~H-6(9c~)-oxide diastereoisomers.
Example 87 A solution of 0.55 g of 5c-9~,llci,15S-trihydroxy-prostenoic acid methyl ester in 2.5 ml of DME is added to a solution of 0.5 g of mercuric acetate in 2 ml of water/ 4 ml of DME. After 15 minutes, the reaction mixture is treated with a solution of 0.08 g of sodium borohydride in 1.2 ml of water, the mercury is separated~ the DME is removed under vacuum, and the residue is extracted several times with dichloromethane. The organic phase is evap-orated to dryness, aclsorbed on silica gel and eluted with ethyl ether/ethyl acetate to give 0.21 g of 11~,15S-dihydroxy-6c~H-6(9~)-oxide-prostenoic acid mcth~l ester and 0.18 g of the 6~EI-6(9~)-oxide isomer.
/d l 3~

Example 88 A solution of 116 mg o~ 5c-9~ ,15S-trihydroxy-17-cyclohexyl-20, 19,18-trinor-prost-5-en-13-ynoic acid methyl ester-11,15-bis-THP-ether in 1.5 ml of methanol is treated with 64 mg of mercuric acetate in 1.5 ml of methanol. After 10 minutes, 25 mg of sodium borohydride is added. Methanol is removed under vacuum~ the mercury is separated and the product is dissolved in water/ethyl acetate. Evaporation of the organic phase to dryness affords crude llu,15S-dihydroxy-6~H-6(9~)-oxide-17-cyclohexyl-20,19,18-trinor-prost-13-ynoic acid methyl ester-11,15-bis-THP-ether (100 mg); this is treated in acetone (4 ml) with 2.5 ml of 0.2N oxalic acid overnight at 40C. After re-moval of the acetone under vacuum, the mixture is extracted with ethyl acetate.
Evaporation of solvent gives a residue t~hich is puri~ied on silica gel (elu-ent, ethyl ether) to give 28 mg of 11~,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-6~H-6~9~)-oxide-prost-13-ynoic acid methyl ester, [~]D = + 17.2, [~]365 = +54, and 12.5 mg of the 6~H-6(9~)-oxide-isomer, [~D = + 26.5, [~]365 = ~ 84 ~EtOH); M 406, M-H2O 388.
Under the same conditions, 5c-9~ ,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid methyl ester-11,15-bis-THP-ether gives 11~,15S-dihydroxy-16S-methyl-6~H-6(9~)-oxide-prost-13-ynoic acid methyl ester and its 6~H-6(9~)-oxide isome-r.
Example 89 0.24 g o~ 13t-11~,15S-dihydroxy-6~H,6(9~)-oxide-16-methyl-16-butoxy-20,19,18-trinor-prostenoic acid methyl ester and 0.13 g of the 6~H-6(9~)-oxide isomer are obtained from the reaction of 1.01 molar equivalent of mercuric acetate (636 mg) in 10 ml of methanol and 1.1 g of 5c,13t-9~ ,15S-trihy-droxy-16-methyl-16-butoxy-20,19,18-trinor-prostadienoic acid methyl ester-ll, 15-bis-T}IP-etller in 5 ml of methanol. The mercury compound so prepared is reduced in situ by the cautious addition of 85 mg of sodium borohydride in 3,~ ''' ~

3~3~

small portions. The methanolic solution is then decanted from the solid resi-due and reduced in volume. 10 ml of 0.2N aqueous oxalic acid and 20 ml o~
acetone are added, and the resulting mixture is held at 50C for 12 hours.
The organic solvents are removed under vacuum, and ~he resulting solution is saturated with sodium sulfate and extracted with ethyl acetate. The organic phase is washed with 30% ammonium sulfate (2 x 5 ml) and 2.5 ml of water;
after drying over NaSO4, it is evaporated to give a crude residue which is purifi.ed on silica gel using an eluent containing an increasing fraction of benzene-methyl acetate, to give the isomeric 6~H-6(9~)-oxide and 6~H-6(9~)-oxide.
From the above reaction with 16-_-chloro-phenoxy,16-_-fluoro-phenoxy, and 16-m-trifluoromethyl-phenoxy-5c,13t-9~ ,15S-trihydroxy-20, 19,18,17-tetranor-prost-5,13-dienoic acid methyl ester-11,15-bis-THP-ether and the analogous 17-phenyl-18,19,20-trinor-derivative were obtained respec-tively:
13t-11~,15S-dihydroxy-6~H-6(9~)-oxide-17-phenyl-20,19,18-trinor-prostenoic acid methyl ester, [~]D = + 28 ;
13t~ ,15S-dihydroxy-6~H-6(9~)-oxide-16-m-chloro phenoxy-20,19,18,17-tetranor-prostenoic acid methyl ester, [~]D = + 31 , 13t-11~,15S-dihydroxy-6~H-6(9a)-oxide-16-_-fluoro-phenoxy-20,19,18,17-tetranor-prostenoic acid methyl ester, [~]D = -~ 30C;
13t-llN,15S-dihydroxy-6~H-6(9c~)-oxide-16-m-trifluoromethyl-phenoxy-20,19,18, 17-tetranor-prostenoic acid methyl ester, [~]D = -~ 33 ;
and thelr 6~H-6~9~)~oxide ison)ers ~hich show [~D ranging between +8 and 12 in CHC13.
Example 90 Using the 15S-fluoro-17-cyclohexyl-Sc,l3t-9~ ,15S-trihydroxy-2a,1~,18-tr:lnor-prost~-5,13-dienoic acid methyl ester-11,15-bis-THP-ether, in . ~ j~ -J~

the procedure of example 89, the 13t-lla,15S-dihyclroxy-6aH-G~9a)-oxide-16S-fluoro-17-cyclohexyl-20~19,18-trinor~prost-13 enoic acid m0thyl ester, and its 6~ 6(9a)-oxide diastereoisomer are obtained.
Exam~le 91 0,12 g of 13t-lla,15S-dihydroxy-6~1-6(9N~-oxide-prost-13-enoic acid methyl ester in 6 ml of methanol is reacted with a 0.5 N aqueous solution of lithium hydrate (2 ml~. After six hours9 the methanol is removed under vacuum.
The residue is diluted with water ~2 ml) and extracted with ethyl ether to ~emove neutral impurities. The alkaline aqueous phase is acidified by treat-ment with 4 ml of 30% aqueous NaH2P04 and extracted several times with ethyl ether. The later combined ether extracts are washed with water ~2 x 1 ml~ and dried; removal of the solvent affords 91 mg of 13t-lla~15S-dihydroxy-6~H-6~9a)-oxide-prost-13-enoic acid~ m.p. 78 - 80C, [a]D = + 31 ~EtOH). This procedure is used for saponification of the esters from the preceding examples to the corresponding free acids.
Example 92 lla,155~dihydroxy-6~H-6(9a)-oxide-16S-methyl-prost-13~ynoic acid ~Q.ll g) in methylene chloride is treated with 1.5 molar equivalent of di-azomethane in methylene chloride. After 15 minutes, solvent is removed under ~acuum and the residue adsorbed on silica gel. Elution with ethyl ether/
benzene (70:30) gives, in the following order, 12 mg of lla-hydroxy-l5s-methoxy-6~H-6(9a)-oxide-16S-methyl-prost-13-ynoic acid methyl ester and 78 mg of lla,15S-dihydroxy-6~H-6(9a)-oxide-16S-methyl-prost 13-ynoic acid methyl ester. Using in this procedure diazoethane instead of the diazomethane, lla-hydroxy-15S-ethoxy-6~ 6~9a)-oxide-16S-methyl-prost-13-ynoic acid ethyl ester is obtained~

Example 93 A solution of 12 (0-33 g) in methylene chloride is added to a sus-pension of finely divided calcium carbonate in 6 ml o~ methylene chloride con-taining 0.54 g of 5c,13t-9~ ,15S-trihydroxy-prostadienoic acid methyl ester-11,15-bis-tetrahydropyranyl ether (PGF2~-bis-tetrahydropyranyl ether methyl es~er). The reaction mixture is cooled in an ice/water bath and kept in darkness~ After three hours of stirring, inorganic compounds are removed by filtration and the organic phase is washed with 0.25 N sodium thiosulfate and water. Removal of the solvent affords 0.66 g of crude 13t-5-iodo-6~H-6 ~9a)-oxide~ 9l5S-dihydroxy_prost-13-enoic acid methyl ester-11,15-bis-tetra-hydropyranyl ether. A solution of this in 10 ml of acetone is added to 8 ml of O.lN oxalic acid and heated to 45 - 46C for 4 hours. The acetone is then removed at reduced pressure and the aqueous suspension is extracted with ethyl acetate (3 x 12 ml); the organic phase is washed until neutral and evaporated to dryness. The residue (0.42 g) is separated on silica gel with ethyl ether eluent. Elution of the high Rf fraction with acetone gives 0.14 g of 13t-5-iodo-6aH-6~9~)-oxide-11~,15S-dihydroxy-prost-13-enoic acid methyl ester, while the low Rf portion is 0.20 g of 13t-5-iodo-6~H-6~9~)-oxide-11~, 15S-dihydroxy-prost-13-enoic acid methyl ester.
The methyl ester of the following acids were prepared analogously:
13t-16S-methyl-5-iodo-6~H-6~9~)-oxide-11~,15S-dihydroxy-prost-13-enoic acid;
13t-20-methyl-5-iodo-6~H-6~9~)-oxide-11~15S-dihydroxy-prost-13-enoic acid, [~]D = ~ 23 ~ 365 = ~ 78 ~CHC13);
13t-5-iodo-6~H-6~9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoic acid;
13t-5-iodo-6~H-6~9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoic acid;

lJ - l~
., .

qs~

13t-5-iodo-6 ~1-6(9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-13--enoic acid;
13t-5-iodo-6~1-6(9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-yhenoxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6~1-6(9~)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-11~,15S-dihydroxy-prost-13-ynoic acid;
13t-5-iodo-6~1-6(9~)-oxide-11~,15S-dihydroxy-prost-13-ynoic acid;
5-iodo-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy prost-13-ynoic acid;
5-iodo-6~H-6(9~)-oxide-20-methyl-11~,15S-dihydroxy-prost-13-ynoic acid, [~]D = ~ 20 (CHC13).
Example 94 To a solution of 0.22 g of 5c,13t-9~ ,15S-trihydroxy-15-methyl-PGF2~-methyl ester in 10 ml of C1l2C12 and 0.1 ml of pyridine is added drop-wise to a solution of 180 mg of iodine in methylene chloride. The resulting mixture is stirred for 1 hour. After dilution with water and washing of the organic phase l~ith O.lN sodium thiosulfate and water until neutral~ the solu-tion is evaporated in vacuum to a small volume and adsorbed on a silica gel plate 0.5 mm in thickness. After development with ethyl ether and elution with acetone, 0.052 g of 13t-15-methyl-5-iodo-6~H-6(9~)-oxide-11~,15S-di-hydroxy-prost-13-enoic acid methyl ester and 0.021 g of the isomeric 5-iodo-6~1-6(9~)-oxide are obtained.
Example 95 0.288 g of 5c-16,16-dimethyl-9~ ,]5S-trihydroxy-prost-5-enoic acid methyl ester in a solution of 60 mg of pyridine in methylene chloride (8 ml) is reacted with 115 ml of bromine in methylene chloride. After 30 minutes, starting material has completely disappeared; the organic phase is washed with water, then 5% aqueous metabisulfite, and then water until neu-/0~
- 1~

~8~

tral to gi~e, after removal of the'solvent and purification by TLC on silica gel with ethyl cther as eluent, 0.083 g of 16,16-dimethyl-5-bromo-6~H-6(9~)-oxide-prostanoic acid methyl ester and 0~04 g of 6oH-diastereoisomer~
The following compounds were prepared analogously:
13t-16,16-dimethyl-5-bromo-6~l-6~9a)-oxide-lla,15S-dihydroxy-prost-13-enoic acid;
13t-16,16-dimethyl-5-bromo-6~H-6~9a)-~oxide-lla,15S~dihydroxy-prost-13-enoic acid.
Example 96 To a solution of hydrotribromide pyrrolidone ~1.1 molar equivalents~
in anhydrous tetrahydrofuran ~6 ml) is added a solution of 5c,13t-9a,11a,15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5,13-dienoic acid methyl ester-11,15-bis-tetrahydropyranyl eth~r (0,7 g) in 6 ml of tetrahydrofuran~ The mixture is stlrred for 12 hours, the precipitatc which forms is removed by filtration, and the tetrahydrofuran solution is diluted with 2 volumes of acetone and treated with 4 g of potassium iodide. After 4 hours at room temperature, the iodine liberated is decomposed with sodium metabisulfate.
1.5 volumes of O.lN aqueous oxalic acid is then added and the mixture heated to 48 C for 4 hours. The mixture is reduced under vacuum and extracted with ethyl acetate. Separation on TLC gives 0.1~ g of 13t-5-bromo-6H-6(9a)-oxide-lla,15S dihydroxy-18~19,20-trinor-17_cyclohexyl-prost_13_enoic acid methyl ester and 0,11 g of the 5-bromo-6~H-6(9~)-oxide.
Using procedures of the examples 95 and 96, the following 6(9~)-oxides were obtained:
5-b~olno 6~l~6~9a~oxide 11~,15S~dihydroxy~18,19,20 trinor 17-cyclohexyl prost-13~ynoic acid methyl ester;
5-bromo-6~l-6t9a)-oxide-11-~,15S dihydroxy-prostanoic acid;

~ /0 -~, 13t-S-bromo-6~H-6C9a~-oxide~ ,15S~dihydroxy-prost-13~enoic acid;
13t-20-methyl-5-bromo 6~H~6~9a)-oxide~ ,15S-dihydroxy prost-13-enoic acid;
13t-15-methyl-5-bromo-6~H-6(9a)-oxide-lla,15S-dihydToxy~prost-13~enoic acid;
13t-15-methyl-5-bromo-6~-6(9a)-oxide-ll~,lSS-dihydroxy-prost-13-enoic acid;
13t-16S-methyl-5-bromo-6~H-6~9~oxide-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~-oxide-lla,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoic acid;
13t-5-bromo~6~H-6(9~-oxide-lla,15S-dihydroxy-17,18,13,20-tetranor-16-m-tri-fluoromethyl-phenoxy-prost-13-enoic acid.
Example 97 A solution of 0.1 x 10 3 M of a methyl ester, prepared according to examples 93 to 96 in 2 ml of methanol is treated with 1 ml of an aqueous solution of llthium hydrate ~0.2 x 10 3 moles). The mixture is stirred for 3 hours, evaporated nearly to dryness, diluted with 5 ml of water, and extracted with ethyl ether.
The organic phase is washed with O.lN LiOH ~2N) and water, and is then discarded. The aqueous phase is acidified to pH 4.8 with 30% aqueous NaH2PO4 and extracted with ethyl ether to give the free acid.

-~o_

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of formula (I) (I) wherein R is a member selected from the group consisting of (a) a free or esterified carboxy group; (b) wherein each of the R' groups, which are the same or different, is C1-C6 alkyl or phenyl; (c) -CH2OH; (d) wherein Ra and Rb are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkanoyl and phenyl; (e) a radical ; (f) ;

Z1 is hydrogen or halogen;
p is zero or an integer of 1 to 7;
R1 is hydrogen, hydroxy, C1-C6 alkoxy, ar-C1-C6-alkoxy, acyloxy;
Y is a member selected from the group consisting of -CH2-CH2-, , (cis) and (trans), wherein Z2 is hydrogen or halogen;
one of R2 and R5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl, and the other is hydroxy, C1-C6 alkoxy, ar-C1-C6-alkoxy or R2 and R5 , taken together, form an oxo group; each of R3 and R4, which are the same or different, may be hydrogen, C1-C6 alkyl or fluorine or R3 and R4, taken together with the carbon atom to which they are linked, form the radical or the radical each of n1 and n2, which are the same or different, is zero or an integer of 1 to 6;
X is a member selected from the group consisting of -O-, -S- and -(CH2)m-, wherein m is zero or 1;
R6 is a member selected from the group consisting of:
(a') a C3-C9 cycloaliphatic radical, unsubstituted or substituted by one or more substituents selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy;

(b') a saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, halo-C1-C6-alkyl, C1-C6 alkyl and C1-C6 alkoxy; provided that when X is -O- or -S-, R6 is not cycloalkyl; and the pharmaceutically or veterinarily acceptable salts thereof, said process comprising:
a) halocyclizing a compound of formula (II) (II) wherein p, Y, n1, n2, R3, R4, X and R6 are as defined above, D is cis- or trans-CH=CH-, R'' is (a'') a free or esterified carboxy group; (b'') a group wherein each of the R' groups is as defined above (c'') the group -CH2-R7, wherein R7 is hydroxy or a known protecting group bound to the -CH2- group by an ethereal oxygen atom; (d") wherein Ra and Rb are as defined above; (e") a radical of formula ; (f") -C?N;

R'1 is hydrogen, hydroxy, C1-C6 alkoxy, ar-C1-C6-alkoxy, acyloxy or a known protecting group bound to the ring by an ethereal oxygen atom;
one of R'2 and R'5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and the other is hydroxy, C1-C6 alkoxy, ar-C1-C6-alkoxy or a known pro-tecting group bound to the chain by an ethereal oxygen atom, or R'2 and R'5, taken together, form an oxo group, so obtaining, after the removal of the known protecting groups, if present, a compound of formula (I) wherein Z1 is halogen and, if necessary, deetherifying and/or, if desired, dehalogenating the obtained compound to give a compound of formula (I) wherein Z1 is hydrogen;
or b) reducing a compound of formula (III) (III) wherein R, p, R1, Y, R2, R5, R3, R4, n1, n2, X and R6 are as defined above;
Q is halogen or a group ?HG(+)z(-) , wherein Z(-) is OH(-) or the anionic residue of an acid, so obtaining a compound of formula (I) wherein Z1 is hydrogen; and, if desired, reducing a compound of formula (I) wherein R2 and R5 taken together, form an oxo group and Y is -CH=CZ2- wherein Z2 is as defined above, to give a compound of formula (I) wherein one of R2 and R5 is hydrogen and the other is hydroxy and Y is -CH=CZ2- wherein Z2 is as defined above, or, if desired, converting a compound of formula (I) wherein R2 and R5, taken together, form an oxo group and Y is -CH=CZ2- wherein Z2 is as defined above, into a compound of formula (I) wherein one of R2 and R5 is hydroxy and the other is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and, if desired, etherifying a compound of formula (I) wherein one of R2 and R5 is hydroxy and the other is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and Y
is -CH=CZ2- wherein Z2 is as defined above to give a compound of formula (I) wherein one of R2 and R5 is C1-C6 alkoxy or ar-C1-C6-alkoxy and the other is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and Y is -CH=CZ2-wherein Z2 is as defined above, and/or, if desired, hydrogenating a compound of formula (I) wherein Y is -CH=CZ2 wherein Z2 is hydrogen, to give a compound of formula (I) wherein Y is -CH2CH2- or, if desired, dehydrohalogenating a compound of formula (I) wherein Z1 is hydrogen and Y is -CH=CZ2- wherein Z2 is halogen, to give a compound of formula (I) wherein Y is and Z1 is hydrogen or, if desired, hydrogenating a compound of formula (I) wherein R2 and R5, taken together, form an oxo group and Y is -CH=CZ2- wherein Z2 is hydrogen, to give a compound of formula (I) wherein R2 and R5, taken together, form an oxo group and Y is -CH2CH2- or, if desired, dehydrohalogenating a compound of formula (I) wherein Z1 is hydrogen, R2 and R5, taken together, form an oxo group, and Y is -CH=CZ2- wherein Z2 is halogen, to give a compound of formula (I) wherein Z1 is hydrogen, R2 and R5, taken together, form an oxo group and Y is and, if desired, reducing a compound of formula (I) wherein R2 and R5, taken together, form an oxo group, to give a compound of formula (I) wherein one of R2 and R5 is hydrogen and the other is hydroxy, or, if desired, converting a compound of formula (I) wherein R2 and R5, taken to-gether, form an oxo group, into a compound of formula (I) wherein one of R2 and R5 is hydroxy and the other is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and, if desired, etherifying a compound of formula (I) wherein one of R2 and R5 is hydroxy and the other is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl, to give a compound of formula (I) wherein one of R2 and R5 is C1-C6 alkoxy or ar-C1-C6-alkoxy and the other is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl; and/or, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, salifying a compound of formula (I) and/or, if desired, obtaining a free compound of formula (I) from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers.

2. A process according to claim 1 wherein Y is -CH=CH- (trans) or , R6 is a C5-C7 cycloaliphatic radical and Z1 is hydrogen, the process including a dehalogenation step to convert Z1 from a halogen to hydrogen if necessary.

3. A process according to claim 1 wherein R or R'' is a carboxy or methoxy-carbonyl group, p is 3, Z1 is hydrogen, bromine, chlorine or iodine. R1 or R1' is hydroxyl or protected hydroxyl or acetoxy, Y is or (trans) wherein Z2 is hydrogen or bromine, R2 and R5 or R2' and R5' together form an oxo group or R2 or R2' is hydrogen and R5 or R5' is hydroxy or protected hydroxy, R3 and R4 are each hydrogen or fluorine, X is (CH2)m wherein m is zero, n1 and n2 are both zero and R6 is cyclopentyl, cyclohexyl, cycloheptyl, 2'-tetrahydrofuryl or 2'-tetrlhydrothienyl.

4. A process according to claim 3 wherein Z1 is hydrogen or bromine, Y is (trans) wherein Z2 is hydrogen or bromine, R2 and R5 or R2' and R5' together form an oxo group, R3 is hydrogen, R4 is hydrogen or fluorine and R6 is cyclohexyl.

5. A process according to claim 3 wherein Z1 is hydrogen or bromine, R1 or R1' is hydroxyl or protected hydroxyl, Y is (trans) wherein Z2 is bromine, R2 or R2' is hydrogen, R5 or R5' is hydroxy or protected hydroxy and R6 is cyclohexyl.

6. A process according to claim 3 wherein R or R" is a carboxy group, Z1 is hydrogen, bromine or iodine, R1 or R1' is hydroxy or protected hydroxy, Y is or (trans) wherein Z2 is hydrogen, R2 or R2' is hydro-gen, R5 or R5' is hydroxy or protected hydroxy, R3 is hydrogen and R4 is hydrogen or fluorine.

7. A process according to claim 6 wherein R6 is cyclohexyl, cyclo-heptyl, 2'-tetrahydrofuryl or 2'-tetrahydrothienyl.

8. A process according to claim 3 wherein Z1 is hydrogen or bromine, R1 or R1' is hydroxy or protected hydroxy, Y is -C?C-, R2 or R2' is hydrogen, R5 or R5' is hydroxy or protected hydroxy, R3 is hydrogen, R4 is hydrogen or fluorine and R6 is cyclohexyl.

9. A compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

10. A process for the preparation of 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.,15-di-hydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester which comprises reducing the corresponding 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.-hydroxy-15-oxo-16S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester.

11. A process according to claim 10 in which the reduction is effected by reaction with sodium borohydride.

12. A process according to claim 10 wherein the 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.-hydroxy-15-oxo-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester is prepared by reacting 5-(6'-exoformyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octan-3'{-yl(pentanoic acid methyl ester with [2-oxo-3(S,R)-fluoro-4-cyclohexyl-butyl]-dimethylphosphonate.

13. 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.,15-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester when prepared by a process according to claim 10, 11 or 12 or an obvious chemical equivalent thereof.

14. A process for the preparation of 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha.,15-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester which comprises reducing the corresponding 15-oxo-compound.

15. A process according to claim 14 in which the reduction is effected by reaction with sodium borohydride.

16. 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha.,15-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester when prepared by a process according to claim 14 or 15 or an obvious chemical equivalent thereof.

17. A process for the preparation of 11.alpha.,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-6.beta.H-6(9.alpha.)-oxide-prost-13-ynoic acid methyl ester which com-prises dehydrating and reducing 5c-9.alpha.,11.alpha.,15S-trihydroxy-17-cyclohexyl-18,19,20-trinor-prost-5-en-13-ynoic acid methyl ester 11,15-bis-THP-ether and hydrolyz-ing the 11,15-bis ether so obtained.

18. A process according to claim 17 in which the dehydration and reduc-tion is effected by reaction with mercuric acetate followed by reaction with sodium borohydride.

19. 11.alpha.,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-6.beta.H-6(9.alpha.)-oxide-prost-13-ynoic acid methyl ester when prepared by a process according to claim 17 or 18 or an obvious chemical equivalent thereof.