CA1194021A - Heteroprostaglandin derivatives and processes for preparing them - Google Patents

Abstract

Stephan GERO, Jeanine CLEOPHAX, Jean-Claude BARRIERE and André CIER

HETEROPROSTAGLANDIN DERIVATIVE AND PROCESSES FOR PREPARING THEM

Abstract of the disclosure Prostanoic acid derivatives represented by the general formula :

in which X represents hydrogen or hydroxy, X1 represents hydrogen or X
and X1, when they are taken together with the carbon atom to which they are attached, represent a carbonyl group and Z represents hydrogen or hydroxy and pharmaceutically acceptable alkali metal salts thereof.

They can be used as bronchodilators and/or inhibitors of blood-plateletaggregation.

Description

HETEP~O-PROSTAGLANDIN DERIVATIVES AND PRO OE SSES EOR PREPARINC' THEM.
This invention relates to prost~glandin derivatives and is concerned with novel compounds related in structure to prostanoic acid which has the structural formula :

:~ 3 10~ ~ 2~ CH2~ \CH/ \CH2/

CH2~ / C~ 2~CE /~e 2~ CE2/ lo and which,in accordance lith common usage, can also be written as follo~s :

~,/COOT~

~ , , The presant invention is also concerned with a process for preparing the said novel compounds.
The prostaOlandin darivatives of the invention which are ll-llydroxy-l3-oxa-pros-tanoic acid derivatives, can be represented by the general formula ", / 1 ~ " ~ ~ ~ COOE

HO

7 in which X represents hydrogen or hydro~y, X1 represents hydrogen or X
and X1 when they are -ta~.en together with the carbon atom to which the~
' ~

are a-ttached represent a carbonyl group and Z represents hyclrogen or hydroxy.
The invention also relates to the pharmacologi-cally acceptable salts of the compounds of formula I such as, for example, the salts resulting from the action of -the said compounds of formula I and an alkali me-tal hydroxide such as sodium hydroxide.
In ano-ther aspec-t the present inven-tion relates to a process for preparing pros-tanoic acid derivatives of the general formula (I) ~"~
~ ~O~H (I) ~""~~0 ~
HO z wherein X represents a hydrogen atom or a hydroxy group, Xl represents a hydrogen atom, or X and Xl taken together with the carbon atom to which they are attached represent a carbonyl group, and Z represents a hydrogen atom or an hydroxy group and pharmaceutically acceptable alkali metal salts thereof characterized in that 25 (a) to obtain an acid of general formula (I) wherein X represents a hydrogen atom or a hydroxy group and Xl represents a hydrogen atom, a compound of general formula D' ~ CO2H

RO

2~

wherein R represents an hydroxy-protec-ting group of the formula -CH2Rl, Rl being an aryl or aralkyl radical, D' represents a radical / CH2 or /~H~ OR, R being as defined above, and z' represents a hydrogen atom or a radical O-R, R being as defined above, is hydrogen-olysed on platinum charcoal or palladium char-coal at room temperature and in a suitahle medium (b) to obtain an acid of general formula (I) wherein X and Xl taken together with the car-bon atom to which they are attached represent a carbonyl group, a (6-carboxyhexyl)-3(R)-heptyloxy derivative of general formula r X~ ~,,LO2H
~ 1-~0 H~ z wherein Z is as defined above, is dethio-acetalised with mercuric chloride in a suitable solvent and in the presence oE
boron trifluoride e-therate and (c) -to ob-tain a pharmaceu-tically acceptable alkali metal salt of an acid of general formula (I), a suitable alkali metal hydro-xide is :reacted wi-th an acid of general formula II).
The present invention also relates to novel chiral

- 3 -compounds. These compounds are particularly useful as intermediate compounds for preparing prostaglandin deriva-tives and especially the prostaglandin derivatives of formula I above.
The novel chiral compounds in question are cyclo-pentene derivatives which can be represented by the general Eormula:

i ~ -B
~ Ia RO~

in which R represents a hydroxy-protecting group of the formula -CH2Rl in which Rl represents an aryl or aralkyl radical, O O
B represents -CH or -CH ~ and A is such that:

- when B represents -CH, A represents CH2 or \ C "

- when B represents -CH ~ , A represents / C~ ~ , ~ CH2, ~ C = O or \ CHIllOH
With respect to Rl, suitable meanings for aryl can be, for instance, phenyl substituted or not by a methyl radical and for aralkyl appropriate values can be, for example, benzyl substitu-ted or not in the aromatic moiety by a methyl radical.
As a preferred value for R, benzyl can be cited.
Thus, preferred compounds covered by general formula Ia, are the following:
2-Formyl-~ (R)-benzyloxy-2-cyclopentenone-e-thylenedithio-acetal referred to hereinafter as <~Synthon A.

- 3a -2-Formylpropyleneacetal-4 (R)-benzyloxy-2-cyclopentenone-ethylenedithioacetal referred to hereinafter as Synthon B.
2-Formylpropyleneacetal-4 (R)-benzyloxy-2-cyclopentenone re~erred to hereinafter as Synt~on C.
2-Formylpropyleneacetal-4 (R)-benzyloxy-2-cyclopentenol referred to hereinaf-ter as Synthon D.
l-Formyl-3 (R)-benzyloxy-1-cyclopen-tene reEerred to herein-after as <~Syn-thon E.
l-Formylpropyleneacetal-3 (R)-benzyloxy-l-cyclopentene referred to hereinaf-ter as Synthon F.
The p~esent invention in accordance with another aspect al50 rela-tes to a process Eor preparing the compounds of formula Ia. In particular, the present invention relates to a process for the preparation of cyclopentene derivati~es represented by the general formula ~Ia) A

-B (Ia) ~0 RO
wherein R represen-ts a hydroxy-protecting group of the formula -CH2Rl in which Rl represents an aryl or aralkyl Il /o radical, B represents -CH or -CH ~ and A is such that:

- when B represents -CH, A represents ~ CH2 or ~ C

- when B represen-ts -CH ~ , A represents \ C ~ ~ , \ / S
~ CH2, = C=O or = CHIIIOH, characteri~ed in that (a) to obtain a compound of formula (Ia) wherein - 3b -P2~

R is as defined above, B represents -CH and CH2 or / C ~ ~ an hexanedial derivative of general formula:
qR

~C=O
~H
o in which R has the same meaning as yiven above and ~ represents / C ~ ~ 2 is cyclised under inert atmosphere with pyrrolidine acetate or piperidine acetate in a suitable solvent and at a temperature in the range of from -10C to room temperature, (b) to obtain a compound of formula (Ia) wherein R is as defined above, s represents -CH ~ and A represents ~ CH2 or \ C

a cyclopentene derivative of formula ~-COiH

R~
wherein R is as defined above and A repre-sents ~ CH2 or / C ~ ~ , is treated with - 3c -.

1,3-propanediol at a temperature in the range of from room-temperature to 40C in a suitable anhydrous solvent in the presence of p-toluenesulphonic acid, (c) to ob-tain a compound of formula (Ia) wherein R is as defined above, B represents ~0 -CH ~ and A represents ~ C=O, a cyclo-~O
pentene derivative of formula ~ -C~O ~

~`
RO
wherein R is as defined above, is treated with neutral diphenylselenic anhydride at room-temperature and in a suitable soIvent and (d) to obtain a compound of formula (Ia) wherein R is as defined above, B represents ~O ~
-CH ~ and A represents,,CHlllOH, a cyclo-pentene deriva-tive of formula Ll ~-c~

.

RO

- 3d -wherein R is as defined above, is treated with diisobutyl aluminum hydride in a suit-able anhydrous solvent and at a tempera-ture in the range of from -10C to room-temperature.
The invention is also concerned with a method of using Synthons A to F as intermediate products for the pre~
paration of the compounds of Eormula I above.
In particular the present invention is also concerned with a me-thod of using Synthons B, D and F
referrecl to above for the prepara-tion of derivatives for-mula II) above, whereby a cyclopentane derivative of general formula:

~ \\~O ~ XXXIII

RO
Z' in which R represents a hydroxy-protecting group of the formula -C~2Rl in which Rl represents an aryl or aralkyl radical, Z' represents hydrogen or a radical -OR and E

2S represents / C~ ~ , \ CH2 or \ CHlllOR, R having the same meaning as given above for bo-th radicals, may be submitted to the following reactions:
a) hydrolysis of the formylpropyleneacetal group in an acid medium to ob-tain an aldehyde group h) trea-tment of the aldehyde group with the dianion of (5-carboxypen-tyl)-triphenylphosphonium bromide in accordance with -the conditions of the Wittig reaction to fix an ethylene carbon chain - 3e -2~

c) hydrogenolysis of platinum charcoal or palladium char-coal to saturate the ethylenic chain and deprotect the hydroxyl groups followed, when necessary, by dethio-acetalisation with mercuric chloride to forM a keto group, so as to obtain the required compounds of formula (I) above, the compounds of formula XXXIII being themselves obtained as follows:
A) - treatment of Synthons B or F with boron hydride followed by oxyda-tion of the borane formed to fix a hydroxyl group on the ethylenic bond, - reaction with a n-halogenoheptane derivative to etherify the hydroxyl group so formed and optionally:
elther : reduction of the ethylenedithioacetal group with Raney nickel or : dethioacetalisation with mercuric chloride to form a ketone group, reduction with lithium tri-sec-butylbol-ohydride to form a hydroxyl group and protection of the hydroxyl group so as to form the compounds of formula XXXIII
s) - protection of the free hydroxyl group of Synthon D
- treatment of the O-protected derivative obtained with boron hydride and subsequent oxidation of the borane so formed to fix a hydroxyl group on the ethylenic bond - reaction with a n-halogenoheptane derivative to etherify the hydroxyl group so formed so as to obtain the compounds of formula XXXIII in which E
represents ~ C~ O-R.
For the last fifteen years or so, prostaglandins have constituted a diversified and actively investi.gated research field. The chemical work that has been done in this field has resulted in the to-tal syn-thesis of numerous prostaglandins and their analogs.

- 3f -Since thromboxan (TXA2) and prostacyclin (PGI2) were discovered wi-th their physiological activities which oppose each other, a considerable amount of research work has been devoted to this type oE compound.
Bo-th subs-tances are biosyn-thetized in living organisms from arachidonic acid via endoperoxide (PGH2).
Thromboxans are formed in human platelets and induce platelet aggrega-tion, whereas prostacyclin, which is released from the vascular walls, inhibits such aggrega-tion. Thus, theoretically, -these -two compounds regula-te the forma-tion of each other and failure or disturbance of -this process of regulation causes the TXA2-PGI2 balance to be upset which in turn leads to cardiovascular diseases such as thrombosis, infarction and the like.
Prostanoic acid derivatives having a 13-hetero-atom and endowed with an inhibitory action on platelet aggregation have already been described in British Patent Application No. 2,028,805 A and in J. Med. ~hem. vol. 22, - 3g -~19~

No. 11 pp. 1402-1408 (1979).
In British Patent Application No. 2,028,oO5 A the heteroatom is nitrogen while in the J. ~led. Chem. reference in question the heteroatom is oxygen, a two-nitrogen bridge being fixed between the 9- and 11-positions giving rise to a 9,11-a~o derivative.
It has now been found that a new series of prostanoic acid derivatives, namely 11-hydroxy-prostanoic acid derivatives, in which the carbon atom in the 13-position has been replaced by an oxygen atom, presents pharma-cological properties generc~lly found in the prostaglandin series, more particularly an inhibitory effect on blood-platelet aggregation and/or a bronchodilating action.
In view of their pharmacological properties, the 13-oxa-prostaglandin derivatives of the invention are capable of being used therapeutically in the treatment of pathological states which affect the respiratory system, and especially asthma. Furthermore, these compounds can be used as antithrombotic agents -and in the treatment and prevention of cardio-vascular diseases or pathological conditions such as myocardial infarc-tion.
~nerefore, another object of the invention relates to a method of pl'OVO-king bronchodilati~ or inducing inhibition of blood-platelet aggregation in a host needing such treatment, method which comprises administering to said host an effective amount of at least one 13-oxa-prostaglandin of the invention.
For human therapy the compounds of the invention will be used at daily 25 dosages of 0.1 to l~o mg/kg by oral route and of 0.3 to 120 mg by aerosol administrations Yet another object of the present invention is to provide pharmaceutical and veterinary compositions comprising as an essential active ingredient at least one oxaprostaglandin of formula I or a pharmaceutically accep-3 table salt thereof~ in association with a pharmaceutical carrier orexcipient therefor.
All the compounds of the invention can be obtained from Synthons A to ~.
The process for preparing these Synthons A to ~ comprises a number of original steps starting from (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclohexanone, this latter compound being obtained from quinic acid, as described, for instance, by CLEOPHAX, LE30~L, GER0, AKHTAR, BARNETT, PEARCE in J.A.C.S., 1976, 98, 7110.
The process of the invention for the preparation of the chiral interme-diate compounds in question as well as for the preparation of the 13-oxa-prostaglandins of the invention can be summarized as follows :
A. Preparati n of S~nthon A
a) Reaction of (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclo-hexanone of formula :
nTT

~ II

in the presence of boron trifluoride etherate, with ethanedithiol at room-temperature and in an aprotic solvent such as, for example, benzene, toluene, chloroform or dichloromethane, to provide (3R, 4S, 5R)-3,4,5-trihydroxy-cyclohexanone-ethylenedithioacetal of formula :
OH

S ~ ~OH III
H

b) Treatment of the dithioacetal III with 1,1-dimethoxycyclohexalle in the presence of an acid catalyst such as, for example, sulphuric acid or p-toluenesulphonic acid, at room-temperature and in an aprotic solvent, for instance, N,N-dimethylformamide, to obtain (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclohexanone-ethylenedithio-acetal of formula :

OH

~ IV

~ ~ ~) Y

c) Protection of the free hydroxyl group of compound IV with a bromide of the formula R Br in which R has the same meaning as above, prefe-rably benzyl, in the presenca of an alkali metal hydride, for instance sodium hydride, preferably at 0C and in an aprotic solvent such as, for instance, N,N-dimethylformamide, dimethylsulfoxide or hexamethyl-enephosphoramide to prDvide (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclohexanone-ethylenedithioacetal derivatives o~ general formula :

S~ oCH2-R

L S ~
V
o in which R1has the same meaning as aoove and which can be used either isolated or not in the following step :
d) Treatment of the ether V with a stron~ inorganic acid, for instance hydrochloric acid, in an alcohol, for instance methanol, ethanol or isopropanol, and at the reflux temperature of the medium, to provide (3R, 4S, 5R)-3,4,5-trihydroxy-cyclohexanone-ethylenedithioacetal derivatives of general formula :
OCH2-R ~
L ~ ~ '' VI

OH

in which R1has the same meaning as above.
e) Oxidation of the diol VI by means of neutral lead tetraacetate or tri-phenylbismuth carbonate in an appropriate solvent, for example, toluene, and at room-temperature, to obtain 4-oxo-ethylenedithioacetal-hexane-dial derivatives of seneral formula :

lCH2-R `
-S~ cj \/ &= VII
10 S ~

"

in which R1has the same meaning as above.
f) Cyclisation of the acyclic dialdehyde VII in situ and under inert 15 atmosphere with pyrrolidine acetate or piperidine acetate in an appro-priate solvent, such as benzene or toluene, and at a temperature ran-ging from -10C to room-temperature, preferably at 0C5 to obtain 2-formyl-2-cyclopentenone-ethylenedithioacetal derivatives of general formula: It- ~' S S

~ -CHO VIII

in which R1has the same meaning as given above or Synthon A.
B. Pre~aration of Synthon B
Synthon ~ hereabove is treated with 1,3-propanediol at room-temperature and in the presence o p-toluenesulfonic acid, the treatment being carried out in an anhydrous solvent, for example benzene or toluene, which provides 2-formylpropyleneacetal-2-cyclopentenone-ethylenedithioacetal derivatives of general formula :

6 6 ' S S

5~ C f ?9 IX

~o 2 in which R1has the same meaning as given above or Synthon B.
C~ Preparation of Synthon C
Synthon B is:treated with neutral diphenylselenic anhydride at room-tem-perature and in an appropriate solvent, for instance dichloromethane, to provide 2-formylpropyleneacetal-2-cyclopentenone derivatives of general formula : 0 S~,,C\~ ~

C~2-R'l in which R~has the same meaning as given above or Synthon C.
D Preparation of Synthon D-.

Synthon C is treated with diisobutyl aluminium hydride in an appropriateanhydrous solvent, for instance benzene or toluene, and at a temperature ranging from -10C to room-temperature preferably at 0C to obtain 2-formylpropyleneacetal-2-cyclopentenol derivatives of general formula :

CH
L ~

2 'I

g~

~ 9 in which Rlhas the same meaning as given above or Synthon D.
E. Preparation of Synthon ~
a) Treatment of diols VI above under reflux with Raney nickel (catalyst of finely clivided nickel obtained by dissolving out with alkali the aluminium from a nickel-aluminium alloy)in an appropriate solvent, for instance ethanol, to provide (1R, 2S, 3R)-1,2,3-trihydroxy-cyclohexane derivatïves of general formula :

OCH~-R~

~ OH . XII
OH

in which R~has the same meaning as given above~
b) Oxidation of diols XII by means of neutral lead tetraacetate or triphenyl-bismuth carbonate in an appropriate anhydrous solvent, for example chlo-roform, and at room-temperature to obtain hexanedial derivati~es of genera:
formula :

C
~ \ /C=O XIII

\ /H
~_C

in which R~has the same meaning as given above.
c) Cyclisation of the acyclic dialdehydes XIII in situ and under inert atmosphere with pyrrolidine acetate or piperidine acetate in an appro-priate solvent, such as toluene, and at a temperature ranging from -10C to room-temperature, preferably at 0C, to obtain 1-formyl~1-cyclopentene derivatives of general formula :

~3-C~IU

~`
2 ~ XIV

in which R1has the same meaning as given above or Synthon E.
F. Preparation of Synthon F
Synthon E hereabove is treated with 1,3-propanediol at a temperature between room-temperature a~d 400C, for instance at 30C, and in the presence of p-toluenesu7fonic acid, the treatment being carried out in an anhydrous solvent, for example benzene or toluene, which provides 1-formylpropyl-eneacetal-1-CYclpentene derivatives of general formula :

3 -CH ~ XV

OCH -R~

in which R~has the same meaning as given above or Synthon ~.
G. Preparation of the 13-oxa-profita~landins of formula I
Synthon B or Synthon F is first treated with boron hydride in tetrahydro-furan at a temperature ranging from 0C to room-temperature and the borane so formed is oxidiæed with hydrogen peroxide in the presence of sodium hydroxide, at a temperature ranging from 0C to room-temperature, to obtain cyclopentane derivatives of general formula :

i 9 5 ~ ~ ~ / XVI
. P.1H2C0 \\~\\\ H

1~ 4~ ~1 in which D represents \ C ~ ] or = CH2 and R1has the same meaning as given above.
Different procedures are then applied to compounds XVI in accordance with the chemical structure of the 13-oxa-prostaglandin of formula I to be obtained.
I~ When X and X taken together with the carbon atom to which they are attached represent a carbonyl group and Z represents hydrogen or hydroxy.

a) Ireatment of compounds XVI in which D represents / C ~ in the presence of an alkali metal hydride, for instance sodium hydride, at room-temperature and in an appropriate solvent, for example N,N~
dimethylformamide, with a 1-halogero-n-heptane derivative of general formula :

CH2 \ CH2 \ CH2 \ c~3 XVII

in which Hal represents chlorine, bromine or iodine, and Z' represents hydrogen or a protected hydroxyl group of the formula OR in which R
has the same value as given above, thus providing 2(S)-formylpropylene-acetal-3(R)-heptyloxy derivatives of general formula :

S L ~ ~ XVIII

~1 o ~L ",~

3 R1H2CO ~

in which Z' and R~have the same meaning as given above.
b) Hydrolysis of compounds XVIII in the presence of trifluoroacetic acid in chloroform or hydrochloric acid in acetone or hydrochloric acid in anhydrous chloroform/isopropanol, under inert atmosphere, to obtain 2(S)-formyl-3(R)-heptyloxy derivatives of general formula :

~ CN

5-- 0/ ~ /

Z' XIX

in which Z' and R~have the same meaning as given above.
c) Treatment of compounds XIX under inert atmosphere, with the dianion of (5-carboxypentyl)-triphenylphosphonium bromide at room-temperature and in an appropriate anhydrous solvent such as, for instance, ethyl ether, in accordance with the conditions of the Wittig reaction, to obtain 2(S)-(6-carboxy-1-hexenyl)-3(R)-heptyloxy derivatives of genera~
formula :

S S
\C C/
~ \\\ ~(CH2)4-COOH XX

1 2 C ~ ~ ~
Z' in which Z' and R~have the same meaning as given above.
d) Deprotection of the hydroxyl groups of compounds XX by hydrogenolysis on platinum charcoal or palladium charcoal at room-temperature and in an appropriate medium, for instance an acetic acid/eth~nol medium, to obtain 2(S)-(6-carboxyhexyl)-3(R)-heptyloxy derivatives of general formula :

S S

~ ~ ~\ ~ COOH XXI

~~0/ \ ~
HO
Z
in which Z has the same meaning as in formula I.
e) Dethioacetalisation of compounds XXI with mercuric chloride in an appropriate solvent, such as aceione, and in the presence of boron tri1uoride etherate to give 2(S)-(6-carboxyhexy1)-3(R)-heptyloxy 10derivatives cf general formula :
o HO
z wherein Z has the same meaning as in formula I, which are the desired 13-oxa-prostaglandins of formula I.
II. When X and X each are hydrogen and Z represents hydro~en or hydrox~.
a) ~reatment of compounds X~ with a n-halogenoheptane deriv~tive as des~
20cribed in para G Ia) hereabove to obtain :
- when D represents = CH2 , 2(R)-heptyloxy-cyclopentane derivatives o general formula :

jC ~ l XX I

9 ~ 5 1~ ~0~
R~-H2C0 ~
Z' in which Z' and R1have the same meaning as given above.

- when D represents C ~ , the compounds of for~ula XVIII above / ~
which, after reduction under reflux and on Raney nickel, provide a mixture OI non-isolated products of general formu;a :

\ ~

~0~~

~ I
\\'~0/

~0/~
R,~-H2C0 7. l in which Z' and R~have the same meaning as given above, this mixture beir,g further hydrogenated at atmospheric pressure on Adams platinum (cata-lyst of platinum oxide prepared from chloroplatinic acid) to give the

4~

compounds of formula XXII above.
b) Hydrolysis of compounds XYII in the presence of an appropriate acid, for example trifluoroacetic acid or formic acid to give 2(R)-heptyloxy derivatives of general formula :

R
CH YUIII

~H2CO

in which Z' and P~have the same meaning as given above.
c) T-eatment of compounds XXIII, under inert atmosphere, with the dianion of (5-carboxypentyl)-triphenylphosphonium bromide at room-temperature and in an appropriate anhydrous solvent, for instance ethyl ether or dimethylsulfoxide~ in accordance ~lith the conditions of the Wittig reaction to obtain 1(S)-(6-carboxy-1-hexenyl)-2(R)-heptyloxy derivatives of general formula :

~ \\ ~ ~ COOH Y~IV

in which Z' and R1have the same meanin6 as given above.
d) Deprotection of the hydroxyl groups of compounds XXIV by hydrogenolysi6 on platinum charcoal or palladium charcoal at room-temperature and in ~n appropriate modium, for instanco an acetic acid/eth~nol medium, to obtain 1(S)-(6-carboxyhexyl)-2(R)-heptyloxy derivatives of general formula :

~9~

COOH

~ ~0/\_ ~~\~
HO -Z

wherein Z has the same meaning as in formula I, which are the desired 13-oxa-prostaglandins of formula I.
III. When X re~resents hydroxy, X1 represents hydrogen and Z repre_ents h~droGen or h~drox~.
These compo~nds can be obtained starting from 2(S)-formylpropyleneacetal-3(R) heptyloxy-cyclopentane derivatives OI general formula :

R~H2Co ~
c--~ XX~

~/'` ~`
~ H2C

in which Z' and R1have the same meaning as given above, these compounds being obtained in accordance with the following steps which comprise :
either \ / S ~
a) Treatment of compounds XVI, in which D represents C ~ with a n-halogenoheptane as described in para GIa) hereabove to obtain compounds XVIII.
b) Dethioacetalisation of compounds XVIII with mercuric chloride in an appropriate solvent, such as acetone, and in the presence of boron trifluoride etherate to give 1-sxo-~(R)-heptyloxy derivatives of general formula :

- ~7 -CH / I XXVI

~-/ ^ ~
R-H C0 ~~~

in which Z' and R1have the same meaning as given above.

c) Reduction.of the ketonic function using lithium tri-sec-butylboro-hydride as catalyst to give 3(R)-heptyloxy-cyclopentanol derivatives of general formula :
O /o/~
~ C / XXVII

in which Z' and R1have the same meaning as given above.
d) Protection of the free hydroxyl group of compounds XXVII with a bromide of the formula R Br in which R has the same meaning as above, prefe-rably benzyl, in the presence of sodium hydride &nd in an appropriate aprotic solvent to give the 3(R)-heptyloxy-cyclopentane derivatives which correspond to the compounds of general formula XXV.
or a) Protection of the free hydroxyl group of Synthon D with a bromide of -the formula R Br in which R has the same meaning as above~ preferably benzyl, in the presence of an alkali metal hydride, for instance sodium hydride, preferably at 0C and in &n aprotic solvent such as, for ins-r~
tance, N,N-dimethylformamide, dimethylsulfoxide or hexamethylenephospho-.,~. ~ .

ramide, to provide 2-formylpropyleneacetal-2-cyclopentene derivatives of general formula :

R~-H2CO CH

~ ~ O / XXVIII
\~ 11 R,,~-H2C~

in which R~has the same meaning as given above.
b) Treatment of compounds XXVIII with boron hydride as descxibed in para G) hereabove to obtain 2(S)-formylpropyleneac-etal-3(R)-hydroxy-cyclopentane derivatives of general formula :
0~

XXIX

~ ~ OH

in which R~has the same meaning as given above.
c) Treatment of compounds XXIX with a n halogenoheptane derivative as described in para GIa) hereabove to obtain 2(S)-formylpropyleneacetal-cyclopentane derivatives which correspond to the compounds of general formula XXV.
The compounds XX~ above are then submitted to the following reactions.
a) Hydrolysis in the presence of an appropriate acid, for example triflu-oroacetic acid, to obtain 2(S)-formyl-cyclopentane derivatives of general formula :

O
~ \\~CH XXX

R H CO

in which Z' c~nd R1have the same meaning as given above.
b) Treatment of compounds XXX under inert atmosphere with the dianion of (5-carboxypentyl)-triphenylphosphonium bromide at room-temperature and in an appropriate anhydrous solvent such as, for instance, ethyl ether in accordance with the conditions of the Wittig reaction to obtain 2(S)-(6-carboxy-1-hexenyl)-cyclopentane derivatives of general formula :

~ ~ COOH XXXI

in which Z' and R~have the same meaning as given above.
c) Deprotection o~ the hydroxyl groups of compounds XXXI by hydrogenolysis on plat-num charcoa1 or palladium charcoal at room-temperature and in an appropriate medium, for instance an acetic acid/ethanol medium, to obtain 2(S)-(6-carboxyhexyl)-3(R)-heptyloxy derivatives of general formula : OH

Z5 ~ ~\ COOII XXXII

~0/
HO

wherein Z represents hydrogen or hydroxy which are the desired 1~-oxa-prostaglandins of formula I.
With respect to the pharmaceutically acceptable salts of the heteropros-taglandins of formula I, these will be obtained, in a classical manner, by reacting the acid of formula I with an appropriate alkali metal hydro-xide, for instance, sodium hydroxide.
As regards the halogenoheptane derivati~esof formula XVII in which ~' represents an -OR group,these can be obtained from (S)-(-)heptane-1,2-diol described by K. MORI in Agr. Biol. Chem. 40, 1617 (1976).
This diol is tritylated to obtain the 1-0-trityl derivative and the 2-hydroxy is then protected using a bromide of the formula R Br in which R
has the meaning given above, preferably benzyl.
The 1-0 trityl is then deprotected and the free hydroxyl so regenerated is substituted by a halogen atom using conventional procedures so as to provide the compounds of lormula XVII in which Z' represents the -OR
group in questio~.
Tests were carried out in order to e~aluaie the pharmacological properties of the 13-oxa-prostaglandins of the invention.
Bronchodilatory ~ction This action was determined by verifying the relaxant action on the iso-lated guinea-pig trachea previo~lsly contracted with carbachol i.e. carba-moylcholin hydrochloride.
~or this purpose, spiral strips of about 3 mm in width of the tracheal tissue were maintained in a survival medium. The isometric tension of the guinea-pig tracheal preparations was continuously registered. An initial tension of 8 g was applied to each preparation. After a rest period of 60 minutes, a sub~aximal contraction was obtained by adding carbachol to the bath. When the contractile response of the preparation became reproducible 11(R)-hydroxy-13-oxa-prostanoic acid of formula I
was added to the bath either when the carbachol-induced contraction was at its maximum so as to appreciate its relaxant action or when the prepa-ration was completely relaxed so as to evaluate the influence o~ the acid on the basal tonus.
Under these conditions, 11(R)-hydroxy-13-oxa-prostanoic acid provoked a moderate decrease of the basal tonus of the guinea-pig tracheal prepara-tion.
The amplitude of this decrease depended on the dose employed of the pros-tanoic acid derivative.
Furthermore, the relaxant action at concentrations of about 10 5 and about 4.10 5 mol of 11(R)-hydroxy-13-oxa-prostanoic acid on preparations contrac-ted by 8.~o mol of carbachol was also found to be moderate~
In addltion, it was found that the relaxant effect in question was not similar to a ~ adrenoreceptor stimulant effect since in the presence of ~0 10 mol of propranolol, the relaxant effeci was not modified in either trial.
Inhibitory action on platelet a~gre~ation This test was performed in Yitro on citrated h~man plasma using thrombine as ag~regant agent.
Aggregation was carried out after incubation of the fraction of plasma rich in plateletsfor 20 min. at room-temperature in the presence of 5 ~l of ~1(R)-hydroxy-13~oxa-prostanoic acid of the invention in dimethylsulphoxide at a concentration of 1 mg/ml. The conlrols were incubated in a similar manner with 5 ~l of dimethy1sulphoxide.
The samples to be used for titration of thromboxane B2 were taken after 3 min. aggregation using 0.4 U/ml ofthrombine and in the presence of 100 ~g/ml of indomethacine and 100 ~g/ml of imidazole (100 ~l per 400 ~l of fraction rich in platelets).
The thromboxane B2 was then determined.
~5 In this test, the amounts of thromboxane B2 found were 857 n ~ml when the studied compound was present.
This -thus shows that when the oxaprostaglandin of the invention was used there was a 77%-decrease in thromboxane B2 and a 47%-inhibition of platelet ag~regation.
The therapeutic compositions of the invention can be made up in any form which is suitable for their administration in human and veterinary therapy.
For ease of administration, the composition will normally be made up in a dosage unit form appropriAte to the desired mode of administration, for example, a compressed tablet for perlingual administration, a pill, a powder, a capsule, a syrup, an emulsion for oral administration, a SU8-pension for oral or aerosol administration, a suppository for rectal ~L~3~Q~,~

administration or a sterile solution or suspension for parenteral adminis-tration.
The therapeutic compositions in question will be prepared in accordance with known techniques by associating at least one compound of the invention with an appropriate diluent or excipient and then, if required, making up the resul-ting admixture in the desired dosa~e unit form~
~xamples of suitable diluents and excipients are distilled water, ethanol, -talc, mc~gnesium stearate, starches, sugars and cocoa butt~r.
The preparation of compounds of the invention is illustrate by the follo-wing Examples.
EXA~LE 1 Preparation ~f 2-formyl-4(R -benzylox~-2-cyclo~entenone-ethylenedithioacetal or Synthon A (compound VIII with_~= phenyl) a) (3R, 4S, 5R)-3,4,5-trihydroxy-cyclohexanone-ethylenedithioacetal ________________________________________________________________ (compound III) ______________ To 8g of (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclohexanone (compound II) dissolved in 40 ml of anhydrous chloroform, 16 ml of ethane-dithiol and 1.6 ml OI freshly distilled boron trifluoride etherate were added. After one hour at room-temperature, thin layer chromatography was performed (solvent 3/1 chloroform/ethyl ether) and the starting compound was found to ha~e disappeared. The desired compound III precipitated as it WAS formed in the reaction medium and tJaS then dissolved by adding methanol.
The solution was neutralized with sodium bicarbonate, filtered and the sol-vents were evaporated off. The resulting solid was dissolved again in hot acetone and the insoluble salts were then filtered~
In this manner, compound III was obtained after crystallization from ace-tone.
Yield : 95%
M.P. : 12~-130C
aD : -41 (methanol, C=1.4% W/V) b) (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclohexanone-______________________ _______________________________ ___ __ ___ et~ylenedithioacetal (compound IV) ___ _______________.._ ____________ To 7g of the previously obtained compound III, dissolved in 30 ml of N,N-dimethylformamide, were added 8 ml of 1,1-dimethoxycyclohexane and o.5 ml of concentrated sulphuric acid. The methanol formed in the reaction was evaporated off ~rom time to time using a water pump so as to facilitate a shift in equilibrium leading to the desired compound IV. The reaction was terminated after two days at room-temperature as determined by thin layer chromatography (solvent : 3/1 chloroform/ethyl ether). The solution was diluted with dichlorome-thane and neutralized with sodium bicarbonate.
After filtration, the organic phase was washed with water and then dried on sodium sulphate and concentrated under reduced pressure~
In this manner, compound IV was obtained after crystallization from petroleum ether.
Yield : 95%
M.P. : 138-~40C
~D : -44 (chloroform, C=1.0Z~ W/V) 3 C N.M.R.
_ __ __ _ __ __ _ 15 N C. 1 2 3 4 5 6 7 8 __ _ ~(ppm);62.97 46.46 73.7679.67 71.55 41.59 40.16; 25.02 _ ~ (ppm) 23.72 24.04 . 35.35 110.09 38.01 38.21 c) (3R, 4S, 5R)-~,4-0-cyclohexylidene-5-0-ben~yl-3,4,5-trihydroxy-cyclo-_____________________________.________________________._____________ hexanone ethylenedithioacetal (compound V with R1= phenyl) ________________________________________________ _________ Into a three-necked flask were introduced o.845 g of sodium hydride and 47 ml of N,N-dimethylformamide under nitrogen at 0C. After that, 9 g of compound IV were added followed by 3.6 ml (1.3 equivalent) of ben3yl bromide once -the solid was dissolved. The reaction medium showed a orange-yellow colour. The reaction was terminated after three hours as determinedby thin layer chromatography (solvent : 3/l chloroform/ethyl ether). The hydride in excess was removed by adding methanol and the reaction mixture was first poured into iced water and then extracted with dichloromethane.
The organic phase was washed with water and dried on sodium sulphate~ Eva-poration of the solvents gave a yellow oil.
In this manner, the required compound V was obtained after crystallization - from aqueous ethanol.

Yield : 95~
M.P. : 68-690C
aD : ~5 (chloroform, C=1.06% W/V) Elementcil analysis C21 H28 3 2 Mol. Wt. : 3~2.587 calculated (%) C : 64.25 H : 7.19 . S : 16.34 .
found (%) C : 64~15 H : 6.96 S : 16.52 d) (3R, 4S, 5R)-5-0-benzyl-3,4,5-trinydroxy-cyclohexanone-ethylenedithio-acetAl (compound VI with R~- phenyl) The following reaction was effected directly from the raw compound V
(yellow oil) obtained previously.
In 120 ml of-methAnol ware dissolved 12 g of ra~ compound V. After that, 10 ml of 12 N-hydrochloric acid were added and the medium was heated to When the hydrolysis was complete, as determined by thin layer chromato-graphy (solvent : 3/1 chloroform/ethyl ether), the reaction medium WAS
diluted with dichloromethane and neutralized with sodium bicarbonate.
The solution was then filtered and evaporated. The residue was taken up in dichloromethane and the organic phase was washed ~lith water, dried on sodium sulphate, filtered and evaporated.
In this manner, the required compound VI was obtained after crystalliza-tion from ethanol or ethyl acetate.
Yield : 885o M~P. : 135-136C
25 aD : -72 (chloroform, C=1.03~ W/V) Elemental analys_s C15 H20 3 2 Mol. Wt. 312.457 calculated (%) C : 57.66 H : 6.45 S : 20.53 :
found (~o) C : 57.65 H : 6.5} S : 20.23 p~

13G N M R (d5 pyridine) N C 1 2 3 4 ; 5 6 7 8 9 -~(ppm) 65.4 . 40.2 . 69.2 ; 72.3 . 79.3 46.4 38.2 39.5 . 71.4 e) 2(R)-ben~yloxy-4-oxoethylenedithioacetal-hexanedial (compound VII
_~___________________________________________________________.___ in which R~= phenyl) __________ _________ In a coloured flask, 1.33 ~g (3 mM) of lead tetraacetate was dried using a vane pump so as to remove all traces of acetic acid. After this opera-tion, 100 ml of anhydrous toluene and 0.624 g (2 mM? of compound VI
previously obtained were added. The reaction medium was then stirred at room-temperature.
After an hour and a half, the reaction was terminated as determined by thin layer chromatography (solvent : 3/1 chloroform/ethyl ether) and 3 ml of ethylene glycol were then added to remove the lead tetraacetate in excess. ~lhen this excess has reacted, the solution became clear. The reaction medium was then diluted ~.ith dichloromethane and the organic phase was washed once with water, then with a saturated solution of sodium bic~rbonate and final1y with water to neutralityr The organic phase was then dried on sodium sulphate, filtered and evaporated.
In this manner, the required compound ~II was obtained in a quantitative yield in the form of a colourless oil wh ch acquired a yellow tint in the course of time and had therefore be used without delay.
aD : -11 ~chloroform, C=2.45~/V) As this compound is a particularly unstable product, it was reduced for characterization purposes thus giving 2(R)-benzyloxy-4-oxoethylenedithio-acetal-hexanediol.
~lemen-tal ~nalysis of this diol 15 22 3 2 Mol. Wt. : 314~473 _ calculated (%) . C : 57.29 H : 7.05 . S : 20.39 .
found ~%) C : 57.3 H : 6.47 . S : 20.18 ~4uaz:~
-- 2~ --~D: -20 (chloroform, C=1.45~ W/V) f) 2-E`ormyl-4(R)-benzyloxy-2-cyclopentenone-ethylenedithioacetAl _____________________________________________________________ (compound VIII in which R1= phenyl) __________________________________ In 20 ml of anhydrous toluene, 0.620 g of the raw compound VII previously

5 obtained was dissolved under nitrogen at 0C. After that, 0.5 ml of a 1N~
solution of pyrrolidine acetate in a~hydrous benzene was added. ~he reac-tion medium was allowed to stand for 18 hours at 0C under nitrogen At the end of this reaction time, thin layer chromatography (~ol~irent: 3/1 chloroform/ethyl ether) showed that the starting compound had completely 10 disappeared. The reaction medium was then diluted with dichloromethane and the organic phase was washed with water to neutrality, dried on sodium sulphate, fi~tered and evaporated.
In this manner, the required compound VIII or Synthon A was obtained in the form of a pale yellow oil which was stored at 0C in a coloured flask~
15 Yield: 95,0 N.MI~R. of the proton at 60 MHz _____________________________ :
c~(ppm) : H
2.7 2H5 (A-B system octuplei) 3-45 2H7 + 2H7, (multiplet) 20 ; 4.4 CH2 (phenyl) (singlet) 4.7 : H4 (sextuplet)

6.65 H3 (doublet)

7.2 : phenyl 9 5 H6 (singlet) . .
25 I.R. (CHCl ) __ -- 3 1685-1705 cm unsaturated c~,~-aldehyde M.S. (electron impact) _ ___ M _ 292 (201, 186, 91, 77, 65) 30 Preparation of 2-formylpropyleneacetal-4(R)-benzyloxy-2-cyclo~entenone-ethylenedithioacetal or Synthon B (compound IX in which R~l _ phen~l) The xeaction was carried out directly from the previously obtained ~satu-rated a,~-aldehyde.
In 50 ml of dry toluene, 0~550 g of compound VIII obtained in Example 1 f was dissolved and 1.5 ml of 1,3-propanediol together with a trace o p-toluenesulphonic acid were then added. At the end of a 2L~hour reactiontime, 3/4 of the volume was evaporated off using a rotatory evaporator~
After that, 1.5 ml of 1,3-propanediol and 50 ml of anhydrous toluene were added to shift the equilibrium in favour of the desired compound.
This operation was carried out again 24 hours later. The reaction was a7most terminated after 72 hours as determined by thin layer chromato-~raphy (solvent : 3/7 ethyl acetate/petroleum ether). However, there was still some of the starting aldehyde (5 to 10/') leftL ~he reaction medium was diluted with dichloromethane, and neutralized with sodium bicarbonate. ~fter filterin~ the salts, the organic phase was ~ashed with water, dried on sodium sulphate, filtered ar,d evaporated. The compound so obtained was then separated by thin layer chromatography (solvent :
3/7 ethyl acetate/petroleum ether). After the strip with the lower Rf value had been eluted with ethyl acetate and the solvents had been filtered and evaporated off, a colourless oil was obtained.
In this manner, the required compound IX or Synthon B was obtained after crystallization from petroleum ether.
Yield : 800,' M.P~ : 70-71C
~D : + 860 (chloroform, C=1.12/o W/V) 3C N.M.R. (d5 pyridine) _ __ __ _____ . N C . 1 2 . 3 . 4 5 ~ . 6` 7 8 . 8' 9 . l ~(ppm) (~) 1L;6.3 131.6 80.3 53.8 41.3 40.5 97.3 67.3 67.3 25.8 .7C
(~) not identified on the spectrum (quaternary carbon) ~lemental analysis 30 C18 H22 3 2 Mol. Wt4 : 350~506 ; calculated (~) C : 61.68 H : 6.32 S : 18.29 found (%) C : 61.41~ H : 6.28 ,S : 18.37 N.M.R. of the proton at 250 MHz (C~Cl ) ___________ 3 , ; ~ (ppm) , X
7.34 phenyl . 6.34 H3 J (H3-H4) ~ 2Hz 5-25 . 7 .
, 4.65 4 .
4-55 .CH2 (phenyl) 4.22 8a H8'a 3-9 H8e + H8'e 3.4 .2H6 + 2H6, . _ _ _ _ 2.95 5b ~ ~ 5b H5a) = 13,5 Hz : : ~ J(H ~ H4 ) = 6,5 Hz :
2.5 5a ~ sb ~ H5a) = 13.5 Hz . ~ J(H5~ - H4 ) = 5 Hz 2,2 9a -- -- -. 1.4 ' 9e .__ _ .

Pre aration of 2-form l ro leneacetal-4(R)-benz lox -2-c clo entenone P Y P PY Y Y Y P_ or Synthon C (compound X in which R1 - phenyl) To 0.180 g of compound IX obtained in Example 2 dissolved in 5 ml of anhy-drous dichloromethane was added 0.203 g (1.1 equivalent) of diphenylselenic anhydride (Ph2Se203) free from any trace of nitric acid.
After that, one drop of propylene oxide per 50 mg of starting compound was added so as to remove likely nitric acid remnants. At the end of a 20-hour reaction time, thin layer chromatography (solvent : 3/7 ethyl acetate/
petroleum 0ther) showed that the starting compound had disappeared and that a compound with a lower Rf value had been formed.
The reaction medium was slightly diluted with dichloromethane, neutralized with sodium bicarbonate, filtered and separated by thin layer chromato-graphy (solvent : ~/7 ethyl acetate/petroleum ether). ~he strip with the lower Rf value under U.V. light was eluted with ethyl acetate, filtered and the solvent was evaporated off.
In this manner, the required compound X or Synthon C was obtained in the form of a colourless oil cristallizinO from petroleum ether~
Yield : 680~
M.P. : Lt2-430C
[a~D = ~ 4Z (chloroform, C = lW/V) ~lemental anal~sis 16 18 4 Mol. Wt. : 274.316 Calculated (~) C : 70.5. H : 6.61 = . = = . ~ . . = .. . .
; found (,') . C : 70.14H : 6.60 N~M~Ro of the proton at 250 MHz (CHCl_) ____________~------~~~~~~~~~~~~~~~~~-~~~~

r ~ - (ppm) H _ -7.~ phenyl 5-3 H6 _ .
. L~.7 4 _ 20 . 4.6 CH2 (phenyl) 4.18 7a 7'a 3-9 H7e ~ N7'e _ _.
2.75 ; 5b ~ ( 5b _ H5a) = 18.5 Hz _ ~ (H5b H4 ) = 6 Hz . 2.43 . 5a ~ (H5b ~ H5a) = 18.5 Hz J (H5 - H4 ) _ 2~5 Hz ~, . 2.15 8a _ Hoe _ ~9~

EXAMPI,E 4 Preparation of 2-formYlpropYleneacetal-4(R2~benz~lox~-2-c~clopentenol or Synthon D (compound XI in which R1 ~ phenyl) To 2.44 g of compound X obtained in Example 3 dissolved in 53 ml of anhy-drous toluene, there were added, drop-by-drop, under nitro~en atmosphere and at 0C, 13.1 ml of diisobutyl aluminium hydr~de (1M commercial solution in hexane).
Thirty minutes later, thin layer chromatography (solvent : 3/1 chloroform~
ethyl ether) showed tha-t all the starting product has disappeared.
The reaction was stopped by slowly adding methanol at 0C. The solution was then poured into iced water saturated with sodium chloride and then taken up in dichloromethane. The organic fraction was dried on sodium sulphate and then evaporated to dryness. The oil so obtained was dissolved in a 3/1 mixture of chloroform/ethyl ether and this solution was first filtered on Celite (a commercially available diatomaceous silica product, the word "Celite" being a registered Trade Mark) and then evaporated to dryness. The desired product was crystallized from a dichloromethane/
petroleum ether mixture. The mother-liquors showed in ~.M.R. of the proton, the presence of another product which was the other isomer.
In this manner, the required compound XI or Synthon D was obtained.
Yield : 89~
M.P. : 88-900C
~1emental analysis C16 H20 4 Mol. Wt. : 276.336 _ _ _ 25 ; calculated ~%) C : 69.54H : 7.29 found (S') ; C : 69.36. H : 7.3 M.S.
_ ____ M = 276.

3o Preparation of 1-formyl-3(R)-benzyloxy-1-cyclopentene or Synthon E
(compound XIV in which R = phenyl) a) (1Rl 2S, 3R)-3-0-benzyl-1,2,3-trihydroxy-cyclohexane (compound XII in which_R1 __ph_nyl) In 80 ml of 95-ethanol was dissolved 1.3 g of compound VI obtained in Example 1d. When the product was completely dissolved, Raney nickel was added in considerable excess and the medium was refluxed for 12 hours. The reaction mixture was filtered on Celite and thoroughly rinsed with ethanol so as to eliminate all the Raney nickelO The oil so obtained was taken up in chloroform and filtered on Whatmann paper. The required compound crystal-lized ~rom petroleum ether.
In this manner, the required compound XII was obtained in a yield of 70~0.
M.P. : 59-60C (petroleum ether) 10 ~D = -830 (chloroform, C = 1.3 ~/V) Elemental analysis 13 18 3 : Mol. Wt. : 222.287 calculated (,~0) C : 70.24 H : 8.16 . .
. ~ound (%) C : 70.12 H . 8.11 M.S.
_ __ _ M = 222 b) 2(R)-benzyloxy-hexanedial (compound XIII in which R = phenyl) _____________________________--_----~ ---- 1 In 120 ml of anhydrous c~loroform were dissolved 2.34 g of compound XII
previously obtained and 5.7 g of lead tetraacetate were added by small frac-tions. The reaction was carried out protected from light and followed bythin layer chromatography (solvent : ethyl acetate/petroleum ether).
Ninety minutes later, the reaction terminated and ethyleneglycol was added to eliminate the lead tetraacetate in excess, When the solution was clear, it was taken up in dichloromethane washed with water, with sodium bicarbonate and again with water. The chloroform phase was dried on sodium sulphate and evapora-ted to dryness.
In this manner, the required compound XIII was obtained and directly reacted in the following step.
N.M.R. of the 2 aldehyde protons at 60 MHz : 9.6 ppm ~0 I.R. spectrum : C~lO at 1720 cm c) 1-Formyl-3(R)-ben~yloxy-1-cyclopentene (compound XIV in which R1 = phenyl ______________________________________________________________ _______ Compound XIII previously obtained was dissolved in 100 ml of dry toluene and - ~2 -reacted, under nitrogen atmosphere and at 0C, with 1 ml of a 2 N benzane solution of pyrrolidine acetate. The reaction medium was allowed to stand for about 8 hours at 0C and then poured into iced water. After being taken up in dichloromethane, the organic phase was dried on sodium sulphate and concentrated under reduced pressure. The a,~-unsaturated aldehyde so obtained, in the form of a clear yellow oil, was relatively unstable and was directly used, without purification in the following step.
In this manner the required compound XIV or Synthon E was obtained.
N.M.R. at 60 ~lz :
.
; ~ (ppm) . H

9.8 : aldehyde 7.~ phenyl 6.8 : = C~ :

I.R. spectrum : CH0 a,~ unsaturated : 1600 cm to 1710 cm 2X~ E 6 Preparation of 1-form~lpropyleneacetal-3(R)-benzyloxy-1 cyclopentenone or Synthon F (compound XV in which R1 = phenyl) To compound XIII obtaired in Example 5b dissolved in 100 ml of dry toluene~
there were added 10 ml of 1,3-propanediol and a trace of p-toluenes~phonic acid. The mixture was stirred at 30C with a rotatory evaporator for one hour and then kept under stirring for a further 24 hours. When the reaction was terminated, the reaction medium was diluted with dichloromethane and neutralized with sodium bicarbonate.
After 30 minutes of stirring at room-temperature, the solution was filtered and extracted with dichloromethane. After being washed with water, the orga-nic phase was dried on sodium sulphate and evaporated under reduced pressure to obtain a dark oil which was purified by thin layer chromatography (solvent 1/2 ethyl acetate/petroleum ether).
In this manner the reo.uired compound XV or Synthon F was obtained in the 3 form of a colourless oil.
Yield : 55~ (from compound XII) aD = ~ 74(chloroform, C - 1.4 W/V) ~ 33 -Elem~ntal analysis C16 H20 03 Mol. Wt~ : 260.333 _ _ _ calculated (%) C : 73.81H : 7~74 -found (,0) C: 73.81H : 7.71 lUU~lU ~/OJ `J ~r I ~

5 M.S.
M = 260.
EX~MPLE 7 Preparntion of 11(R)-hydroxy-13-oxa-prostanoic acid (X=X =Z=H) a) 1(S)-formylpropyleneacetal-2(R)-hydroxy-~(R)-benzylo~y-cyclopentane 10 (compound XVI in which D represents CY2 and R1 = phenyl) In a three-necked flask maintained under nitrogen or argon atmosphere was dissolved 1~5 g of compound XV obtained in Example 6 or Synthon E in 20 ml of freshly distilled tetrahydrofuran. hfter cooling to 0C, 2 equivalents of a lM commercial solution of boron hydride in tetrahydrofuran were added.

The medium was allowed to stand at O~C and tnen for 15 minutes at room-tem-perature~ After that, the reaction mi~-ture was oxidized. ~or this purpose, the diborane in excess was destroyed at 0C by adding, drop-by-drop, 1 ml of water, then 1.5 ml of a 3N-sûlution of sodium hydroxide and finally 3 ml of hydrogen peroxide. At the end of a 4-hour reaction-time, potassium carbonate was added. The mixture was diluted with ethyl ether and the ethe-real phase was decanted out, washed with water, dried on sodium sulphate and evaporated under reduced pressure.

After separation by thin layer chromatography (solvent : 1/2 ethyl acetate/

petroleum ethe~ there were obtained 0.950 g of the required alcohol (one isomer) and 0.190 g of the starting product.

In this manner, the required compound XVI was provided.

emental analysis C 1l 0 Mol. Wt. : 278.348 , cnlclllntcd (qO) C : 69.ol~ ~l 7.96 -30 . found (%) C : 68.85 H : 7.94 i aD = + 5 (7-5 mg/ml) b) 1(S)-formylpropyleneace~al-2(R)-heptyloxy-3(R)-benzyloxy-cyclopentane (compound XXII in which Z' = H and R1 = phenyl) Under nitrogen atmosphere and at 0C, 0.390 g of the required compound X\II
5 previously obtained was added in 10 ml of N,N-dimethylformamide, to o.600 g of an oily suspension of sodium hydride. Once the hydrogen evolution ter-minated, 0.7 ml of n-iodoheptane was added and the temperature was allowed to returl1 to room temperature. 'l~lo hours later, the reaction was complete fll1d the mixture WaS cooled to 0C and diluted with dichloromethane. The 10 hydride in excess was destroyed by adding methanol and the solution was poured into iced water saturated with sodium chloride.
After extraction with dichloromethane, the organic phase was dried on sodium sulphate and then evaporated under reduced pressure. After separa-tion by thin layer chromatography there was obtained 0.350 g of the requi-15 red ether.In this manner the required compound XXII was provided.
aD = + 5~ (chloroform, C = 1 W/V) E;lemental analysis C23 H36 4 Mol. Wt. : 376.537 .
calculated (~) C : 73.26 H : 9.63 -found (,0) C : 73-18 H: 9.62 .
Using the same procedure, 1(S)-formylpropyleneacetal-2(R)-[2(S)-benzyloxy-heptyloxy]-3(R)-benzyloxy-cyclopentane was prepared.
Elemental analy sls 25 C29 H42 5 Mol. Wt. : 470. 650 .
calculated (~) . C: 74.00 H: 8.99 found (~o) C: 73096 H: 8.95 c) 1(S)-formyl-2(R)-heptyloxy-3(R)-benzyloxy-cyclopentane (compound XXIII
in which 2' = H and R = phenyl) ________________---- 1 ---------30 Under nitrogen a-tmosphere, 0.740 g of the required compound XXII previously QZl obtained was dissolved in 5 ml of anhydrous chloroformO After that, 20 ml of 8~-formic acid were added and the reaction was monitored by thin layer chromatography (solvent : chloroform). After 24 hours, a further quantity of 10 ml of formic acid was added and the reaction was allowed to stand under nitrogen atmosphere for 24 hours.
The reaction medium was cooled and sodium bicarbonate was added.
When the pH of the medium was 4, the solution was poured into iced water saturated with sodium chloride~ This aqueous phase was taken up in di-chloromethane. The organic phase was washed with an aqueous solution of sodium bicarbonate to neutrality and then with water. After drying on sodium sulphate and evaporation of the solvents in a coloured flask, o.630 g of a clear yellow oil was obtained.
In this manner the required compound XXIII was provided.
I.R. spectrum : strip at 1705 cm M.S.
----M = 318 Using the same procedure, 1(S)-formyl-2(R)-[2(S)-benzyloxy-heptyloxy]
3(R)-benzyloxy-cyclopentane was prepared.
M~S.
_ __ _ M = 424 d) 1(S)-(6-carboxy-1-hexen-~l)-2(R)-heptyloxy-3(R)-benzyloxy-cyclopentane ._ ___________________________________________________________~______ (compound XX~V in which Z' = H and R = phenyl) ____________________________------- 1 ---------To 0.940 g of sodium hydride were added 19.6 ml of freshly distilled di-methylsulphoxide and the mixture was heated to 70~C for 1 hour. The solu-tion of sodium methylsulphinyl methide, which became a greyish green colour,was then transferred to a three-necked flask containing 4.48 g of (5-carboxypentyl)-triphenylphosphonium bromide maintained under argon atmos-phere. The medium, which immediately turned red, was allowed to stand for one hour at room-temperature.
After that, o.624 g of compound XXIII previously obtained dissolved under argon atmosphere in 19 ml of dimethylsulphoxide was added drop-by-drop to the ylide solution. The reaction medium was then allowed ~o stand for about 8 hours at room-temperature. The mixture was then poured into iced water containing a little sodium bicarbonate and the flask was rinsed with a 1~1 mixture of ethyl ether/petroleum ether. The aqueous phase was collected Z~

and -then acidified to pH = 3 by adding oxalic acid. The aqueous phase was washed four times with ethyl ether and the ethereal phases were collected, dried on sodium sulphate and evaporated off under reduced pressure. The mixture so obtained was purified by chromatography on a column (eluent :
1/1 ethyl acetate/petroleum ether).
In this manner, the required compound XXIV was obtained.
Yield : 33,C' aD = ~45 (chloroform, C = 0.35 W/V) Ele~ental analysis 10 Cz6 H40 4 Mol. Wt. : 416.606 calculated (æ) c 74.95 H : 9.68 found (5') C : 75.17 H : 9.70 M.S~
_ __ _ M = 416 Using the sa~e procedure, 1(S)-(6-carbox~-1-hexenyl)-2(R)-[2(S)-benzyloxy-heptyloxy~-3(R)-benzyloxy-cyclopentane was prepared.
Elemental analysis 32 46 5 Mol. Wt. : 510.715 :
: calculated (,Co) : C : 75.25 : H : 9.07 .
ound (~') C : 75.19 H : 9.0 M.S
_ __ _ ~.
M = 510 e) 11(R)-~ydroxy-13-ox3-prostanoic acid ___________________________________ Compound XXIV previously obtained was dissolved in a 1/1 mixture of acetic acid/eth~nol in the presence of 10~o-palladium charcoalO After a 48-hour period of hydrogenation in a Parr apparatus, the reaction medium was fil-~tered on Whatmann paper and then chromatographed on a column.
In this manner 11(R)-hydroxy-13-oxa-prostanoic acid was obtained.
Yield : 90~o aD = + 19 (chloroform, C = 0.73 W/V) ~7 Elementsl analysis 19 36 4 Mol. Wt. : 328.497 .
: calculated (%) : C : 69.47 : H : 11,04 : found (%) : C : 69.54 : H : 10.97 M.S.
M = 328 Usin~ the same procedure, 11(R)-hydroxy-13-oxa-15(S)-hydroxy-prostanoic acid was prepared.
Elemental analysis 10 C1g H36 5 Mol. Wt.: 344.492 - :
: calculated (~) C : 66.24 : H : 10.53 -: found (70) : r 66.18 : H : 10.60 M.S.
_ __ _ M = 344 EXA~IPLE 8 Preparation of 11(R~-hydroxy-13-oxa-prostanoic acid a) 2(S)-formyl~ropy~ ac~ta1-3(R)-hvdroxy-4(R)-bo~Tyloxy-cyclopentanone-ethylenedithioacetal (compound XVT in w'nich D represon-ts C S~
and R1 - phenyl) In a 50 ml three-necked flask maintained under nitrogen atmosphere was dissolved 0.700 g of compound IX obtained in Example 2 or Synthon B in about 5 ml of freshly distilled tetrahydrofuran. Using a syringe, 10 ml of a 1 M-commercial solution of boron hydride (BH3) ~n tetrahydrofuran was slowly added at 0C under nitrogen. The reaction medium was allowed to stand for about 15 hours at room-temperature during which time a light current of nitrogen was passed through the flask. The borane that formed was then oxidized. For thi, purpose -the hydride in excess was removed by slowly adding water (about 2 ml) at O~C. Still at the same temperature, 2 ml of a 3N-solution of sodium hydroxide were added followed by 2 ml of 30~o-hydrogen peroxide so as to oxidize the product. At the end of a 4 hour reaction-time, the reaction mixture was diluted with dichloromethane and poured into iced water saturated with amn~onium chloride. The solution was taken up in dichloromethane and the oE~anic phase was washed with water to neutrality, dried on sodium sulphate and e~aporated off. The oil so obtained, which still contained some of the starting compound, was sepa-rated by thin layer chromatography and the product with the lower R~
~alue was collected (sol~ent : 1/1 ethyl ether/petroleum ether).
In this manner, the required compound XVI was obtained in the form of a colourless oil.
Yield : 35~
aD: -4 (CDCl3, C = 1.27~o W/V) Elemental analysis 18 24 2 4 Mol. Wt. : 368.52 calculated (,') C : 58.66 H : 6.56 found (,~) - C : 58.99 H : 6 .74 N M.R. of the proton at 250 MHz (CDCl /TMS) _:_________---- 3 -(ppm) H

1. 4 8e 2.1 8a :
2. 37 5a 2 _ 2.6 5b _ _ _ 2.9 OH ~disappeared after addition 3.21 2H9 ~ 2~l9 3.82 7c 71 c : 3.95 : H3 . _ ~6 _ _ 5.18 . 7a 7'a 5.28 H

5.6 . CH2 (10) .
7.35 phenyl __C_N M.R._(CDCl3/TM

.
N C ; 1 2 3 4 5 6 :
: ~(ppm): 66.3 : 60.6 : 79 : 82.6 : 49.5 : 103.8 _ N C : 7 : 7' : 8 : 9 : 9' :10 : "_ : : : : : : :
10 : J (ppm) : 6608 : 66.8 : 2507 :40.7 :39.1 : 7107 M~S.
_ _ _ _ M = 368 b) 2(S)-fo.rmylpropy~ eneacetal-3(R)-heptyloxy-4(R)-ben2yloxy-cyclopenta-none ethylenedithioacetal (compound XVIII in which Z' = H and R = phenyl) ________________________________ -------------------------1 ---------15 Under nitrogen, a solution of 0.1 g of compound XVI previously obtained wasadded, in 5 ml of N,N-dimethylformamide, to a suspension of o.OL~ g of sodium hydride in 5 ml of N,N-dimethylformamide.
Once hydrogen evolution was terminated, 0.7 g of n-iodoheptane was introdu-ced. The reaction was monitored by thin layer chroma-tography (solvent: 1/1 20 ethyl ether/petroleum ether) and when this reaction terminated, the reaction medium was cooled to O~C and diluted with 10 ml of dichloromethane. The hydride in excess was removed by adding methanol. The solution was poured into sodium chloride-saturated iced water and then taken up in methylene chloride. The organic phase was washed three times with water, dried on 25 sodium sulphate and concentr~ted. The resultin~ oil was then separAted by thin layer chromatography (solvent: 1/1 ethyl ether/petroleum ether).
In this manner, the required compound XVIII was obtained in the form of a colourless oil.

Yield: 607~
Elemental analy si s 25 38 4 2 Mol~ Wt. : 466.71 calculated (~) : C: 64.34 : H: 8.20 : S: 13.74 : found (,~) : C : 64.42 : H: 8.o5 : S: 13.86 M.S.
_ _ _ _ Mt. 466 3C l~ M R . ( CDCl3/TMS) _ :
N C 1 : 2 : 3 : 4 : 5 : 6 : r7 7, ~ : : : : : : : :
10 :C) (ppm) : 67.8 : 58.6 : 84.5 : 84.1 : 48.2 : 102.7 : 66.3 : 66.5 :
:
N C: 8 : 9 : 9 ' : 10 : 11 : 12 : 13 : 14 ~ : : : : : : : :
,~ (ppm) : 25 :39 : 3&.5 : 70.8 :2~.7 : 317 : 29 :25~,5 :

N C :15 :16 :17 ~ : : : :
(ppm) : 22.5 :13 : 71.6 15 N.M.R. of the proton at 250 MHz _______________________________ :
d' (ppm) H
0.9 , CH3 (17) 1.27 . CH2 (13-14-15-16) 1.55 ~ 2(12) + H8e _ 20 . 2.1 Tl8 a 2,4 2 5 3.2 2(H9 + H9,) 3.5 CH~ (11) :
3.8 7e 7'e 4.1 H7 ~ H7, , H3~ H4 -. 4.6 CH2 (10) 4.95 H6 (doublet) J(H6 ~ H2) = 10 H7 .
7.3L~ phenyl .. ~
c) 1(S)~formylpro~yleneacetal-~(R)-heptyloxy-3(R)-benzyloxy-cyclopentane ___ _________________________________________________________________ (compound XXII in which Z' = H and R = ~henyl) ______________________------------ 1 ---------A solution of 0.1 g of compound X~III pre~iously obtained in ethanol was refluxed for about 15 hours in the preserce of Raney nickel. After filtra-tion on Celite the mixture was evaporated to dryness.
The 3 C N.M.R. and the proton N.~.R. spectra showed the presence of two products, one of which was unsaturated. The mixture was reduced, ln the presence of Adams platinum and at atmospheric pressure, which led to one single compound.
In this manner, compound XVI was obtained.
Yield : 6~' ~D : ~~ 5 (chloroform, C = 10 mg/ml) M.S.
_ __ M = 376 Elemental analysis 23 36 4 Mol. Wt. : 376.537 : crllclllc~ted (,~c~,): C : 73-3~ 9.63 25 ~ found (~)C : 73.18 ; H : 9.62 13 C N.M.R. (CDCl_/TMS) ____~____________,~_____ 2:L

N C 1 2 3 4 5 . 6 . 7 .
: ~ (ppm) : 48.8 :85.4 : 85 : 29.9 : 22.7 : 103.3 : 67 N C . 7' 8 9 10 11 12 13 ~ (ppm) 67 25.8 69~7 29.9 31.8 29.2 26.1 : N C : 14 : 15 : 16 ~ (ppm) 22.6 14.1 70.9 .

N.~l.R. of the proton at 250 MHz _______________ _______________ S ~ppm) H
7,35 . ~hen~l _ 10 ; 4.55 benzyl 4-45 ,H6 (doublet) J (~6 ~ H2) = 6 Hz _ ; 4.15 7e .
; 3~75 ;~I2~ H3~ H7a _ _ _ _ .
3.80 multiplet 0-CH (9) (chain) : . 2 2.05 1 H8a , 1.7 ;2H1 + 2H5 + H8e (complex mass) _ _ _ . _ ; 1.45 CH2 (10) 1.3 .CH2 (11-12-13-14) . o,9 .CH3 (15) d) 1(S)-formyl-2(R)-heptyloxy-3(R)-benzyloxy-cyclopen-tane (compound XXIII in __~__________________~____________________.______________________~_______ ~hich R = phenyl) In 4 ml of chloroform was dissolved 0.115 g of compound XXII previously obtained and then were added at 0C 3 ml of a 50~o-aqueous solution of tri-fluoroacetic acid. The reaction medium was then allowed to stand for 36 hours at room-temperature. After dichloromethane had been added, the reaction medium was neutralized with sodium bicarbonate, filtered and taken up in water. The aqueous phase was washed with dichloromethane, dried and evaporated. The mixture residue so obtained contained 50~ of the desired aldehyde and a residue of 40,~ constituted by the starting product. The aldehyde was separated by thin lay0r chromatography (solvent : chloroform) In this manner, compound XXIII was obtained.
M S.
M = 318 (227, 155, 129, 107, 92, 91, o3, 67, 65, 57, 55) N.M.R. of the ~roton at 60 ~z ______________ _______________ Doublet of the aldehyde proton at 9.2 ppm e) 1(S)-(6-carboxy-1-hexeny1)-2(R)-he~tyloxy-3(R)-benzyloxy~cyclopentane ._ ___________________.____________________________________._________ (compour.d XXIV in which Z' = H) _______________________________ This compound was obtained in accordance with the method described in Example 7 d) above.
f) 11(R)-hydroxy-13-oxa-prostanoic acid ____________________________________ Thi compound was obtained in accordance with the method described in Example 7 e) above.
~ YAMPLE 9 Prep~ration of 9(S)-hydroxy-11(R) hydroxy-13-cxa-prostanoic acid a) 1($)-Ben~yloxy-2-formylpropyleneacetal-4(R)-benzyloxy-2-cyclopentene ____________________________________________________________________ (compound XxvITI in which R = phenyl) ___________________--------1 ---______ ~o 0.1~7 g of sodium hydride were added 3 ml of N,N-dimethylformamide and the temperature was lowered to 0C.
After that, o.690 ~ of compound XI obtained in ~xample 4 or Synthon n, previously dissolved in 15 ml of N,N-dimethylform~nide, were introduced 30 followed by o.637 g (1~5 equivalent) of ben~yl bromide under nitrogen atmosphere and at 0C. ~'he medium was allowed to stand for ~ hours and monitored by thin layer chromato~raphy (solvent 3/1 chloro~orm/ethyl ether).
At the end of this period of time, the reaction medium was cooled and the hydride in excess was removed by adding methanol~

2~

The solution was poured drop-by-drop into iced water and then taken up with dichloromethane~ The organic phase was dried on sodium sulphate, filtered and evaporated to dryness.
ln this manner, the required compound XXVIII was obtained in the form of a colourless oil.
Yield : 90%
~ = ~460 ( chloroform, C = 1.17 W/V) Elemental analysis 23 26 4 Mol~ Wt. : 366. 461 : calculated (~0)C: 75.38 : ~ : 7.15 .
: found (~): C : 75.~5 : H : 7.18 (M -1)= 365 b) 1(S)-Benzyloxy-2(S)-formylpropyleneacetal-3(R~-hydroxy-4(~)-benzyloxy-_________________________________________________________________.____ cycloPentane (compound XXIX in which ~ = phenyl) _____:________________--------------- 1 ---------The whole reaction was carried out under nitrogen atmosphere and the appa-ratus was previously dried at 150C.
To 3.7 g of compound XXVIII previously obtained in 50 ml of freshly distilled tetrahydrofuran, was added drop-by-drop and at 0C 1 equivalent of a lM
commercial solution of boron hydride in tetrahydrofuran. After that, the reaction medium was allowed to stand at 0C for 2 hours and then overnight at room-temperature. The hydride in excess was destroyed at 0C by slowly adding the minimum quantity of water. Oxidation to alcohol was obtained by adding, at 0C, 2 ml of 6~ sodium hydroxide and 1.8 ml of ~O,~O-hydrogen pero~ide, The reaction was allowed to stand for 4 hours at room-temperature and then potassium carbonate was added. The mixture was filtered and co-piously rinsed with ethyl ether.
The ethereal phase so obtained was dried on sodium sulphate, filtered and evaporated to dryness. The alcohol so provided was crystallized from aqueous ethanol and the resulting mother liquors were separated out by chromatography on a column of silica gel (solvent : 1/2 ethyl acetate/
petroleum ether).

In this manner the required compo~md XXIX was obtained in a yield of 45%.
M.P. : 76-770C (ethanol/water) aD = +480 (chloroform, C = o.83 W/V) Elemental analysis C23 H28 5 Mol. Wt. : 384.477 : calculated (,o) : C : 71.85 : H : 7.34 _ . _ _ _ _ : founcl (~): C : 71.o6 : H : 7.33 c) 1(S)-Benzyloxy-2ts)-formylpropyleneace-bal-~(R)-hep-tyloxy-4(R)-ben cyclopentane (compound X~V in which Z' = H and R = phenyl) _________ ____ ______________-__-_------------ 1 ---------In a three-necked flask were placed 3 equivalents of an oily suspensionof sodium hydride under nitrogen atmosphere. After washing with dry hexane, 5 ml of N,N-dimethylformamide were added. ~he temperature was lowered to 0C and then 1g of compound XXIX previously obtained dissolved in 15 ml of N,~-dimethylformamide, was added.
Once hydrogen evolutior terminated, 1.~ ml of n-iodohep~ane (~ol Wt. 229, d = 1.37) was added. After about 8 hours at room-temperature, the reaction medium was cooled to 0C, diluted with dichloromethane and the hydride in excess was removed by adding methanol. The solution was then poured into iced water saturated with sodium chloride taken up with dichloromethane and dried on sodium sulpna~e. After evaporation to dryness, the desired product so obtained was purified by chromatography on a silica gel column (solvent : 1/2 ethyl acetate/petroleum ether).
In this manner the required compound XXV was obtained in the form of a colourless oil.
25 Yield : 75%
Elemental c~nalysis C30 H42 5 Mol. Wt. : 482.66 : calculated (~) : C : 74.65: H : 8.77 : found (~0) : C : 74.59: H : 8.82 3 aD = (chloroform, C = 1.7 W ~ ) -- 1~6 --Using the same procedure, 1(5)-benzyloxy-2(S)-formylpropyleneacetal-3(R)-~2(S)-benzyloxy-heptyloxy]-4(R)-benzyloxy-cyclopentane was prepared.
lemental analysis 36 48 6 Mol~ Wt. : 576.774 __ _ ._ : calculated (%) : C : 74.96 : H : 8.38 : found (,0) : C: 74. 89 : H : 8.40 d) 1(S)-Benzyloxy-2(S)-formyl-3(R)-heptyloYy-4(R)-benzyloxy-cyclopentane (compo~1d XXX in which Z' - H and R1 - phenyl) Under argon atmosphere, 1.5 ml o~ a 80,0-aqueous solution of formlc acid 10 was added to o.o85 g (0.176 m mol) of compound XXV previously obtained.
After about 8 hours at room-temperature, the reaction mixture was diluted with dry dichloromethane and sodium bicarbonate was added to obtain a pH
of about 4. The solution was taken up with anhydrous chloroform, washed with water to neutral pH, dried on sodium sulphate, filtered and evaporated to dryness.
In this manner, o.o63 g of the requirèd compound XXX was obtained in the form of an oil which e~entually turned yellow.
Yield : 9G~ -1 I.R. spectrum : CH0 at 1720 cm ~lemental analysis 27 36 4 Mol. Wt. : 424.581 : calcula-ted (%) : C : 76.38 : H : 8.54 : found (%) : C : 75.98 : H o.L~9 ~ sin~ the same procedure, 1(S)-benzyloxy-2(S)-formyl-3(R)-[2(S)-benzyloxy-heptylo~y]-4(R)-benzyloxy-cyclopentane was obtained.
Elemental analysis 31~ 42 5 Mol. Wt. : 530.705 : calcula-ted (%) : C : 76.94 : H : 7.97 O
: found (,') : C : 77.0 : H : 8.01 . .
e) 1(S)-Benzyloxy-2(S)-(6-earboxy-1-hexenylj-3(R)-heptyloxy-4(R)-benzyloxy-________________________________________________________________________ eyclopentane (eompound XXXI in whieh Z' - H and R1 - phenyl) This compound was obtained in aeeordanee with the Method deseribed in Example 7 d) above.
Elernent~l analysis C33 H46 5 Mol. Wt. : 522.726 : ealculated (%) : C : 75.82 : H : 8.87 : fourd (%) : C : 75.60 : H : 8.91 Using the same proeedure, 1(S)-benzyloxy-2(S)-(6-carboxy-1-hexenyl)-3(R)-~2(S)-benzyloxy-heptyloxy]-4(R)-benzyloxy-eyclopentane was provided, lemental analysis C40 H52 6 Mol. Wt. : 628.85 :
: caleulated (',~) : G : 76.39 : H : 8.35 :
: found (~) : C : 76.10 : H : 8.~9 `f) 9(S)-Hydroxy-11(R)-hydroxy-13-oxa-prostanoie aeid _______________________________________________ This eompound was obtained in aeeordanee with the method deseribed in Example 7e above.
E~lemental analysis 19 36 5 Mol. Wt. : 344.492 :
: c-~lculated (~) : C : 66.24 : H : 10.5~
:
: found (%) : C : 65.95 : H : 10.80 M~- _ 344 Using the same procedure, 9(S)-hydroxy-11(R)-hydroxy-13-oxa-15(S)-hydroxy-prostanoic acid was obtained.
Elemental analysis 19 36 6 Mol. Wt. : 360.491 : calculated (%) : C : 63.30 : H : 10.06 : ~ound (%) : C : 63.33 H : 9.05 _ .
M.S.
____ M = 360

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing 11-hydroxy-13-oxa-prostanoic acid derivatives of the general formula (I) (I) wherein X represents a hydrogen atom or an hydroxy group, X1 represents a hydrogen atom and Z represents a hydrogen atom or an hydroxy group and pharmaceutically acceptable alkali metal salts thereof characterized in that a compound of general formula wherein R represents an hydroxy protecting group of the formula -CH2R1,R1 being an aryl or aralkyl radical, D' represents a radical or CH?OR, R being as defined above, and Z' represents a hydrogen atom or a radical O-R, R being as defined above, is hydrogenolysed on platinum charcoal or palladium charcoal at room temperature and in a suitable medium, and if desired, the obtained acid of formula (I) is reacted with a suitable alkali metal hydroxyde to obtain a pharmaceutically acceptable alkali metal salt thereof.

2. 11-Hydroxy-13-oxa-prostanoic acid derivatives of the general formula (I) (I) wherein X represents an hydrogen atom or an hydroxy group, X1 represents a hydrogen atom and Z
represents a hydrogen atom or an hydroxy group and pharma-ceutically acceptable alkali metal salts thereof, whenever prepared by a process as defined in claim 1 or an obvious chemical equivalent thereof.

3. A process as defined in claim 1 wherein said medium is an acetic acid/ethanol medium.

4. 11-Hydroxy-13-oxo-prostanoic acid derivatives of the general formula (I) and pharmaceutically acceptable alkali metal salts thereof, as defined in claim 2 whenever obtained by a process as defined in claim 3 or an obvious chemical equivalent thereof.

5. A process as defined in claim 1 wherein R1 represents phenyl, phenyl substituted with a methyl radical, benzyl or benzyl substituted with a methyl radical in the aromatic moiety.

6. 11-Hydroxy-13-oxa-prostanoic acid derivatives of the general formula (I) and pharmaceutically acceptable alkali metal salts thereof, as defined in claim 2 whenever obtained by a process as defined in claim 5 or an obvious chemical equivalent thereof.

7. A process as defined in claim 1 wherein said medium is an acetic acid/ethanol medium, and R1 represents phenyl, phenyl substituted with a methyl radical, benzyl or benzyl substituted with a methyl radical in the aromatic moiety.

8. 11-Hydroxy-13-oxa-prostanoic acid derivatives of the general formula (I) and pharmaceutically acceptable alkali metal salts thereof, as defined in claim 2 whenever obtained by a process as defined in claim 7 or an obvious chemical equivalent thereof.

9. A process for preparing 11(R)-hydroxy-13-oxa-prostanoic acid of formula and pharmaceutically acceptable alkali metal salts thereof, characterized in that 1(S)-(6-carboxy-1-hexenyl)-2(R)-heptyloxy-3(R)-benzyloxy-cyclopentane is hydrogenolysed on palladium charcoal at room temperature and in a suitable medium said medium being an acetic acid ethanol medium, and, if desired, the obtained acid is reacted with a suitable alkali metal hydroxide to obtain a pharmaceutically accept-able alkali metal salt thereof.

10. 11(R)-hydroxy-13-oxa-prostanoic acid of formula and pharmaceutically acceptable alkali metal salts thereof, whenever obtained by a process as defined in claim 9 or an obvious chemical equivalent thereof.

11. A process for preparing oxa-15(S)-hydroxy-prostanoic acid of formula and pharmaceutically acceptable alkali metal salts thereof characterized in that 1(S)-(6-carboxy-1-hexenyl)-2(R)-[2(S)-benzyloxy-heptyloxy]-3(R)-benzyloxy-cyclopentane is hydrogenolysed on palladium charcoal at room temperature in a suitable medium, said medium being an acetic acid/ethanol medium and, if desired, the obtained acid is reacted with a suitable alkali metal hydroxide to obtain a pharmaceuti-cally acceptable alkali metal salt thereof.

12. 11(R)-hydroxy-13-oxa-15(S)-hydroxy-pros-tanoic acid of formula whenever prepared by a process as defined in claim }11 or an obvious chemical equivalent thereof.

13. A process for preparing 9(S) hydroxy-11(R) hydroxy-13-oxa-prostanoic acid of formula and pharmaceutically acceptable alkali metal salts thereof characterized in that 1(S)-benzyloxy-2(S)-(6-carboxy-1-hexenyl)-3(R)-heptyloxy-4(R)-benzyloxy-cyclopentane is hydrogenolysed on palladium charcoal at room temperature in a suitable medium, said medium being an acetic acid/ethanol medium and if desired, the obtained acid is reacted with a suitable alkali metal hydroxide to obtain a pharmaceutically acceptable alkali metal salt thereof.

14. 9(S) hydroxy-11(R) hydroxy-13-oxa-prostanoic acid of formula and pharmaceutically acceptable alkali metal salts thereof whenever prepared by a process as defined in claim 13 or an obvious chemical equivalent thereof.

15. A process for preparing 9(S)-hydroxy-11(R)-hydroxy-13-oxa-15(S)-hydroxy-prostanoic acid of formula and pharmaceutically acceptable alkali metal salts thereof, characterized in that 1(S)-benzyloxy-2(S)-(6-carboxy-1-hexenyl)-3(R)- [2(S)-benzyloxy-heptyloxy]-4(R)-benzyloxy-cyclopentane is hydrogenolysed on palladium charcoal at room temperature in a suitable medium, said medium being an acetic acid/ethanol medium, and if desired, the obtained acid is reacted with a suitable alkali metal hydroxide to obtain a pharmaceutically acceptable alkali metal salt thereof.

16. 9(S)-hydroxy-11(R)-hydroxy-13-oxa-15(S)-hydroxy-prostanoic acid of formula and pharmaceutically acceptable alkali metal salts thereof, whenever prepared by a process as defined in claim 15 or an obvious chemical equivalent thereof.

17. A process for preparing prostanoic acid derivatives of general formula (I) wherein Z representa a hydrogen atom or an hydroxyl group and pharmaceutically acceptable alkali metal salts thereof, characterized in that a (6-carboxyhexyl)-3(R)-heptyloxy derivative of general formula wherein Z is as defined above, is dethioacetalised with mercuric chloride is a suitable solvent and in the presence of boron trifluoride etherate and if desired the obtained acid of formula (I) is reacted with an appropriate alkali metal hydroxide to obtain a pharmaceutically acceptable alkali metal salt thereof.

18. Prostanoic acid derivatives of general formula (I) (I) wherein Z represents a hydrogen atom or an hydroxyl group and pharmaceutically acceptable alkali metal salts thereof, whenever prepared by a process as defined in claim 17 or an obvious chemical equivalent thereof.

19. A process as defined in claim 17 wherein said solvent is acetone.

20. Prostanoic acid derivatives of general for-mula (I) as defined in claim 18 and pharmaceutically acceptable alkali metal salts thereof whenever prepared by a process as defined in claim 19 or an obvious chemical equivalent thereof.

21. A process for preparing prostanoic acid derivatives of the general formula (I) wherein X represents a hydrogen atom or a hydroxy group, X
represents a hydrogen atom, or X and X1 taken together with the carbon atom to which they are attached represent a carbonyl group, and Z represents a hydrogen atom or an hydroxy group and pharmaceutically acceptable alkali metal salts thereof characterized in that (a) to obtain an acid of general formula (I) wherein X represents a hydrogen atom or a hydroxy group and X1 represents a hydrogen atom, a compound of general formula wherein R represents an hydroxy-protecting group of the formula -CH2R1, R1 being an aryl of aralkyl radical, D' represents a radical or, R being as defined above, and Z' represents a hydrogen atom or a radical O-R, R being as defined above, is hydrogeno-lysed on platinum charcoal or palladium char-coal at room temperature and in a suitable medium (b) to obtain an acid of general formula (I) wherein X and X1 taken together with the carbon atom to which they are attached repre-sent a carbonyl group, a (6-carboxyhexyl)-3(R)-heptyloxy derivative of general formula wherein Z is as defined above, is dethio-acetalised with mercuric chloride in a suitable solvent and in the presence of boron trifluoride etherate and (c) to obtain a pharmaceutically acceptable alkali metal salt of an acid of general formula (I), a suitable alkali metal hydroxide is reacted with an acid of general formula (I)

22. Prostanoic acid derivatives of the general formula (I) (I) wherein X represents a hydrogen atom or a hydroxy group, X1 represents a hydrogen atom, or X and X1 taken together with the carbon atom to which they are attached represent a carbonyl group, and Z represents a hydrogen atom or an hydroxy group and pharmaceutically acceptable alkali metal salts thereof, whenever obtained by a process as defined in claim 21 or an obvious chemical equivalent thereof.