BE873731A - 9-DEOXY-9A-METHYLENE ISOSTERES OF PG12 AND METHOD FOR PREPARING THEM - Google Patents

Description

       

    <EMI ID = 1.1>

  
process for preparing them The present invention relates to 9-deoxy-

  
  <EMI ID = 2.1>

  
in question? as also pharmaceutical compositions and veterinary compositions which contain them.

  
The compounds to which the scope of the present invention extends are substances which correspond to the general structural formula (II which follows:

  

  <EMI ID = 3.1>


  
in which

  
R is chosen from the group formed by the following radicals: <EMI ID = 4.1> <EMI ID = 5.1>

  

  <EMI ID = 6.1>


  
  <EMI ID = 7.1>

  
are independently selected from hydrogen, the radicals

  
  <EMI ID = 8.1>
  <EMI ID = 9.1>
  <EMI ID = 10.1>

  
  <EMI ID = 11.1>

  
  <EMI ID = 12.1>

  

  <EMI ID = 13.1>


  

  <EMI ID = 14.1>


  
can represent a hydrogen atom,

  
  <EMI ID = 15.1>

  
are attached, form a radical

  

  <EMI ID = 16.1>


  
  <EMI ID = 17.1>

  

  <EMI ID = 18.1>


  
  <EMI ID = 19.1>

  
  <EMI ID = 20.1>

  
and -NH-CH2-;

  
X is chosen from the group formed by the following radicals: <EMI ID = 21.1>
  <EMI ID = 22.1>
  <EMI ID = 23.1>
  <EMI ID = 24.1>

  

  <EMI ID = 25.1>


  
  <EMI ID = 26.1>

  
previously indicated;

  
  <EMI ID = 27.1>

  
can be zero or represent whole numbers that range in value from zero to 12, such that each sum

  
  <EMI ID = 28.1>

  
p and q are independently equal to zero or represent integers whose value varies from 1 to 3, such that the sum p + q is an integer whose value varies from 1 to 6;

  
  <EMI ID = 29.1>

  
substituted or substituted by one or more of the following substituents: halogens, C1-C6 haloalkyl groups;

  
  <EMI ID = 30.1>

  
or unsaturated, unsubstituted or substituted by one or more of the following substituents: halogens, haloalkyl radicals

  
  <EMI ID = 31.1>

  
also to salts acceptable in human pharmacy and in veterinary pharmacy, to optical antipodes, to geometric isomers and to diastereomers of the compounds of formula (I), as well as to their mixtures.

  
In the description of the compounds in accordance with the

  
  <EMI ID = 32.1>

  
from substituents on a ring in the a configuration, i.e. below the plane of the ring, to substituents on a system

  
  <EMI ID = 33.1>

  
  <EMI ID = 34.1>

  
i.e. above the plane of the nucleus, at a substituent of the

  
  <EMI ID = 35.1>

  
a side chain substituent in the R configuration. A wavy line (&#65533;) indicates the existence of a substituent of undefined stereochemistry, i.e. in this case the substituents

  
  <EMI ID = 36.1>

  
endo or exo configuration and the side chain substituents may be in the R configuration or in the. S.

  
The compounds of formula (I) and their derivatives,

  
which are described herein, have a cis junction between the condensed nuclei A and B; the hydrogen atoms bonded to the bicyclic system at the junction are both

  
outside the angle of the dihedral formed by the nuclei in the natural configuration.

  
The side chain on the cyclopentane nucleus A

  
  <EMI ID = 37.1>

  
and in exo configuration with respect to the bicyclic system.

  
In compounds to which the scope of this

  
  <EMI ID = 38.1>

  
sibles arising from the configuration of the exocyclic double bond to ring B, depending on whether the link of the chain to this double bond (ce chain) is on the same or opposite side of the chain on the cyclo- ring.

  
  <EMI ID = 39.1>

  
exocyclic bond is defined as being in, cis configuration, in the second case it is defined as being in trans configuration. In formula (I) and in the formulas which follow, the symbol ¯ "signifies that the scope of the present invention extends to the two geometric isomers, whether they are separated or whether they are in the form of melan-

  
  <EMI ID = 40.1>

  
The above notation relates to natural compounds. However, the enantiomorphs to which the scope of the present invention extends exhibit stereochemical characteristics at all asymmetric sites, which are opposite to those found in naturally occurring compounds. Therefore, they are enantiomorphic images of the latter and their names or designations include

  
  <EMI ID = 41.1>

  
mixtures d, l contain equimolar amounts of the natural compounds and the corresponding enantiomorphs.

  
The alkyl, alkenyl, alkynyl, alkoxy and

  
  <EMI ID = 42.1> and aryl, more particularly phenyl.

  
R preferably represents a free or esterified carboxyl group, or a salt of such a group.

  
  <EMI ID = 43.1>

  
methyl, ethyl and propyl radicals.

  
Preferred C2-C7 acyloxy groups are

  
  <EMI ID = 44.1>

  
Preferred C2-C6 alkanoyl radicals are acetyl and propionyl.

  
Preferred C2-CS alkylene radicals are ethylene and propylene radicals.

  
  <EMI ID = 45.1>

  
benzyloxy group.

  
Preferred C2-C10 alkenyl radicals are

  
  <EMI ID = 46.1>

  
mentioned above, but are preferably ethynyl radicals.

  
  <EMI ID = 47.1>

  
when Z represents a halogen atom. it is preferably chlorine or bromine.

  
  <EMI ID = 48.1>

  
it is preferable that this group is the methyl radical.

  
  <EMI ID = 49.1>

  
can be a mono- or bi-cyclic ring, containing, as heteroatom, at least one nitrogen, sulfur or oxygen atom. However, the heterocycle is preferably monocyclic as defined above, in particular tetra-

  
  <EMI ID = 50.1>

  
When R represents an esterified carboxyl group,

  
  <EMI ID = 51.1>

  
equal to zero, 1, 2 and 3.

  
Salts acceptable in human or veterinary pharmacy of the compounds of formula (I) can be formed with both inorganic and organic acids and bases.

  
As pharmacy acceptable inorganic acids

  
  <EMI ID = 52.1>

  
hydrochloric acid, hydrobromic acid and sulfuric acid 9 while the organic acids acceptable in human or veterinary pharmacy include citric, fumaric, tartaric, malic, maleic, tallow methane and methane acids.

  
  <EMI ID = 53.1>

  
Mention may be made of hydroxides of alkali metals or of alkaline earth metals, of zinc and of aluminum. As organic bases which are acceptable in human pharmacy or in veterinary pharmacy, there may be mentioned amines, such as the following: methyl-

  
  <EMI ID = 54.1> <EMI ID = 55.1>

  
acceptable in human pharmacy or in veterinary pharmacy, derived from one of the bases listed above.

  
In the present specification, reference is made to the compounds to which the scope of the present invention extends as to

  
  <EMI ID = 56.1>

  
next :

  

  <EMI ID = 57.1>
 

  
  <EMI ID = 58.1>

  
7-nor-methylene respectively.

  
The same notation (homo, dihomo, nor, dinor, etc.) is used to indicate the elongation (the first case)

  
  <EMI ID = 59.1>

  
of one, two or more than two carbon atoms, relative to the number of carbon atoms of prostacyclanolque acid.

  
As examples of this nomenclature, the two compounds of the formulas (Ia) and (Ib) which follow are called by the full names which follow the formulas:

  

  <EMI ID = 60.1>


  

  <EMI ID = 61.1>


  
  <EMI ID = 62.1>

  
In accordance with the present invention, the preferred compounds of formula (I) are those in which R represents

  
  <EMI ID = 63.1>

  
phenyl optionally substituted in the manner previously indicated, a saturated monoheterocyclic group (preferably tetrahydrofuryl or tetrahydrothienyl) or a mono-

  
  <EMI ID = 64.1>

  
the meanings indicated above.

  
The acids which follow are particularly advantageous compounds in accordance with the invention:

  
  <EMI ID = 65.1>

  
  <EMI ID = 66.1>

  
  <EMI ID = 67.1>

  
  <EMI ID = 68.1> <EMI ID = 69.1>

  
  <EMI ID = 70.1>

  
compounds listed above as also their acceptable salts in human pharmacy or in veterinary pharmacy.

  
The compounds in accordance with the present invention

  
are prepared in accordance with a process characterized in that the following operations are carried out:

  
1) alkylation of a compound of formula (II) which follows:

  

  <EMI ID = 71.1>


  
  <EMI ID = 72.1>

  
C1-C6 or a protecting group linked to the bicyclic system or to the side chain through a bond

  
  <EMI ID = 73.1>

  
together form a protective group for the ketone function,

  
with va compound of formula (III)

  

  <EMI ID = 74.1>


  
in which

  
  <EMI ID = 75.1>

  
an ether bond; d ")

  

  <EMI ID = 76.1>


  
  <EMI ID = 77.1>

  
  <EMI ID = 78.1>

  

  <EMI ID = 79.1>


  
  <EMI ID = 80.1>

  
the meanings indicated above, this alkylation being, if desired, followed by the removal of any protecting group present;

  
2) alkylation of a compound of formula (IV)
  <EMI ID = 81.1>
 in which

  
  <EMI ID = 82.1>

  
in. )

  

  <EMI ID = 83.1>


  
  <EMI ID = 84.1>

  
  <EMI ID = 85.1>

  
  <EMI ID = 86.1>
  <EMI ID = 87.1>
  <EMI ID = 88.1> previously indicated meanings;

  

  <EMI ID = 89.1>


  
  <EMI ID = 90.1>

  
group

  

  <EMI ID = 91.1>


  
where m2 has the preceding meanings

  
as indicated,

  
with a compound of the formula (V)

  

  <EMI ID = 92.1>


  
  <EMI ID = 93.1>

  
the meanings indicated above, so as to obtain a compound of formula (VI)
  <EMI ID = 94.1>
   <EMI ID = 95.1>

  
as indicated and, if desired, the protecting groups can be removed in a compound of formula (VI),

  
so as to obtain a compound of formula (I) in

  
which Y represents a group -CH = CZ- (trans), Z has

  
  <EMI ID = 96.1>

  
together form an oxo group and / or, if desired, a compound of formula (VI) can be reduced in which

  
Z represents a hydrogen atom or a compound of

  
  <EMI ID = 97.1>

  
together form an oxo group, so as to obtain, after removal of the protecting groups, a compound of

  
  <EMI ID = 98.1>

  
if desired, a nucleophilic addition can be carried out

  
  <EMI ID = 99.1>

  
compound of formula (VI) or a compound of formula CI)

  
  <EMI ID = 100.1>
-CH = CZ- (trans), Z has the meanings previously <EMI ID = 101.1>

  
so as to obtain, after removal of any protecting groups, a compound of the formula (I) wherein Y represents a group -CH2-C &#65533;, - or -CH-CZ- (trans), Z has the meanings previously indicated and

  
  <EMI ID = 102.1>

  
while the other of these symbols represents a sluggish <EMI ID = 103.1>

  
if desired, the ether type derivative of a compound of formula (I) in which Y represents

  
  <EMI ID = 104.1>

  
  <EMI ID = 105.1>

  
  <EMI ID = 106.1>

  
removal of any protecting groups, a

  
  <EMI ID = 107.1>

  
group -CH2-CH2 or -CH = CZ- (trans), Z has the meanings previously indicated and one of the symbols R3

  
  <EMI ID = 108.1>

  
ua group -CH = CZ- (trans), Z represents one. halogen atom,

  
  <EMI ID = 109.1> together an oxo group and any hydroxyl, oxo or carboxyl radicals are free or protected from

  
the manner previously indicated, so as to obtain, after the elimination of any protecting groups, a compound of the formula (I) in which Y represents

  
  <EMI ID = 110.1>

  
and / or, if desired, the derivatives of the lactone or salt type of a compound of formula (I) can be prepared and / or, if desired, a free compound of formula (I) can be prepared from its salt and / or, if

  
As desired, a mixture of isomeric compounds of formula (I) can be separated into its individual isomers.

  
In the methods described above, if one or more substituents are specified for a compound, the others have all the meanings previously indicated in connection with the definition of formula (I).

  
The protective groups of the hydroxyl functions are ether or ester residues which are easily converted into hydroxyl groups under mild conditions, for example by acid hydrolysis. Preferred protecting groups include silyl ether groups, e.g.

  
  <EMI ID = 111.1>

  
lic, dimethyl-tert-butyl, dimethyl-isopropyl <EMI ID = 112.1>

  
oxathianyl,

  

  <EMI ID = 113.1>


  
  <EMI ID = 114.1>

  
The groups protecting the ketone function are preferably ketal and thioketal residues:

  
groups

  

  <EMI ID = 115.1>


  
  <EMI ID = 116.1>

  
the meanings indicated above.

  
Alkylations of a compound (II) with a compound
(III) are performed in the = $ manner only those of a com-

  
  <EMI ID = 117.1>

  
in question can be carried out in any inert solvent, for example a linear or cyclic ether, such as

  
than diethyl ether, tetrahydrofuran, dioxane

  
or dimethoxyethane; in an aliphatic hydrocarbon

  
or aromatic, such as n-hexane, n-heptane, benzene or toluene; in a halogenated hydrocarbon, such as dichloromethane or carbon tetrachloride, such as

  
also in mixtures of these solvents.

  
Dimethyl sulfoxide, hexamethylphosphoramide and other aprotic solvents are of particular interest, more especially when E in <EMI ID = 118.1>

  
carbanion by reaction with an alkali hydride which, in turn, can generate carbanions with the compounds of

  
  <EMI ID = 119.1>

  
corresponding phosphonates; this solvent is therefore particularly advantageous, given that the carbanions (III) and (IV) can be generated in situ.

  
For carrying out the above-mentioned alkylations, the reaction temperature can vary from the freezing point to the boiling point of water, although it is particularly preferred to operate at room temperature.

  
The reaction of a compound (II) on a compound (III) generates a mixture of geometric isomers, in this sense

  
that the new exocyclic double bond formed during the reaction may be in the cis or trans position.

  
The reaction between a compound (IV) and a compound (V) generates only one of the cis and trans isomers or these two isomers

  
  <EMI ID = 120.1>

  
posed cis, trans or a mixture of these two forms. If desired, the individual geometric isomers can be separated by fractional crystallization from a solvent or by chromatography, whether thin layer, column or liquid-liquid phase, at low, medium or high pressure. You can use silica gel or

  
magnesium silicate as a support with a solvent

  
such as cyclohexane, n-hexane, benzene, methylene chloride, ethyl ether, isopropyl ether, ethyl acetate or methyl acetate, as the mobile phase.

  
When necessary, the groups protecting the ether function can be removed from the hydroxyl functions by moderate acid hydrolysis, for example using mono- or poly-carboxylic acids, such as acetic acid, formic acid, citric acid, oxalic acid or tartaric acid, in a solvent, such as water, acetone, tetrahydrofuran, dimethoxyethane or a low molecular weight alcohol, or

  
  <EMI ID = 121.1>

  
that, in a low molecular weight alcohol, such as ethanol or anhydrous methanol, or with a resin of

  
  <EMI ID = 122.1>

  
0.1 - 0.25 N polycarboxylic acid (such as oxalic acid or citric acid) in a suitable low boiling solvent which is miscible with water and which can easily be removed in vacuo at the end of the reaction.

  
The silyl ether type residues can be selectively removed in the presence of other protecting groups with F 'ions in solvents, such as tetrahydrofuran and dimethylformamide.

  
Protective ester groups can be removed by carrying out the typical saponification procedures which follow.

  
Protecting groups of the ketal and thio type

  
  <EMI ID = 123.1>

  
form of acetal or thioacetal groups, by moderate acid hydrolysis, tried as described above.

  
  <EMI ID = 124.1>

  
selectively removed in the presence of other protecting groups with, for example, mercuric chloride in acetonitrile or acetone in aqueous solution or in a mixture thereof, in the presence of an alkaline metal carbonate earthy., such as calcium or magnesium.

  
  <EMI ID = 125.1>

  
oxo group, is preferably carried out in liquid ammonia, with or without a co-solvent (for example an alcohol

  
  <EMI ID = 126.1>

  
of an alkaline earth metal, such as lithium, sodium, potassium or calcium. At the end of the reaction, a weak acid, such as sulfate or ammonium chloride or an aliphatic alcohol, such as ethanol or propanol, is used as the source of protons. Temperature <EMI ID = 127.1>

  
at reflux.

  
Nucleophilic addition to the free carbonyl group

  
  <EMI ID = 128.1>

  
  <EMI ID = 129.1>

  
secondary or tertiary alcohol, depending on the nucleophilic group.

  
A secondary alcohol is preferably prepared with an alkali metal or alkaline earth metal borohydride (such as sodium, lithium, calcium or magnesium) or with zinc borohydride, so as to generate, after removal of any protecting groups, a compound (I) in which Y represents a

  
  <EMI ID = 130.1>

  
previously indicated and one of the symbols R3

  
and R4 represents a hydrogen atom, while the other represents a hydroxyl group. 0.5 to 6 moles of reducing agent are used per mole of carbonyl derivative (VI) or (I), in an aqueous or anhydrous solvent, for example, a linear or cyclic ether, such as ethyl ether, tetra-

  
  <EMI ID = 131.1>

  
aliphatic or aromatic bide, such as n-heptane or benzene, a halogenated hydrocarbon, such as methylene chloride or a solvent containing hydroxyl functions, such as methyl alcohol, ethyl alcohol or isopropyl alcohol, such as also mixtures of these compounds.

  
  <EMI ID = 132.1> the boiling point of the solvent, but it preferably fluctuates between -25 [deg.] C and +25 [deg.] C.

  
A tertiary alcohol is prepared by reaction with an organometallic derivative, so as to obtain, after removal of any protective groups, a

  
  <EMI ID = 133.1>

  
a halogen atom, preferably chlorine or bromine), a lithium cuprate, such as a compound of the formula

  
  <EMI ID = 134.1>

  
aryl, in particular phenyl, and M represents an alkali or alkaline earth metal). The reaction between the carbonyl compound and one of these organometallic derivatives is preferably carried out with 1.05 mol (or slightly more

  
  <EMI ID = 135.1>

  
anhydrous solvent, for example an aprotic solvent, such as

  
  <EMI ID = 136.1> preferably from -60 [deg.] C to 20 [deg.] C.

  
Whether secondary or tertiary alcohol

  
  <EMI ID = 137.1>

  

  <EMI ID = 138.1>


  
  <EMI ID = 139.1>

  
using fractional crystallization techniques

  
and chromatography described above.

  
The optional preparation of ethers from these secondary and tertiary alcohols to generate, after removal of any protecting groups, compounds of the formula (I) in which Y represents a

  
  <EMI ID = 140.1>

  
however the other of these symbols represents one. atom <EMI ID = 141.1>

  
be carried out by reaction on a diazoalkane with optional aryl substitution, in the presence of a catalyst, such as

  
  <EMI ID = 142.1>

  
organic solvent such as dichloromethane. This preparation can also be carried out by reaction of the hydroxyl group (either free or in the form of a salt) with an alkyl or arylalkyl halide, in the presence of a base such as silver oxide, in a solvent such as

  
  <EMI ID = 143.1>

  
The optional dehydrohalogenation of a compound of formula (I) in which Y represents a group <EMI ID = 144.1> the antrum of these symbols represents a hydrogen atom, a C1-C6 alkyl group, C2-C10 alkenyl 'alkynyl

  
  <EMI ID = 145.1>

  
together form an oxo group, so as to obtain the corresponding compound (I) in which Y represents a

  
  <EMI ID = 146.1>

  
and alkali metal alcoholates or amides. From 1 to 5 moles (preferably 1.5 to 1.8 moles) of the agent are used.

  
  <EMI ID = 147.1>

  
preferably carries out the reaction in an oxygen-free atmosphere, in an inert solvent, such as

  
  <EMI ID = 148.1>

  
some water. In the absence of ammonia, it is preferred to work at room temperature.

  
The optional dehydrohalogenation of a compound

  
  <EMI ID = 149.1>

  
Z represents a halogen atom, so as to obtain a corresponding derivative in which Y represents a group <EMI ID = 150.1> carbonyl and subsequent preparation of ethers from the alcohol produced.

  
The reactions which follow are all carried out by carrying out standard methods: optional transformation of a compound of formula (I) into another, optional preparation of a lactone or of a salt, preparation of the compound (I) ) free from its salt and separation of Individual isomers from a mixture.

  
For example, a compound of

  
  <EMI ID = 151.1>

  
hydrogen from a compound in which one of the

  
  <EMI ID = 152.1>

  
as long as the other of these symbols represents a hydroxyl group, by preparing the tosylate from alcohol, for example by treatment with tosyl chloride in the presence of a base and reduction of the tosylate with a compound

  
  <EMI ID = 153.1>

  
an anhydrous solvent, such as ethyl ether or tetrahydrofuran, at a temperature which varies from room temperature to the boiling point of the solvent. Analogously, a compound of the formula (I) can be prepared

  
  <EMI ID = 154.1>

  
gene, from a compound in which one of the symbols

  
  <EMI ID = 155.1>

  
the other of these symbols represents a hydroxyl group and a compound of the formula (I) can be prepared in which

  
  <EMI ID = 156.1>

  
which D represents a group

  

  <EMI ID = 157.1>


  
A compound of formula (I) can be prepared in which R3 and R4 together form an oxo group,

  
  <EMI ID = 158.1>

  
represents -on hydrogen atom, while the other of these symbols represents a hydroxyl group, by the oxida-

  
  <EMI ID = 159.1>

  
inert, preferably chlorinated, such as methylene chloride or chloroform, at room temperature,

  
  <EMI ID = 160.1>

  
dicyanobenzoquinone, in an inert solvent, such as dioxane, benzene or a mixture, at a temperature which

  
  <EMI ID = 161.1>

  
In a similar way, we. can prepare a

  
  <EMI ID = 162.1>

  
hydroxyl and a compound (I) can be prepared in which

  
D represents a group

  

  <EMI ID = 163.1>


  
from a compound in

  
which D represents a group

  

  <EMI ID = 164.1>


  
When only one of several functions of the secondary alcohol type is to be oxidized, the other functions in question must be protected as described above; the protecting groups are then removed at the end of the reaction.

  
A compound of the formula (I) can be prepared

  
  <EMI ID = 165.1>

  
hydroxyl. Here again, when only one. of several functions of the secondary alcohol type must react, the other functions in question must be protected; the protecting groups are then removed at the end of the reaction.

  
A compound of formula (I) can be prepared in which R represents a carboxylic ester group

  
  <EMI ID = 166.1>

  
of a compound in which R represents a free carboxyl group, according to standard methods, for example by

  
  <EMI ID = 167.1> with a diazoalkane.

  
The optional conversion of a compound of formula (I) wherein R represents a carboxyl group

  
  <EMI ID = 168.1>

  
into a compound in which R represents a free carboxyl group, can be carried out by carrying out standard saponification procedures: treatment with an alkali metal or alkaline earth metal hydroxide in water. or an aqueous alcohol, followed by acidification.

  
The optional preparation of a compound of

  
  <EMI ID = 169.1>

  
(Rn a hydroxy) from a compound in which R represents a free or esterified carboxyl group, can be effected by reduction of the ester with a compound of the

  
  <EMI ID = 170.1>

  
furan, at reflux.

  
The optional conversion of a compound of formula (I) in which R represents a free carboxyl group, into a compound in which R represents a group

  

  <EMI ID = 171.1>


  
  <EMI ID = 172.1>

  
indicated) can be carried out by treatment with a

  
  <EMI ID = 173.1>

  
condensation, for example a carbodiimide, such as dicyclohexylcarbodiimide. A compound of formula (I) in which R represents a carboxylic ester group can be converted into a compound in which R represents

  
a group

  

  <EMI ID = 174.1>


  
by treatment with an amine of

  
  <EMI ID = 175.1>

  
reflux temperature, for 2 to 3 hours.

  
The possible preparation of a compound of

  
formula (I) in which R represents a radical

  

  <EMI ID = 176.1>


  
from a compound in which R represents a

  
free carboxyl group, can be carried out by first forming the corresponding acid halide (preferably the chloride, optionally with thionyl or oxalyl chloride in dioxane or dichloroethane under reflux), then the derivative of the amide type (for example with ammonia), this formation being followed by dehydration to nitrile

  
  <EMI ID = 177.1>

  
the reaction of nitrile with sodium azide

  
  <EMI ID = 178.1>

  
temperature that varies from room temperature to 100 * C. This reaction of the carboxyl group to generate the compound

  
  <EMI ID = 179.1>

  

  <EMI ID = 180.1>


  
preferably carried out

  
on the starting material.

  
The optional conversion of a compound of formula (I) in which R represents a free or esterified carboxyl group into a compound in which R represents a -CHO group can be carried out using conventional methods, for example the preparation of chloride. corresponding from acid or ester and Rosenmmd reaction. subsequent, as described in the following work:
Org. Reactions, 4, 362 (1948).

  
A compound of the formula (I) can be prepared

  
  <EMI ID = 181.1>

  
the meanings indicated above) from a compound in which R represents a free or esterified carboxyl group, by reacting the hydrochloride of the carboximidic ester (prepared according to conventional methods) with a suitable alcohol, according to the method described in

  
  <EMI ID = 182.1>

  
optional of a compound of formula (I) in which

  
R represents a group

  

  <EMI ID = 183.1>


  
  <EMI ID = 184.1>

  
(where X 'represents a

  
  <EMI ID = 185.1>

  
which acetone is changed over time

  
its formation, or by reaction on an ortho-ester in which the alcohol is removed by distillation as it is

  
as it is trained. The acetal can also be prepared from the corresponding thioacetal by reaction with a suitable alcohol or a suitable glycol, in the presence

  
  <EMI ID = 186.1> exchange catalyst and an alkaline earth metal carbonate, in an inert solvent.

  
Thioacetalization, for example the preparation

  
  <EMI ID = 187.1>

  
represents a group

  

  <EMI ID = 188.1>


  
  <EMI ID = 189.1>

  
  <EMI ID = 190.1>

  
mentioned) from a compound in which R represents

  
  <EMI ID = 191.1>

  
  <EMI ID = 192.1>

  
in the presence of a catalyst, such as boron trifluoride etherate, in an inert solvent, preferably a halogenated or aromatic hydrocarbon (methylene chloride, chloroform, benzene, toluene).

  
Ketals and corresponding thoacetals can be prepared from ketones according to the procedure described above for acetals and thioacetals.

  
The preparation of a lactone and of a salt from a compound of formula (I), as also the preparation of a compound (I) from its salt, is carried out by carrying out standard methods .

  
Individual isomers are separated from mixtures of isomeric compounds (I) using standard techniques, such as fractional crystallization and chromatography.

  
  <EMI ID = 193.1>

  
seducing the meanings indicated above) by the reaction of a compound of the formula (VU)

  

  <EMI ID = 194.1>


  
  <EMI ID = 195.1>

  
cations indicated above, on at least one molar equivalent of one of the following bases: alkali metal hydride,

  
  <EMI ID = 196.1>

  
potassium hydride, lithium hydride or calcium hydride, an alkali metal or alkaline earth metal alcoholate, such as sodium tert-butoxide or

  
  <EMI ID = 197.1>

  
react a compound of the formula (VIII)

  

  <EMI ID = 198.1>


  
  <EMI ID = 199.1>

  
in an organic solvent, such as benzene, acetonitrile or diethyl ether and then treating the phosphonium salt produced with an equivalent amount of an inorganic stock, such as sodium hydroxide, sodium hydroxide. potassium, sodium carbonate or sodium bicarbonate.

  
Compounds of formula (V) are prepared in a manner analogous to those described above in connection with the preparation of compounds of formula (III), from compounds of formula (IX)

  

  <EMI ID = 200.1>


  
  <EMI ID = 201.1>

  
meanings previously indicated, or from compounds of the formula (X)

  

  <EMI ID = 202.1>


  
  <EMI ID = 203.1>

  
previously indicated meanings.

  
Compounds of formulas (VU) and (IX) are prepared by carrying out conventional methods, for example, those described by Corey et al. in J. Amer. Chem. Soc.,
90, 3247 (1968) and 88, 5654 (1966). The compounds of formulas (VIII) and (X) are also prepared by carrying out conventional methods.

  
The compounds of formulas (II) and (IV) are novel compounds and, as such, the scope of the present invention extends to them, as also to their processes. preparation.

  
The compounds of formula (II) are prepared

  
  <EMI ID = 204.1> ment indicated, according to a method characterized in that the following steps are implemented

  
  <EMI ID = 205.1>

  

  <EMI ID = 206.1>


  
  <EMI ID = 207.1>

  
on a compound of formula (V) so as to obtain a compound of formula (XII)

  

  <EMI ID = 208.1>


  
  <EMI ID = 209.1>

  
quées; .

  
  <EMI ID = 210.1>

  
to a compound of the formula (XIII)

  

  <EMI ID = 211.1>


  
  <EMI ID = 212.1>

  
a compound of the formula (XIV)

  

  <EMI ID = 213.1>


  
  <EMI ID = 214.1>

  
  <EMI ID = 215.1>

  
other hydroxyl groups, if present, are protected from the. as indicated above.

  
  <EMI ID = 216.1>

  
which Y represents a group -NE-CE, -, by reacting a compound of formula (XV)

  

  <EMI ID = 217.1>


  
in which G, p and q have the meanings above

  
  <EMI ID = 218.1>

  
previously indicated with the exception of the hydroxyl group,

  
  <EMI ID = 219.1>

  

  <EMI ID = 220.1>


  
  <EMI ID = 221.1>

  
the meanings indicated above, in the presence of a reducing agent, this reaction being understood as the removal

  
  <EMI ID = 222.1>

  
protectors, if present.

  
The compounds of the formula (II) in which Y represents a group -NH-C = 0 are prepared by reacting.

  
  <EMI ID = 223.1>
  <EMI ID = 224.1>
 in which Hal represents a halogen atom,

  
  <EMI ID = 225.1>

  
have the meanings indicated above, in the presence of a base, this reaction being followed by the elimination of the protective group at G and optionally of the other protective groups, if they are present.

  
The reaction between a compound of the formula (XI)

  
and a compound of formula (V) is carried out in the same manner as that described above with respect to compounds of formulas (IV) and (V).

  
The possible conversion of a compound of

  
  <EMI ID = 226.1>

  
by carrying out reactions analogous to those described above with regard to the preparation of a compound of formula (I) into another, for example nucleophilic addition

  
  <EMI ID = 227.1>

  
silyl ether residue (for example a trialkylsilyl ether group, such as trimethyl ether, dimethyl-tertbutyl, dimethylisopropyl or dimethylethylsilyl, but preferably dimethyl-tert-butyl) or an acetal-ether residue (for example, tetrahydropyranyl ether, tetrahydropyranyl ether, tetrahydropyranyl ether, tetrahydranyl ether, hydrofuranyl ether, dioxanyl ether, oxathianyl ether, but preferably tetrahydropyranyl ether).

  
  <EMI ID = 228.1>

  
formula (XIII) is removed as previously described

  
  <EMI ID = 229.1>

  
silyl and with acid hydrolysis to an acetalether. When a protecting group G 'has to be removed in the presence of other labile ether groups, the latter should

  
  <EMI ID = 230.1>

  
represents an acetal-ether group,

  
When G represents a protected carbonyl group, the latter is preferably protected in the form of a

  
  <EMI ID = 231.1>

  
preferably dimethoxyacetal or a ketal or thio- radical

  
  <EMI ID = 232.1>

  

  <EMI ID = 233.1>


  

  <EMI ID = 234.1>


  
  <EMI ID = 235.1>

  
The removal of protecting groups in a compound of formula (XIII), as also the possible protection of free hydroxyl groups in a compound

  
of formula (XIV), for example in the form of acetal ethers or silyl ethers, can be carried out as previously indicated.

  
The optional oxidation of a compound of formula (XIV) in which G 'represents a hydroxyl group, can be carried out using standard oxidation methods for secondary alcohols, for example, treatment of the alcohol in an organic solvent such as acetone, with a solution of chromic anhydride in sulfuric acid, this operation being followed by the implementation of normal processes.

  
  <EMI ID = 236.1>

  
of formula (XV) and an anhydride (XVI) is carried out in. typical reaction conditions for this process. preferably, using a mixed hydride, such as NaBH4 or LiAlH4 as a reducing agent.

  
The reaction between compounds of formulas (XV) and (XVII) is carried out under normal conditions for

  
amines acylaates.

  
The compounds of formula (IV) are prepared according to a process characterized in that the steps

  
  <EMI ID = 237.1>

  
  <EMI ID = 238.1>
  <EMI ID = 239.1>
   <EMI ID = 240.1>

  
b

  
  <EMI ID = 241.1>

  
the formula (XIX)

  

  <EMI ID = 242.1>


  
  <EMI ID = 243.1>

  
into another of the formula (XX)

  

  <EMI ID = 244.1>


  
  <EMI ID = 245.1>

  
aldehyde function in T.

  
The reaction between compounds of the formulas
(XVIII) and (III) is carried out under similar conditions

  
  <EMI ID = 246.1>

  
two isomeric olefins differing in their configuration
(cis or trans) on the Newly formed exocyclic double bond. Individual isomers of formula (XIX) can be separated by fractional crystallization or

  
by chromatography, as previously described "

  
The optional conversion of a compound of the formula (XIX) into a compound of the formula (XX) can be carried out as described above in connection with analogous reactions involving compounds of the formula CI).

  
For example, one can prepare a compound of formula (XX)

  
in which D represents a group

  

  <EMI ID = 247.1>


  
  <EMI ID = 248.1>

  
given the meanings previously indicated), from a compound of formula (XIX) in which D represents

  
a group

  

  <EMI ID = 249.1>


  
by implementing ester-

  
  <EMI ID = 250.1>

  
a group

  

  <EMI ID = 251.1>


  
  <EMI ID = 252.1>

  
cations previously indicated), from a compound of

  
the formula (XIX) in which D represents a group

  

  <EMI ID = 253.1>


  
by implementing the usual ketalization and thioketalization processes.

  
The groups protecting the aldehyde function in a compound of formula (XX) are removed as previously described, preferably by acid hydrolysis. <EMI ID = 254.1>

  
or by treatment with mercuric chloride, when protected as a thioacetal. When the

  
  <EMI ID = 255.1>

  
selectively in the presence of other protected carbonyl functions, the latter must be acetals or ketals if the aldehyde is a thioacetal and thioacetals or thioketals when the aldehyde is an acetal.

  
  <EMI ID = 256.1>

  
according to a method characterized in that the following steps are carried out:

  
  <EMI ID = 257.1>

  

  <EMI ID = 258.1>


  
in which p and q have the meanings

  
  <EMI ID = 259.1>

  
carbonyl protected as described above, to a compound of formula (XXII)

  

  <EMI ID = 260.1>


  
in which p, q and G have the meanings indicated above;

  
  <EMI ID = 261.1>

  

  <EMI ID = 262.1>


  
  <EMI ID = 263.1>

  
the formula (XXIV)

  

  <EMI ID = 264.1>


  
  <EMI ID = 265.1>

  
to a compound of the formula (XXV)
  <EMI ID = 266.1>
   <EMI ID = 267.1>

  

  <EMI ID = 268.1>


  
  <EMI ID = 269.1>

  
tions previously indicated, can be prepared from a compound of formula (XXIV) according to processes such as, for example by reaction in the presence of a base, on a

  
  <EMI ID = 270.1>

  
  <EMI ID = 271.1>

  

  <EMI ID = 272.1>


  
  <EMI ID = 273.1>

  
from a compound of the formula (XXIB) by oxidation '

  
  <EMI ID = 274.1>

  
and chromic anhydride, or by oxidation, carried out according to the method of Mbffatt, in a mixture of benzene and dimethyl sulfoxide, with dicyclohexylcarbodiimide, in the presence of pyridinium trifluoroacetate.

  
  <EMI ID = 275.1>

  
meanings indicated above, but preferably representing the methyl radical), is carried out in the presence of 2 to 4 moles of a base, such as sodium methoxide,

  
  <EMI ID = 276.1>

  
moles of carbonic diester per mole of ketone, the reactants being as such or in an inert solvent, in an atmosphere free of oxygen and free of water. Temperature

  
  <EMI ID = 277.1>

  
with an alkali metal or alkaline earth metal borohydride in aqueous solution, preferably at a pH which

  
  <EMI ID = 278.1>

  
Generally speaking, the reduction is completed in space

  
30 miaules and destroying the excess reagent by the addition of an easily reducible compound, such as acetone,

  
and a proton donor, such as acetic acid.

  
The individual optical antipodes of a compound

  
of the formula (XXIV) in which G has the signifi-. previously indicated cations, can be separated by saponification of the ester using standard methods, forming a salt of the product acid with an optical base. <EMI ID = 279.1>

  
amphetamine or arginine and separating the diastereomeric salts thus obtained by fractional crystallization, for example. The optically active acid is then recovered by conversion to the sodium salt and subsequent acidification of its aqueous solution to a pH which does not interfere with the protective group at G.

  
Optionally, hydrolysis of the protecting groups can precede optical resolution; The protecting groups are then restored at the end of the process.

  
of seperation.

  
The optically active free acid prepared in this way is then converted into an optically active ester.
(XXIV) using conventional methods, for example

  
  <EMI ID = 280.1>

  
If desired, using an identical method, the racemic compounds (XXV) can be separated into the individual optical antipodes.

  
It is also possible to solve compounds (XXIV) and (XV) where G represents a carbonyl group protected in their optical antipodes, deprotect the carbonyl group in G, react it with an optically active primary amine, for example arginine, lysine , alanine, 1-phenyl-

  
  <EMI ID = 281.1>

  
correspondingly active; these bases can then be separated according to known methods, for example by fractional crystallization or by liquid chromatography under high pressure, the group can be hydrolyzed

  
  <EMI ID = 282.1>

  
separate the optically active keto-esters into optical antipodes (XXIV) and (XXV) by ketalization or acetalization ,:
performed in a conventional manner.

  
  <EMI ID = 283.1>

  
formula (XXIV) into another of formula (XXV) can be effected on a racemic or on the individual isomers separated as described above. During this transformation, the configuration of the free hydroxyl group on the cyclopentane ring is reversed. The process involves esterification of the hydroxyl group, by treatment with

  
2 to 4 molar equivalents of triphenylphosphine and 2 to 4 molar equivalents of a carboxylic acid such as acid

  
  <EMI ID = 284.1>

  
ethyl, in an inert solvent, such as here aromatic hydrocarbon, optionally halogen, such as benzene

  
  <EMI ID = 285.1>

  
A compound of the formula (XXVI) is prepared

  
from a compound of formula (XXIV) or (XXV) using known methods. For example, the free hydroxyl group can be converted into a compound of <EMI ID = 286.1>

  
preparation of ether already described with regard to analogous reactions of compounds of formula (I).

  
The free hydroxyl group can be oxidized from a

  
  <EMI ID = 287.1>
  <EMI ID = 288.1>
   <EMI ID = 289.1>

  
aluminum.

  
When reducing a compound of the formula

  
  <EMI ID = 290.1>

  
product obtained is the corresponding primary alcohol which can also be prepared from the free acid according to

  
  <EMI ID = 291.1>

  
Free acid is prepared by saponification of the ester.

  
  <EMI ID = 292.1>

  
previously indicated.

  
The compounds of formula (XV) are prepared by carrying out known processes, starting, for example, from a compound of formula (XXVII) in which any functions of the secondary alcohol type are protected.

  
  <EMI ID = 293.1>

  
silyl ether, or in the form of silyl ether if -OR * represents an acetal-ether group. For example, a compound of formula (XV) can be prepared from a compound of formula (XXVII), according to a process involving the following steps:

  
  <EMI ID = 294.1>

  
treatment, for example, with an aetonic solution of an alkali metal azide;

  
  <EMI ID = 295.1>

  
product of formula (XV) into another.

  
The compounds of formulas (XVI) and (XVII) are

  
  <EMI ID = 296.1>

  
of known methods.

  
The compounds of formula (XVIII) are prepared from the compound of formula (XI) in which,

  
  <EMI ID = 297.1>

  
preferably, a residue of the silyl ether type and, when <EMI ID = 298.1>

  
  <EMI ID = 299.1>

  
hydroxyl, this checkerboard is protected, preferably in the form of an acetal-ether or in the form of an ester, by carrying out the following steps:

  
  <EMI ID = 300.1>

  
ketone group with Jones reagent; . possible selective elimination of the protective group

  
  <EMI ID = 301.1>

  
The compounds of formulas (XXIA) and
(XXIB) according to known methods. For example, a compound
(SCIA.) In which p - q = 1 is prepared by reduction

  
  <EMI ID = 302.1>

  
followed by the elimination of the ketal from the carbonyl function. In both cases, the hydroxy ketone produced (XXI) with

  
  <EMI ID = 303.1>

  
  <EMI ID = 304.1>

  
The two isomers can easily be separated, using the corresponding silyloxy racemate, by fractional crystallization or by chromatography, as already described several times above.

  
  <EMI ID = 305.1>

  
(XXVIII) which has a cis junction between the two nuclei.

  

  <EMI ID = 306.1>


  
according to a process involving the protection of

  
  <EMI ID = 307.1>

  
above), standard hydroboration of the double bond and subsequent removal of the ketone-protecting group, carried out as described above.

  
  <EMI ID = 308.1>

  
alkane ", thesis presented at the University of Sciences and Techniques of Languedoc, Académie de Montpelier,

  
n [deg.] of order C.N.R.S.A.O. 11257 (t975):

  
  <EMI ID = 309.1>

  
ketalization or thioketalization, oxidation, Bayer-Willinger reaction and subsequent formulation of the product using methods analogous to those described above.

  
  <EMI ID = 310.1>

  
in which p is equal to zero and q is equal to zero or else p is equal to 1 and q is equal to zero, from the

  
  <EMI ID = 311.1>

  
2-one (J. Chem. Soc., Perkin, 1, 1767 (1965)) according to known methods: for example, said bromhydrin can be converted into its acetal, thioacetal, ketal or thioketal,

  
  <EMI ID = 312.1>

  
using the known methods of organic chemistry, such as, for example, drafting with chromium (II) "salts,: Catalytic hydrogenation in the presence of Pd / CaCO, or of Pd / C and in the presence of a hydrogen halide acceptor, or reduction with tributyltin hydride.

  
A compound of the formula (XXIB) can be prepared in which p is equal to 2 and q is equal to 1 or else

  
q is equal to 2 and p is equal to 1, for example, from a compound of the formula (XXVIII) by a process characterized in that the carbonyl group is reduced to alcohol,

  
  <EMI ID = 313.1>

  
in that one carries out a hydroboration, carried out according to conventional methods, of the olefinic double bond, in that one oxidizes, releases the protected hydroxyl group, operations which are followed by acetalization or ketalization.

  
  <EMI ID = 314.1>

  
one obtains, in turn, in the manner described by

  
  <EMI ID = 315.1>

  
vol.X, page 1 (1972).

  
The compound of formula (XXVIII) can also be used as a starting material for the preparation.

  
  <EMI ID = 316.1>

  
feel a group

  

  <EMI ID = 317.1>


  
  <EMI ID = 318.1>

  
silyl ether and in which, when one of the symbols

  
  <EMI ID = 319.1>

  
an acetal-ether group or an ester group, according to the reaction scheme indicated below:

  

  <EMI ID = 320.1>
 

  
The compound (XXVIII) is converted, according to known methods, for example those previously described,

  
in p-ketc-ester (XXIX) which is then reduced to P-hydroxy-ester (XXX) in which the hydroxyl group is protected in the form of acetal-ether; the compound obtained

  
  <EMI ID = 321.1>

  
The compounds of formula (I) demonstrate the same pharmaceutical activities as natural prostacyclin.

  
  <EMI ID = 322.1>

  
to which the scope of the present invention extends have a particular advantage characterized by their superior stability in the pH range which varies from zero to 11, more particularly, at physiological pH. This results in a longer lasting and much more constant biological activity. The source of this superior stability lay in the different chemical structure of these compounds when compared to that of natural prostacyclin. Since there is a heteroatom oxygen in the

  
  <EMI ID = 323.1>

  
  <EMI ID = 324.1>

  
extremely sensitive to acids. The reaction product <EMI ID = 325.1>

  
nothing of the characteristic biological activity of natural prostacyclin. On the other hand, the compounds to which the scope of the present invention extends do not contain oxygen in the bicyclic system and therefore do not constitute enol-ethers. Since they are not highly labile like natural derivatives, they can be administered by mouth.

  
In addition, compounds of formula (I) in which there is a triple bond in the positions

  
  <EMI ID = 326.1>

  
  <EMI ID = 327.1>

  
hydroxyl), are much more resistant to metabolic degradation induced by an enzyme (eg 15-PGdehydrogenase), than natural prostacyelin.

  
We know perfectly well the pharmaceu-

  
  <EMI ID = 328.1>

  
Thus, for example, when inhaled by asthma patients, prostacyclin prevents non-specific induced bronchoconstriction (e.g.

  
  <EMI ID = 329.1> stimulator on the uterus in women and monkeys;

  
  <EMI ID = 330.1>

  
lytic in test animals and is able to protect the gastric mucosa from ulcers induced by non-steroidal antiphlogistic substances, eg acetylsalicylic acid (ASA.) and indomethacin in submitted animals in the test, for example the rat.

  
In the case of natural prostacyclin, these activities are combined with a marked chemical instability which makes this product unsuitable for use in pharmacies. As already described, the compounds of formula (I) exert pharmaceutical activities similar to those of natural prostacyclin, it being understood, however, that

  
  <EMI ID = 331.1>

  
in the compounds in accordance with the invention.

  
The following table shows the inhibitory effect

  
  <EMI ID = 332.1>

  
  <EMI ID = 333.1>

  
hypotensive in the anesthetized rat, exerted by two components

  
  <EMI ID = 334.1>

  

  <EMI ID = 335.1>


  
(1) PGI2

  
  <EMI ID = 336.1>

  
As to their activities analogous to that of prostacyclin and prostaglandin, the compounds to which the scope of the present invention extends can be used in human medicine and in veterinary medicine, in all cases where the use of prostacyclin natural and natural prostaglandins is therapeutically indicated.

  
For example, the compounds in question are suitable for the treatment of asthma, due to the pronounced bronchodilator effect which they exert. For this application, they can be administered by various routes:
Thus they can be administered orally in the form of tablets, capsules, pills or liquids such as drops or syrups, rectally, in the form of suppositories, by the intravenous route. intramuscularly or subcutaneously, by inhalation in the form of aerosols or spray solutions, or by insufflation in the form of powders. Doses of approximately 0.01 to 4 mg / kg can be administered 1 to 4 times a day, but the exact dose will obviously depend on the age, weight and condition of the patient, as also. the mode of administration used.

  
For anti-asthmatic applications, the compounds according to the present invention can be combined with other anti-asthmatic products, namely

  
  <EMI ID = 337.1>

  
ephedrine, etc .; xanthine derivatives, such as theophilline and aminophillin; and corticosteroids, such as prednisolone and ACTH.

  
In addition, the compounds to which the scope of the present invention extends demonstrate oxytocic activity and can also be used in place of oxytocin to induce labor or to expel a dead fetus, both in the field of human obstetrics and veterinary obstetrics. For this application, the compounds are administered intravenously by

  
  <EMI ID = 338.1>

  
in labor, or they are administered by mouth.

  
The compounds in accordance with the present invention

  
  <EMI ID = 339.1>

  
therefore perfectly for fertility control, with the advantage of much less stimulation of smooth muscles

  
and be free from the side effects of natural prostaglandins, such as vomiting and diarrhea.

  
In addition, the compounds in accordance with the invention

  
  <EMI ID = 340.1>

  
Reading to reduce and control excessive gastric secretion in mammals. In this way, they minimize or eliminate the formation of gastrointestinal ulcers and accelerate the healing and scarring of any ulcers already present in the tract.

  
  <EMI ID = 341.1>

  
in accordance with the invention by infusion, intravenously or by intravenous, subcutaneous or intramuscular injection; the doses in the case of intravenous infusion varying from 0.1 mcg to 500 meg / kg / nm. The total daily dose for both injection and infusion is in the range of 0.1 to 20 mg / kg depending on the age, weight and condition of the patient or animal and the patient. method of administration used.

  
However, as in the case of natural prostacyclins, the most important pharmaceutical property of the compounds to which the scope of the present invention is

  
  <EMI ID = 342.1>

  
clumping, decrease adhesion and exert a thrombostatic and thrombolytic effect on clots

  
  <EMI ID = 343.1>

  
is also associated with a relaxation of the coronary arteries. For these reasons, the compounds according to the invention are suitable for the prevention and treatment of myocardial infarction and, in general, for the treatment and prevention of thrombosis, for the treatment of pathological conditions, such as atherosclerosis. , arteriosclerosis

  
  <EMI ID = 344.1>

  
normal administration, i.e. administration by intravenous, subcutaneous,

  
  <EMI ID = 345.1>

  
prefers to resort to intravenous administration, in doses which vary from 0.005 to 20 mg / kg / day, depending in this case also on the age, weight and (the condition of the patient and the mode of administration.

  
As mentioned above, the compounds in accordance with the present invention are suitable for human and veterinary therapy, their modes of administration

  
being very diverse. They can be administered orally in the form of tablets, capsules, drops or syrups, rectally in the form of suppositories, parenterally in the form of solutions or suspensions injected by the injection route. -cutaneous or intramuscular; intravenously, preferably in emergency cases; by Inhalation in the form of aerosols or spray solutions; in the form of sterile implants with prolonged activity; or through the vagina, for example in the form of vaginal suppositories.

  
The compositions suitable for human pharmacy and for veterinary pharmacy of the compounds according to the invention can be prepared in a conventional manner using common diluents and / or excipients. For example, sterile and isotonic aqueous solutions are preferred for infusion or intravenous injection. Sterile aqueous solutions or suspensions in an aqueous or non-aqueous medium are used in the case of subcutaneous or intramuscular injections. A sterile pad or silicone rubber capsule or capsule impregnated with or containing the active ingredient can be used as a sterile implant.

  
Typical diluents and excipients include water, gelatin, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium magnesium stearate, glycols , starch, gum arabic, gum tragacanth, alginic acid, alginates, lecithin, polysorbates, vegetable oils, etc.

  
The compounds can be administered with a vaporizer using an aqueous solution or suspension thereof, preferably in the form of their salts, eg sodium salts. The compounds can also be suspended or dissolved in one of the propellants.

  
  <EMI ID = 346.1>

  
from a pressurized contents container, such as an aerosol can. When the compound is not soluble in the propellant, it is necessary to add

  
a co-solvent to the pharmaceutical composition, for example, ethanol, dipropylene glycol and / or a substance with a surfactant effect.

  
In the following examples, the abbreviations

  
  <EMI ID = 347.1>

  
The examples which follow illustrate the present invention without, however, limiting the latter. EXAMPLE 1

  
1.1 g of sodium borohydride was added
(0.029 mol), with stirring, to a solution of 11.6 g

  
  <EMI ID = 348.1>

  
After 45 min at this temperature, the excess reagent was decomposed by the slow addition of 20 ml of acetor.

  
The mixture was then neutralized with 1.4. ml of acetic acid and evaporated in vacuo to give a residue which was taken up in water and chloride

  
methylene. The organic phase was evaporated to dryness and filtered through silica gel (using a mixture of hexane and 70:30 ethyl ether as

  
  <EMI ID = 349.1>

  
A solution of this compound (0.065 mol) in 27 ml of anhydrous dimethylformamide was treated with 12.8 g of

  
  <EMI ID = 350.1>

  
it was cooled, diluted with 2 volumes of water and

  
extracted with ethyl ether (3 x 40 ml and 2 x 20 ml).

  
  <EMI ID = 351.1>

  
5% and then with water until neutral and evaporated to dryness so as to obtain 15.8 g of crude product (yield: 95%). Purification on silica gel gave 2.85 g of 7-exo-hydroxy-bicyclo-

  
  <EMI ID = 352.1>

  
dimethyl-tert-butylsilyl ether.

  
A solution of the latter compound was stirred
(11.8 g, 4.63 x 10- <2> mole) in 295 ml of carbonate

  
  <EMI ID = 353.1>

  
inert and carefully treated with 6.95 g of 80% sodium hydride. When evolution of hydrogen ceased, the reaction mixture was heated to 75-80 [deg.] C for 40 minutes. After cooling, we diluted

  
  <EMI ID = 354.1>

  
carefully treated with 13 g of glacial acetic acid. The organic phase was then separated with a pH buffer.

  
  <EMI ID = 355.1>

  
  <EMI ID = 356.1>

  
purification on silica gel (45 g / g, with a mixture

  
  <EMI ID = 357.1>

  
and the whole was treated, with stirring, with 0.9 g of sodium borohydride. After stirring for 15 min, the excess reagent was destroyed by the addition of 12 ml of ac-

  
  <EMI ID = 358.1>

  
extract the residue several times with ethyl ether. The combined organic extracts were washed with 5 ml of water and evaporated to dryness to give a residue which was crystallized from water.

  
  <EMI ID = 359.1>

  
mother liquor on 25 g of silica gel; elution with

  
a 90:10 mixture of n-heptane and ethyl ether gave an additional 2 g of sufficiently pure product to be used as is.

  
  <EMI ID = 360.1>

  
  <EMI ID = 361.1>

  
heated to reflux for 30 min. After concentration in vacuo, the mixture was acidified to pH 5.1 and extracted with ethyl acetate. Evaporation

  
  <EMI ID = 362.1>

  
  <EMI ID = 363.1>

  
of acetonitrile per 2.81 g of d - (+) - ephedrine. 4 hours of this treatment at room temperature made it possible to obtain 2.9 g of a salt which was crystallized twice in

  
  <EMI ID = 364.1>

  
mother liquors and evaporated to dryness to obtain a residue which was dissolved in water and treated with 0.68 g of sodium hydroxide in water.

  
  <EMI ID = 365.1>

  
and the solution of the sodium salt was acidified to pH 5, then extracted with ethyl acetate. We

  
  <EMI ID = 366.1>

  
obtain a residue which was treated with 2.2 g of 1-ephedrine so as to obtain, after several crystallizations, 2.3 g

  
  <EMI ID = 367.1>

  
exo-carboxymethyl ester in 30 ml of anhydrous methylene chloride per 2.19 g of 2,3-dihydropyran and 39 mg of acid

  
  <EMI ID = 368.1>

  
which was then dried by taking it up in anhydrous benzene (2 x 15 ml) and carrying out an evaporation

  
to dryness. This product was added in 30 µl of anhydrous ethyl ether, dropwise and over 15 min.

  
  <EMI ID = 369.1>

  
anhydrous ethyl ether. Stirring was continued for 30 minutes before destroying the excess reagent by the cautious addition of 5 ml of acetone, followed by that of ethyl ether saturated with water. Then 10 g of anhydrous sodium sulfate was added. Filtration of the organic solution and evaporation to dryness

  
  <EMI ID = 370.1>

  
The following compounds were prepared in this way from optically active starting materials:

  
  <EMI ID = 371.1>

  
laying.

  
EXAMPLE 4

  
  <EMI ID = 372.1>

  
DMtB-silylether in 40 ml of benzene, first by

  
  <EMI ID = 373.1>

  
and then, with stirring, with 5.30 g of azo-bis-carboxy-

  
  <EMI ID = 374.1>

  
tion, the organic phase was washed with sulfuric acid.

  
  <EMI ID = 375.1>

  
(3 x 15 ml) and finally water until neutral. Evaporation to dryness resulted in a mixture of

  
  <EMI ID = 376.1>

  
methyl ester-7-DMtB-silyl ether.

  
The crude reaction product was dissolved in

  
  <EMI ID = 377.1>

  
treated it with 0.5 g of anhydrous potassium carbonate.

  
  <EMI ID = 378.1>

  
and evaporated to dryness. The residue was adsorbed on silica gel and elution was carried out with hexane and a mixture of hexane and ethyl ether so as to obtain: <EMI ID = 379.1> dissolved in methanol, solution which was treated with 0.3 g of CaCO3 supporting 5% Pd and which was hydrogenated at ambient temperature and pressure

  
  <EMI ID = 380.1> was saponified in the manner described in Example 2 with 5% potassium carbonate in a mixture of methanol and water 80:20, so as to obtain d, l- 3-exo-7-endo-

  
  <EMI ID = 381.1>

  
silyl ether. This product was then separated into its individual optical antipodes with (+) and (-) amphetamine.

  
The reaction on ethereal diazomethane converted

  
  <EMI ID = 382.1>

  
carboxy acid-7-DMtB-silylether as a derivative of the methyl ester type. The subsequent reaction with 2,3-dihydro-

  
  <EMI ID = 383.1>

  
silyl ether.

  
The enantiomorphs (-) and the racemate were prepared analogously.

  
EXAMPLE 5

  
5 g of d, l-7-endo-hydroxy-bicyclo-

  
  <EMI ID = 384.1>

  
aqueous solution of the potassium salt in order to remove neutral impurities therefrom, they were acidified and extracted with ethyl ether. The extracts mentioned last were combined and evaporated to dryness so as to obtain 4.5 g of the acid d, l which was then separated into its optical antipodes with (+) and (-) ephedrine.

  
1.32 g of (-) - 7-endo-hydroxy- was then dissolved

  
  <EMI ID = 385.1>

  
in 20 ml of tetrahydrofuran and the solution was treated with 10 ml of 1 M BH3 in tetrahydrofuran. After 4 hours at room temperature, the excess of

  
  <EMI ID = 386.1>

  
1.5N. THF was then removed in vacuo and the aqueous phase extracted with ethyl ether. The combined organic extracts were washed until neutral and evaporated to dryness to obtain 1.02 g of

  
  <EMI ID = 387.1>

  
The (+) isomer and the racemate were prepared analogously.

  
EXAMPLE 6

  
2.7 g of d, l-7-endo-hydroxy-2-exo-

  
  <EMI ID = 388.1>

  
for 10 hours, with stirring. The reaction mixture was then concentrated in vacuo, caused to adsorb.

  
  <EMI ID = 389.1> slight pink tint. After further stirring for 14 to 20 minutes, 1.5 ml of isopropanol were added dropwise and the green solution thus obtained was diluted with 6 volumes of benzene. The organic phase was washed

  
  <EMI ID = 390.1>

  
the aqueous phases combined with benzene. The combined benzene extracts were dried and evaporated to

  
  <EMI ID = 391.1>

  
similar.

  
FREE'7

  
Under external cooling and stirring in order to maintain the reaction temperature in the vicinity of
20-22 [deg.] C, a solution of 6.57 g of potassium tert-butoxide in 65 ml of dimethyl ether tallow was added dropwise to 6.76 g of 4-carboxybutyl bromide. triphenylphosphonium in 40 ml of tallow dimethyl ether. After the addition, the mixture was diluted with an equal volume of water, acidified to pH 5 and extracted with ethyl ether. The aqueous phases were discarded and the organic extracts were re-extracted several times.

  
  <EMI ID = 392.1>

  
alkaline to a pH of 5 and re-extracted with a mixture of ethyl ether and pentane 50:50. The combined organic extracts were brought to a small volume, then treated with ethereal diazomethane until a yellow color persisted, and then evaporated to dryness. The residue was then dissolved in 50 ml of acetone, treated with 20 ml of an aqueous solution.

  
  <EMI ID = 393.1>

  
the combined organic extracts were evaporated to dryness. Purification of the residue thus obtained on silica gel

  
  <EMI ID = 394.1>

  
  <EMI ID = 395.1>

  
The individual isomers could be separated by liquid-liquid chromatography under elevated pressure, into the 5-trans-d, 1 and 5-cis-d, l isomers; we called the last one

  
  <EMI ID = 396.1>

  
By replacing 4-carboxybutyltriphenylphosphonium bromide in the above method with one of the following Wittig reagents: 3-carboxypropyltriphenylphosphonium bromide, 5-carboxypentyltriphenylphosphonium bromide, 4-carboxy-2-oxylphosphonium bromide, onphenylphosphonium have been able to prepare methyl esters of the following acids:

  
  <EMI ID = 397.1>

  
as also their 5-trans isomers and the enant-individual natet antipodes.

  
EXAMPLE 8

  
  <EMI ID = 398.1>

  
a solution of pyridinium trifluoroacetate (prepared by adding 25 ml of a mixture of benzene and tallow oxide

  
  <EMI ID = 399.1>

  
pyridine). After 4 hours of stirring, the reaction mixture was diluted with 100 µl of benzene and 3 g of oxalic acid in water was added dropwise. The dicyclohexylurea was removed by filtration, the organic phase was separated and washed with water (5 x 6 ml). Reduction in volume gave a benzene solution of the 12p-formyl derivative which was taken. added at once to a

  
  <EMI ID = 400.1>

  
  <EMI ID = 401.1>

  
sodium (80% dispersion in mineral oil) in an inert gas atmosphere, with continued stirring until the evolution of hydrogen ceases. After the addition of the formyl derivative to this sodium salt of the phosphonate, stirring was continued for 20 min.

  
The reaction mixture was then neutralized with <EMI ID = 402.1>

  
the organic phase was reduced to a small volume, its adsorption was caused on silica gel and elution was carried out with a mixture of cyclohexane and

  
  <EMI ID = 403.1>

  
  <EMI ID = 404.1>

  
of the following acids:

  
  <EMI ID = 405.1>

  
as also their geometric 5-trans isomers, in the nat-, enant- and d, l forms.

  
  <EMI ID = 406.1>

  
per 0.82 g of benzoyl chloride. After 8 hours at the

  
  <EMI ID = 407.1>

  
and the mixture was extracted with ethyl ether of

  
  <EMI ID = 408.1> <EMI ID = 409.1>

  
acetone in vacuo and the residue was extracted with ethyl ether so as to obtain, after purification

  
  <EMI ID = 410.1>

  
pyridine. After 6 hours at room temperature, this mixture was diluted with 20 ml of benzene and filtered. The filtrate was evaporated in vacuo and the residue taken up in 2N sulfuric acid and benzene. After washing with 2N sulfuric acid and water until neutral, the organic extract was evaporated to dryness.

  
  <EMI ID = 411.1>

  
THF in vacuo and the residue was extracted with ethyl ether. The combined extracts were reduced in volume, adsorbed onto silica gel, and eluted with a mixture of hexane and ether so as to obtain

  
  <EMI ID = 412.1> <EMI ID = 413.1>

  
Orthomethyl cycl-5-enoate in the form of a mixture of 5-cis and 5-trans olefins which were then separated by liquid-liquid chromatography under high pressure.

  
Subsequent treatment with aqueous methanol and sulfuric acid gave the corresponding methyl esters.

  
The reaction of 0.3 g of methyl ester on

  
  <EMI ID = 414.1>

  
EXAMPLE 10

  
  <EMI ID = 415.1>

  
  <EMI ID = 416.1>

  
A solution of this compound in 10 ml of CH 2 Cl 2 and 10 ml of ethanol, cooled to -20 [deg.] C, was treated with
90 mg of NaBH4 and then stirred for 2 hours.

  
The excess reagent was then destroyed with a 15% aqueous solution of acetic acid, the solvent was evaporated and the residue adsorbed on silica gel. Elution

  
  <EMI ID = 417.1>

  
Methyl prostacycl-5-enoate and 0.13 g of the 4R-hydroxy isomer.

  
The individual products were then saponified with 20% aqueous methanol and 19% potassium carbonate so as to obtain, after acidification and extraction

  
  <EMI ID = 418.1>

  
The oxidation of these products in accordance with the procedure described in Example 8 made it possible to obtain the derivatives of the 12-formyl type.

  
EXEMPT 11

  
  <EMI ID = 419.1>

  
before. This compound was then oxidized to aldehyde according to the process described in Example 8, so as to obtain the

  
  <EMI ID = 420.1>

  
The reaction of 0.12 g of the latter compound [pound] -in benzene on the phosphonate prepared from 0.177 g

  
  <EMI ID = 421.1> <EMI ID = 422.1>

  
  <EMI ID = 423.1>

  
methyl.

  
Analogously, using the (4-cyclo-

  
  <EMI ID = 424.1>

  
implementation of the processes described in Examples 8 and 11 gave the following products:

  
  <EMI ID = 425.1> methyl in 7 ml of methylene chloride and 7 ml of etha &#65533;

  
  <EMI ID = 426.1>

  
of. 15R isomer.

  
This same process for reducing derivatives of the type
15-oxo in accordance with Examples 8, 11 and 12, made it possible to obtain the methyl esters of the following acids:

  
  <EMI ID = 427.1>

  
and 1,4-lactones of the following acids <EMI ID = 428.1> as also their geometric 5-trans isomers, in the forms nat-, enant- and d, l.

  
EXAMPLE 14

  
A solution of 0.35 g of 5c, 13t-15- was cooled.

  
  <EMI ID = 429.1>

  
5 ml of 5% methylmagnesium iodide in ethyl ether

  
  <EMI ID = 430.1>

  
and cooled with a 20% aqueous solution of ammonium chloride. The organic phase was washed with water, sodium bicarbonate and water, dried over water.

  
  <EMI ID = 431.1>

  
porée under vacuum so as to obtain a mixture of 15S and 15R alcohols. Separation on silica gel with a mixture of ethyl ether and 80:20 isopropyl alcohol as eluent

  
  <EMI ID = 432.1>

  
15R isomer.

  
EXAMPLE 15

  
  <EMI ID = 433.1>

  
EXAMPLE 16

  
A solution of 0.26 g of acid was cooled.

  
  <EMI ID = 434.1> anhydrous methylene) and then with 5% diazomethane in methylene chloride, until a yellow tint persists. The solution was washed with 5% aqueous NaHCO 3 solution, and then with water until neutral,

  
  <EMI ID = 435.1>

  
EXAMPLE 17

  
  <EMI ID = 436.1>

  
  <EMI ID = 437.1>

  
[3.3.0] octane in 15 ml of anhydrous methylene chloride <EMI ID = 438.1>

  
Filter earth was added after 15 min of stirring and the mixture was filtered to obtain a solution.

  
  <EMI ID = 439.1>

  
After evaporating the solvent in vacuo, the residue was taken up in anhydrous benzene and this solution was added.

  
  <EMI ID = 440.1>

  
for approximately 1 hour, until the evolution of hydrogen ceases. Stirring was continued for
20 minutes after the addition of the aldehyde to the solution of the carbanion phosphonate. The organic phase was then neutralized with an excess of a 25% aqueous solution of

  
  <EMI ID = 441.1>

  
to dryness so as to obtain a residue which was purified on silica gel (mixture of cyclohexane and ethyl ether as eluent), so as to obtain 0.81 g

  
  <EMI ID = 442.1>

  
  <EMI ID = 443.1>

  
20 ml of benzene was added and the excess of

  
  <EMI ID = 444.1>

  
  <EMI ID = 445.1>

  
continued stirring for a further 5 minutes.

  
  <EMI ID = 446.1>

  
and the resulting mixture was stirred for an additional 15 min, after which the reaction mixture was distributed

  
  <EMI ID = 447.1>

  
the organic phase was dried, concentrated to a small volume, adsorbed on silica gel and eluted with a mixture of cyclohexane and ethyl ether.

  
  <EMI ID = 448.1> to a stirred suspension of 36 mg of 80% sodium hydride in 5 ml of benzene. Stirring was continued until the evolution of hydrogen ceased and then was added.

  
  <EMI ID = 449.1>

  
While stirring, the mixture in question was taken up in benzene and a 20% aqueous solution of monosodium phosphate. The organic phase was separated, concentrated to a small volume, adsorbed on silica gel and eluted with a mixture of benzene and ethyl ether.

  
  <EMI ID = 450.1> <EMI ID = 451.1>

  
in Example 20 and when the phosphates were used

  
following:

  
  <EMI ID = 452.1> EXAMPLE 22

  
A solution of 0.3 g of d, l-2-exo- (2'-

  
  <EMI ID = 453.1>

  
0.1 M solution of zinc borohydride in ethyl ether (10 ml). After stirring for 2 hours, the reaction mixture was cooled with a saturated solution of sodium chloride and 2N sulfuric acid. The layer was separated.

  
  <EMI ID = 454.1>

  
a separated by liquid-liquid chromatography with isopropyl ether as solvent, so as to obtain

  
  <EMI ID = 455.1>

  
of methylene chloride and 3 ml of ethanol to a temperature

  
  <EMI ID = 456.1>

  
  <EMI ID = 457.1>

  
  <EMI ID = 458.1> <EMI ID = 459.1>

  
0.11 g of the 3'R isomer. EXAMPLE 24

  
  <EMI ID = 460.1>

  
unsaturated prepared as described in the examples
19, 20 and 21, the following compounds were obtained:

  
  <EMI ID = 461.1>

  
  <EMI ID = 462.1>

  
p-toluenesulfonic. After 4 hours at room temperature, the organic phase was washed successively with a solution.

  
  <EMI ID = 463.1>

  
  <EMI ID = 464.1>

  
tetrabutylammonium. The resulting mixture was stirred for <EMI ID = 465.1>

  
to a small volume so as to obtain a residue which was purified on silica gel (ethyl ether as

  
  <EMI ID = 466.1>

  
EXAMPLE 26

  
By repeating the operating mode described in the example
25 with compounds prepared according to the procedures described in Examples 22, 23 and 24, it was possible to pre-

  
  <EMI ID = 467.1>

  
endo-dihydroxy;

  
  <EMI ID = 468.1>

  
The reaction mixture was kept overnight at room temperature, diluted with 3 volumes of benzene and filtered. The filtrate was then evaporated to obtain a residue which was partitioned between benzene and 2N sulfuric acid. The aqueous fraction was reextracted with benzene, which was successively obtained. <EMI ID = 469.1>

  
EXAMPLE 28

  
A stirred and cooled solution was treated

  
  <EMI ID = 470.1>

  
  <EMI ID = 471.1>

  
oxidation described in Examples 27 and 28 on

  
  <EMI ID = 472.1>

  
  <EMI ID = 473.1>

  
EXAMPLE 50

  
A solution of 2.1 g of d, 1-2-exo- was reduced

  
  <EMI ID = 474.1>

  
Without separation of the 3'S and 3'R alcohols, this product was reacted in 30 ml of methylene chloride on 0.4 g.

  
  <EMI ID = 475.1>

  
thoxy-pentyl) -dimethyl phosphonate in 10 ml of tetrahydrofuran, dropwise, to a stirred suspension of 68 mg of NaH (80%) in 10 ml of anhydrous tetrahydrofuran.

  
Stirring was continued until the evolution of hydrogen ceased and then a solution of 0.67 g was added.

  
  <EMI ID = 476.1>

  
chased tetrahydrofuran under aim. The residue was extracted with ethyl ether and the organic extract was dried over Na2SO4 and evaporated. Adsorption of the residue

  
on silica gel and elution with a mixture of cyclohexane and ethyl ether gave 0.76 g of d, l-5t, 13t-

  
  <EMI ID = 477.1>

  
orthotrimethyl-11,15-bis-TH-Prostacycla-5,13-dienoate.

  
A solution of this product in 15 ml of anhydrous methanol was treated with 6 mg of p-toluenesulfonic acid for 5 hours at room temperature. 0.1 ml of pyridine was added, the solution was evaporated to dryness and the residue was purified on silica gel.

  
  <EMI ID = 478.1>

  
orthotrimethyl dienoate and 0.21 g of the 15R epimer. EXAMPLE 32

  
By repeating the operating mode described in the example

  
  <EMI ID = 479.1>

  
in Examples 27, 28 and 29, the trimethylorthoesters of the following acids were obtained:

  
  <EMI ID = 480.1>

  
as also their 15R epimers.

  
Each of the orthoesters of Examples 31 and 32 was then transformed into its methyl ester. heating it to reflux in methariol (15 ml / g) with 2 ml of 0.2 N oxalic acid and recovering the product by evaporation of the

  
  <EMI ID = 481.1>

  
80% aqueous generated free acid.

  
EXAMPLE 33

  
  <EMI ID = 482.1>

  
reflux in 6 ml of methanol and 1, 2 ml of 0.2N oxalic acid, for 2 hours. Evaporation of methanol in vacuo and extraction with ethyl ether gave 0.42 g of the corresponding methyl ester.

  
A solution of this product in 6 ml of anhydrous ethyl ether was added dropwise to a stirred 0.1 M solution of zinc borohydride (10 ml) over 10 minutes. After 1 hour of stirring at room temperature, the reaction mixture was treated with sulfuric acid.

  
2 N. The organic phase was separated, washed until neutral and evaporated to dryness so that

  
  <EMI ID = 483.1>

  
Methyl cycla-5,13-dienoate and 0.14 g of the 4R-epimer methyl ester.

  
A solution of the last-mentioned compound in 5 ml of methanol was treated with 0.05 g of sodium hydrate.

  
  <EMI ID = 484.1>

  
room temperature for 6 hours. Removal of methanol in vacuo, acidification to pH 5.6, and rapid extraction with ethyl acetate gave

  
  <EMI ID = 485.1>

  
stirred of this compound in ethyl acetate with 0.5 part of resin of the tallow polystyrene type (hydrogen ion form)

  
  <EMI ID = 486.1>

  
quantitative.

  
Analogously, the epimeric 7-lactone 4S was prepared.

  
EXAMPLE 34

  
  <EMI ID = 487.1>

  
After 30 min of stirring, the reaction mixture was cooled with 2 ml of acetone and 5 ml of saturated monosodium phosphate. Evaporation of methylene chloride and ethanol in vacuo and extraction, repeated with ethyl ether gave, after drying and evaporation of the organic extracts

  
  <EMI ID = 488.1>

  
tional overnight at room temperature and partitioned between ice-cold 2N sulfuric acid and ethyl ether. The combined organic extracts were washed with brine, dried and evaporated at temperature.

  
  <EMI ID = 489.1>

  
Without further purification, this product was dissolved in anhydrous ethyl ether and treated with 50 mg of lithium aluminum hydride in ethyl ether. After stirring for 2 hours at room temperature and 1 hour at reflux, the reaction mixture was treated with 2 ml of ethyl acetate and then with ethyl ether.

  
  <EMI ID = 490.1>

  
EXAMPLE 35

  
Under an atmosphere of an inert gas, a stirred suspension of 0.4 g of NaH was heated (75% dispersion

  
  <EMI ID = 491.1>

  
dimethyl, to 60-65 "C, for 4 hours. The mixture was then cooled to room temperature and then cooled to room temperature.

  
  <EMI ID = 492.1>

  
stirring for 3 hours, the mixture was diluted with 35 ml of water and the aqueous phase was extracted with ethyl ether

  
(5 x 12 ml) and a mixture of ethyl ether and benzene
(7x12 ml). The combined organic extracts were re-extracted

  
  <EMI ID = 493.1> until neutral and then discarded. The combined aqueous alkaline extracts were acidified to pH 5.3 and extracted with a mixture of ethyl ether and pentane 1: 1. Washing until neutral, drying on

  
of Na2SO4 and removal of the solvent gave 0.86 g

  
  <EMI ID = 494.1>

  
This product was then esterified by treatment with diazomethane and the pyranyl protecting groups were removed as follows:

  
The methyl ester was dissolved in methanol

  
  <EMI ID = 495.1>

  
methyl which was then separated into its individual isomers by liquid-liquid chromatography.

  
EXAMPLE 36

  
With stirring and external cooling for

  
  <EMI ID = 496.1>

  
treated with a solution of freshly sublimated potassium tert-butoxide in 12 ml of anhydrous dimethyl ether tallow with

  
  <EMI ID = 497.1> dimethyl sulfoxide. After 8 hours of shaking

  
at room temperature, the mixture was diluted with a

  
equal volume of water, it was acidified to a pH of 5 and extracted with a mixture of ethyl ether and pentane 1: 1. The acidic aqueous phase was discarded and the combined organic extracts were extracted with 0.8 N NaOH (5 x 20 ml) and then with water until neutral. While removing the organic phase, the aqueous alkaline extracts were acidified and extracted with a mixture of ethyl ether and pentane 1: 1. The combined extracts were dried over Na2SO4, filtered and treated with diazomethane in ethereal solution until a yellow color persisted. Evaporation. to dryness has engendered

  
  <EMI ID = 498.1>

  
Crude methyl-11,15-bis-THP-ether en-13-ynoate. Removal of the protective pyranyl group, followed by liquid-liquid chromatography generated 5c-11cc, 15S-

  
  <EMI ID = 499.1>

  
methyl, as well as the geometric isomer 5t. EXAMPLE 37

  
  <EMI ID = 500.1>

  
one-3,3'-bis-THP-ethers, prepared according to the processes described in Examples 27, 28, 29 and 30, in the process of Examples 35 and 36, the methyl esters of the following acids were obtained:

  
  <EMI ID = 501.1>

  
as also their geometric 5-trans isomers, plus the
15R epimers of the aforementioned compounds and of the geometric isomers in question.

  
These products were then saponified so as to. get free acids.

  
EXAMPLE 38

  
  <EMI ID = 502.1>

  
at ambient temperature and pressure, in the presence of 0.1 g of calcium carbonate supporting 5% palladium, until absorption of 1.01 equivalent of hydrogen. Filtration and evaporation to dryness gave 0.42 g

  
  <EMI ID = 503.1>

  
ties described in Examples 35, 36 and 37, made it possible to obtain a product which was esterified with diazomethane

  
and depyranilized so as to obtain 0.12 g of 11a, 15S-dihydroxy-

  
  <EMI ID = 504.1>

  
separated the 5-cis and 5-trans geometric isomers by liquid-liquid chromatography.

  
EXAMPLE 39

  
The use of (3-carboxy-propyl) bromide -

  
  <EMI ID = 505.1>

  
EXAMPLE 40

  
  <EMI ID = 506.1>

  
EXAMPLE 41

  
A solution of 0.37 g of 5c, 13t- was heated.

  
  <EMI ID = 507.1>

  
The precipitate was filtered off and the benzene solution was purified on a short column of alumina, ma-

  
  <EMI ID = 508.1>

  
The organic phase was separated, the volume reduced and purified on silica gel (mixture of ethyl ether.

  
  <EMI ID = 509.1>

  
methylene-prostacycla-5,13-methyl dienoate and 0.072 g of the 15R-hydroxy-epimer.

  
EXAMPLE 42

  
A solution of 2.2 g of 3-endo-

  
  <EMI ID = 510.1>

  
anhydrous, with 4 ml of ethylene glycol and 0.2 g of p-toluenesulfonic acid monohydrate and the whole was brought to. reflux for 12 hours while collecting the water which had formed during the reaction. We. then added 0.25 ml of pyridine and the mixture was cooled. The organic phase was washed with water, NaHCO3 and then with water and evaporated to dryness to obtain.

  
  <EMI ID = 511.1>

  
ethylenedioxide.

  
A solution of this product was cooled in
40 ml of acetone down to -5 [deg.] C and treated to this

  
  <EMI ID = 512.1>

  
A solution of 1.57 g of this compound in 3 ml of dimethylformamide was treated with 1.3 g of dimethyl-tert-butyl-silyl chloride and 0.885 g of imidazole and it was obtained

  
  <EMI ID = 513.1>

  
tert-butylsilylether, quantitatively. EXAMPLE 43

  
By using dithioethylene glycol in the process described in Example 42 instead of ethylene glycol,

  
  <EMI ID = 514.1>

  
laying.

  
EXAMPLE 44

  
  <EMI ID = 515.1>

  
In accordance with the procedure described in example
22, this compound was reduced by zinc borohydride in

  
  <EMI ID = 516.1>

  
ether.

  
A solution of this compound in 25 ml was treated.

  
  <EMI ID = 517.1>

  
The methanol was evaporated in vacuo, the residue was extracted with ethyl ether and the organic phase was evaporated to dryness so as to obtain 0.72 g of d, 1-3-endo-.

  
  <EMI ID = 518.1>

  
by chromatography on silica gel using a mixture of hexane and ethyl ether as eluent and then converted to tetrahydropyranyl ethers by treatment with 2,3-dihydropyran in methylene chloride, as described in example 25. From this

  
  <EMI ID = 519.1>

  
3,3'-bis-tetrahydropyranylether prepared as described in Example 28.

  
Similarly, repeating the procedure described in Examples 42 and 44 made it possible to prepare all of the compounds prepared as described in Examples 27, 28 and 29.

  
  <EMI ID = 520.1>

  
The saponification of 4.8 g of d, l-3-endo-hydroxy-

  
  <EMI ID = 521.1>

  
in a mixture of methanol and water 80:20, at the temperature

  
  <EMI ID = 522.1>

  
  <EMI ID = 523.1>

  
  <EMI ID = 524.1>

  
  <EMI ID = 525.1>

  
  <EMI ID = 526.1>

  
it was treated, drop by drop, with 2.1 g of triethylamine

  
and 12 ml of anhydrous tetrahydrofuran and was then treated with 2.2 g of ethyl chlorocarbonate in 12 ml of anhydrous tetrahydrofuran, while the temperature was maintained.

  
at -10 [deg.] C. After 1 hour of stirring at -10 [deg.] C, we slowly

  
  <EMI ID = 527.1>

  
continued stirring for a further 25 minutes. We have

  
  <EMI ID = 528.1>

  
diluted with water. The 2-exo-carboxy-azide was quickly isolated by filtration and dried in vacuo.

  
A solution of 4.01 g of this compound in 8 ml of pyridine was treated with 4 ml of acetic anhydride and the whole was kept at 5-8 [deg.] C 'for 24 hours. The reaction mixture was then partitioned between ice water, ethyl ether and 2N sulfuric acid. The organic layer was separated, washed to neutrality, dried. and we evaporated it to dryness, so as to obtain

  
  <EMI ID = 529.1>

  
This product was suspended in acid

  
  <EMI ID = 530.1>

  
what was removed excess acetic acid by distillation

  
  <EMI ID = 531.1>

  
  <EMI ID = 532.1>

  
the mixed anhydride obtained from ethoxycarbonyl chloride and 2S-hydroxy-heptanoIque-2-acetate gave the

  
  <EMI ID = 533.1>

  
[3.3.0] octan-7-one-3-acetate. A solution of this compound was then reacted in anhydrous dimethyl tallow,

  
  <EMI ID = 534.1>

  
5-enolque, after saponification.

  
Similarly, the 15R.-epi-

  
  <EMI ID = 535.1>

  
  <EMI ID = 536.1>

  
Ethylene glycol (15 ml) and p-toluenesulfonic acid (0.9 g) were added to a solution of 2-exo-

  
  <EMI ID = 537.1>

  
benzene and the mixture was refluxed for 12 hours, removing the water which formed during the reaction, to the mixture of pyridine (0.6 ml) was added and cooled to temperature. ambient temperature.

  
The organic phase was washed with water, 2.5% aqueous NaHCO3 solution and with water, then

  
we dried it. Benzene (100 mL) was partially removed in vacuo, then the mixture was treated with sodium hydride.

  
  <EMI ID = 538.1>

  
for 8 hours. After cooling to room temperature, the organic phase was washed with a solution.

  
  <EMI ID = 539.1>

  
by dicyclohexylcarbodiimide (46.35 g), pyridine
(5.9 g) and trifluoroacetic acid (5.4 g). After 6 hours the mixture was diluted with benzene (600 ml) and water.

  
  <EMI ID = 540.1>

  
dioxide.

  
A solution of this crude product in dimethyl carbonate (70 mL) was added to a hydride suspension.

  
  <EMI ID = 541.1>

  
mixing until the evolution of hydrogen ceases, at the

  
  <EMI ID = 542.1>

  
  <EMI ID = 543.1>

  
After cooling, the reaction mixture was diluted with benzene (350 ml) and acetic acid.
(8.4 g), washed with water, dried and evaporated to dryness, so as to obtain a mixture (1: 1)

  
  <EMI ID = 544.1>

  
free), using hexane and ethyl ether as eluents.

  
EXAMPLE 48

  
By repeating the operating mode described in the example
47, the oxidation process of 14.85 g of 3-endo-hydroxy-

  
  <EMI ID = 545.1>

  
EXAMPLE 49

  
  <EMI ID = 546.1>

  
(350 ml) to a suspension of sodium hydride (dispersion at
80% in mineral oil, 42g) in dimethyl carbonate (550ml). After the evolution of hydrogen has ceased,

  
  <EMI ID = 547.1>

  
cooled to room temperature, diluted with benzene (2.7 L) and washed with aqueous solution

  
  <EMI ID = 548.1>

  
A solution of this compound was cooled in

  
  <EMI ID = 549.1> <EMI ID = 550.1> then treated with acetic acid (23 ml), warmed to room temperature and the solvents evaporated in vacuo.

  
The residue was partitioned between ethyl acetate and water, the organic phase was dried and evaporated.

  
  <EMI ID = 551.1>

  
dissolved in dry tetrahydrofuran, then treating the solution thus obtained with 2,3-dihydropyran (33 g) and p-toluenesulfonic acid (0.63 g) for 3 hours, at room temperature. Pyridine (0.4 g) was added to the reaction mixture and then after cooling <EMI ID = 552.1>

  
added water in order to destroy the residual hydride. Under vigorous stirring and external cooling

  
at a temperature varying from -5 to 0 [deg.] C, the borane formed by the slow concurrent addition of 110 ml of 3M sodium hydroxide and 110 ml of 30% hydrogen peroxide was oxidized, in maintaining the internal temperature at 20-25 [deg.] C. The oxidation mixture was diluted with benzene (2 L) 'and the layers formed were separated. The aqueous layer was extracted with benzene
(2 x 50 ml). We put the organic layers together, we got them

  
  <EMI ID = 553.1>

  
saturated sodium sulfite solution and saturated sodium chloride solution and were dried, over MgSO4. Evaporation of the solvents made it possible to obtain a crude mixture of 7 and 8 hydroxyl compounds which were separated by chromatography on a silica column (300 g), using ethyl ether as eluent., So as to obtain the following respective compounds:

  
  <EMI ID = 554.1>

  
methyl ester-3-THP-ether (27 g).

  
A solution of 7-hydroxy alcohol (24 g) in dry dimethylformamide (30 ml) was treated with

  
  <EMI ID = 555.1>

  
dazole (8.85 g) and then heated for 5 hours <EMI ID = 556.1>

  
diluted with water (90 ml) and then extracted with ethyl ether. The organic layers were collected, washed with water and evaporated to

  
  <EMI ID = 557.1>

  
silyiether.

  
To a stirred solution of this compound in dry toluene (220 ml), cooled to -70 [deg.] C, was added a solution of 1.4 M DIBA in toluene, over 45 ions. ,:
while maintaining the temperature between -60 and -70 [deg.] C. Stirring was continued for 2 hours, the residual hydride was destroyed by the addition of 2 M isopropyl alcohol in toluene.

  
The reaction mixture was warmed to room temperature and thereto was successively added a

  
  <EMI ID = 558.1>

  
After filtration, the organic phase was washed with water and evaporated in vacuo to obtain the

  
  <EMI ID = 559.1>

  
EXAMPLE 50

  
A solution of (2-oxo-heptyl) - was added

  
  <EMI ID = 560.1>

  
to a stirred suspension of NaH (80% dispersion in mineral oil, 43.5 mg) in dry benzene (10 ml).

  
  <EMI ID = 561.1> silyl ether (0.4g) in toluene (5ml).

  
  <EMI ID = 562.1>

  
EXAMPLE 51

  
A solution of (3-phenoxy-2-oxopropyl) -dimethylphosphonate (2.85 g) in benzene (10 ml) was added to a stirred suspension of NaH (80% dispersion in sodium hydroxide).

  
  <EMI ID = 563.1>

  
continued stirring for 45 min, then a

  
  <EMI ID = 564.1> to dryness so as to obtain, after filtration through silica (38 g), using a mixture of benzene and

  
  <EMI ID = 565.1>

  
  <EMI ID = 566.1>

  
aldehydes described in Example 49, the following substances were obtained:

  
  <EMI ID = 567.1>

  
according to the process described in Examples 50 and 51 (a) were reduced to allyl alcohols and (b) the new hydro- group

  
  <EMI ID = 568.1>

  
so as to generate a secondary alcohol which has (d) oxidized

  
in ketone; finally, after the elimination of all

  
  <EMI ID = 569.1>

  
epimeric allylic by high pressure liquid chromatography on silica. By working at

  
  <EMI ID = 570.1>

  
artwork : <EMI ID = 571.1>

  
varying from -16 to -10 [deg.] C. After 30 min, the residual hydride was destroyed by adding acetone (10 ml) and a solution.

  
  <EMI ID = 572.1> in vacuo and the residue was partitioned between water and methylene chloride. The organic layer was separated, dried and evaporated to dryness to give a mixture of 3'S, 3'R-allyl-silyl-

  
  <EMI ID = 573.1> b) protection of allyl alcohols in the form of THP-ethers:

  
the crude mixture of 3'S, 3'R-allyl alcohols silyl ethers (2.10-2 m) was treated with methylene chloride (30 ml)

  
  <EMI ID = 574.1>

  
p-toluenesulfonic acid (0.038 g) to the stirred solution. The reaction was complete after 2 hours and was then quenched by the addition of pyridine (0.5 ml) and the solvents were removed by evaporation in vacuo to obtain a mixture of 3'S, 3'R-THP. -ether-silylethers; c) desilylation: a solution of the material obtained above in dry tetrahydrofuran (80 ml) was treated for 12 hours at room temperature with dry tetrabutylammonium fluoride (14 g). After concentration in vacuo to a small volume, the residue was taken up on silica (40 g) and, after elution with ethyl ether, the secondary alcohols-3'S, 3'R-THP- were obtained.

  
  <EMI ID = 575.1> d) oxidation: dicyclohexylcarbodiimide (6.5 g), pyridine (1 ml) and trifluoroacetic acid (0.5 ml) were successively added to a stirred solution in a mixture of benzene and tallow dimethyl oxide 75:25

  
  <EMI ID = 576.1>

  
After 4.5 hours, the reaction mixture was diluted with benzene, (100 ml) and with an oxalic acid solution. <EMI ID = 577.1>

  
by filtration, the organic layer was washed until neutral, dried and evaporated to dryness;

  
  <EMI ID = 578.1>

  
dissolved the residue in a mixture of cyclohexane and ethyl acetate (80:20) and the solution was injected into an apparatus

  
liquid chromatography under high pressure, so as to obtain the following keto-alcohols: <EMI ID = 579.1> EXAMPLE 53

  
Under a nitrogen atmosphere, a suspension of NaH was stirred (80% dispersion in mineral oil, 2.1 g)

  
  <EMI ID = 580.1>

  
to the aforementioned suspension, so as to obtain a solution of the ylide of deep red color.

  
After addition of a solution of 2-exo [2'-bromo-

  
  <EMI ID = 581.1>

  
nonan-8-one (1.79 g) in dry dimethyl sulfoxide (6 ml), the reaction mixture was stirred for 1 hour at 28 [deg.] C and

  
  <EMI ID = 582.1>

  
reaction mixture to room temperature, diluted with water (80 ml), acidified to pH

  
4.5 by the addition of 4N H2SO4 and extracted with ethyl ether (4 x 50 mL, 2 x 25 mL). The aqueous layer was discarded, the organic phases were combined, washed with water (this wash liquor was discarded), then washed with N NaOH (5 x 10 ml). ) and using water until neutral. The combined alkaline extracts were acidified to pH 5 and extracted with ethyl ether to give 5 (Z, E) -11a, 15S- acid.

  
  <EMI ID = 583.1>

  
ynolque (a mixture of 5c and 5t isomers). The individual geometric isomers were obtained after chromatographic separation on acidic silica (40 g / each g acid) using cyclohexane-ethyl acetate as eluents.

  
EXAMPLE 54

  
Under a nitrogen atmosphere, to a stirred solution of potassium tert-butoxide (3.36 g), freshly was added.

  
  <EMI ID = 584.1>

  
(0.8 g) in dry dimethyl ether tallow (3 ml), stirred

  
  <EMI ID = 585.1>

  
di, diluted with water (50 ml), acidified to pH 5 and extracted with ethyl ether
(4 x 10 ml). The aqueous phase was discarded, the

  
ethereal extracts combined with water (10 ml, the washing liquor thus obtained being discarded) and with 0.5 N NaOH

  
(4 x 6 ml) and with water until neutral. We acidified

  
the alkaline extracts combined to pH 5 and extracted with ethyl ether. The organic phases were combined, dried and evaporated to dryness so as to

  
  <EMI ID = 586.1>

  
The individual geometric isomers were obtained after chromatographic separation on acidic silica.
(40 g / each g acid) using cyclohexane-ethyl acetate as eluents.

  
  <EMI ID = 587.1>

  
Using the keto alcohols of Example 51 in the process described in Examples 53 and 54, we have

  
  <EMI ID = 588.1>

  
then carried out the oxidation by repeating the procedure described in Example 2 and the treatment with dimethyl carbonate (see the process described in Example 2), so as to

  
  <EMI ID = 589.1>

  
dioxides obtained in accordance with the procedures described in Examples 47, 48 and 56, according to the following procedure:

  
  <EMI ID = 590.1>

  
  <EMI ID = 591.1>

  
(150 mL), cooled to -20 [deg.] C. After further stirring for 30 min at -20 [deg.] C, the residual hydride was destroyed by addition.

  
  <EMI ID = 592.1>

  
dilution with water (20 ml), extracted with methylene chloride. The organic phases were combined, washed to neutrality with water, dried and evaporated to dryness. The residue was equilibrated by treatment with absolute methanol (20 ml) and methylate:

  
sodium (0.54 g) for 12 hours at room temperature;

  
  <EMI ID = 593.1>

  
the following aster-ethylenedioxides:

  
  <EMI ID = 594.1>

  
sulfonic acid (38 mg, 2.10-4 m), for 2 hours, at room temperature. The reaction was stopped by the addition of

  
  <EMI ID = 595.1>

  
  <EMI ID = 596.1>

  
which were used without further purification.

  
  <EMI ID = 597.1>

  
  <EMI ID = 598.1>

  
methyl esters and their 3-THP-ethers obtained by carrying out the process described in Example 57, so as to produce the

  
  <EMI ID = 599.1>

  
in the following operating mode:

  
we. added a solution of 2.10-2- m of the p-ketoester (both

  
  <EMI ID = 600.1>

  
saturated with water. 12 g of dry MgSO4 was added and then

  
  <EMI ID = 601.1>

  
the optically active forms (nat, ent) when the optically active material has been used, originating from the optical resolution described in the remainder of this memory,

  
for the implementation of the reduction process. EXAMPLE 59

  
  <EMI ID = 602.1>

  
  <EMI ID = 603.1>

  
methanol (20 ml) and water (2 ml) with p-toluenesulfonic acid (0.3 g), for 2 hours, at reflux temperature. The solvents were evaporated in vacuo and the residue filtered through a short column of silica.

  
Working according to the procedure described in Example 54, a solution of the

  
  <EMI ID = 604.1>

  
thus obtained in dry tallow dimethyl ether (17 ml) on the ylide formed from potassium tert-butoxide (27 g), dimethyl sulfoxide (280 ml) and 3-carboxy bromide

  
  <EMI ID = 605.1>

  
  <EMI ID = 606.1>

  
using an 80:20 mixture of ethyl ether and benzene, so as to separate the triphenyl phosphoxide. These extracts were discarded and the alkaline phases were acidified to pH 5 and extracted repeatedly with ethyl ether (8 x 200 ml) and with a mixture.

  
  <EMI ID = 607.1>

  
The combined organic extracts were dried, concentrated to a small volume (100 ml), treated with ethereal diazomethane to obtain the methyl ester which was then evaporated to dryness. . The crude material was chromatographed on silica (100 g) (ethyl acetate

  
  <EMI ID = 608.1>

  
(2.2 g) and imidazole (1.55 g), at 15 [deg.] C, for 24 hours, this treatment being followed by dilution with water (24 ml)

  
  <EMI ID = 609.1>

  
chromatographic cation on silica (25 g, mixture of cyclohexane and ethyl ether as eluent), there was obtained

  
  <EMI ID = 610.1>

  
Treatment with pyridine (10 ml), acetic anhydride (5 ml), at room temperature, for
12 hours and hydrolysis with an aqueous solution of methanol

  
  <EMI ID = 611.1>

  
Preparatory chromatography (using high pressure liquid chromatography and refractive index monitoring) on silica

  
  <EMI ID = 612.1>

  
of methylene and ethyl acetate as eluent) a gives the individual 5c and 5t geometric isomers.

  
  <EMI ID = 613.1>

  
propyl-one.

  
EXAMPLE 60

  
Starting from compounds of the 2-exo-hydroxy- type

  
  <EMI ID = 614.1>

  
acetate of Example 59, the corresponding aldehydes were obtained by carrying out the following oxidation process:

  
Dicyclohexylcarbodiimide (0.64 g), pyridine (0.1 ml) and acid were successively added.

  
  <EMI ID = 615.1> 75:25 dimethyl sulfoxide (6 mL). After 4.5 hours, the reaction mixture was diluted with benzene (20 ml) and water (10 ml) and stirred for an additional 30 minutes.

  
  <EMI ID = 616.1>

  
washed the organic layer with water until neutral

  
  <EMI ID = 617.1>

  
to obtain a solution in dry benzene of the following aldehydes:

  
  <EMI ID = 618.1>

  
methyl-11-acetate trimethylene-2-nor-prostacycla-5-enoate

  
  <EMI ID = 619.1>

  
methyl-11-acetate dimethylene-prostacycla-5-enoate
(5 (Z, E); 5c, 5t).

  
These compounds were used in the following Wittig-Horner reactions without further purification.

  
  <EMI ID = 620.1>

  
Methyl 5-enoate-11-acetate in benzene (10 ml) to the above solution. After a further 1 hour, the reaction was stopped by the addition of a solution of acetic acid.
(132 mg) in benzene (5 ml); the organic phase was washed with water until neutral, dried and evaporated to dryness.

  
The residue (1.2 g) was absorbed on silica.
(10 g), eluting with a mixture of cyclohexane and ethyl acetate, so as to obtain 5t, 13t-

  
  <EMI ID = 621.1>

  
when the other aldehydes of Example 60 were used in the process described above:

  
  <EMI ID = 622.1> and the mixture of these 5 (Z, E) isomers

  
  <EMI ID = 623.1>

  
EXAMPLE 62

  
By repeating the procedure described in Example 61,

  
  <EMI ID = 624.1> <EMI ID = 625.1>

  
EXAMPLE 63

  
Pyridine hydrobromide perbromide was added

  
  <EMI ID = 626.1>

  
dry (15 ml). After further shaking for 4 hours

  
at room temperature, the precipitate was filtered off and the organic eluate was partitioned between ice, 2N sulfuric acid and ethyl acetate. The organic layer was washed and cooled with 0.5 N sulfuric acid, brine, 1 96 sodium carbonate solution, water until neutral, so as to obtain 0.71 g

  
  <EMI ID = 627.1>

  
High pressure liquid chromatography carried out on silica with a mixture of methylene dichloride and ethyl ether (85:15) yielded the individual isomers:

  
  <EMI ID = 628.1>

  
in the above-mentioned process, the following substances were obtained:

  
  <EMI ID = 629.1>

  
EXAMPLE 64

  
A 5% ethereal iodide solution was added.

  
  <EMI ID = 630.1>

  
ethyl and toluene 2: 1 (12 ml), cooled to -30 [deg.] C. After stirring for a further 4 hours, we have

  
  <EMI ID = 631.1>

  
with water, dried and evaporated to dryness after addition of pyridine (0.1 ml). We dissolved the residue

  
  <EMI ID = 632.1>

  
anhydrous (0.1 g) for 2 hours. The solution was filtered, evaporated in vacuo and the crude material distributed.

  
  <EMI ID = 633.1>

  
The organic layer was concentrated after the usual processing to a small volume; the residue was taken up on silica (20 g). Elution with a mixture of ethyl ether

  
  <EMI ID = 634.1>

  
Methyl 5,13-dienoate (0.1 g) and its 15R-isomer (0.085 g).

  
The implementation of this process also made it possible to obtain the following compound;

  
  <EMI ID = 635.1>

  
The free acids were obtained by heating, at reflux temperature, a solution of the methyl esters in an 80:20 mixture of methanol and water, in the presence of

  
  <EMI ID = 636.1>

  
tees. The combined alkaline phases were acidified to pH 6 and extracted with ethyl ether. We washed

  
  <EMI ID = 637.1>

  
and evaporated to dryness to obtain the free acids.

  
  <EMI ID = 638.1> <EMI ID = 639.1>

  
correspondents.

  
EXAMPLE 66

  
  <EMI ID = 640.1>

  
61, 62 and 63, the secondary allyl alcohols were obtained by carrying out the following process: a

  
  <EMI ID = 641.1>

  
dry ethyl ether (20 mL) to a stirred solution of 0.25 M zinc borohydride (48 mL) in dry ethyl ether, the addition being dropwise over 30 min. After further stirring for 2 hours, the residual hydride was destroyed by the addition of saturated NaCl solution. The organic layer was separated, washed to neutrality, dried over Na2SO4 and evaporated to dryness. The liquid phase chromatography under high pressure of preparation, carried out on silica, using a mixture of methylene chloride and ethyl acetate as eluent, made it possible to obtain the following compounds:

  
  <EMI ID = 642.1>

  
Following 3-endo-THP-oxy:

  
  <EMI ID = 643.1>

  
Methyl-11-acetate prostacycla-5,13-dienoate and its geometric isomers 5 (Z, E) and 5t.

  
  <EMI ID = 644.1>

  
Methyl-11-acetate cycla-5,13-dienoate and its isomers, geometric 5 (Z, E) and 5c.

  
  <EMI ID = 645.1>

  
  <EMI ID = 646.1>

  
EXAMPLE 67

  
The individual methyl 11-acetate prostacycladienoates were converted both to their 11-hydroxymethyl esters by transesterification in dry methanol with

  
  <EMI ID = 647.1>

  
Free xyls by treatment with K2CO3 in 80% aqueous methanol.

  
EXAMPLE 68
-

  
  <EMI ID = 648.1>

  
dioxides obtained by carrying out by carrying out the process described in Example 66 in the corresponding prostacyclénolque acid, by operating as follows:

  
  <EMI ID = 649.1>

  
dioxide in acetone (15 µl) at reflux with an aqueous solution of N oxalic acid (10 ml), for 8 hours. The acetone was evaporated in vacuo and the aqueous phase extracted.

  
with ethyl ether. After the usual treatment, the combined extracts were evaporated to dryness, so as to obtain

  
  <EMI ID = 650.1>

  
Following: Under a nitrogen atmosphere, potassium tert.-butoxide (1.35 g) was added to dry dimethyl ether tallow (15 ml), followed by addition of potassium bromide.

  
  <EMI ID = 651.1>

  
generate a solution of the ylid with a deep red hue. After the addition of the ketone, the mixture was heated

  
  <EMI ID = 652.1>

  
diluted with water (20 ml), acidified to

  
  <EMI ID = 653.1>

  
(5 x 25 ml).

  
The aqueous phase was discarded and collected

  
  <EMI ID = 654.1>

  
we discarded this washing liquor) and we extracted them

  
  <EMI ID = 655.1> read. The alkaline extracts were combined, acidified to pH 5 and extracted with ethyl ether. The combined organic extracts were washed with

  
  <EMI ID = 656.1>

  
mixture of 5Z and 5E acids.

  
The individual geometric isomers were obtained after chromatographic separation on acidic silica.

  
  <EMI ID = 657.1>

  
In this way, the following acids were prepared:

  
  <EMI ID = 658.1>

  
  <EMI ID = 659.1> <EMI ID = 660.1>

  
the mixture was filtered and the organic phase washed until

  
  <EMI ID = 661.1> <EMI ID = 662.1>

  
Further stirring for 2 hours, acetic acid (5ml) was added and the mixture was evaporated to dryness. The residue was partitioned between water and sodium bichloride.

  
  <EMI ID = 663.1>

  
using water (66 ni). After exhaustive extraction using. of ethyl ether and usual processing, the

  
  <EMI ID = 664.1>

  
(19.1 g). A solution of this compound was treated in

  
  <EMI ID = 665.1> and dried and evaporated to dryness so that

  
  <EMI ID = 666.1>

  
crude silyl ether (20.3 g). A solution of the alcohol thus obtained in a mixture of benzene and dimethyl sulfoxide 75:25 (150 ml) was treated, successively, with

  
  <EMI ID = 667.1>

  
trifluoroacetic acid (1 ml), with stirring. After 5 hours, the mixture was diluted with benzene (400ml), water (50ml), a solution of oxalic acid (6g) in water (75ml), and after stirring - additional of
30 min, the mixture was filtered. The organic phase was washed with water until neutral, so as to obtain

  
  <EMI ID = 668.1>

  
After 12 hours the mixture was treated with pyridine
(1.95 ml) and evaporated to dryness. The residue was filtered through silica (using a mixture of ethyl ether and ethyl acetate as eluent), so as to

  
  <EMI ID = 669.1>

  
hydroxy (10 g).

  
A solution of this compound was heated in

  
  <EMI ID = 670.1>

  
water formed during the reaction. After 14 hours, pyridine (2 ml) was added and the organic phase was cooled.

  
  <EMI ID = 671.1>

  
and using a saturated NaCl solution until neutral.

  
Evaporation of the solvents made it possible to obtain bicyclo-

  
  <EMI ID = 672.1>

  
To a solution of the free acid (4.2 g) in acetonitrile (120 ml), d (+) - ephedrine was added

  
  <EMI ID = 673.1>

  
salt crystallized, giving after a new crystallization

  
  <EMI ID = 674.1>

  
carboxylic salt of d (+) - ephedrinium. All the aqueous liquors were combined, evaporated to dryness; the residue was dissolved in water and the solution worked up

  
  <EMI ID = 675.1>

  
The d (+) - ephedrine was recovered by extraction with ether, then the aqueous alkaline solution was acidified to a

  
  <EMI ID = 676.1>

  
evaporated the combined organic layers to dryness. The residue was diluted with acetonitrile and the procedure described above was repeated using

  
  <EMI ID = 677.1>

  
carboxylic salt of 1 - (-) - ephedrinium. Each of the salts in question was dissolved separately in a mixture of water and NaOH; the optically active base was recovered by extraction with ethyl ether, the alkaline aqueous phase was acidified to a pH of 5-5.1 and extracted with ethyl acetate, so to obtain the following compounds:

  
  <EMI ID = 678.1>

  
which were converted to methyl esters by treatment with diazomethane.

  
EXAMPLE 72 A solution of 26 g of dl-3-endo- <EMI ID = 679.1>

  
ethylenedioxide in acetone (100ml) at reflux with 2N sulfuric acid (20ml) for 4 hours.

  
  <EMI ID = 680.1>

  
the aqueous phase with ethyl acetate. The combined organic extracts were washed until neutral, dried and evaporated to give 21.2 g of

  
  <EMI ID = 681.1>

  
7-one. Has a solution of the ketone in dry acetonitrile
(250 µl), d-1-phenyl-1-ethyl-amine (12.1 g) was added and the solvent was slowly distilled off, recovering 50 ml over 30 minutes. The mixture was slowly cooled to room temperature and

  
  <EMI ID = 682.1>

  
aqueous quantities so as to obtain 6 g of the racemic. Finally, an additional concentration up to a volume of <EMI ID = 683.1>

  
at reflux temperature for 2 hours. We evaporated

  
the solvent under vacuum and, after extraction with ethyl acetate, the combined organic phases were washed until neutral,

  
they were dried and evaporated in vacuo so as to

  
  <EMI ID = 684.1>

  
of Example 57 at optical resolution, so as to obtain the following 3-endo-hydroxy-alcohols: <EMI ID = 685.1>

  
By carrying out the process described in Example 56, these ketones were converted into their derivatives of the ethylenedioxide type.


    

Claims (1)

1. Compounds corresponding to the following general formula (I): <EMI ID = 686.1> in which R is chosen from the group formed by the following radicals: <EMI ID = 687.1> Rb are independently selected from hydrogen, the radicals <EMI ID = 688.1> <EMI ID = 689.1> <EMI ID = 690.1> <EMI ID = 691.1> D is chosen from the group formed by the following radicals: <EMI ID = 692.1> <EMI ID = 693.1> and, independently, R3 and R4 together form an oxo group; <EMI ID = 694.1> r are attached, form a radical <EMI ID = 695.1> Y is chosen from the group formed by the following radicals: -CH2-CH2- '-C = C-, <EMI ID = 696.1> (cis) where Z represents <EMI ID = 697.1> and -NH-CH2; X is chosen from the group -formed by the following radicals: - (CE ..;) - where m3 is equal to zero or to 1, <EMI ID = 698.1> <EMI ID = 699.1> having the meanings previously indicated; <EMI ID = 700.1> can be zero or represent whole numbers that range in value from zero to 12, such that each sum <EMI ID = 701.1> p and q are independently zero, or represent integers ranging in value from 1 to 3, such as <EMI ID = 702.1> or unsaturated, unsubstituted or substituted by one or more of the following substituents: halogens, haloalkyl radicals <EMI ID = 703.1> as also the lactones derived from the compounds of formula (I) and their acceptable salts in human pharmacy or in veterinary pharmacy. <EMI ID = 704.1> straight or branched chain, optionally substituted phenyl <EMI ID = 705.1> <EMI ID = 706.1> 3. Compounds chosen from the group formed by the following substances: <EMI ID = 707.1> <EMI ID = 708.1> as also the salts acceptable in human pharmacy or in veterinary pharmacy of the compounds in question. 4. Compounds selected from the group formed by the following substances <EMI ID = 709.1> sodium salt of 5t, 13t-4S, 11a, 15S-trihydroxy-9a- acid <EMI ID = 710.1> as also the salts acceptable in human pharmacy or in veterinary pharmacy of the compounds in question. 5. Compounds selected from the group formed by the following substances: <EMI ID = 711.1> 16R-fluoro isomer; <EMI ID = 712.1> veterinary pharmacy of the compounds in question. 6. Compounds selected from the group formed by the following substances: <EMI ID = 713.1> <EMI ID = 714.1> as also the salts acceptable in human pharmacy or in veterinary pharmacy of the compounds in question. 7. Process for preparing a compound. Following one urn any one of the preceding claims, characterized in that the following steps are carried out: 1) alkylation of a compound, of formula (II) which follows: <EMI ID = 715.1> in which <EMI ID = 716.1> ci% 06 or a protecting group linked to the bicyclic system or to the side chain via a bond <EMI ID = 717.1> together form one. ketone protecting group, with a compound of the formula (III) <EMI ID = 718.1> <EMI ID = 719.1> <EMI ID = 720.1> <EMI ID = 721.1> have the <EMI ID = 722.1> <EMI ID = 723.1> have the <EMI ID = 724.1> any protecting group present; 2) alkylation of a compound of formula (IV) <EMI ID = 725.1> in which <EMI ID = 726.1> <EMI ID = 727.1> <EMI ID = 728.1> <EMI ID = 729.1> <EMI ID = 730.1> group <EMI ID = 731.1> <EMI ID = 732.1> indicated in the. claim 1, with a compound of the formula (V) <EMI ID = 733.1> in which E has the meanings previously indicated <EMI ID = 734.1> <EMI ID = 735.1> <EMI ID = 736.1> <EMI ID = 737.1> <EMI ID = 738.1> Z represents a hydrogen atom or a compound of the formula wherein Y represents a group -CH CZ- <EMI ID = 739.1> together form an oxo group, so as to obtain, after removal of the protecting groups, a compound of <EMI ID = 740.1> -CH = CZ- (trans), Z has the meanings given-in <EMI ID = 741.1> so as to obtain, after removal of any protecting groups, a compound of the formula (1) in <EMI ID = 742.1> however the other of these symbols represents an atom <EMI ID = 743.1> if desired, the derivative of the ether type can be prepared <EMI ID = 744.1> <EMI ID = 745.1> R3 and R4 represents a hydroxyl group, while the other of these symbols represents a hydrogen atom, <EMI ID = 746.1> which other hydroxyl groups present are protected as described above, so as to obtain, after <EMI ID = 747.1> compound of formula (I) in which Y represents a group -CH2-CH2- or -CH = CZ- (trans), Z has the meanings <EMI ID = 748.1> <EMI ID = 749.1> <EMI ID = 750.1> a compound of: formula CI), in which Y represents a group -CH = CZ- (trans), 2 represents a halogen atom, <EMI ID = 751.1> together an oxo group and any hydroxyl, oxo or carboxyl groups present are free <EMI ID = 752.1> after removal of any protecting groups, <EMI ID = 753.1> 8. Compositions acceptable in human pharmacy or in veterinary pharmacy, characterized in that they comprise at least one compound according to any one of claims 1 to 6 or obtained by carrying out the process according to claim 7, as well as a diluent and / or excipient acceptable in human pharmacy or in veterinary pharmacy. 9. Compounds which correspond to formula (II) which follows: <EMI ID = 754.1> <EMI ID = 755.1> or a protecting group linked to the bicyclic system or to the side chain through an ether bond, <EMI ID = 756.1> together a protecting group for the ketone function. 10. A process for the preparation of compounds of formula (II) according to claim 9, wherein <EMI ID = 757.1> and Z has the meanings indicated in claim 1, characterized in that the following operations are carried out: <EMI ID = 758.1> <EMI ID = 759.1> in which <EMI ID = 760.1> compound of the formula (XII) <EMI ID = 761.1> <EMI ID = 762.1> <EMI ID = 763.1> claim 7; <EMI ID = 764.1> to a compound of the formula (XIII) <EMI ID = 765.1> where G has the meanings previously <EMI ID = 766.1> previously indicated; <EMI ID = 767.1> a compound of the formula (XIV) <EMI ID = 768.1> <EMI ID = 769.1> indicated; dIV) optional oxidation of a compound of formula (XIV) <EMI ID = 770.1> other hydroxyl groups, if present, are protected. 11. Process for the preparation of compounds of <EMI ID = 771.1> <EMI ID = 772.1> of the formula (XV) <EMI ID = 773.1> in which G has the meanings given in claim 10, p and q have the meanings <EMI ID = 774.1> the meanings indicated in claim 7, with the exception of the hydroxyl group ,, on an aldehyde of the formula (XVI) <EMI ID = 775.1> <EMI ID = 776.1> <EMI ID = 777.1> presence of a reducing agent, this reaction being followed by the removal of the protective group in G and optionally <EMI ID = 778.1> <EMI ID = 779.1> formula (II) according to claim 9, wherein Y <EMI ID = 780.1> a compound of the formula (XVII) <EMI ID = 781.1> <EMI ID = 782.1> have the meanings indicated in claim 1, in the presence of a base, this reaction being followed by the removal of the protective group at G and optionally of the other protective groups, if they are present. 13. Compounds of formula (IV) <EMI ID = 783.1> <EMI ID = 784.1> <EMI ID = 785.1> <EMI ID = 786.1> <EMI ID = 787.1> <EMI ID = 788.1> <EMI ID = 789.1> <EMI ID = 790.1> <EMI ID = 791.1> cation 1. 14. A process for preparing compounds of formula (IV) according to claim 13, characterized in that the following operations are carried out: <EMI ID = 792.1> <EMI ID = 793.1> <EMI ID = 794.1> the meanings indicated in claim 1, on a compound of formula (III) so as to generate a compound of formula (XIX) <EMI ID = 795.1> <EMI ID = 796.1> the meanings indicated in claim 7 and T has the meanings indicated above; <EMI ID = 797.1> into another of the formula (XX) <EMI ID = 798.1> <EMI ID = 799.1> the meanings given in claim 7 and T has the meanings given above; c) and finally removal of the groups protecting the function aldehyde in T. 15. Compounds of formula (XI) <EMI ID = 800.1> <EMI ID = 801.1> silyl ether group or an acetal-ether group. 16. Compounds of formula (XII) <EMI ID = 802.1> in which G has the meanings given in <EMI ID = 803.1> <EMI ID = 804.1> dication 7. 17. Compounds corresponding to formula (XIII) <EMI ID = 805.1> in which G has the meanings given in <EMI ID = 806.1> cation 1. 18. Compounds corresponding to formula (XIV) <EMI ID = 807.1> <EMI ID = 808.1> has the meanings indicated in claim 10. 19. Compounds corresponding to formula (XV) <EMI ID = 809.1> <EMI ID = 810.1> fications indicated in claim 7. 20. Compounds corresponding to formula (XVIII) <EMI ID = 811.1> <EMI ID = 812.1> indicated in claim 7 and T represents a protected aldehyde function - <EMI ID = 813.1> <EMI ID = 814.1> having the meanings given in claim 1. 21. Compounds corresponding to the formula (SIX) <EMI ID = 815.1> <EMI ID = 816.1> <EMI ID = 817.1> the meanings indicated in claim 14. 22. Compounds corresponding to formula (XX) <EMI ID = 818.1> <EMI ID = 819.1> meanings indicated in claim 7 and T has the meanings indicated in claim 14. i <EMI ID = 820.1> <EMI ID = 821.1> <EMI ID = 822.1> 24. Compounds corresponding to formula (XXVII) <EMI ID = 823.1> <EMI ID = 824.1> tions indicated in claim 23.