CH660479A5 - PROSTAGLANDIN ANALOGS, THEIR PREPARATION, AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Description

The present invention relates to new prostaglandin I2 analogs, their methods of preparation and the pharmaceutical compositions containing them.

Prostaglandin I2 (also called PGI2 or prostacyclin) is a physiologically active natural substance having the following general formula (I):

3

660,479

1

COOH

HO- -

20

and its chemical name is epoxy-6,9 dihydroxy-11,15 prosta-dien-5,13 oic (5 Z, 13 E) - (9 S, 11 R, 15 S] [Nature, 263, 663 (1976), Prostaglandins, 12, 685 (1976), ibid., 12, 915 (1976), ibid., 13, 3 (1977), ibid., 13, 375 (1977) and Chemical and Engineering News, d. 20, 17 (1976)].

It is well known that PGI2 can be prepared by incubating Prostaglandin G2 (PGG2) or Prostaglandin H2 (PGH2) with microsomal fractions prepared from thoracic aorta, pork, pork mesenteric artery, rabbit aorta or the stomach part of rats. PGI2 has a strong relaxing action on the artery; this action is specific to the artery and does not exert on other smooth muscles.- In addition, PGI2 strongly inhibits the platelet aggregation of blood induced by arachi-donic acid in humans.

Considering the fact that tomboxane A2, prepared by incubation of PGG2 or PGH2 with platelet microsomes in the blood, has a contracting activity on the arteries and an agreeable activity on blood platelets, the properties of PGI2 mentioned above show that PGI2 fulfills a very important physiological role in the living body. PGI2 can be useful in the treatment of arteriosclerosis, atherosclerosis, heart failure, thrombosis, hypertension, angina pectoris or asthma.

Natural PGI2 is so unstable (it is deactivated in a buffer solution at pH 7.6 after 20 minutes at 22 ° C or after 10 minutes at 37 ° C) that the application of PGI2 for medical purposes is difficult.

Extensive research has been done to find processes for the chemical preparation of PGI2 analogs that are more stable, and to find products with pharmacological properties of "natural" PGI2, or more properties to a reinforced degree or pharmacological properties hitherto unknown. The result of extensive research and experimentation has been the discovery of the properties of "natural" PGI2 in certain analogs of PGI2 and their derivatives, certain aspects of its activities being improved or modified.

The present invention therefore provides new prostaglandin analogs of general formula:

Knockout

in which R1 represents a hydrogen atom or a straight or branched chain alkyl radical preferably containing 1 to 6 carbon atoms, Y1 represents a carbonyl or hydroxymethylene radical, zsss. represents a single or a double bond, A1 represents an alkylene radical containing 1, 2 or 3 carbon atoms and optionally carrying a methyl or ethyl substituent, R2 represents a hydrogen atom or a methyl or ethyl radical, R3 represents a d atom hydrogen or R2 and R3 form an alkylene radical containing 2 or 3 carbon atoms, optionally carrying a methyl or ethyl substituent so that the symbols A1, R2 and R3 together with the carbon atoms to which they are linked form a ring cycloalkyl containing 5, 6, 7 or 8 carbon atoms optionally carrying one or two methyl or ethyl substituents or A1 and R3 form together with the carbon atom to which they are linked a phenylene ring optionally substituted by halogen atom (such as chlorine, bromine, fluorine or iodine) or a trifluoromethyl radical or an alkyl or alkoxy radical in a straight or branched chain containing 1 to 6 carbon atoms. A2 represents a valence bond or a methylene radical optionally carrying one or two methyl or ethyl substituents, X1 represents an ethylene, vinylene-trans or ethylene radical, Y2 represents a carbonyl or hydroxymethylene radical and either i) A3 represents a straight alkylene chain or branched containing 1 to 5 carbon atoms, Z1 represents a valence bond or an oxygen or sulfur atom and R4 represents an aliphatic or alicyclic hydrocarbon radical, for example a straight or branched chain alkyl radical containing 1 to 12 atoms carbon optionally substituted by a cycloalkyl radical containing 3 to 8 carbon atoms or a mono, bi or tri-cycloalkyl or mono, bi or tri-cycloalkenyl radical containing up to 10 carbon atoms and optionally substituted by one or two alkyl radicals or straight or branched chain alkenyl each containing up to 3 carbon atoms, such as a cyclohexyl radical, or 6,6-dimethyl bicyclo [3.1.1.] hepten -2 yl-2, or represents a phenyl radical optionally substituted by a halogen atom (such as chlorine, bromine, fluorine or iodine) or by a trifluoromethyl radical or by a straight or branched chain alkyl or alkyl radical containing 1 to 6 carbon atoms, or ii) A3 and Z1 both represent valence bonds and R4 represents an aliphatic or alicyclic hydrocarbon radical, for example a straight or branched chain alkyl radical containing 1 to 12 carbon atoms optionally substituted by a cycloalkyl radical containing 3 to 8 carbon atoms, or a mono, bi or tri-cycloal-coyl or mono, bi or tri-cycloalkenyl radical containing up to 10 carbon atoms and optionally substituted by one or two alkyl or alkenyl radicals in straight or branched chain each containing up to 3 carbon atoms, such as a cyclohexyl or dimé-thyl-6,6 bicyclo [3.1.1.] heptén-2 yle-2, as well as their cyclodextrin clathrates and, when R1 represents u n hydrogen atom, their non-toxic salts.

In this description, when reference is made to the compounds of formula (II), it is understood that reference is also made to cyclodextrin clathrates and to non-toxic salts whenever the context so permits.

As will be noticed by a person skilled in the art, the compounds of general formula (II) have at least 4 chiral centers, these 4 centers being located on the carbon atoms in positions 8, 9, 11 and 12.

In addition to these 4 chiral centers, another chiral center appears when Y1 or Y2 represents a hydroxymethylene radical, and other chiral centers can also appear in the radicals A1, A2, A3, R1, R2 and R4 and in positions 2, 5. and 6. The presence of chiral centers leads, as everyone knows, to the existence of isomerism. However, the compounds of general formula (II) all have a configuration such that the hydrogen atoms attached to the bridged carbon atoms in positions 8 and 9 are in configuration and in relation to each other. Consequently, all the isomers of general formula (II) and their mixtures which have their two hydrogen atoms attached to the carbon atoms bridged in positions 8 and 9, in the eis configuration, form an integral part of the invention. Preferably, the hydrogen atoms attached in positions 8 and 9 are in the same configurations as those of PGI2, that is to say ß and ß respectively. Particularly preferred are compounds in which the side chain attached in position 12 is in relation to the hydrogen atoms attached to the bridged atoms in positions 8 and 9, and compounds in which the hydroxy radical attached in position 11 is in trans relative to the side chain attached in position 12.

Those skilled in the art will also note that can be in configuration (E) or (Z) when this symbol represents a double bond.

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According to one of the characteristics of the invention, the compounds of general formula (II) in configuration (5 Z) can be prepared by irradiation of the compounds of general formula (II) of configuration (5 E) \ one generally uses the ultraviolet irradiation and it is convenient to use the lines at 254 nm emitted by a low pressure mercury vapor lamp.

The compounds of general formula (II) which are especially important are those of general formula:

KO -

-Y

-A2 — C00R1 (III)

iWzV

in which A1, A2, A3, R1, R2, R3, R4, X1, Y1, Y2 and Z1 are defined as above, their enantiomers, their non-toxic salts and their cyclodextrin clathrates.

The classes of compounds of general formula (II) which are especially preferred are those which have one or more of the following characteristics:

i) A1 represents a methylene or ethylene radical,

ii) A2 represents a direct bond or a methylene or di-methylmethylene radical,

iii) A3 represents a direct bond or an alkylene chain containing 1 to 4 carbon atoms,

iv) R1 represents a hydrogen atom or a methyl or ethyl radical,

v) R2 represents a hydrogen atom,

vi) R3 represents a hydrogen atom,

vii) A1, R2 and R3 together with the carbon atoms to which they are linked form a cyclohexyl ring,

viii) A1 and R3 together with the carbon atom to which they are linked form a phenylene radical such as m-phenylene,

ix) R4 represents an alkyl radical containing 1 to 5 carbon atoms or a cyclohexyl or 6,6-dimethyl-bicyclo- [3.1.1.] hepten-2 yl-2 radical,

x) represents a double bond,

xi) X1 represents a vinylene-trans or ethylene radical,

xii) Y2 represents a hydroxymethylene radical and / or xiii) Z1 represents a direct bond, and the other symbols are defined as above.

The individual compounds of particular importance are:

A: (±) -Oxo-6amethano-6.9 dihydroxy-11.15 cyclohexyl-15 penta-nor-16,17,18,19,20 prosten-5 yn-13 methylate - (5 E) - ( 9 5, 11 R), [mixture of (15 R) and 15 (S)],

B: (±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 penta-nor-16,17,18,19,20 prosten-5 yn-13 methylate (5 Z) - ( 9 5, 11 R), [mixture of (15 i?) And (15 S)],

C: Acid (±) -oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 oic- (5 E) - (9 5 , '11 R), [mixture of (15 R) and (15 5)],

D: (±) -Oxo-6amethano-6.9 dihydroxy-11.15 prostadien-5.13 oethyl ester- (5 E, 13 E) - (9 S, il R, 15 R),

E: (±) -Oxo-6a methano-6.9 dihydroxy-11.15 prostadien-5.13 methyl oate- (5 E, 13 E) - (9 5, 11 R, 15 5),

F: Acid (±) - oxo-6a methano-6.9 dihydroxy-11.15 prostadien-5.13 oic- (5 E, 13 E) - {9 S, 11 R, 15 5),

G: (±) -Oxo-6a ethano-2,5 methano-6,9 dihydroxy-11,15 cyclo-hexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 ethyl acetate - (9 5, 11 R), [mixture of (15 R) and (15 S)],

H: (±) -Oxo-6a ethano-2,5 methano-6,9 cyclohexyl-15 dihydroxy-11,15 pentanor-16,17,18,19,20 prostadien-5,13 ethyl oate- (13 E) - (9 S, Il R, 15 5),

I: (±) -Oxo-6a ethano-2,5 methano-6,9 cyclohexyl-15 dihydroxy-11,15 pentanor-16,17,18,19,20 prostadien-5,13 ethyl oate- (13 E) - (9 5, 11 R, 15 R),

J: (±) -Oxo-6a ethano-2,5 methano-6,9 cyclohexyl-15 dihydroxy-5 11,15 pentanor-16,17,18,19,20 prostadien-5,13 demethyl ester- (13 E ) - (9 5, 11 R, 15 5),

K: (±) -Oxo-6a ethano-2,5 methano-6,9 dihydroxy-11,15 prostadien-5,13 demethylate- (13 E) - (9 5, 11 R, 15 5), L: (±) -Dimethyl-2,2 oxo-6a methano-6,9 dihydroxy-11,15 cyclo-îo hexyl-15 pentanor-16,17,18,19,20 prostên-5 yn-13 methylate- ( 5 E) - (9 S, 11 R), [mixture of (15 R) and (15 5)],

M: (±) -Oxo-6a methano-6.9 dihydroxy-11.15 ethyl-16-tetranor-17,18,19,20 prostên-5 yn-13 methylate- [mixture approximately 10/1 of (5 E) and (5 Z)] - (9 5, 11 R), [mixture of (15 R) and (15 S)], 15 N: Oxo-6a methano-6,9 dihydroxy-11,15 {dimethyl -6.6 bicyclo- [3.1.1.] Hepten-2 yl-2- (1 R, 5 R)} - 15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl oate- (5 E) - (9 5, 11 R), [mixture of (15 R) and (15 5)],

O: (±) -Oxo-6a methano-6,9 dihydroxy-11,15 phen-16-tetranor-20 17,18,19,20 prosten-5 yn-13 methylate- [mixture approximately 1/1 of ( 5 E) and (5 Z)] - (9 5, 11 R), [mixture of (15 R) and (15 5)], P: Oxo-6a methano-6,9 dihydroxy-11,15 {dimethyl- 6.6 bicyclo [3.1.1.] Hepten-2 yl-2- (1/1, 5 iî)} - 15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl oate- [ mix about 1/1. of (5 E) and 25 (5 Z) - (9 S, 11 R)], [mixture of (15 R) and (15 5)],

Q: (±) -Dimethyl-2,2 oxo-6a methano-6,9 dihydroxy-11,15 cyclo-hexyl-15 pentanor-16,17,18,29,20 prosten-5 yn-13 methyl oate- [mixture approximately 1/1 of (5 E) and (5 Z)] - (9 5, 11 R), [mixture of (15 R) and (15 5)],

30 R: (±) -Méthano-6,9 trihydroxy-6a, 11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prostên-5 yn-13 methylate- (5 E) - (9 5, 11 R), [mixture of (15 R) and (15 5)],

S: (±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 penta-nor-16,17,18,19,20 prostyn-13 methylateate- (9 S, 11 R), [mixture of (15 R) and (15 S)],

T: (±) -Méthano-6,9 trihydroxy-6a, 11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prostên-5 yn-13 methylate- (5 Z) - (9 S , 11 R) [mixture of (6a R) and (6a S)], [mixture of (15 R) and (15 5)], U: (±) -Oxo-6a methano-6,9 dihydroxy-11 , 15 cyclohexyl-15 penta-40 nor-16,17,18,19,20 prosten-5 yn-13 methyl oate- (5 E) - (9 S, lì R, 15 5),

V: (±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methylate- (5 Z) - (9 5, 11 R, 15 5),

45 W: Mixture of (±) -methano-6.9 trihydroxy-6a, 11.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl and ethyl oate- ( 5 Z) - [mixture of (6a R) and (6a 5)] - (9 5, 11 i ?, 15 5), X: (±) -methano-6,9 trihydroxy-6a, 11,15 cyclohexyl- 15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl oate- (5 £) - [mixture of so (6a R) and (6a S)] - (9 5, Ili1 ?, 15 5),

Y: (±) -Oxo-6a methano-6.9, dihydroxy-11.15 cyclohexyl- 15 m-interphenylene-1.5 octanor-2,3,4,16,17,18,19,20 prosten-5 yn-13 demethylate- (5 E) - (9 S, lì R, 15 5),

Z: (±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl- 15 m-55 interphenylene-1.5 octanor-2,3,4,16,17,18,19,20 prosten-5 yn-13 methyl oate- (5 Z) - (9 5, 11 R, 15 5),

AA: (±) -Oxo-6a methano-6.9 dihydroxy-11.15 prosten-5 yn-13 methyl oate- (5 Z) - (9 5, 11 i ?, 15 5),

BB: Mixture of (±) -methano-6.9 trihydroxy-6a, 11.15 prosten-5 "i yn-13 methyl and ethyl oate- (5 Z) - [mixture of (6a R) and ( 6a 5)] - (9 5, 11 R, 15 S),

CC: (+) - Oxo-6a methano-6,9, dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prostadien-5,13 methyl oate- (5 E) - (9 5, 11 R, 15 5),

65 DD: (+) - Oxo-6amêthano-6,9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prostadien-5,13 demethylate- (5 Z) - (9 5, 11 R, 15 5),

EE: (+) - Methano-6.9 trihydroxy-6a, 11.15 cyclohexyl-15 pentanor-

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16,17,18,19,20 prostadien-5.13 oate of methyl! E- (5 Z) [mixture of (6a R) and (6a S) - (9 S, 11 R, 15 S).

The letters A to EE are assigned to the compounds to facilitate references in the text of the description.

The compounds of general formula (II), their cyclodextrin clathrates and their non-toxic salts have remarkable pharmacological properties, for example properties typical of the related series of natural products known as prostaglandins.

In laboratory screening tests, the compounds cause in vitro in human platelet-rich plasma an inhibition of collagen-induced aggregation as indicated in table (I) below which gives the concentrations of the compounds to test (ED50) in (Jg / ml causing a 50% inhibition of aggregation.

Table I

Compound tested

DES0 (in | ig / ml)

AT

1.43

B

0.092

VS

0.81

E

10.8

G

> 5

In other laboratory tests, the compounds reduce the diastolic blood pressure in rats (anesthetized with pentobarbital) when administered intravenously at the doses indicated in table (II) below which indicates the dose (in jig per kg of animal body weight) necessary to drop the diastolic blood pressure by 25% (ED25).

Table II

Compound tested

OF,; (| i.g / kg)

AT

12.6

B

1.3

VS

13.9

D

> 150

E

111

F

> 30

G

210

H

202

I

2200

J

> 300

K

> 600

L

142

NOT

> 300

O

> 300

P

> 300

Q

> 300

R

> 100

Table II (continued)

Compound tested

DE ,, (ng / kg)

U

13.8

V

1.8

w

13.0

X

> 150

Y

> 600

Z

If 300

AA

1.8

BB

75

CC

> 600

DD

5.0

EE

29.5

In other laboratory tests, the compounds show a relaxing activity on the cut bands of ovine coronary arteries, as shown in Table III which indicates the minimum concentration (in | ig / ml) necessary to produce a measurable increase. (at least 1%) of the length of the artery.

Table III

Compound tested

Minimum concentration ((jg.ml)

AT

> 10

B

0.01

VS

1

G

> 10

PGI2 sodium salt

between 0.001 and 0.01

In other laboratory tests, the activity of compound B on the concentration of the guinea pig ileum is only one hundredth of the activity of the sodium salt of PGI.

These results are an indication of the usefulness of the products in the prevention and treatment of situations such as hypertension, thromboses, arteriosclerosis, atherosclerosis and cardiac situations such as angina pectoris and infarction. myocardium.

In addition, the compounds of general formula (11) are useful in the prevention and treatment of brain conditions such as anoxia.

In the tests, the mice are administered the product to be studied subcutaneously and, 30 minutes later, the mice are subjected to a hypoxic gas atmosphere (4% O 2 and 96% N,). The survival rate given in Table IV below measures the number of mice which experimentally survive for a statistically significant period compared to a group of control mice.

Table IV

Compound tested

Dose (ng / kg body weight of animal)

Survival rate (%)

B

1000

40

0

1000

20

T

1000

20

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Table IV (continued)

Compound tested

Dose (ng / kg body weight of animal)

Survival rate (%)

V

1000

50

W

1000

70

CC

1000

20

DD

1000

50

EE

1000

30

PGI2 methyl ester

300

45

The usefulness is reinforced by the fact that the compounds of general formula (II) are much more stable than natural PGI2, which makes possible their manipulation, their storage and their administration as well as those of their pharmaceutical compositions. ques.

According to a characteristic of the present invention, the compounds of formula (II) in which Y2 represents a hydroxymethylene radical can be prepared by acid hydrolysis of compounds of general formula:

ORs in which A1, A2, A3, R1, R2, R3, R4, ==., X1, Y1 and Z1 are defined as above and R5 represents a suitable acid-labile protective group.

This process is particularly applicable to the preparation of compounds of formula (II) in which R1 represents an alkyl radical, == ■ represents a double bond, X1 represents a vinylene-trans or ethylene radical, Y1 represents a carbonyl radical and Y2 represents a hydroxymethylene radical, that is to say the preparation of compounds of general formula:

0

JJO

OH

in which A1, A2, A3, R2, R3, R4 and Z1 are defined as above, X2 represents a vinylene-trans or ethynylene radical and R6 represents an alkyl radical in a straight or branched chain preferably containing 1 to 6 atoms of carbon, by acid hydrolysis of the compounds of general formula:

0

OR5

in which A1, A2, A3, R2, R3, R4, R5, R6, X2 and Z1 are defined as above in formula (IV).

The hydrolysis of the compounds of formula (IV) is generally carried out under mild acid conditions, for example by treatment with an aqueous mineral acid such as dilute hydrochloric acid or in catalytic amount of perchloric acid, or an aqueous organic acid, for example aqueous acetic acid such as 50-80% aqueous acetic acid (by volume), preferably in the presence of an inert organic solvent, for example a low molecular weight alcohol such as ethanol, or an ether such as diethyl ether or tetrahydrofuran, and optionally in the presence of a cation exchange resin such as Dowex AG50 W-X8 H + resin. The hydrolysis is generally carried out at temperatures between 0 and 100 ° C; when dilute hydrochloric acid is used, the procedure is between 40 and 80 ° C, preferably between 50 and 60 ° C; when using a catalytic amount of perchloric acid, it is carried out between 0 and 40 ° C, preferably between 15 and 25 ° C and, when using aqueous acetic acid, it is operated between 0 and 80 ° C, preferably between 35 and 50 ° C.

The acid-labile protective groups represented by R5 are those which are easily eliminated by acid hydrolysis and do not cause side reactions, for example the tetrahy-dropyrannyl-2 radical which is unsubstituted or substituted by at least one alkyl radical in straight or branched chain containing 1 with 4 carbon atoms, or the tetrahydrofuranyl-2 radical, or the tert.-butyldiphenylsilyl radical, or a trialcoylsilyl radical of general formula:

SiR7R8R9 (VII)

in which R8 and R9, identical or different, each represent a methyl or ethyl radical and R7 represents a straight or branched chain alkyl radical containing 1 to 4 carbon atoms, such as trimethylsilyl, triethylsilyl, dimethylisopropylsilyl or tert.-butyl-dimethylsilyl , or a 1-alkyloxy radical of general formula:

—CH (CH2R1 °) ORn (VIII)

in which R10 represents a hydrogen atom or a straight or branched chain alkyl radical containing 1 to 4 carbon atoms and R11 represents a straight or branched chain alkyl radical containing 1 to 4 carbon atoms, for example the ethoxy radical 1 ethyl.

Preferably, R5 represents the tert.-butyldimethylsilyl or triethylsilyl radical.

As another characteristic of the present invention, the compounds of general formula (IV) in which A1, A2, A3, R1, R2, R3, R4, X1, Y1 and Z1 are defined as above and Rs represents a radical of general formula ( VII) in which R7, R8 and R9 are defined as above can be converted into corresponding compounds of general formula (II) by treatment with a quaternary ammonium fluoride, preferably tetrabutylammonium fluoride, preferably in tetrahydrofuran and preferably at room temperature or at a temperature close to this, followed by treatment with water.

This process is particularly applicable to the preparation of compounds of formula (II) in which X1 represents an ethynylene radical and the other symbols are defined as above.

The compounds of formula (II) can be prepared from other compounds of formula (II). Thus, according to a characteristic of the present invention, the compounds of formula (V) can be converted into compounds of formula (II) in which A1, A2, A3, R1, R2, R3, R4, X1, Y1, Y2 and Z1 are defined as above but in which one or more symbols R1, r = i £, X1, Y1 and Y2 have the following meanings:

a) R1 represents a hydrogen atom,

b) == represents a single bond,

c) X1 represents a vinylene-trans or ethylene radical,

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d) Y1 represents a hydroxymethylene radical,

e) Y2 represents a carbonyl group,

or the salts of compounds of formula (II) in which R1 represents a hydrogen atom, or the cyclodextrin clathrates of the compounds of formula (II), by application or adaptation of one or more known methods for the preparation of acids with from esters, preparation of alcohols from ketones, preparation of ketones from alcohols, reduction of double or triple bonds, preparation of salts from acids or preparation of cyclodextrin clathrates. -

In addition, the esters of formula (II) in which R1 represents an alkyl radical can be prepared by esterification of corresponding carboxylic acids of formula (II) in which R1 represents a hydrogen atom. So,

1) the compounds of formula (II) in which R1 represents a hydrogen atom can be prepared from the corresponding compounds of formula (II) in which R1 represents an alkyl radical by hydrolysis, for example with an aqueous alkali (such as lithine, soda or potash), followed by treatment with a dilute acid such as hydrochloric acid, to give the desired product in the form of carboxylic acid from the solution of the alkali metal salt thus produced,

2) the compounds of formula (II) in which = represents a single bond and / or X1 represents an ethylene radical and / or one or the other of Y1 and Y2 or both together represent a hydroxymethylene radical (hereinafter designated by the name of “compounds of formula IIa”) can be prepared by reduction of compounds of general formula (II) in which represents a double bond and / or X1 represents a vinylene radical and / or one or the other of Y1 and Y2 or both together represent a carbonyl radical (hereinafter referred to as “compounds of formula IIb”),

So:

2a) the compounds of formula Ha in which one or both of Y1 and Y2 represent) a hydroxymethylene radical can be prepared by reduction of the corresponding compounds of formula (IIb) in which only one and one and the other of Y1 or Y2 represent) a carbonyl radical, using means and conditions capable of reducing the carbonyl radicals to hydroxymethylene radicals without affecting the multiple carbon-carbon bonds. The reduction is preferably carried out using a metal borohydride or a metal alkylborohydride (such as sodium or potassium borohydride or tri-sec.-lithium butylborohide), generally carrying out the reaction in medium aqueous, alcoholic or hydroalcoholic at a temperature between - 40 and + 30 ° C, preferably between - 5 and + 15 ° C, optionally in the presence of a base, for example an alkali metal hydroxide (such as soda or aqueous potassium hydroxide) when using a metal borohydride, or (especially when using potassium borohydride) in aqueous or hydroalcoholic solution in a buffered medium at pH between 7 and 9, such as pH 8 (for example by addition of an aqueous citric acid solution) or, when a metal alkylborohydride is used, in an ethereal medium (such as tetrahydrofuran) at a temperature between - 78 and 0 ° C.

The reduction can also be done if desired by the action of aluminum isopropylate in the presence of isopropanol, preferably as a solvent, at elevated temperature, advantageously at reflux of the reaction mixture.

2b) The compounds of formula Ha in which = represents a single bond and / or X1 represents an ethylene radical and Y1 and Y2 each represent a carbonyl or hydroxymethylene radical can be prepared by reduction of the corresponding compounds of formula (IIb) in which == represents a double bond and / or X1 represents a vinylene radical and Y1 and Y2 each represent a carbonyl or hydroxymethylene radical using means and conditions capable of reducing the double bonds without affecting the carbonyl radicals. The reduction is preferably carried out by hydrogenation in the presence of a hydrogenation catalyst, for example rhodium on activated carbon, in the presence of an inert organic solvent, for example a low molecular weight alcohol such as ethanol, generally at room temperature and under high pressure such as a pressure of 15 kg, cm2.

2c) The compounds of formula (IIa) in which = represents a single bond, X1 represents an ethylene radical and Y1 and Y2 both represent hydroxymethylene radicals can be prepared by reduction of the corresponding compounds of formula (IIb) using means and conditions capable of reducing any carbonyl radical present in the hydroxymethylene radical and any vinylene radical present in the ethylene radical.

The reduction is preferably carried out by hydrogenation in the presence of a hydrogenation catalyst, for example palladium on activated carbon, in the presence of an inert organic solvent, for example a low molecular weight alcohol such as ethanol, preferably under high pressure such as a pressure of 15 kg / cm2.

3) The compounds of formula (II) in which one or both of Y1 and Y2 represents (s) a carbonyl radical can be prepared by oxidation of the corresponding compounds of formula (II) in which one or both Y1 and Y2 represent) a hydroxymethylene radical, using means and conditions capable of oxidizing the hydroxymethylene radicals to form carbonyl radicals without affecting the rest of the molecule. The oxidation is preferably carried out by means of pyridium chlorochromate, preferably in dichloromethane. or by means of pyridinium dichromate, preferably in dimethylformamide or dichloromethane, at room temperature or a temperature close to this, or by means of a solution prepared from chromium trioxide, sulfuric acid and water, preferably in the presence of acetone and below room temperature.

4) Under the term "non-toxic salts" is meant the salts whose cations have relatively few harmful effects on the animal body when used in therapeutic doses, so that the beneficial pharmacological properties of parent compound of general formula (II) are unaffected by side effects attributable to these cations. Preferably, the salts are water-soluble. Suitable salts include the alkali metal salts, such as the sodium or potassium salt and the pharmaceutically acceptable (i.e. non-toxic) amine salts.

Amines suitable for forming such salts with carboxylic acids are well known and include, for example, the amines derived in theory from the replacement of one or more hydrogen atoms of ammonia by radicals which may be the same or be different when more than one hydrogen is replaced, chosen from alkyl radicals containing 1 to 6 carbon atoms, hydroxyalkyl containing 2 or 3 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, phenyl, phenylal-coyl containing 7 with 11 carbon atoms and phenylalkyl containing 7 to 15 carbon atoms in which the alkyl portions are substituted by hydroxy radicals. The phenyl radicals and phenyl portions of the phenylalkyl radicals can be unsubstituted or substituted by one or two alkyl radicals containing 1 to 6 carbon atoms. Suitable amines also include those theoretically derived from the replacement of two of the hydrogen atoms of ammonia with a hydrocarbon chain which can be interrupted by nitrogen, oxygen or sulfur atoms, forming together with the atom nitrogen of the ammonia to which these terminal radicals are attached, a 5 or 6-membered heterocycle containing nitrogen, which heterocycle may be unsubstituted or substituted by one or more alkyl radicals containing 1 to 6 carbon atoms. As an example of suitable amino cations, mention may be made of mono, di and trimethylammonium, mono, di and triethylammonium, mono, di and tripropylammonium, mono, di and triisopropylam-monium, ethyldimethylammonium, mono, bis and tris (hydroxy) cations. -2 ethyl) ammonium, ethylbis- (hydroxy-2 ethyl) ammonium, butylmo-no- (hydroxy-2 ethyl) ammonium, tris- (hydroxymethyl) methylam-monium, cyclohexylammonium, benzylammonium, benzyldimethvl-

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ammonium, dibenzylammonium, phenyl (2-hydroxyethyl) ammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, methyl-1 piperidinium, 4-ethyl morpholinium, isopropyl-1 pyrrolidinium, 1,4-dimethyl piperazinium, butyl-1 piperidinium, methyl- 2 piperidinium and 1 ethyl-2 methyl-piperidinium.

The non-toxic salts can be prepared from the parent compound of formula (II) by any known method, for example by the action of compounds of formula (II) (in which R1 represents a hydrogen atom) and of an appropriate base such as an alkali metal hydroxide or carbonate, ammonia or an amine in a suitable solvent which is preferably water in the case of the preparation of alkali metal salts and water or isopropanol in the case of amine salts.

The salts can be isolated by lyophilization of the solution or, if it is sufficiently insoluble in the reaction medium, by filtration, optionally after elimination of part of the solvent.

The salts of compounds of formula (II) in which R1 represents a hydrogen atom are as useful in themselves as pharmaceutically advantageous products as as a means of purifying the parent acids of formula (II), for example by using the differences in solubilities between the salts and the parent acids in water and in organic solvents, by techniques well known to those skilled in the art. The parent acids of formula (II) can be regenerated from their salts by known methods, for example by treatment with a mineral acid such as hydrochloric acid.

5) The cyclodextrin clathrates of prostaglandin analogs of general formula (II) can be prepared by dissolving the cyclodextrin in water or an organic solvent which is miscible in water in the presence of triethylamine and adding to solution l prostaglandin analog previously dissolved in an organic solvent miscible in water. The mixture is then heated and the desired cyclodextrin clathrate is isolated by concentration of the mixture under reduced pressure or by cooling and separation of the product by filtration or decantation. The level of organic solvent and of water can vary depending on the solubility of the starting materials and products. Preferably, the temperature of 70 ° C. is not exceeded during the preparation of the cyclodextrin clathrates. Cyclodextrin clathrates, cyclodextrins a, ß or y or a mixture thereof, can be used for the preparation.

The conversion of prostaglandin analogs to their clathrates is intended to increase their stability.

6) The compounds of formula (II) in which R1 represents an alkyl radical can be prepared by action on a corresponding carboxylic acid of general formula (II) in which R1 represents a hydrogen atom of an alcohol of general formula :

R6OH (IX)

in which R6 is defined as above, by using an excess of alcohol of general formula (IX) which serves as solvent and by operating in the presence of a mineral acid such as hydrochloric or sulfuric acid, preferably at a temperature comprised between 50 and 160 ° C and advantageously at reflux of the reaction mixture or, when R6 can be represented by the formula —CHRI2R13 [in which the symbols R12 and R13 are identical or different and each represent an alkyl radical (the total number of carbon atoms in the two radicals R12 and R13 preferably being equal to 11 maximum) or preferably a hydrogen atom], by the action of a diazoalkane of general formula:

R12R13C = N2 (X)

wherein R12 and R13 are defined as above in an inert organic solvent, preferably a dialkyl ether (such as diethyl ether), preferably at room temperature.

It is also possible to act on a silver salt of the carboxylic acid of formula (II) in which R1 represents a hydrogen atom on an alkyl halide of general formula:

R6Z2 (XI)

in which Z2 represents a halogen atom and R6 is defined as above, optionally in the presence of an inert organic solvent such as an aromatic hydrocarbon (such as benzene) at elevated temperature and advantageously at the reflux temperature of the reaction mixture, or still to act a sodium salt of said carboxylic acid of formula (II) on said alkyl halide in a polar solvent such as hexamethylphosphor-amide, preferably at room temperature.

The expression “known methods” as used in the present description means the methods used or described previously in the literature.

As will easily be appreciated by those skilled in the art, the compounds of formula (II) comprising their isomers originating from the chiral centers mentioned above can be separated by application or adaptation of known methods. For example, the diastereoisomeric forms can be separated by chromatography using the adsorption of solution or vapor phase on a suitable adsorbent support, and the enantiomeric forms of the compounds of formula (II) in which R1 represents a hydrogen atom can be separated by the formation of salts with an optically active base, followed by separation of the diastereomeric pairs obtained, for example by means of fractional crystallization in an adequate solvent system, followed by separate regeneration of the enantiomeric acids.

The compounds of formula (IV) can be prepared by application or adaptation of known methods, for example the methods illustrated in the description of the following reference examples for the preparation of the compounds of formula (VI).

The essential characteristics of the multistage process indicated for the preparation of the compounds of formula (II) are the key intermediates of general formula:

OB

in which the identical symbols R14 represent alkyl radicals each containing 1, 2 or 3 carbon atoms or else together form an ethylene bridge which may be unsubstituted or substituted, on each carbon atom, by identical alkyl radicals each containing 1 , 2 or 3 carbon atoms, the R14 radicals preferably forming together an ethylene bridge, the epoxy radical of figure (XII) preferably being in trans configuration with respect to the hydrogen atoms attached to the carbon atoms at the bridge and their preparation by methods such as the new process illustrated in reference example 3.

The key intermediates of general formula (XII) in which R14 is defined as above can be prepared by the action of compounds of general formula (XIII):

OH

in which one of the symbols R15 and R16 represents a halogen atom such as bromine and the other of the symbols RIS and R16 represents

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has a hydroxy radical, with a base. Preferably, R15 represents a halogen atom in configuration eis with respect to the hydrogen atoms attached to the carbon atoms at the bridgehead, and R16 represents a hydroxy radical in configuration trans with respect to R15.

The reaction can be carried out, for example, using an alkali metal hydroxide such as sodium hydroxide, in an alcoholic medium such as methanol, preferably at room temperature or below it.

The compounds obtained of general formula (XII) can be produced to form compounds of general formula (II) by application or adaptation of the methods illustrated in the following examples and reference examples.

The compounds of formula (XII) in which R14 is defined as above are new compounds and, as such, constitute an additional characteristic of the invention.

The following examples illustrate the preparation of the compounds of the present invention, and the reference examples that of the intermediate compounds of formula (VI). Reference example 3 illustrates the preparation of the key intermediate compounds of formula (XII).

The compounds prepared in the examples and the reference examples contain different chiral centers and, unless special mention, the products are mixtures of all the possible diastereoisomers, and each is accompanied by an equal amount of its enantiomer. However, the two hydrogen atoms attached to the bridgehead carbon atoms in the bicyclooctane rings are always in relation to each other.

According to the convention usually accepted, and in accordance with the structures set out in the drawings of the formulas above,

said bridgehead carbon atoms are said to be in the ß configuration, and the side chain attached to position 12 is in relation to said hydrogen atoms when said side chain is considered in the ß configuration. The designation (±) indicates that such compounds are in the form of their enantiomers in equal amounts.

Example 1 Compounds A and B

125 mg tert.-butyldimethylsilyloxy-3 (tert.-butyldimethylsilyl-oxy-3 cyclohexyl-3 propyn-1 yl) -2 (methoxycarbonyl-4 butylidene) -7 bicyclo [3.3.0] octanone-6, prepared as described in reference example 9 in the form (±) - tert.-butyldimethyl-silyloxy-3a [tert.-butyldimethylsilyloxy- (mixture of 3a and 3ß) cyclohexyl-3 propyn-1 yl] -2ß methoxycarbonyl-4 butylidene- (£) -7 bicyclo [3.3.0] octanone-6, containing about 11% isomer (7 Z), also known as oxo-6a methanone-6.9 bis (tert.-butyldimethylsilyloxy) - l 1.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl oate- (5 E) - (9 S, 11 R), [mixture of (15 R) and ( 15 S)] are treated with 7 cm 3 of a mixture of glacial acetic acid, water and tetrahydrofuran (13/7/2 by volume) and the mixture is stirred for 6 a quarter hours at 45 ° C. The mixture is then diluted with 50 cm3 of diethyl ether and washed successively with 10 cm3 of a saturated aqueous solution of sodium chloride, 3 times 20 cm3 of a solut saturated aqueous ion of sodium bicarbonate, 10 cm3 of water and 10 cm3 of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 53.7 mg of hydroxy-3 (3-hydroxy-3-cyclohexyl-propyn-1 yl) -2 (methoxycarbonyl-4 butylidene) -7 bicy-clo [3.3.0] octanone-6 is obtained. , in the form of a mixture (approximately 8/1 by weight) of (±) - hydroxy-3a hydroxy- (mixture of 3a and 3ß) cyclohexyl-3 propyn-1 yl) -2ß [nwthoxycarbonyl-4 butylidene- (E)] - 7 bicyclo [3.3.0] octanone-6, also known as (±) oxo-6a methano-6,9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19 , 20 prosten-5 yn-13 methylate- (5 E) - (9 S, 11 R), [mixture of (15 R) and (15 51)] and (±) -hydroxy-3a [hydroxy - (mixture of 3a and 3ß) cyclohexyl-3 propyn-1 yl-] 2ß [iMthoxycarbo-nyl-4 butylidene- (Z)] - 7 bicyclo [3.3.0] octanone-6, also known as (± ) oxo-6a methano-6,9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methylate- (5 Z) - (9 S, 11 R) , mixture of (15 R) and (15 5).

A 20 mg sample of the mixture is subjected to high pressure liquid chromatography and gives 6.5 mg of product as (E) isomer:

NMR spectrum (CDC13: 8 in ppm):

multiplets at 0.7-3.0, at 3.9-4.2 and at 6.3-6.7 singlet at 3.6-3.7 Mass spectrum: m / e = 388. 370 and 0, 8 mg of product as isomer (Z):

NMR spectrum (CDC13; 8 in ppm):

multiplets at 0.7-2.9, 3.9-4.2 and 5.8-6.1 singlet at 3.6-3.7 UV spectrum (ethanol):

Xmax = 247 nm, gmax = 10,000

Example 2

Compound C

A mixture of 17 mg of hydroxy-3 (3-hydroxy-cyclohexyl-3 propyn-1 yl) -2 methoxycarbonyl-4 butylidene) -7 bicyclo [3.3.0] octa-none-6, prepared as described in the example 1, in the form of a mixture (approximately 8/1 by weight) of (±) -hydroxy-3 [hydroxy- (mixture of 3a and 3ß) cyclohexyl-3 propyn-1 yl] -2 [(methoxycarbonyl- 4 butylidene- (£)] - 7 bicyclo [3.3.0] octanone-6, also known as (±) oxo-6a methano-6,9 dihydroxy-11,15 cyclohexyl-pentanor-16,17, 18,19,20 prosten-5 yn-13 methyl oate (5 E) - {9 5, 11 R), [mixture of (15 R) and (15 S)] and (±) -hydroxy-3a [ hydroxy- (mixture of 3a and 3ß) cyclohexyl-3 propyn-1 yl)] - 2ß [methoxycarbonyl-4 butylidene- (Z)] - 7 bicyclo [3.3.0] octa-none-6, also known as (±) oxo-6a methano-6.9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methylate (5 Z) - (9 S, 11 R), [mixture of (15 R) and (15 5)], 0.02 cm3 of tetrahydrofuran and 0.30 cm3 of an IN aqueous solution of lithium hydroxide e it is stirred for 90 minutes at 5 ° C. The mixture is then taken up in water and extracted with 3 times 1 cm 3 of diethyl ether.

The organic extracts are combined and washed with 1 cm3 of a saturated aqueous solution of sodium bicarbonate and then with 1 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. 5.4 mg of starting product are thus recovered.

The initial aqueous layer is acidified to pH 4 with 0.20 cm3 of a saturated aqueous solution of oxalic acid, treated with 0.5 cm3 of a saturated aqueous solution of sodium chloride and extracted with 4 times 2 cm3 of diethyl ether . The organic extracts are combined and dried over sodium sulfate and concentrated under reduced pressure. 4.5 mg of hydroxy-3 (3-hydroxy-cyclohexyl-3 propyn-1 yl) -2 (carboxy-4 butylidene) -7 bicyclo [3.3.0] octanone-6 are thus obtained. in the form of (±) - hydroxy-3a [hydroxy- (mixture of 3a and 3ß) 3-cyclohexyl propyn-1 yl] -2ß [4-carboxybutylidene- (£ T)] - 7 bicy-clo [3.3. 0] octanone-6, also known as (±) oxo-6a methano-6.9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 oic (5 E) - (9 S, II R), [mixture of (15 R) and (15 S).

UV spectrum (ethanol:

tanax = 247 nm: smax = 10,000 Mass spectrum:

m / c = 374 (M +), 356 (M + -H20)

Example 3 Compounds D and E

61 mg tert.-butyldimethylsilyìoxy-3 [tert.-butyldimethylsilyl-oxy-3 octén-1 yl- (£)] - 2 (methoxycarbonyl-4 buty! Idene) -7 bicy-clo [3.3.0] octanone-6 , prepared as described in reference example 16 and in the form of (±) - [tert.-butyldimethylsilyloxy-3a tert.-butyldimethylsilyloxy-3 octén-1 yl- (E)] - 2p [methoxycarbonyI-4 buty- lidene- (£)] - 7 bicyclo [3.3.0] octanone-6, also called (±) - oxo-6a methano-6.9 bis- (tert.-butyldimethylsilyloxy) -11.15 prostadien-

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5.13 methyl oate-Cf ^ lS E) - (9 S, Il R) are treated with a mixture of 6.4 cm3 of glacial acetic acid, 3.4 cm3 of water and 1 cm3 of tetrahydrofuran and the mixture is stirred for 48 hours at 20 ° C. After concentration under reduced pressure, 42 mg of an oil are obtained which is subjected to chromatography on silica gel in a short column and under medium pressure, eluting with l ethyl acetate then with a mixture of ethyl acetate and me-thanol (19/1 by volume). 11.4 mg of hydroxy-3 [hy-droxy-3a octen-1 yl- (£)] - 2p [(methoxycarbonyl-4 butylidene] -7 bicy-clo [3.3.0] octanone-6, are thus obtained. in the form of (±) -hydroxy-3a [hydroxy-3ß octen-1 yl- (£)] 2p [methoxycarbonyl-4 butylidene- (£)] - 7 bicy-clo [3.3.0] octanone-6, also known under the name of (±) -oxo-6a methano-6.9 dihydroxy-11.15 prostadien-5.13 methyl oate- (5 E, 13 E) - {9 S, 11 R, 15 R) and 14 mg of hydroxy-3 [hydroxy-3a octén-1 yl- (£)] - 2 (methoxycarbonyl-4 butylidene) -7 bicyclo [3.3.0] octanone-6, in the form of (±) -hydroxy-3a [ hydroxy-3ct octén-1 yl- (is)] - 2p [4-methoxycarbonyl butylidene- (£)] - 7 bicyclo [3.3.0] octanone-6, also called (±) oxo-6a methano-6,9 dihydroxy -11.15 prostadien-5.13 methyl oate- (5 E, 13 E) - (9 5, 11 R, 15 5).

Example 4 Compound F

A mixture of 10 mg of hydroxy-3 [hydroxy-3a octén-1 yl- (£)] - 2 (4-methoxycarbonyl butylidene) -7 bicyclo [3.3.0] octanone-6, prepared as described in the example 3 and in the form of (±) - hydroxy-3a [hydroxy-3a octén-1 yl- (£)] - 2p [methoxycarbonyl-4 butylidene- (£)] - 7 bicyclo [3.3.0] octanone-6, also called (±) - oxo-6a methano-6.9 dihydroxy-11.15 prostadien-5.13 methyl oate- (5 E, 13E) - (9 5, 11 R, 15 S), 9.5 mg of lithine, 0.30 cm3 of methanol and 0.30 cm3 of water is stirred for 3.5 hours at 20 ° C. The mixture is taken up at 20 ° C with stirring with 1.5 cm3 of water and 1 cm3 dichloromethane. The organic layer is separated and the aqueous layer is extracted again with 2 times 1 cm 3 of dichloromethane. The organic layers are combined, dried over a mixture of potassium carbonate and sodium sulfate (1/1 by weight), then concentrated under reduced pressure. 2.8 mg of starting product are thus recovered. ''

The initial aqueous layer is carefully acidified with 0.20 cm3 of dilute hydrochloric acid (2N) and then extracted with 4 times 2 cm3 of ethyl acetate. The organic extracts are combined and washed with 2 cm3 of water, 2 cm3 of a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate. After concentration in vacuo, an oil is obtained which is chromatographed on silica gel in a short column and under medium pressure, eluting with a mixture of chloroform, methanol and acetic acid (90/10/1 by volume ). 4.2 mg of hydroxy-3 [hy-droxy-3a octén-1 yl- (£)] - 2 (carboxy-4 butylidene) -7 bicyclo [3.3.0] oc-tanone-6 are thus obtained. form of (±) - hydroxy-3ct [hydroxy-3a octén-1 yl- (£)] - 2ß carboxy-4 butylidene- (£)] - 7 bicyclo [3.3.0] octanone-6, also known as (±) - oxo-6a methano-6,9 dihy-droxy-11,15 prostadien-5,13 oic, (5 E, 13 E) - (9 5, 11 R, 15 S). UV spectrum (ethanol):

Âmax = 250 nm; emax = 10,000 NMR spectrum (CDC13; S in ppm):

multiplets at 0.7-2.9, 3.5-4.5, 5.4-5.7 and 6.3-6.7

Example 5 Compound G

15 mg tert.-butyldimethylsilyloxy-3 (tert.-butyldimethylsilyl-oxy-3 cyclohexyl-3 propyn-1 yl) -2 (ethoxycarbonyl-4 cyclohexyli-dene) -7 bicyclo [3.3.0] octanone-6, prepared as described in reference example 18 in the form of (±) - tert.-butyldimethylsilyloxy-3a [tert.-butyldimethylsilyloxy- (mixture of 3a and 3ß) 3-cyclohexyl-1 propyn-1 yl] -2P (4-ethoxycarbonyl cyclohexylidene ) -7 octanone-6, also known as (±) -oxo-6a ethano-2,5 2,5-methano-6,9 bis- (tert.-butyldimethylsilyloxy) -l 1,15 cyclohexyl-15 pentanor-16, 17,18,19,20 prosten-5 yn-13 ethyl oate-9 5, 11 R), [mixture of

(15 R) and (15 5)] are treated with 0.481 cm3 of a mixture of glacial acetic acid, water and tetrahydrofuran (13/7/2 by volume) and the mixture is stirred for 13 hours at 45 ° C. After cooling, the mixture is diluted with 5 cm3 of a saturated aqueous solution of sodium chloride and extracted with 3 times 2 cm3 of ethyl acetate. The organic extracts are combined, washed with 3 times 1 cm3 of a 2M aqueous solution of sodium carbonate, 2 times 1 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 11 mg of a pale yellow viscous liquid are obtained which are chromatographed on a short column under medium pressure. This gives 6.7 mg of hydroxy-3 (3-hydroxy-3-cyclohexyl-propyn-1 yl) -2 (4-ethoxycarbonyl cyclohexylidene) -7 bicyclo [3.3.0] octanone-6 in the form of (±) - hydroxy-3a [hydroxy- (mixture of 3a and 3ß) cyclohexyl-3 propyn-1 yl] -2ß ^ thoxycarbonyl-4 cyclohexylidene) -7 bicy-clo [3.3.0] octanone-6, also known as (±) - oxo-6a ethano-2,5 methano-6,9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 ethylate (9 5, 11 R) - [mixture of (15/2) and (15 S)].

Mass spectrum:

m / e = 428 (M +), 410 (M + -H20)

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.75-3.0 and 3.6-4.3 triplets at 1.25 UV spectrum (ethanol):

Xmax = 259.5 nm; smax = 19400

Example 6

Compounds H to T

By following a procedure analogous to that described above, for example in the examples given above, the following compounds of formula (II) were prepared:

(±) -Oxo-6a ethano-2,5 methano-6,9 cyclohexyl-15 dihydroxy-11,15 pentanor-16,17,18,19,20 prostadien-5,13 ethyl oate- (13 E) - (9 5, 11 R, 15 5).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.7-2.9, 3.9-4.2 and 5.4-5.7 (±) -Oxo-6a ethano-2,5 methano-6,9 cyclohexyl-15 dihydroxy-11 , 15 pentanor-16,17,18,19,20 prostadien-5,13 ethyl oate- (13 E) - (9 S, UR, 15R).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-2.9, 3.8-4.2 and 5.5-5.7 (±) -Oxo-6a 2,5-methano-6,9-cyclohexyl-15 dihydroxy-11 , 15 pentanor-16,17,18,19,20 prostadien-5,13 methyl oate- (13 E) - (9 S, 11 R, 15 5).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-2.8, at 3.7-4.0 and at 5.4-5.6 singlet at 3.65

(±) -Oxo-6a ethano-2,5 methano-6,9 dihydroxy-11,15 prostadien-5,13 methyl oate- (13 E) - (9 5.11 R, 15 S).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 1.2-2.8, at 3.8-4.2, at 5.5-5.7 triplet at 0.92 singlet at 3.7

(±) -Dimethyl-2,2 oxo-6a methano-6,9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methylate- (5 E) - (9 5.11 R), [mixture of (15 R) and (15 5)].

NMR spectrum (in CDC13; 8 in ppm)

multiplets at 0.8-2.9, at 4.0-4.3, 6.4-6.5 singlets at 0.8 at 0.9, at 3.6-3.7 (±) -Oxo- 6a methano-6,9 dihydroxy-11,15 phenyl-16 tetranor-17,18,19,20 prosten-5 yn-13 methyl oate- [mixture approximately 10/1 of (5 E) and (5 Z) - (9 5, 11 R \ [mixture of (15 R) and (15 5)].

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.7-1.4, 1.5-3.2, 3.8-4.3, 4.5-4.8, 6.4-6.7 and 7.2-

7.5

singlet at 3.65

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UV spectrum (ethanol):

Xmax = 247 mm; smax = 9700.

Oxo-6a methano-6,9 dihydroxy-11,15 {dimethyl-6,6 bicyclo- [3.1.1] hepten-2 yl-2- (1 R, 5 J?} - 15 pentanor-16,17,18 , 19.20 prosten-5 yn-13 methylate- (5 E) - (9 S, 11 R), [mixture of (15 R) and (15 5)].

NMR spectrum (in CDC13: 8 in ppm):

multiplets at 0.8-1.0, 1.2-1.4, 1.4-2.9, 3.0-3.2, 4.1-4.3, 4.3 -4.4, 5.5-5.6, 6.5-6.7

singlets at 0.7, 1.34 and 3.7 (±) -Oxo-6a methano-6.9 dihydroxy-11.15 phenyl-16,16-tetranor-17,18,19,20 proten-5 yn-13 methyl wadding [mixture approximately 1/1 of (5 E) and (5 Z)] - (9 5, 11 R), [mixture of (15 R) and (15 S)].

NMR spectrum (in CDC13: 5 in ppm):

multiplets at 0.8-3.1, 4.0-4.3, 4.5-4.7, 5.9-6.1 and 6.5-6.7 singlet at 3.7

Oxo-6a methano-6,9 dihydroxy-11,15 {6,6-dimethyl-bicyclo- [3.1.1] hepten-2 yl-2- (1 R, 5 R)} - 15 pentanor-16,17,18 , 19.20 prosten-5 yn-13 methyl oate- [mixture approximately 1/1 of (5 E) and (5 Z)] - (9 S, 11 R), [mixture of (15 R) and (15 5).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.7-1.0, 1.0-3.1, 4.1-4.3, 4.3-4.4, 4.7-4.9, 5.2 -5.3, 5.5-5.55, 5.9-6.1 and 6.5-6.6

singlets at 0.64 and 3.66 (±) -Dimethyl-2,2 oxo-6a methano-6,9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn- 13 methylate - [mixture approximately 1/1 of (5E) and (5 Z)] - (9 5, 11 R), [mixture of (15 R) and (15 S)].

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-3.0, 3.6-3.8, 4.0-4.3, 5.9-6.1 and 6.4-6.6 (±) -Methano -6.9 trihydroxy-6a, 11.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl oate- (5 E) - (9 S, 11 R), [mixture (15 R) and (15 S)].

NMR spectrum (in CDC13; S in ppm):

multiplets at 0.9-3.2, 4.1-4.3, 4.3-4.4, 5.4-5.55 singlet at 3.67

(±) -Oxo-6a methano-6.9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prostyn-13 oate demethyl- (9 5, 11 R), [mixture of (15 R) and (15 S)].

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-2.0, 2.0-2.9 and 4.1-4.3 singlet at 3.65

and (±) -methano-6.9 trihydroxy-6a, 11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methylate- (5 Z) - [mixture of ( 6a R) and (6a 5)].

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-3.0, 3.35-3.6, 4.1-4.3, 4.5-4.7 and 5.15-5.3 singlet at 3.7

Example 7 Compounds U to EE

By following a procedure analogous to that described above, for example in the examples given above, the following compounds of formula (II) were prepared:

(±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 demethylate- (5 E) - (9 S, lì R, 15 S).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-2.9, at 4.1-4.3 singlet at 3.68 triplet at 6.58

(±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methylate- (5 Z) - (9 S, 11 R, 15 5).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-2.0, 2.2-3.0, 4.1-4.3 singlet at 3.66 triplet at 6.0

Mixture of (±) -methano-6.9 trihydroxy-6a, l 1,15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl and ethyl oate- (5 Z) - [mixture of (6a R) and (6a 5)] - (9 5, 11 R, 15 S).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-2.9, 3.3-3.4, 3.9-4.0 and 4.1-4.3 singlet at 3.64 doublet at 4.58 triplet at 5, 14 Mass spectrum of tris-trimethylsilylated ethers:

m / e = 620 (M +); 606 (M +)

(±) -Methano-6.9 trihydroxy-6a, l 1.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl oate- (5 £) - [mixture of 6a R and 6a 5] - (9 5, 11 R, 15 5).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-2.8, at 3.0-3.2 singlet at 3.64 doublets at 4.18, at 4.28 triplet at 5.5

(±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 m-inter-phenylene-1.5 octanor-2,3,4,16,17,18,19,20 prosten-5 yn -13 methylate-5 (E) - (9 5, 11 R, 15 5).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-2.65, 2.8-3.4, 4.0-4.4, 7.4-7.6, 7.7-7.8 and 8.0- 8.1

singlets at 3.98 and 8.24 (±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 m-inter-phenylene-1.5 octanor-2,3,4,16,17 , 18,19,20 prosten-5 yn-13 methyl oate- (5 (Z) - (9 5, 11 R, 15 5).

(±) -Oxo-6a methano-6.9 dihydroxy-11.15 prosten-5 yn-13 methyl oate- (5 Z) - (9 5, 11 R, 15 S).

NMR spectrum (in CDC13: 8 in ppm):

multiplets at 1.1-3.4, at 4.1-4.3, at 4.3-4.5 triplets at 0.92 and 6.0 singlet at 3.68

Mixture of (±) -methano-6.9 trihydroxy-6a, 11.15 prosten-5 yn-13 methyl and ethyl oate- (5 Z) - [mixture of (6a R) and (6a S)] - (9 S, 11 R, 15 5).

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 0.8-1.0, 1.1-2.8 and 4.1-4.4 triplet at 5.21 doublet at 4.59 singlet at 3.7

(±) -Oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 pentanor-16,17,18,19,20 prostadien-5,13 methyl oate- (5 E) - {9 S, 11 R, 15 5).

Rotatory power [at 0.125% (weight / volume) in CH3OH]: [a] o = +24 "

(±) -Oxo-6a methano-6,9 dihydroxy-11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prostadien-5,13 methyl oate- (5 Z) - (9 5, 11 R, 15 5).

Rotatory power [at 0.125% (weight volume) in CH3OH]: [ag = +78.4

(±) -Méthano-6,9 trihydroxy-6a, 11,15 cyclohexyl-15 pentanor-16,17,18,19,20 prostadien-5,13 methylate- (5 Z) - [mixture of (6a R ) and (6a 5) - (9 5, 11 R, 15 5).

Rotatory power [at 0.41% (weight / volume) in CH3OH]: [a] o = +56.1

Reference example 1

The mixture is refluxed for 36 hours in a device fitted with a Dean and Stark separator a mixture of 4.2 g of (±) -bicy-clo [3.3.0] octén-2 one-6, prepared as described by NEE et al. J. Org. Chem. 46, 67 (1981). of 30 cm3 of toluene, 12.3 cm3 of ethylene glycol and 10 mg of p-toluenesulfonic acid. After cooling, the reaction mixture is washed with 20 cm3 of a saturated aqueous solution of sodium carbonate and the organic layer is

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separate. The aqueous layer is then extracted with 3 times 20 cm3 of ethyl acetate. The organic layers are combined and washed with 10 cm3 of water and then with 10 cm3 of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated in vacuo. 5.1 g of (±) -spiro {(bicyclo [3.3.0] octene-6) -2.2 '- (dioxolane-1.3)} are thus obtained.

NMR spectrum (in CDC13; 8 in ppm):

multiplets at 1.5-1.8, 2.3-2.7, 3.0-3.6 and 5.4-5.7 singlet at 3.8-4.0,

pure enough to be used as is in the next step.

Reference example 2

A stirred solution of 12.5 g of (±) -spiro {(bicyclo [3.3.0] octene-6) -2.2 '- (dioxoIanne-1,3)}, prepared as described in the reference example 1 in 250 cm3 of acetone and 50 cm3 of water is treated at 3 ° C with 12.2 g of 1,3-dibromo-5,5-dimethyl hydantoin in small portions at a time, in the space of one hour. The solution is then allowed to warm to 20 ° C and stirred for 24 hours. The acetone is removed under vacuum (14 mmHg) and the residue is treated with 50 cm3 of water. The mixture is then extracted with 4 times 50 cm3 of dichloromethane; the organic extracts are combined and washed, first with 10 cm3 of water and then with 25 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo (14 mmHg). 16 g of oil are thus obtained which is dissolved in 300 cm3 of toluene. The solution is treated with 50 cm 3 of ethylene glycol and 0.5 g of p-toluenesulfonic acid and then heated at reflux for 30 hours in a device provided with a Dean and Stark separator. The solution is then cooled and washed, first with 30 cm3 of an aqueous solution of sodium bicarbonate, then with 20 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, stirred in the presence of bleaching black then filtered and concentrated in vacuo. 9.4 g of (±) -bromo-6ß hydroxy-7a spiro {(bicyclo [3.3.0] octane-2,2 '- (dioxolane-1,3)} are thus obtained in the form of a pale yellow oil, IR spectrum: 3420 cm-1.

Reference example 3

A solution of 7.5 g of (±) -bromo-6ß hydroxy-7a spiro {(bicy-clo [3.3.0] octane-2,2 '- (dioxalane-1, 3)}, prepared as described in reference example 2, in 18 cm3 of methanol is added to a stirred solution of 2.7 g of sodium hydroxide in 45 cm3 of methanol and the mixture is stirred for 20 hours at 20 ° C. The methanol is then removed in vacuo and the remaining mixture is taken up in 100 cm3 of water The mixture is then extracted with 4 times 25 cm3 of dichloromethane The organic extracts are combined, washed with 20 cm3 of a saturated aqueous solution of sodium chloride, dried over sulphate anhydrous sodium and concentrated in vacuo to give 4.5 g of a crude oil which is chromatographed on silica gel in a short column and under medium pressure, eluting with a mixture of ethyl acetate and hexane (1/5 by volume). This gives 1.2 g of (±) -epoxy-6a, 7a spiro {(bicyclo [3.3.0] octane) -2.2 '- (dioxo-lanne-1, 3)}.

Elementary analysis:

Calculated: C 65.9 H 7.7%

Found: C 65.8 H 8.0%

NMR spectrum (CDC13; 5 in ppm):

multiplets at 1.6-2.9 singlets at 3.4 and 3.9

Reference example 4

A suspension of 9.2 g of the lithium ethyl acetate-ethylenediamine complex in 250 cm 3 of tetrahydrofuran is stirred and treated under an argon atmosphere with 5.6 g of cyclohexanecarboxaldehyde in solution in 50 cm 3 of tetrahydrofuran. The mixture is stirred for 20 hours at 20 ° C. 200 g of ice are added to the mixture and extracted with 4 times 50 cm3 of diethyl ether. The organic extracts are combined and washed successively with 10 cm3 of 2N hydrochloric acid and 10 cm3 of a saturated aqueous solution of sodium bicarbonate then dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil which is chromatographed in a short column of silica gel under medium pressure, eluting with 200 cm 3 of hexane then with a mixture of hexane and ethyl acetate (4/1 by volume). 4.2 g of (±) -cyclohexyl-3 hydroxy-3 propyne are thus obtained.

NMR spectrum (CDC13; 8 in ppm):

multiplets at 0.7-2.2, 2.3-2.6, 2.65-2.9 and 3.9-4.3

Reference example 5

A mixture of 3.9 g (±) -cyclohexyl-3 hydroxy-3 propyne, prepared as described in reference example 4, 4.8 g of imida-zole, 5 g of triethylchlorosilane and 8 cm3 of dimethylformamide is stirred for 4 hours at 20 ° C under an argon atmosphere. 50 cm3 of water and 50 cm3 of ethyl acetate are then added. The organic layer is then decanted and the aqueous layer is extracted with 2 times 50 cm3 of ethyl acetate. The organic layers are combined and washed with 20 cm3 of water and with 10 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. 7.9 g of (±) -cyclohexyl-3 triethylsilyloxy-3 propyne are thus obtained.

NMR spectrum (CDC13; 8 in ppm):

multiplets at 0.2-2.0, 2.15-2.25 and 3.85-4.05 This product is pure enough to be used as is in subsequent phases of synthesis.

Reference example 6

A solution of 3.2 g of (+) - 3-cyclohexyl-3-triethylsilyloxy-3-propyne, prepared as described in reference example 5, in 12 cm3 of anhydrous toluene is treated with stirring and at 0 ° C with 8.3 cm3 of a 1.5M solution of butyllithium in hexane in 2 minutes while maintaining an argon atmosphere. After 1 hour at 0 ° C., the mixture is treated with 4.8 cm3 of a solution of diethylaluminum chloride in hexane (at 25% by weight) and stirred for a further 75 minutes at 0 ° C. The mixture is then treated dropwise in 2 minutes with a solution of 900 mg of (±) -epoxy-6a, 7a spiro {(bicyclo [3.3.0] octane) -2,2 '- (dioxolane-1, 3)} prepared as described in reference example 3, in 4 cm3 of toluene and the solution is heated at 80 ° C for 16 hours. The reaction mixture is cooled to room temperature, then is taken up with 50 cm3 of an aqueous solution of sodium sulfate and 50 cm3 of ethyl acetate. The organic layer is separated and the aqueous layer is extracted with 2 times 30 cm3 of ethyl acetate. The organic layers are combined and washed with 15 cm3 of water, then with 15 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration in vacuo, 3.9 g of crude oil are obtained which is chromatographed on a short column of silica gel under medium pressure, eluting with a mixture of ethyl acetate and hexane (50/50 in volumes). 635 mg of (±) - (3-cyclohexyl-3-triethylsilyloxy-1 propyn-1 yl) -7ß hydroxy-6a spiro {(bicyclo [3.3.0] octane) -2,2'- (1,3-dioxolane) are obtained. } and 432 mg of (±) - (3-cyclohexyl-3-triethylsilyloxy-1 propyn-1 yl) 6ß hy-droxy-7a spiro {(bicyclo [3.3.0] octane) -2,2'- (dioxolane-1,3 )}.

NMR spectrum (CDC13; 8 in ppm):

multiplets at 0.0-0.9, 0.9-1.8, 1.8-3.2, 3.2-3.8 and 5.5-6.0 Mass spectrum:

m / e = 405 (M + -C2HS).

Reference example 7

A mixture of 170 mg of (±) - (3-cyclohexyl-3-triethylsilyloxy-1 propyn-1 yl) - 6ß hydroxy-7a spiro {(bicyclo [3.3.0] octane) -2.2 '- (dioxolane-1,3 )} prepared as described in Reference Example 6, 4.8 cm3 of glacial acetic acid and 3.2 cm3 of water is stirred for 16 hours at 20 ° C. 25 cm3 of a solution are then added saturated aqueous sodium bicarbonate and extracted with 4 times 25 cm3 of ethyl acetate. The organic extracts are combined and washed with 10 cm3 of water, then with 10 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After

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concentration under vacuum, 141 mg of (±) - (3-cyclohexyl-3-hydroxy-1-propyn-1 yl) - 2ß hydroxy-3a bicyclo [3.3.0] octanone-6 are obtained in the form of an oil.

NMR spectrum (CDCl3; 5 in ppm):

multiplets at 0.7-3.1 and 4.0-4.4

Reference example 8

A mixture of 141 mg of (±) - (3-cyclohexyl-3 hydroxy-3 propyn-1 yl) -2ß hydroxy-3ct bicyclo [3.3.0] octanone-6, prepared as described in reference example 7, of 360 mg of tert.-butyldimé-thylchlorosilane, 290 mg of imidazole and 4 cm3 of dimethylforma-mide is stirred for 18 hours at 20 ° C. The mixture is then taken up with 50 cm3 of water, then extracted with 3 times 20 cm3 of hexane. The organic extracts are combined and washed with 10 cm3 of an aqueous solution of sodium bicarbonate, then dried over magnesium sulfate. After concentration in vacuo, 215 mg of (±) -tert.-butyldimethylsilyloxy-3a (tert.-butyldimethylsilyloxy-3 cyclohexyl-3 propyn-1 yl) -2ß bicyclo [3.3.0] octanone-6 are obtained.

NMR spectrum (CDC13; 5 in ppm):

multiplets at 0.0-0.3, 0.7-3.2 and 3.9-4.3 Mass spectrum:

m / e = 447 (M + -tert.-butyl).

Reference example 9

A 210 mg solution of (±) -tert.-butyldimethylsilyloxy-3a (tert.-butyldimethylsilyloxy-3 cyclohexyl-3 propyn-1 yl) -2ß bicy-clo [3.3.0] octanone-6, prepared as described in 1 reference example 8, in 6 cm3 of anhydrous tetrahydrofuran is cooled to -78 ° C. and treated dropwise in 2 minutes with stirring and under an argon atmosphere with 0.55 cm3 of a 1M solution of bis- (trimethylsi -lyl) lithium amide in tetrahydrofuran. The solution is stirred for 20 minutes at -78 ° C and then treated dropwise with 158 mg of 4-methoxycarbonyl-butanal and the mixture is stirred for a further 15 minutes at -78 ° C. The mixture is then taken up with a solution of 0.06 cm3 of glacial acetic acid in 1 cm3 of diethyl ether and the mixture is allowed to warm to room temperature. 2 cm 3 of a saturated aqueous ammonium chloride solution are then added, then 30 cm 3 of an aqueous sodium chloride solution and 30 cm 3 of diethyl ether. The organic layer is separated and the aqueous layer is extracted with 3 times 20 cm 3 of diethyl ether. The organic extracts are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 332 mg of crude oil. This oil is then dissolved in 3 cm3 of anhydrous benzene, the solution is cooled to 5 ° C and treated with 70 mg of methanesulfonyl chloride and 70 mg of triethylamine. The mixture is stirred for 50 minutes at 20 ° C then treated with 0.38 cm3 of 1.8-diaza-bicyclo [5.4.0] undecene-7 and stirred for 16 hours at room temperature. The crude mixture is taken up with 0.15 cm3 of glacial acetic acid then 10 cm3 of water and 20 cm3 of diethyl ether. The organic layer is decanted and the aqueous layer is extracted with 3 times 10 cm3 of diethyl ether. The organic layers are combined and washed successively with 10 cm3 of an aqueous solution of sodium bicarbonate then with 10 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, a crude oil is obtained which is chromatographed on a short column of silica gel under medium pressure, eluting with a mixture of ethyl acetate and hexane (1/9 by volume). 138 mg of tert.-butyldimethylsilyloxy-3 (tert.-butyldimethylsilyloxy-3-cyclohexyl-3 propyn-1 yl) -2 (metoxy-carbonyl-4-butylidene) -7 bicyclo [3.3.0] octanone-6 are thus obtained. form of (±) -tert.-butyldimethylsilyloxy-3a [tert.-butyldimethylsilyloxy- (mixture of 3a and 3ß) 3-cyclohexyl-propyn-1 yl] -2ß [4-methoxycarbonyl-butylidene- (£)] - 7 bicyclo [ 3.3.0] octanone-6, containing about 11% of the (7Z) isomer, also known as (±) -oxo-6a methano-6.9 bis- (tert.-butyldimethylsilyloxy-l 1.15 cyclo -hexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 methyl oate-

(5E) - {9S, 11 R), [mixture of (15 / ï)], containing about 11% of (5 Z) isomer.

NMR spectrum (CDCl3; S in ppm):

multiplets at 0.0-0.2, 0.8-1.0, 1.0-2.9, 3.9-4.2 and 6.3-6.7 singlet at 3.6 -3.7 Mass spectrum:

m / e = 559 (M + -tert.-butyl)

UV spectrum (ethanol):

^ .max = 249 nm; smax = 10,600.

Reference example 10

A stirred solution of 1.3 g of (±) -trimethylsilyloxy-3 octyne-1 in 6 cm3 of anhydrous toluene is cooled to 0 "C and is treated with 4.4 cm3 of a 1.5M solution of butyllithium in 1 hexane, under an argon atmosphere and stirring is continued for 30 minutes at 0 ° C. The stirred mixture is then treated dropwise with 2.6 cm3 of a solution of diethylaluminum chloride in hexane (25 % by weight) and stirring is continued for a further 90 minutes, the mixture is then treated dropwise over 2 minutes with a solution of 0.48 g of (±) - epoxy-6a, 7a spiro {(bicyclo [3.3 .0] octane) -2.2 ′ - (dioxolane-1.3)}, prepared as described in reference example 3, in 2 cm3 of toluene, and the solution is stirred for 2 hours at 5 ° C., then for 8 hours at 80: C. The mixture is then taken up in 10 cm3 of a saturated aqueous solution of sodium sulphate and then 50 cm3 of ethyl acetate The mixture is then filtered through diatomaceous earth. is separate and the aqueous layer is extracted again with 2 times 15 cm3 of ethyl acetate. The organic layers are combined and washed with 10 cm3 of water then with 10 cm3 of a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After concentration under vacuum, 1.5 g of oil are obtained. This oil is dissolved in 20 cm3 of methanol and treated with 4 cm3 of water and 1 g of potassium carbonate with stirring at 20 "C. The mixture is stirred for a further 4 hours at 20 ° C. The methanol is then removed under vacuum and the residue is extracted with 4 times 15 cm 3 of diethyl ether The organic extracts are combined and dried over anhydrous sodium sulfate and concentrated in vacuo 1.2 g of an oil is obtained which is chromatographed on a short silica gel column under medium pressure, eluting with a mixture of ethyl acetate and hexane (50/50 by volume), thus obtaining 337 mg of (±) - (3-hydroxy-octyn-1 yl) -7ß hydroxy-6ct spiro {(bicyclo [3.3.0] octane) -2.2 '(dioxolane-1,3)} and 191 mg of (±) - (hydroxy-3 octyn-1 yl) -6ß hydroxy- 7a spiro {(bicyclo [3.3.0] octane) -2,2 '- (dioxolane-1, 3)}.

NMR spectrum (CDCl3; S in ppm):

multiplets at 0.7-1.0, 1.0-3.0, 3.5-4.1 and 4.1-4.5

Reference example 11

A stirred suspension of 124 mg of lithium aluminum hydride in 10 cm3 of tetrahydrofuran is treated dropwise under an argon atmosphere with a solution of 200 mg of (±) - (3-hydroxy-octyn-1 yl) - 6ß hydroxy-7a spiro {(bicyclo [3.3.0] octane) -2,2'- (dioxolane-1,3)}, prepared as described in reference example 10, in 5 cm3 of tetrahydrofuran. The mixture is then heated at reflux for 8 hours and is then treated successively with 0.16 cm3 of water, 0.16 cm3 of 15% aqueous sodium hydroxide solution (weight / volume), 4.8 cm3 of water and 35 cm3 of diethyl ether. The mixture is then stirred for 10 minutes and filtered through diatomaceous earth. The organic layer is decanted, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gives 168 mg of (±) - [(3-hydroxy-octén-1 yl- (£) -6ß hydroxy-7a spi-ro {(bicyclo [3.3.0] octane) -2,2 '- (dioxolane- 1,3)} sufficiently pure to be used as it is in the subsequent synthesis steps NMR spectrum (CDCI 3; S in ppm):

multiplets at 0.7-1.1, 1.1-3.1, 3.7-4.5 and 5.4-5.7.

Reference example 12

A mixture of 135 mg of (±) - [hydroxy-3 octén-1 yl- (E)] - 6ß hy-droxy-7a spiro {(bicyclo [3.3.0] octane) -2,2 '- (dioxolane- l, 3)}, prepared

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as described in the reference example, 11.5 cm3 of acetonitrile, 1.4 cm3 of 2N aqueous sulfuric acid and 1.7 cm3 of water is left to stand for 60 hours at 20 "C. The acetonitrile is then removed under reduced pressure and the residue is taken up in a saturated aqueous solution of sodium bicarbonate up to pH 7. The mixture is then extracted with 3 times 10 cm 3 of ethyl acetate The extracts are combined and washed with 10 cm3 of a saturated solution of sodium chloride and dried over anhydrous sodium sulfate After concentration under reduced pressure, 107 mg of (±) -hydroxy-3a [3-hydroxy-octen-1 yl- (£) - is obtained. 2ß bicyclo [3.3.0] octanone-6, sufficiently pure to be used as it is in the subsequent state of synthesis NMR spectrum (CDC13; 8 in ppm):

multiplets at 0.7-1.1, 1.1-3.1, 3.7-4.3 and 5.4-5.7

Reference example 13

A stirred solution of 1.7 g of tert.-butyldimethylsilyloxy-3 iodo-1 octene-1 in 10 cm3 of diethyl ether is treated with 5.8 cm3 of a 1.6M solution of butyllithium in hexane at - 78 ° C under an argon atmosphere and the mixture is stirred for 1 hour at -78 ° C. The mixture is then treated dropwise with a solution prepared by reaction of 600 mg of copper pentyne with 1.5 g of hexamethylphosphortriamide in 5 cm3 of diethyl ether and stirred for a further 1 hour at -78 ° C. The mixture is then treated dropwise with a solution of 760 mg of (±) -epoxy-6a, 7a spiro {(bicyclo [3.3 .0] octane) -2.2 '- (dioxolane 1.3)} prepared as described in reference example 3, in 1 cm3 of diethyl ether. The mixture is stirred for 3 hours at -78 ° C and then left to stand for 17 hours at -20 ° C. The mixture is taken up with 20 cm3 of a saturated aqueous solution of ammonium chloride at -20 ° C and stirred for 2 hours at 20 ° C. The mixture is extracted with 4 times 20 cm3 of diethyl ether and the extracts are combined and washed successively with 10 cm3 of 2N hydrochloric acid, 10 cm3 of water, 10 cm3 of a saturated aqueous solution of sodium carbonate and 5 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration under vacuum, 2.4 g of an oil are obtained which is chromatographed on a short column of silica gel under medium pressure, eluting with a mixture of petroleum ether (PE: 40-60 ° C) and diethyl ether (3/1 by volume). This gives 240 mg of (±) - [tert.-butyldimé-thylsilyloxy-3 octén-1 yl- (J?)] - 6ß hydroxy-7a spiro {(bicyclo [3.3.0] oc-tane) -2, 2 '- (1,3-dioxolane)}.

Mass spectrum:

m / e = 424 (M +); 406 (M + -H20) and 367 (M + -tert.-butyl).

NMR spectrum (CDCl3; 8 in ppm):

multiplets at 0.0-0.2, 0.6-2.7, 3.5-4.3 and 5.4-5.6

Reference example 14

A mixture of 240 mg of (±) - [tert.-butyldimethylsilyloxy-3 octén-1 yl- (£)] - 6P hydroxy-7ct spiro {(bicyclo [3.3.0] octane) -2,2 '- (dioxolane -1.3)}, prepared as described in reference example 13, of 15 cm3 of acetonitrile, 5 cm3 of water and 4 cm3 of 2N sulfuric acid is stirred for 72 hours at 20 ° C. The acetonitrile is then removed under vacuum and the residue is extracted with 4 times 20 cm3 of ethyl acetate. The organic extracts are combined and washed successively with 10 cm3 of a saturated aqueous solution of sodium bicarbonate, then with 10 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration in vacuo, 140 mg of (±) -hydroxy-3a [3-hydroxy-octen-1 yl- (£)] - 2ß bicyclo [3.3.0] octane-6 is obtained, sufficiently pure to be used as it is in the next step of synthesis.

NMR spectrum (CDCl3; 8 in ppm):

multiplets at 0.7-1.1, 1.1-3.1, 3.7-4.3 and 5.4-5.7

Reference example 15

A mixture of 107 mg of (±) -hydroxy-3ct [hydroxy-3 octén-1 yl- (E)] - 2 bicyclo [3.3.0] octanone-6, prepared as described in reference example 12 or 14 , 241 mg of tert.-butyldimethylchlorosilane, 190 mg of imidazole and 3 cm3 of dimethylformamide is stirred

for 20 hours at room temperature. 30 cm3 of water are then added, then 30 cm3 of hexane and the organic layer is separated. The aqueous layer is extracted with 2 times 30 cm3 of hexane. The organic layers are combined and washed successively with 10 cm3 of a saturated aqueous solution of sodium bicarbonate, 10 cm3 of water and 10 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 181 mg of (±) -tert.-butyl-dimethylsilyloxy-3a [tert.-butyldimethylsilyloxy-3 octén-1 yl- (£)] - 2ß bicyclo [3.3.0] octanone-6 are obtained. , pure enough to be used as is in the next stage of synthesis.

NMR spectrum (CDCl3; 8 ppm):

multiplets at 0.0-0.3, 0.7-1.7, 1.7-3.1, 3.7-4.2 and 5.3-5.5 Mass spectrum:

m / e = 437 (M + -tert.-butyl)

Reference example 16

A stirred solution of 180 mg of (±) -tert.-butyldimethylsilyl-oxy-3a [tert.-butyldimethylsilyloxy-3 octén-1 yl- (£)] - 2ß bicy-clo [3.3.0] octanone-6 in 6 cm3 of anhydrous tetrahydrofuran is treated dropwise in two minutes at -78 ° C under an argon atmosphere with 0.48 cm3 of a 1M solution of lithium bis- (trimethylsilyl) amide. The solution is stirred for 10 minutes at -78 ° C and then treated dropwise in one minute with 104 mg of 4-methoxycarbonyl-butanal. The mixture is further stirred for 10 minutes at -78 ° C. The mixture is then treated with a solution of 0.10 cm3 of glacial acetic acid in 1 cm3 of diethyl ether at -78 ° C and then allowed to warm to temperature ambient. The mixture is then treated with 2 cm3 of a saturated aqueous solution of ammonium chloride, then with 4 cm3 of a saturated aqueous solution of sodium chloride and 20 cm3 of ethyl acetate. The organic layer is separated and the aqueous layer is extracted with 3 times 25 cm3 of ethyl acetate. The organic layers are combined and washed with 10 cm3 of a saturated aqueous solution of sodium bicarbonate, then 10 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 250 mg of an oil are obtained which is dissolved in 3 cm 3 of benzene. The solution is cooled to 5 ° C. under an argon atmosphere and is then treated with stirring with 60 mg of methanesulfonyl chloride, then a solution of 65 mg of triethylamine in 0.5 cm3 of benzene. The mixture is allowed to warm to room temperature for one hour. The mixture is then treated with 120 mg of diaza-1,8 bicyclo [5.4.0] undecene-7 and stirred for 3 hours at 20 ° C. The crude mixture is taken up with 0.10 cm3 of glacial acetic acid, 10 cm3 of water and 20 cm3 of ethyl acetate. The organic layer is decanted and the aqueous layer is extracted with 3 times 10 cm3 of ethyl acetate. The organic layers are combined and washed successively with 10 cm 3 of a saturated aqueous solution of sodium bicarbonate and 10 cm 3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, a crude oil is obtained which is purified by chromatography on a short column of silica gel under medium pressure, eluting with a mixture of ethyl acetate and hexane (1/9 by volume ). This gives 61.7 mg of tert.-butyldimethylsilyloxy-3 [tert.-butyldimethylsi-lyloxy-3 octén-1 yl- (£)] - 2 (methoxycarbonyl-4 butylidene) -7 bicy-clo [3.3.0] octanone-6, in the form of (±) -tert.-butyldimethylsilyl-oxy-3 [tert.-butyldimethylsilyloxy-3 octén-1 yl- (2:)] - 2ß [iMthoxycar-bonyl-4 butylidene - (. E) ] -7 bicyclo [3.3.0] octanone-6, also known as (±) -oxo-6a methano-6,9 bis- (tert.-butyldi-methylsilyloxy-11,15 prostadien-5,13 oate methyl- (5 £, 13 E) - (9 S, 11 R).

Reference example 17

A stirred solution of 50 mg of (±) -tert.-butyldimethylsilyloxy-3a (tert.-butyldimethylsilyloxy-3 cyclohexyl-3 propyn-1 yl) -2ß bicy-clo [3.3.0] octanone-6, prepared as described in Reference example 8, in 1.55 cm3 of anhydrous tetrahydrofuran is treated in two

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minutes at -70 ° C under argon atmospheres with 0.12 cm3 of a 1.0M solution of lithium bis- (trimethylsilyl) amide in tetrahydrofuran. The mixture is stirred at -70 ° C for 10 minutes then treated dropwise in two minutes with 34 mg of ethyl oxo-4 cy-clohexylcarboxylate and the mixture is stirred for a further 3 hours 20 minutes at -70 ° C The mixture is then taken up with a solution of 0.012 cm3 of glacial acetic acid in 0.103 cm3 of diethyl ether and the mixture is allowed to warm to room temperature. The mixture is then taken up in 20 cm3 of water and extracted with 4 times 3 cm3 of ethyl acetate. The organic extracts are combined, washed with 2 times 2 cm3 of a saturated aqueous solution of sodium bicarbonate and then 2 times 2 cm3 of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. 113 mg of viscous oil are thus obtained. This oil is chromatographed on a short column of silica gel under medium pressure, eluting with a mixture of ethyl acetate and hexane (1/6 by volume). This gives 29 mg of (±) -tert.-butyldimethylsilyloxy-3a (tert.-butyldimethylsilyloxy-3 cyclohexyl-3 propyn-1 yl) -2P (ethoxycarbonyl-4 hydroxy-1 cyclohexyl-1) -7 bicy-clo [ 3.3.0] octanone-6.

Mass spectrum:

m / e = 617 (M + -tert.-butyl)

NMR spectrum (CDCl3; 5 in ppm):

multiplets at 0.0-0.2, 0.7-0.9, 0.5-3.0, 3.9-4.3 triplet at 1.2 doublet at 3.3

. Reference example 18

A stirred solution of 29 mg of (±) -tert.-butyldimethylsilyloxy-3a (tert.-butyldimethylsilyloxy-3 cyclohexyl-3 propyn-1 yl) -2ß (ethoxycarbonyl-4 hydroxy-1 cyclohexyl-1) bicyclo [3.3 .0] octa-none-6 in 0.172 cm3 of benzene is treated at room temperature under an argon atmosphere with 6.5 mg of metha-nesulfonyl chloride and 5.3 mg of triethylamine and stirred for 75 minutes. The mixture is then treated with 0.04 cm3 of diaza-1,8 bicy-clo [5.4.0] undecene-7. The mixture is stirred for a further 1 hour 45 minutes and is then treated with 6.5 mg of methanesulfonyl chloride and stirred for a further 2 hours and 25 minutes. The mixture is diluted with 10 cm3 of water and extracted with 3 times 3 cm3 of ethyl acetate. The organic extracts are combined and washed with 2 times 0.5 cm3 of a saturated aqueous solution of sodium chloride,

dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 32 mg of an amber-colored oil are thus obtained. This liquid is chromatographed on a short column of silica gel under medium pressure, eluting with a mixture of ethyl acetate and hexane (1/6 by volume). This gives 16 mg of tert.-butyl-dimethylsilyloxy-3 (tert.-butyldimethylsilyloxy-3 cyclohexyl-3 propyn-1 yl) -2 (ethoxycarbonyl-4 cyclohexylidene) -7 bicy-clo [3.3.0] octanone-6 in the form of (±) -tert.-butyldimethylsilyloxy-3a [tert.-butyldimethylsilyloxy- (mixture of 3a and 3ß cyclohexyl-3 propyn-1 yl] -2ß (ethoxycarbonyl-4 cyclohexylidene) -7 bicy-clo [3.3. 0] octanone-6, also known as (±) -oxo-6a ethano-2,5 methano-6,9 bis- (tert.-butyldimethylsilyloxy-ll, 15 cyclohexyl-15 pentanor-16,17,18 , 19.20 prosten-5 yn-13 ethyl oate- (9 S, 11 i?) - mixture of (15 R) and (15 S).

Mass spectrum:

m / e = 599 (M + -tert.-butyl)

NMR spectrum (CDCl3; 5 in ppm):

multiplets at 0.0-0.2, 0.7-0.9, 0.5-3.0 and 3.9-4.3 triplets at 1.2

The present invention relates to pharmaceutical compositions which comprise at least one compound of general formula (II) or, when R1 represents a hydrogen atom, a non-toxic salt or a cyclodextrin clathrate of this compound, with an acceptable pharmaceutical adjuvant or coating . In clinical practice, the compounds of general formula (II) can be administered orally, rectally, vaginally or parenterally.

The modes of presentation of the pharmaceutically active compounds are well known to those skilled in the art and the doctor, the pharmacist or the veterinarian will determine the most suitable vehicle according to factors such as the desired effect, size, age, the sex, the conditions of the patient and, for veterinary uses, the animal species to be treated, and the physical properties of the active compound. The compositions may also contain, as is usual in the art, products such as solid or liquid diluents, wetting agents, preservatives, flavorings, colorants or others.

Solid compositions for oral administration include tablets, pills, dispersible powders and granules. In such solid compositions, one or more active compounds can be mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid or lactose. The compositions can also include, as is common practice, adjuvants other than inert diluents such as lubricants such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing other diluents commonly used in the art such as water and paraffin oil. Besides inert diluents, such compositions may also include adjuvants such as wetting agents, stabilizers, sweeteners, flavorings, perfumes and preservatives.

The compositions according to the invention for oral administration also include capsules made of absorbable materials, such as gelatin, containing one or more active substances with or without additional diluents or excipients.

Solid compositions for vaginal administration include ova formulated in a manner known per se and containing one or more active compounds.

Solid compositions for rectal administration include suppositories formulated in a manner known per se and containing one or more active compounds.

The preparations according to the invention for parenteral administration include aqueous sterile solutions, aqueous or non-aqueous suspensions or emulsions. As examples of non-aqueous solvents or suspending agent, mention may be made of propylene glycol, a polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as oleate ethyl. These compositions can also comprise adjuvants such as preservatives, wetting agents, emulsifying or dispersing agents. They can be sterilized for example by filtration through a bacteriological filter, by incorporation of sterilizing agents in the compositions, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions to be dissolved at the time of use in sterilized water or any other sterile injectable medium.

The compounds of formula (II) may, if preferred, be administered orally by any method known per se to administer by inhalation a medicament which is not gaseous under normal conditions of administration. Thus, one can nebulize a solution of active principle in a pharmaceutically acceptable solvent, for example water, by using a mechanical nebulizer, for example the Wright nebulizer, giving an aerosol of finely divided liquid particles well suited for inhalation.

The active ingredients can also be administered orally by inhalation in the form of aerosols obtained from pharmaceutically self-propelled compositions.

The percentage of active principle in the compositions of the invention can be variable, the only condition required being that the proportion is such that the correct dose makes it possible to obtain the desired therapeutic effect. Obviously, several unit formulations

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can be administered at the same time. In general, preparations should normally contain at least 0.025% by weight of active substance when the product is administered by injection; for oral administration, the preparations contain at least 0.1% by weight of active substance. The dose used depends on the desired therapeutic effect, the route of administration and the duration of treatment. In adults, doses are generally between 0.0002 and 2.0 mg / kg body weight. More particularly, in adult men, each dose per person is generally between 0.05 and 500 pg parenterally in the treatment of hypertension or diseases due to peripheral circulation disorders, and between 0.05 and 500 (ig parenterally in the treatment of cerebral thrombosis, myocardial infarction and arteriosclerosis. If necessary, these doses can be repeated at will.

The following example illustrates the pharmaceutical compositions according to the invention.

Example of composition

In 5 cm3 of ethanol, 500 μg of (±) -oxo-6a methano-6.9 dihydroxy-11.15 cyclohexyl-15 pentanor-16,17,18,19,20 prosten-5 yn-13 oate are dissolved. methyl- (5 Z) - (9 S, 11 R), (mixture of 5 (15 µl) and (15 S) (compound B). The solution is then sterilized by passage through a bacteriological filter and divided into 0.1 cm3 portions in 1 cm3 ampoules, thus obtaining ampoules each containing 10 jxg of (±) -oxo-6a methano-6.9 dihy-droxy-11.15 cyclohexyl-15 pentanor- 16,17,18,19,20 prostên-5 yn-13 10 methyl oate- (5 Z) - (9 S, 11 R), [mixture of (15 R) and (15 5)]. The contents of one ampoule are then diluted at the time of use with a suitable amount of an aqueous buffer solution to give a solution which can be administered by injection.

Analogous compositions can be prepared by replacing compound B with suitable amounts of any of the other compounds A or C to EE mentioned above.

R

Claims (4)

660,479 1. Prostaglandin analog, characterized in that it corresponds to the general formula: bond, X 'represents a trans-vinylene or ethylene radical, Y1 represents a carbonyl radical and Y2 represents a hydroxy-methylene radical, characterized in that an acid hydrolysis of a compound of general formula is carried out: A1 -, - A2 — C00R1 (II) X'Y2A3Z'R4 in which R1 represents a hydrogen atom or a straight or branched chain alkyl radical, Y1 represents a carbonyl or hydroxymethylene radical, represents a single or a double bond, A1 represents an alkylene radical containing 1, 2 or 3 carbon atoms and optionally carrying a methyl or ethyl substituent, R2 represents a hydrogen atom or a methyl or ethyl radical, R3 represents a hydrogen atom or also R2 and R3 form an alkylene radical containing 2 or 3 carbon atoms, optionally carrying a substituent methyl or ethyl so that the symbols A1, R2 and R3 together with the carbon atoms to which they are linked form a cycloal-coyl ring containing 5, 6, 7 or B carbon atoms optionally bearing one or two methyl or ethyl substituents or alternatively A1 and R3 form together with the carbon atom to which they are linked a phenylene ring optionally substituted by a halogen atom or a trifiuoromethyl radical or a straight or branched chain alkyl or alkyloxy radical containing 1 to 6 carbon atoms, A2 represents a valence bond or a methylene radical optionally carrying one or two methyl or ethyl substituents, X1 represents an ethylene, vinylene-trans or ethylynylene radical, Y2 represents a carbonyl or hydroxymethylene radical and either i) A3 represents a straight or branched alkylene chain containing 1 to 5 carbon atoms, Z1 represents a valence bond or an oxygen or sulfur atom and R4 represents an aliphatic hydrocarbon radical that or alicyclic, or represents a phenyl radical optionally substituted by a halogen atom or by a trifluoromethyl radical or by an alkyl or alkyl radical containing a straight or branched chain. 1 to 6 carbon atoms, or ii) A3 and Z1 both represent valence bonds and R4 represents an aliphatic or alicyclic hydrocarbon radical, as well as their cyclodextrin clathrates and, when R1 represents a hydrogen atom, their salts non toxic. 2 1 A —COOK (IV) X'CHA3Z'R4 I OR5 in which A1, A2, A3, R1, R2, R3, R4, = zr, X1, Y1 and Z1 are defined as in claim 1, and R5 represents a radical of general formula: If R7R8R9 (VII) 40 in which R8 and R5, identical or different, each represent a methyl or ethyl radical and R7 represents a straight or branched chain alkyl radical containing 1 to 4 carbon atoms. 6. Method according to one of claims 3 to 5, characterized in that the prostaglandin analog obtained in which R1 represents a hydrogen atom is transformed into a non-toxic salt. 7. Process for the preparation of a cyclodextrin clathrate 45 of a prostaglandin analog of formula (I) according to claim 1 in which R1 represents an alkyl radical in a straight or branched chain, characterized in that a prostaglandin analog of formula (I) as prepared below is prepared above by means of the method according to one of claims 3 to 5 and that the compound thus obtained is then transformed into its cyclodextrin clathrate. 8. Pharmaceutical composition, characterized in that it contains as active ingredient a prostaglandin analog according to claim 1 or one of its cyclodextrin clathrates or, when R1 represents a hydrogen atom, one of its non-toxic salts, 55 combination with a pharmaceutically compatible adjuvant or coating. in which A1, A2, A3, R1, R2, R3, R4, =, X1, Y1 and Z1 are defined as in claim f and R5 represents an acid-labile protective radical. 2. Method for the preparation of a prostaglandin analog according to claim 1 having the configuration (5 Z), characterized in that one irradiates by means of ultraviolet radiation a compound according to claim 1 representing the configuration (5 E). 2 3. Process for the preparation of a prostaglandin analog according to claim 1 in the formula of which Y2 represents a hydroxymethylene radical, characterized in that a compound of general formula is hydrolyzed: A2 — COOK1 (IV) X'CHA3Z'R4 OR5 (H2) A1CECH5) A2C00R6 (VI) X2CHA3Z'R4 GOLD Wherein A1, A2, A3, R2, R3, R4 and Z1 are defined as in claim 1, R5 is defined as in claim 3, R6 represents a straight or branched chain alkyl radical and X2 represents a vinylene radical trans or ethylene. 5. Process for the preparation of a prostaglan-20 dine analog according to claim 1, characterized in that a compound of general formula is treated with a quaternary ammonium fluoride and then with water: 4. Method according to claim 3 for the preparation of a prostaglandin analog according to claim 1 in the formula of which R1 represents an alkyl radical, —'— represents a double