CH624669A5 - Process for the preparation of new prostaglandin analogues - Google Patents

Abstract

The new prostaglandin analogues of formula VI in which R3 is a 1,1-dimethylpentyl or 2-ethyl-( )-heptyl group and the C-C double bonds represented are trans, their methyl esters, their non-toxic salts and the cyclodextrin clathrates of these acids or esters are useful for treating hypertension (high blood pressure), contraception, menstrual regulation, termination of pregnancy and initiation of labour in gravid female mammals. They are prepared from the compounds of formula VII, in which R4 is an ether residue and R5 and R6 are ester residues, by reaction with a dialkyl phosphonate, followed by reduction of the 15-oxo group to a hydroxyl group, which is protected by etherification, then hydrolysis of the R5 and R6 groups, oxidation of the alpha -9-hydroxyl group to an oxo group and hydrolysis of the protective groups. <IMAGE>

Description

       

  
 

** ATTENTION ** start of the DESC field may contain end of CLMS **.

 



   5. Process for the preparation of prostaglandin analogs of general formula:
EMI2.1
 in which R3 represents the dimethyl-l, l pentyl or the ethyl-24 heptyl group, the zigzag line indicates the attachment of the hydroxy group to the carbon atom according to the configuration x or '3, and the double bonds between the carbon atoms 2-3 and 13-14 are trans, characterized in that a compound of general formula is reacted:

  :
EMI2.2
 in which Rq represents a tetrahydropyrannyl-2 group unsubstituted or substituted by at least one alkyl radical, or represents a tetrahydrofurannyl-2 or ethoxy-1 ethyl group, Rs represents a straight or branched alkyl group containing from 1 to 4 atoms carbon, R6 represents an alkylcarbonyl group containing from 2 to 5 carbon atoms, and the double bond represented is trans, with the sodium derivative of a dialkyl phosphonate of general formula:
EMI2.3
 in which R7 represents an alkyl group containing from 1 to 4 carbon atoms and R3 is as defined above, to obtain a compound of general formula:

  :
EMI2.4
 in which R3, R4, R5 and R6 are as defined above and the carbon-carbon double bonds shown are trans, the oxo-15 group of the resulting compound is reduced to hydroxy group to obtain a compound of general formula:
EMI2.5
 in which the various symbols are as defined above, the zigzag line ho indicates the attachment of the hydroxy group to the carbon atom according to the configuration or ss, and the double bonds shown are trans, the compound obtained is reacted with dihydropyran unsubstituted or substituted by at least one alkyl radical, or with dihydrofuran or ethyl vinyl ether, to obtain a compound of general formula:

  :
EMI2.6
 in which the various symbols and symbols are defined above and the double bonds shown are trans, the resulting compound is reacted with methanol in an alkaline medium to obtain a compound of general formula:
EMI2.7
 in which the symbols and are as defined above and the double bonds shown are trans, the hydroxy-9x group of the compound of general formula (XII ') is oxidized to the oxo group, and the OR4 groups of the resulting compound are hydrolyzed, of general formula:

  :
EMI2.8
 wherein R3, R4 and are as defined above and the carbon-carbon double bonds shown are trans, into hydroxy groups to obtain a compound of the general formula (VI ') above.



   6. A method of preparing cyclodextrin clathrate of a prostaglandin analog of formula (VI '), characterized in that a prostaglandin analog of formula (VI') is prepared by the method according to claim 5 and that reacts the product with cyclodextrin.



   The present invention relates to a process for the preparation of new prostaglandin analogs.



   In Belgian patent No. 809169, analogs of A2transprostaglandins having the general formula have been described and claimed, among others.
EMI3.1




  in which A represents a group of formula:
EMI3.2

X represents an ethylene (-CH2CH2-) or trans vinylene (- CH = CH-) chain, R1 represents a straight or branched chain alkyl radical containing from 1 to 10 carbon atoms or a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms and carrying a phenyl substituent or a cycloalkyl substituent having from 5 to 7 carbon atoms, R2 represents a hydrogen atom or a straight or branched chain alkyl radical containing from 1 to 4 carbon atoms, the zigzag line indicates the attachment of the hydroxy group to the carbon atom in configuration x or ss, and the double bond between carbon atoms 2 and 3 is trans,

   and their alkyl esters having from 1 to 10 carbon atoms in a straight or branched chain, as well as the cyclodextrin clathrates of these acids or esters and the non-toxic salts of these acids, excluding A2trans-PGEI. In said Belgian patent, it was indicated that these compounds had the interesting and well known pharmacological properties typical of prostaglandins, selectively, including in particular the hypotension activity, the activity of inhibiting the aggregation of blood platelets. , The activity of inhibiting gastric acid secretion and gastric ulceration and bronchodilator activity, and are useful for the treatment of hypertension, for the treatment of peripheral circulation disorders, for prevention and the treatment of cerebral thrombosis and myocardial infarction,

   for the treatment of gastric ulcers and for the treatment of asthma.



   It has now been found that the analogs of A2transprostaglandins of general formula (I) in which A represents the
EMI3.3


 <tb> grouping <SEP> from <SEP> formula:
 <tb> <SEP> O <SEP> / <SEP> (V)
 <tb> <SEP> OH
 <tb> <SEP> OH
 <tb>
X represents the trans vinylene chain, R1 represents the dimethyl-l, l pentyl group [that is to say the group - C (CH3) 2 - (CH2) 3 H3] or the ethyl-2- group;

   heptyle [ie the group
   - CH2 - CH - (CH2) 4 = CH3] and R2 represents a hydrogen atom C2H3 gene [ie, dimethyl-16.16 A2trans-PGEI and ethyl-17-E e3- dihomo-A2trans-PGEî ] and their methyl ester, as well as the cyclodextrin clathrates of these acids and esters and the non-toxic salts of these acids, have eminent pharmacological properties to an unexpected degree.



   The process according to the present invention therefore leads to prostaglandin analogues hitherto unknown which have the general formula:
EMI3.4
 in which R3 represents the dimethyl-l, l pentyl group or the ethyl group: heptyl, the zigzag line m indicates the attachment of the hydroxy group in configuration '3or, preferably, x, and the double bonds between the carbon atoms 2 -3 and
 13-14 are trans, and their methyl ester, as well as the cyclodextrin clathrates of these acids and esters and the non-toxic (eg sodium) salts of these acids.



   The present invention relates to the preparation of all these compounds in their natural form as shown.



   As can be seen, the compounds represented by the general formula (VI) have four chiral centers, these four centers being located on the carbon atoms of the alicyclic ring listed 8, 1 1 and 12 and on the carbon atom 15 , to which is attached a hydroxy group. Another chiral center occurs when the symbol R3 represents an ethyl group; heptyle. The presence of chiral centers leads, as we know, to the existence of isomerism. All the isomers of general formula (VI), and their mixtures, must be considered as belonging to the field of general formula (VI).



   It has been found that the prostaglandin analog of formula (Vl) in which R3 represents the dimethyl-l, l pentyl group, as well as its methyl ester and its non-toxic salts, have an exceptionally good abortive activity and an exceptionally good activity stimulation of uterine contraction, activities not mentioned in Belgian Patent No. 809169 for any specific compound whatsoever corresponding to the general formula (I) which was described therein, and these compounds are therefore useful for interrupting the pregnancy and labor induction in pregnant female mammals and for estrus control, contraception and menstrual regulation in female mammals, said compounds also have hypotensive action.



   It has been found that the prostaglandin analog of formula (VI) in which R3 represents the ethyl-2-E group, heptyl, as well as its methyl ester and its non-toxic salts, have exceptionally good hypotensive activity and are therefore useful for the treatment of hypertension and peripheral circulation disorders.



   The prostaglandin derivatives prepared by the process according to the present invention have a relatively low power for triggering diarrhea by comparison with their powers from the point of view of the advantageous pharmacological properties mentioned above, and can therefore be used, for the purposes indicated , at appropriate dosages, which do not cause diarrhea as an undesirable side effect.

 

   The compound of the invention which is preferred from the point of view of its abortive activity and its activity of stimulating uterine contraction is the methyl ester of dimethyl-16.16 trans-PGE1, and that which is preferred from the point of view in view of its hypotensive action is the methyl ester of ethyl-l7-l, w dihomo-A2trans-PGEI.



   For example, in standard laboratory tests, in oral administration to the conscious rat in a state of spontaneous hypertension,
The methyl ester of ethyl-17-4 w-dihomo-A2trans-POE, causes drops in blood pressure of 15 mmHg, 10 mmHg and 14 mmHg, respectively 1/2 h, 1 h and 3 h after administration, at a dose of 0.1 mg / kg of body weight of the animal, of the falls of 33, 19, 13 and 1 1 mmHg, respectively V2 h, 1 h, 3 and 5 h after administration, at the dose of 0.3 mg / kg of body weight, and falls of 44, 39, 21 and 20 mmHg, respectively 1/2 h, 1 h, 3 and 5 h after administration, at the dose of 1, 0 mg / kg body weight.



   In the above experiments, soft faeces were observed in only one in six rats for the dose of 0.3 mg / kg body weight, and was observed in none of the six rats for doses of 0.1 and 1.0 mg / kg body weight. These results show that the methyl ester of ethyl-17-4 o-dihomo-A2trans PGEI has a strong hypotensive activity and a very weak activity of production of diarrhea (side effect).



   The methyl ester of dimethyl-16.16 A2trans-PGEI: a) stimulates uterine contraction when administered intravenously to the pregnant spleen, 20 'd of gestation, at a dose of 0.5 ug / kg body weight of the animal; b) causes a drop in blood pressure when administered intravenously to the dog anesthetized with allobarbital, at a dose of 1 g / kg of body weight, and c) causes diarrhea at a dose of 1200, ug / kg of body weight, for oral administration, in 50% of the treated mice.



   Among the pharmacological activities of the methyl ester of dimethyl-16.16 A2trans-PGEI: a) the uterine contraction activity is the useful effect, and b) the hypotensive activity, and c) the production activity diarrhea are considered to be unwanted side effects.

  The pharmacological actions, on rats, of the methyl ester of dimethyl-16.16 A2trans-PGEs and of prostaglandin analogs already described in Belgian patent N 809169, for example methyl-16 (R) a2trans-PGE1, phenyl 16-4 -trinor-A2trans-PGEz and methyl-15-t A2trans-PGEi, are compared in the following table:

  :
 Board
 (a) (b) (c) (b) / (a) (c) / (a)
 Activity of Activity Activity of
 hypotensive contraction production
 uterine (llglkg) diarrhea (lag / kg) (llg / kg)
Methyl-16 (R) A2trans-PGEI 5 0.05 85 0.05 / 5 = 0.01 85/5 = 17 Phenyl-16-4 w-trinor-A2trans-PGE1 20 0.02 1940 0.02 / 20 = 0.001 1940/20 = 97 Methyl-15-4 A2trans-PGEl 5 1 20 1/5 = 0.2 20/5 = 4
Dimethyl-16,16-dimethyl ester A2trans-PGE1 0.2-0.5 1 1200 1 / 0.5 = 2 1200 / 0.5 = 2400
 As can be seen from this table, the methyl ester of dimethyl-16.16 A2trans-PGE1 produces a powerful desired effect (uterine contraction),

   which is at least 10 times more important than that of other compounds. In addition, the selectivity index [separation of the desired activity from the side effects, either the ratio (b) / (a) or (c) / (a)] of this methyl ester is much higher than that of known compounds. These figures show that this ester has a powerful uterine contraction activity, far superior to that of the other compounds tested, and is of better and safer use than the latter for the termination of pregnancy and the induction of labor in pregnant female mammals and for estrus control, contraception and menstrual regulation in female mammals.



   In accordance with the present invention, the A2transprostaglandins of general formula (VI) and their methyl ester are prepared, respectively by the methods defined in claims 1 and 5, according to which a compound of general formula is reacted:
EMI4.1
 in which Rq represents a tetrahydropyrannyl-2 group which is unsubstituted or substituted by at least one alkyl radical, or represents a tetrahydrofurannyl-2 group or an ethoxy-ethyl group, Rq preferably being the tetrahydropyrannyl-2 group,
Rs represents a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, and R6 represents an alkylcarbonyl group containing from 2 to 5 carbon atoms, with the sodium derivative of a dialkoyl phosphonate of general formula:

  :
EMI4.2
 in which R7 represents an alkyl group containing from 1 to 4 carbon atoms and R3 is as defined above, to obtain a compound of general formula:
EMI4.3
 in which the various symbols are as defined above, the oxo-15 group of the compound of general formula (IX) is reduced to a hydroxy group by methods known per se, to obtain a compound of general formula:

  :
EMI4.4
  in which the various symbols are as defined above and the zigzag line - indicates that the attachment of the hydroxy group to the carbon atom is in configuration or P, the compound obtained is reacted with unsubstituted or substituted by dihydropyran minus an alkyl radical, or with dihydrofuran or ethyl vinyl ether, to obtain a compound of general formula:
EMI5.1
 in which the various symbols are as defined above, and the zigzag line w indicates that the attachment of the group OR4 to the carbon atom is in configuration a or, 8.



  In the process according to claim 1, the resulting compound is hydrolyzed in an alkaline medium, whereas in the process according to claim 5, it is reacted with methanol in an alkaline medium, to obtain a compound of general formula:
EMI5.2
 in which R represents respectively a hydrogen atom or a methyl group, and R3, R4 and rw have the meanings indicated above, the hydroxy-9x group of the compound of general formula (XII) is oxidized by groups known per se oxo, and the OR4 groups of the resulting compound are hydrolyzed, of general formula:

  :
EMI5.3
 in which R, R3, Rq and have the meanings indicated above, in hydroxy groups to obtain a PGE compound of general formula (VI) or its methyl ester. In the general formulas (VII), (IX), (X), (XI), (XII) and (XIII), the carbon-carbon double bonds represented are trans as are all the other double bonds represented by
EMI5.4
 or
EMI5.5
 in the formulas which follow; a cis double bond in the following formula (XIV) is represented by
EMI5.6

 The reaction between an aldehyde of general formula (VII) and the sodium derivative of a dialkylphosphonate of general formula (VIII) takes place under the conditions normally used for the Witting reaction.

  This reaction is preferably carried out by suspending sodium hydride in an inert organic solvent, for example tetrahydrofuran or 1,2-dimethoxyethane, and by adding the dialkyl phosphonate of general formula (VIII). The resulting dialkyl phosphonate sodium derivative can then be reacted with the compound of general formula (VII) at a temperature of 20 to 45 ° C to stereoselectively form the trans enonic compound of general formula (IX).



   The reduction of the oxo-15 group of a compound of general formula (IX) to a hydroxy group is conveniently carried out: 1 "using an excess of sodium borohydride in an alkanol containing from 1 to 4 carbon atoms , for example methanol, at low temperature, preferably from -30 to -60 "C, or 2" using zinc borohydride in a suitable inert organic solvent, for example 1,2-dimethoxy ethane, at a temperature of
   - 10 to 10 "C. The product thus obtained is a mixture of isomers of general formula (X) in which the hydroxy-15 group is in x or 8 configuration. If desired,

   the isomer having the hydroxy group in configuration x can be separated from that which ra in configuration '3 by column chromatography on silica gel.



  The separate isomers can be used in the processes described here to obtain prostaglandin analogs of general formula (VI) or their methyl esters in which the hydroxy group in position 15 is in the x or 3 configuration.



   The reaction of a compound of general formula (X) with a dihydropyran, dihydrofuran or ethyl vinyl ether is carried out in an inert organic solvent, for example methylene chloride, in the presence of a condensing agent. , for example p-toluenesulfonic acid.



   Alkaline hydrolysis of the compounds of general formula (XI): 1 "can be carried out using an aqueous solution of an alkali metal hydroxide or carbonate, for example sodium or potassium, in the presence of a water-miscible solvent, for example tetrahydrofuran or an alkanol containing from 1 to 4 carbon atoms, which gives compounds of general formula (XII) in which R represents a hydrogen atom, or 2 " using anhydrous potassium carbonate within anhydrous methanol, which gives compounds of general formula (XII) in which R represents the methyl radical.



   The transformation of the hydroxy group at position 9 of the PGF compounds of general formula (XII) into an oxo group can be carried out by methods known per se for the transformation of an alicyclic ring of PGF into a ring of PGE, for example at using a solution of chromic acid (for example obtained from chromium trioxide, manganese sulphate and sulfuric acid in water) or using Jones reagent.



   The OR4 groups of the compounds of general formula (XIII) can be converted into hydroxy groups by hydrolysis under moderate conditions, using an aqueous solution of an organic acid, for example acetic acid, or with using a dilute aqueous mineral acid, for example hydrochloric acid, advantageously in the presence of an organic solvent miscible with water, for example tetrahydrofuran or an alkanol containing from 1 to 4 carbon atoms, such as methanol. This moderate hydrolysis can be carried out at a temperature ranging from room temperature to 60 "C (preferably at a temperature below 45" C) using an acid mixture, for example a mixture of hydrochloric acid and tetrahydrofuran or methanol, or a mixture of acetic acid, water and tetrahydrofuran.

 

   The compounds of general formula (VII) in which the various symbols are as defined above are new compounds. They can be prepared by a new synthetic route from known compounds of formula (XIV) represented below (cf. Belgian patent N "838582) by the series of reactions represented below in scheme A, in which the various symbols are as defined above.



  Diagram A
EMI6.1

 Compounds of general formula (XIV) can be reduced to produce compounds of general formula (XV). The reduction can be conveniently carried out by hydrogenation in the presence of a hydrogenation catalyst, for example palladium on black, palladium black or platinum dioxide, in an inert organic solvent, for example a lower alkanol, such as
 methanol or ethanol, at room temperature, at atmospheric pressure or under pressure, for example under pressure
 of hydrogen ranging from atmospheric pressure to 15 kg / cm2.



   The compounds of general formula (XVII) can be prepared
 res by the process by which we react tn compound of for
 general mule (XV) with a compound of general formula:
EMI7.1
 in which Rg and Rg, which may be identical or different, each represent a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, or a cycloalkyl group containing from 3 to 6 carbon atoms, for example lithic diisopropylamide , to obtain a lithic compound of formula
EMI7.2


 <tb> general:

   <SEP> OLi
 <tb> <SEP> I
 <tb> <SEP> (xxIII)
 <tb> <SEP> OR4
 <tb> <SEP> OR
 <tb> <SEP> 4
 <tb> in which RS and Rs are as defined above, this lithic compound is reacted with benzeneselenenyl bromide (that is to say C6HsSeBr), or diphenyl diselenide, or a dialkyl or diphenyl disulfide of general formula RloSSRlo, in which the symbols Rlo both represent alkyl groups containing from 1 to 4 carbon atoms, or phenyl radicals, the resulting intermediate is hydrolyzed to obtain a compound of general formula (XVI), the resulting compound with hydrogen peroxide or sodium periodate, and the resulting compound of general formula is decomposed:

  :
EMI7.3
 in which the various symbols are as defined above, to transform the grouping
EMI7.4
 attached to position 8 of the cyclopentane ring in one
EMI7.5


 <tb> grouping <SEP> COOR
 <tb> <SEP> A2trans <SEP>, ' <SEP> 5
 <tb> in which Rs is as defined above. 



   The reaction between a compound of general formula (XV) and a lithiated amine of general formula (XXII) is carried out in an inert organic solvent, for example tetrahydrofuran, at low temperature, for example at -78 C, the ratio molar equivalents of compound of general formula (XV) to those of compound of general formula (XXII) in the reaction mixture being adjusted so as to obtain a lithic compound of general formula (XXIII). 



   The reaction is preferably carried out between the lithic compound of general formula (XXIII) and benzeneselenenyl bromide, diphenyl diselenide or dialkyl or diphenyl disulfide, within an inert organic solvent, for example tetrahydrofuran, l examethylphosphotriamide, diethyl ether, n-hexane or n-pentane or a mixture of two or more of these bodies, at low temperature, for example at - 78 C. 



   When the product of general formula (XVI) is a compound in which Q represents - SeCsHs, this product is then treated: 1 "with hydrogen peroxide in a mixture of ethyl acetate and tetrahydrofuran or methanol, to a temperature below 30 "C:

  : or 2 "with sodium periodate in the presence of water and a lower alkanol, preferably methanol, at a temperature below 20" C, to form a compound of general formula (XXIV) in which O = Q - represents - Se (O) C6Hs and, by stirring the reaction mixture at a temperature of 25 to 30 C, causes the decomposition of the compound of general formula (XXIV) into an A2trans compound of general formula (XVII), which can separate from the reaction mixture by methods known per se and, if desired, purify by column chromatography on silica gel. 



   When the product of general formula (XVI) is a compound in which Q is a group - SRlo in which Rlo is as defined above, this product is treated with hydrogen peroxide or sodium periodate in the same manner as described above for a product of general formula (XVI) in which Q is a benzeneselenenyl group, to obtain a compound of general formula (XXIV) in which Q is a group -SRlo, Rlo being as defined above, compound which can be separated from the reaction medium by methods known per se. 



   When the compound of general formula (XXIV) is one in which Q represents an alkylthio-SRlo group in which Rlo represents an alkyl group containing from 1 to 4 carbon atoms, this compound is dissolved in toluene and the solution is stirred, preferably in the presence of a small amount of calcium carbonate, at a temperature of 100 to 120 C, to decompose this compound into an A2trans compound of general formula (XVII). 

  When the compound of general formula (XXIV) is one in which Q represents the phenylthio group, this compound is dissolved in carbon tetrachloride and the solution is stirred, preferably in the presence of a small amount of calcium carbonate, to a temperature of approximately SOC, to decompose this compound into an A2trans compound of general formula (XVII). 



   The compounds of general formula (XVIII) can be prepared by reacting compounds of general formula (XVII) with trimethylchlorosilane in an inert organic solvent, for example methylene chloride, in the presence of a base, for example pyridine or a tertiary amine, at low temperature, for example from -30 to 0 "C.    



   The compounds of general formula (XIX) can be prepared by reacting a trimethylsilyl ether of general formula (XVIII) with an appropriate acyl chloride or anhydride, in an inert organic solvent, for example methylene chloride, in the presence of a base, for example pyridine or a tertiary amine, at low temperature, for example from 0 to 30 "C.    



   The compounds of general formula (XXI) can be prepared by treating the compounds of general formula (XIX) by methods known per se for the elimination of the trimethylsilyl group, for example by treatment with an acid: it is better not to use a strong acid, in order to avoid the risk of elimination of the Rq group.    

 

   The compounds of general formula (XXI) can also be prepared by acylation of the compounds of general formula (XVII) [by the means mentioned above for the transformation of the compounds of general formula (XVIII) into those of general formula (XIX)] into compounds of general formula (XX), and hydrolysis of the latter compounds using an alkali metal carbonate, for example potassium or sodium, in an alkanol containing from 1 to 4 carbon atoms, for example methanol, at a moderately low temperature, for example from 0 to 5 "C.    



   The compounds of general formula (XXI) can be transformed into compounds of general formula (VII), under moderate conditions and in a neutral medium, for example using a chromium trioxide / pyridine complex or Jones reagent, or a dimethyl- or methylphenyl-N-chlorosuccinimide sulfide complex or a dimethyl- or methylphenyl / chlorine sulfide complex [cf.   J.  Bitter.  Chem.  Soc.  , 94, 7586 (1972)], or a dicyclohexylcarbodiimide / dimethylsulfoxide complex [cf. 



   J.  Bitter.  Chem.  Soc.   , 87, 5661 (1965)], at moderately low temperature. 



   The compounds of general formula (XIV) used as starting materials in the series of reactions represented in scheme A can be prepared by the methods described in Belgian patent NO 838582, starting from the known compound of formula (XXV) [prepared as described in J.  Bitter.  Chem.  Soc.   , 91, 5675 (1969) and ibid. , 92, 397 (1970)] by the series of reactions represented below in scheme B, in which Ac represents the acetyl group and the other symbols are as defined above. 



  Scheme B
EMI8. 1

 The compounds of formula (XXVI) can be prepared by hydrolysis in an alkaline medium of the compounds of formula (XXV), for example by using potassium carbonate in methanol.  The compounds of formula (XXVII) can be obtained by acetylation of the compounds of formula (XXVI) under moderate conditions and they can be converted into compounds of general formula (XXVIII) by reaction with a dihydropyran of dihydrofuran or ethyl vinyl ether in an inert organic solvent, for example methylene chloride, in the presence of a condensing agent, for example ptoluenesulfonic acid. 

  The compounds of general formula (XXIX) can be prepared by reduction of the compounds of general formula (XXVIII) using diisobutylaluminum hydride in toluene, at a temperature below -60 "C.     The dimesyl anion, previously prepared from sodium hydride and dimethyl sulfoxide, is reacted with 4-carboxy-nbutyltriphenylphosphonium bromide to form 4-carboxy-n-butylideenetriphenylphosphorane.  To this compound, a compound of general formula (XXIX) is added and this mixture is allowed to react in dimethylsulfoxide, at room temperature, to obtain compounds of general formula (XXX). 

  The acids of general formula (XXX) are then esterified to obtain compounds of general formula (XIV) by reaction with: 1 "a diazoalkane, for example diazomethane; 2" alcohols in the presence of dicyclohexylcarbodiimide as a condensing agent; 3 of the alcohols after formation of a mixed anhydride by addition of a tertiary amine, then a pivaloyl halide or an arylsulfonyl or alkylsulfonyl halide (cf.  British patents Nos. - 1362956 and 1364125 of the proprietor); 40 of alkyl halides, for example methyl iodide, and: a) potassium carbonate in acetone [cf.   J.  Org.  Chem.  , 34, 3717 (1969)], b) sodium bicarbonate in N, N-dimethylacetamide or N, N-dimethylformamide [cf.   Advan.  Org. 

  Chem.  , 5, 37 (1965)], c) calcium oxide in dimethylsulfoxide [cf.   Synthesis, 262 (1972)], or 5 of the dialkyl acetals of N, N dimethylformamide, for example N, N-dimethylformamidedimethylacetal, within anhydrous benzene [cf.   Helv.  Chim. 



  Acta, 48, 1746 (1965)]. 



   The dialkoyl phosphates of general formula (VIII) can be prepared by reacting a solution of n-butyllithium in diethyl ether with a solution of a dialkyl methylphosphonate of general formula:
EMI9. 1
 in which R7 is as defined above, for example dimethyl or diethyl methylphosphonate, in tetrahydrofuran, at a temperature below - SOC, then by adding dropwise to the reaction mixture a solution of a compound of general formula:

  :
   RIIOOCR3 (XXXII) in which Rlí represents an alkyl group containing from 1 to 4 carbon atoms, and R3 is as defined above, in tetrahydrofuran, at a temperature below - SOC, for 2 to 4 h, and finally with stirring for 2 to 18 h at a temperature ranging from room temperature to OC, which gives the desired dialkyl phosphonate of general formula (VIII). 



   The lithiated amines of general formula (XXII) used in the above process according to the invention, for example lithic diisopropylamide, as well as benzeneselenenyl bromide and diphenyl diselenide, can be prepared by known methods, for example as described in J.  Bitter.  Chem.  Soc.   , 95.6139 (1973).    



   The methyl esters of the A2transprostaglandins of general formula (VI) can be obtained by reaction of the acids with: 1 "diazomethane; 2" methanol in the presence of dicyclohexylcarbodiimide as condensing agent, and methanol after formation of a mixed anhydride by adding a tertiary amine, then a pivaloyl halide, or an arylsulfonyl or alkylsulfonyl halide (cf.  British patents
Nos. 1362956 and 1364125). 



   The compounds of general formula (VI) can, if desired, be converted, by methods known per se, into salts
 non toxic. 



   The term non-toxic salts used in the present text means salts whose cations are relatively harmless to the animal organism when they are used in therapeutic doses, so that the beneficial pharmacological properties of the compounds of general formula (VI ) are not affected by side effects attributable to these cations.  Preferably, these salts are soluble in water.  Among the suitable salts, there may be mentioned the alkali metal salts, for example of sodium and potassium, the ammonium salts and the pharmaceutically acceptable (i.e. non-toxic) amine salts. 

  Amines which are suitable for forming such salts with carboxylic acids are well known and include, for example, amines derived, in theory, from the replacement of one or more hydrogen atoms of ammonia by groups, which may be the same or different when more than one hydrogen atom is replaced, chosen, for example, from alkyl groups containing from 1 to 6 carbon atoms and hydroxyalkyl groups containing from 1 to 3 carbon atoms. 



   These non-toxic salts can be prepared from the acids of general formula (VI), for example by reaction of stoichiometric amounts of an acid of general formula (VI) and the appropriate base, for example a metal hydroxide or carbonate alkaline, ammonium hydroxide, ammonia or an amine, in a suitable solvent.  The salts can be isolated by lyophilization of the solution or, if they are sufficiently insoluble in the reaction medium, by filtration, after removal of part of the solvent if necessary. 



   The analogs of A2transprostaglandins of general formula (VI) and their methyl esters can, if desired, be converted into cyclodextrin clathrates.  These clathrates can be prepared by dissolving the cyclodextrin in water and / or an organic solvent miscible with water and adding to the solution the prostaglandinic compound in an organic solvent miscible with water.  The mixture is then heated and the cyclodextrin clathrate formed is isolated by concentrating the mixture under reduced pressure or by cooling it and separating the product by filtration or decantation.  The proportion of organic solvent relative to water can be varied depending on the solubilities of the starting materials and the reaction products. 

  Preferably, the temperature is not allowed to rise above 70 ° C. during the preparation of the cyclodextrin clathrates.  Cyclodextrins x, ss or 7 or their mixtures can be used for their preparation.  The transformation into their cyclodextrin clathrates serves to increase the stability of prostaglandinic compounds. 



   The following reference examples and examples illustrate the preparation of the new prostaglandin analogs of the present invention.  In these examples, IR, NMR, CCM and CCGS respectively signify infrared absorption spectrum, nuclear magnetic resonance spectrum, thin layer chromatography and column chromatography on silica gel.  When solvent ratios are indicated in the chromatography and other treatments, the quantities are expressed in volumes. 

 

  Reference example 1:
 (Methoxycarbonyl-6 hexyl) -2x hydroxymethyl-3 (tetral, vdro-
 pyrannyl-2 o Yy) -4x cyclopentanol-lx
 14.2 g of (methoxycarbonyl-6 hexene-2 cisyl) 2x hydroxymethyl-3p (tetrahydropyrannyl-2 oxy) -4x cyclopenta nol-lx (prepared as described in Belgian patent No. 838582) are hydrogenated under a pressure of 1 atm, in 300 ml of methanol containing 3 g of catalyst at 5% by weight of palladium on black.  The reduction is stopped when an equivalent of hydrogen has been absorbed. 

  The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure, which gives 13.8 g of the desired compound having the following physical characteristics:
 TLC (development solvent: benzene / ethyl acetate = 1/1): Rf = 0.28
 IR (liquid film): 3450, 1740, 1440, 1030 cm-1;
 NMR (solution in CDCl3): 5.00-4.55 (1H, m), 3.70 (3H, s). 



  Reference example 2:
   (6-phenylseleno-methoxycarbonylf hexyl) -2 hydroxymethyl
   3ss (tetrahydropyrannyl-2 oxy) 4a cyclopentanol-lx
 Under a nitrogen atmosphere, a solution of 19.4 ml of diisopropylamine in 350 ml of tetrahydrofuran is cooled to -78 ° C., and 114 ml of a 1.2M solution of n-butyllithium in n is added dropwise thereto. -hexane.  The mixture is stirred at
 - 78 for 20 min to produce lithic diisopropylamide. 



  To the solution of lithic diisopropylamide, a solution of the 13.8 g of (6-methoxycarbonyl-hexyl) -2a hydroxymethyl-3ss (tetrahydropyrannyl-2 oxy) -4'z cyclopentanolla prepared in reference example 1 is added dropwise. in 100 ml of tetrahydrofuran, at -78 ° C., and the mixture is stirred at the same temperature for 30 min.  A solution of 18.2 g of diphenyl diselenide in 50 ml of tetrahydrofuran is added dropwise to the reaction mixture at -78 "C, and this mixture is stirred at the same temperature for 1 h, then at O" C for 20 min.  It is then poured into an aqueous solution of ammonium chloride and extracted with ethyl acetate. 

  The extract is washed with water and with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.  The residue is purified by CCGS using as eluent a mixture (3/2) of benzene and ethyl acetate, which gives 15.8 g of the desired compound having the following physical characteristics:
 TLC (developing solvent: benzene / ethyl acetate = 1/1): Rif = 0.37;
 IR (liquid film): 3450, 1740, 1580, 1440, 1030 cm-1;
 NMR (solution in CDCl3): 7.75-7.10 (5H, m), 5.00-4.55 (1H, m), 3.70 (3H, s). 



  Example of reverence 3:
   (Methoxyearbonyl-6 hexene-5 transyl) -2a hydroxymethyl-3ss
 (tetrahydropyrannyl-2 oxy) -4a cyclopentanol-lx
 To a solution of the 15.8 g of the product prepared in reference example 2 in a mixture of 200 ml of ethyl acetate and
 100 ml of tetrahydrofuran, 4.5 g of sodium carbonate and 6.2 ml of 30% hydrogen peroxide are added and the mixture is stirred at 30 ° C. for 30 min. 

  The reaction mixture is then poured into water, washed with an aqueous solution of sodium carbonate, with water and with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under pressure. scaled down; 10.4 g of the sought compound are obtained
 having the following physical characteristics:
 TLC (development solvent: benzene / acetate
   ethyl = 1/1): Rf = 0.28;
 IR (liquid film): 3450, 1735, 1660, 1440, 1030 cm -1;
 NMR (solution in CDCl3): 6.90 (1H, dt), 5.82 (1H, d),
 5.00-4.55 (1H, m), 3.70 (3H, s). 



   Reference example 4:
   Acetoxy-lx (medox, ycarbonyl-6 hexene-5 transyl) -2x kvdrnx, y mét-l-3P (tetrakydropyrannyl-2 oxy) -4x cyclopentane
 Under a nitrogen atmosphere, a solution is added dropwise.
 tion of 4.3 ml of trimethylchlorosilane in 20 ml of methylene chloride to a solution of 10.4 g of the product prepared in reference example 3 in a mixture of 150 ml of methylene chloride and 18.8 ml of pyridine, at -20 "C, and the mixture is stirred at the same temperature for 20 min. 

  To the solution thus obtained, a solution of 2.45 ml of acetyl chloride in 50 ml of methylene chloride is added dropwise.
   - 20 the mixture is stirred at room temperature for 30 min.  Then 3 ml of ethanol are added to the reaction mixture in order to decompose the excess acetyl chloride.  The pyridine in the solution is neutralized with 80 g of sodium bisulfate and the resulting precipitate is filtered off.  The filtrate is concentrated under reduced pressure.  The residue is dissolved in 300 ml of ethyl acetate, 100 ml of a saturated aqueous solution of oxalic acid are added and the mixture is vigorously stirred at room temperature for 30 min. 

  The reaction mixture is extracted with ethyl acetate, the extract is washed with water, with an aqueous solution of sodium bisulfate, with water and with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.  The new residue is purified by CCGS using as eluent a mixture (3/1) of benzene and ethyl acetate; 7.2 g of the sought compound are obtained, having the following physical characteristics:
 TLC (developing solvent: benzene / ethyl acetate = 1/1): Rf = 0.51;
 IR (liquid film): 3450, 1735, 1660, 1440, 1030cm-1;
 NMR (solution in CDCl3): 6.90 (1H, dt), 5.82 (1H, d), 5.25-4.90 (1H, m), 4.85-4.45 (1H, m) , 3.71 (3H, s), 2.05 (3H, s). 



  Reference example 5: Acetoxy-la (methoxyearbonyl-6 hexene-5 transyl) -2'z formyl-
   3ss (tetrakydropyrannyl-2 oxy) -4x cyclopentane
 Under a nitrogen atmosphere, 34 ml of pyridine is dissolved in 440 ml of methylene chloride, 20.2 g of chromium trioxide are added with stirring, and the mixture is stirred at room temperature for 15 min. 

  88 g of diatomaceous earth is added to the reaction mixture, which is then cooled to OC C.     A solution of 7.2 g of acetoxy-la (methoxycarbonyl-6 hexene-5 transyl) -2x hydroxymethyl-3ss (tetrahydropyrannyl-2 oxy) -4'z cyclopentane (prepared as described in reference example 4) is added. ) in 100 ml of methylene chloride, at O "C.     After 10 min of stirring at 0 ° C., 155 g of sodium bisulfate are added to the reaction mixture and stirring is continued for a further 10 min.  The resulting precipitate is filtered through a bed of magnesium sulfate and the filtrate is concentrated under reduced pressure. 

  The residue is purified by CCGS using as eluent a mixture (5/1) of benzene and ethyl acetate, which gives 5.85 g of the desired compound having the following physical characteristics:
 TLC (developing solvent: benzene / ethyl acetate = 2/1): Rf 0.67;
 IR (liquid film): 1735, 1660, 1440, 1250, 1030cm-1;
 NMR (solution in CDCl3): 10.00-9.70 (1H, m), 6.90 (1H, dt), 5.82 (1H, d), 5.30-4.96 (1H, m) , 4.75-4.10 (2H, m), 3.72 (3H, s), 2.06 (3H, s). 



  Example 1:
   Acetoxy-9a (tetrahydropyrannyl-2 oxy) -J J 'z oxo-iS dimethyl
 16.16 prostadiene-2 trans-13 methyl transoate
 Under a nitrogen atmosphere, a solution of 1.62 g of 2-dimethyl-3,3-oxo-dimethyl hephylphosphonate (prepared as described in British patent N 1398291) in 6 ml of tetrahydrofuran is added to a suspension of 230 mg sodium hydride (purity 63%) in 50 ml of tetrahydrofuran and the mixture is stirred at room temperature for 30 min.  To the solution thus obtained is added a solution of 1.98 g of the product prepared in reference example 5 in 10 ml of tetrahydrofuran, at room temperature, and the solution is stirred at the same temperature for 1 h.  

  The reactivity of the reaction mixture is neutralized with acetic acid, filtered through a bed of silica gel and the filtrate is concentrated under reduced pressure.  The residue is purified by CCGS using as eluent a mixture (8/1) of benzene and ethyl acetate; 2.36 g of the sought compound are obtained, having the following physical characteristics:
 TLC (developing solvent: benzene / ethyl acetate = tl): Rf = 0.71;
   IR (liquid film): 1730, 1660, 1630, 1440, 1030 cm - 1;
 NMR (solution in CDCl3): 7.20-6.50 (2H, m), 6.16 (1H, d),
 5.80 (1H, d), 5.30-4.90 (1H, m), 4.80-4.50 (1H, m), 3.72 (3H, s),
 2.06 (3H, s), 1.10-0.70 (9H, m). 



   Example 2:
   Acetoxy-9a (tetrahydropyrannyl-2 oxy) -JJ'z hydroxy-lSa dimé
   thyl-16.16 prostadiene- trans-13 methyl transoate
 To a solution of the 2.36 g of the product prepared in Example 1,
 in 40 ml of methanol, 700 mg of borohydride are added
 sodium, at - 40 C, and the solution is stirred at this temperature for
 for 20 min.  The reactivity of the reaction mixture is neutralized by
 acetic acid and concentrated under reduced pressure.  We
 dissolve the residue in ethyl acetate and wash the solution
 with an aqueous solution of sodium bicarbonate and with a
 aqueous sodium chloride solution, dried over sulfate
 magnesium and concentrated under reduced pressure. 

  We purify
 the new residue by CCGS using as eluent a
 mixture (4/1) of benzene and ethyl acetate; we get 790 mg
 of the compound sought, 810 mg of its hydroxy-15ss isomer and
   480 mg of a mixture of the two.  The compound sought presents the
 following physical characteristics:
 TLC (development solvent: benzene / acetate
   ethyl = 2/1): Rf 0.38, (hydroxy-15ss isomer: Rf = 0.47);
   IR (liquid film): 3450, 1730, 1660, 1440, 1030, 980 cm-l;
 NMR (solution in CDCl3): 7.20-6.70 (1H, m), 6.10-4.90
 (4H, m), 4.80-4.50 (1H, m), 3.72 (3H, s), 2.06 (3H, s), 1.10-0.70
 (9H, m). 



  Example 3:
   Acetoxy-9x bis (tetrahydropyrannyl-2 oxy) -llcr, 15 &alpha; dimethyl
 16.16 prostadiene-2 trans-13 methyl transoate
 To a solution of the 790 mg of the hydroxy-15a isomer prepared in example 2 in 15 ml of methylene chloride, 5 mg of ptoluenesulfonic acid and 0.3 ml of 2,3-dihydro-pyran are added and the mixture is stirred mix at room temperature for 20 min. 

  The reaction mixture is diluted with 50 ml of ethyl acetate, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure; 930 mg of the crude desired compound is obtained having the following physical characteristics:
 TLC (developing solvent: benzene / ethyl acetate = 2/1): Rf 0.67;
   IR (liquid film): 1730, 1660, 1440, 1030, 980 cm -1;
 NMR (solution in CDC13): 7.20-6.70 (1H, m), 6.10-4.90 (4H, m), 4.80-4.50 (2H, m), 3.72 ( 3H, s), 2.06 (3H, s), 1.10-0.70 (9H, m). 



     Example 4:
   Hydroxy-9x bis (tetrahydropyrannyl-2 oxy) -llx, lSa dimethyl
   16.16 prostadiene-2 trans-13 methyl transoate
 To a solution of the 930 mg of the product prepared in Example 3 in 12 ml of methanol, 400 mg of potassium carbonate are added and the mixture is stirred at 40 ° C. for 1 h 2 h. 



  The reactivity of the reaction mixture is neutralized with acetic acid and extracted with ethyl acetate.     The extract is washed with an aqueous solution of sodium bicarbonate, with water and with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. 



  The residue is purified by CCGS using as eluent a mixture (6/1) of benzene and ethyl acetate; 745 mg of the sought compound is obtained having the following physical characteristics:
 TLC (development solvent: benzene / ethyl acetate = 2/1): Rf = 0.47
   IR (liquid film): 3450, 1730, 1660, 1440, 1030,980cm-1;
 NMR (solution in CDC13): 7.20-6.70 (1H, m), 6.10-5.30
 (3H, m), 4.80-4.50 (2H, m), 3.72 (3H, s), 1.10-0.70 (9H, m). 



   Example 5:
 Oxo-9 dihydroxy-J 1'z, 15'z dinethyl-16, 16 prostad'iéne-2 trans- 13
 methyl transoate [or methyl ester of 16,16 dimethyl A2trans-PGE / J
 To a solution of the 745 mg of the product prepared in
 Example 4 in 22 ml of diethyl ether, a solution is added
 chromic acid (obtained from 0.94 g of chromium trioxide, 4.55 g of manganese sulfate and 1.06 ml of sulfu acid
 in 22 ml of water), and the mixture is stirred at 0 "C for 1 h. 



  The reaction mixture is then extracted with diethyl ether
 lique and the extract is washed with an aqueous solution of chloride
 sodium, dried over magnesium sulfate and concentrated under reduced pressure; 732 mg of oxo-9 bis are obtained
 (tetrahydropyrannyl-2 oxy) -l la, l5a dimethyl-16,16, prostadiene-2 trans-13 methyl transoate having the following physical characteristic:
 TLC (developing solvent: benzene / ethyl acetate = 2/1): Rf = 0.74. 



   To a solution of the 732 mg of the compound thus obtained in
 1.9 ml of tetrahydrofuran, 19 ml of an aqueous solution of acetic acid at 65% by volume are added and the whole is stirred at 55-60 C for 1 h.  The reaction mixture is then extracted with ethyl acetate, the extract is washed with water and with an aqueous solution of sodium chloride, it is dried over magnesium sulphate and concentrated under reduced pressure ; we obtain
 119 mg of the sought compound having the following physical characteristics:
 TLC (development solvent: chloroform / tetrahydrofuran / acetic acid = 10/2/1): Rf = 0.51;
   IR (liquid film):

   3400, 2940, 2850, 1750, 1730, 1660, 1440, 1280 cm- ';
 NMR (solution in CDCl3): 7.10-6.75 (1H, m), 5.95-5.40 (3H, m), 3.71 (3H, s), 4.20-3.60 ( 2H, m), 2.75 (1H, dd), 1.00-0.75 (9H, m). 



  Example 6:
 Acetoxy-9a (tetrahydropyrannyl-2-oxy) -Ilcr oxo 5 ethyl-1 75
   o-dihomoprostadien-2-trans-I 3 methyl transoate
 By proceeding as described in Example 1, but replacing the 2-dimethyl-3,3-oxo-dimethyl hephylphosphonate with 1.62 g of 2-dimethyl-44-oxo-ethyl nonphosphonate (prepared as described below) ), 2.3 g of the sought compound having the following physical characteristics are obtained:
 TLC (developing solvent: benzene ethyl acetate = 2/1): Rf = 0.70;
   IR (liquid film):

   1730, 1660, 1630, 1440, 1030cl 1;
 NMR (solution in CDCl3): 7.20-6.50 (2H, m), 6.16 (1H, d),
 5.80 (1H, d), 5.35-4.90 (1H, m), 4.85-4.50 (1H, m), 3.72 (3H, s), 2.06 (3H, s), 1.10-0.70 (6H, m). 



   The 2-dimethyl dimethyl nonylphosphonate is synthesized as follows:
 65 g of dimethyl methylphosphonate are dissolved in 465 ml of tetrahydrofuran and the solution is cooled to -70 ° C. under a nitrogen atmosphere.  To the solution thus prepared, is added dropwise, in about 15 min, at a temperature below
 - 50 C, the butyllithium solution produced from 85.3 g of butyl bromide and 10.7 g of lithium in 400 ml of diethyl ether.  

  Then, after stirring for 10 min, 44 g of ethyl 3-ethyl octanoate in 140 ml of tetrahydrofuran are added dropwise to the reaction mixture, at a temperature below - SOC, at a temperature below - SOC. temperature for 2 h, then at room temperature for another 2 h, after which 92 g of acetic acid are added.  The reaction mixture is concentrated under reduced pressure, the residue is dissolved in water, this solution is extracted with diethyl ether, the ether extract is washed with water, dried over magnesium sulfate and it is concentrated under reduced pressure. 

  The new residue is distilled under reduced pressure, and 55 g of dimethyl nonylphosphonate 2-oxo-ethyl are obtained in the form of a colorless oil (P. E.  113-121 C at 0.2 mmHg). 



   IR (liquid film): 2950, 2860, 1710, 1455, 1270, 1190, 1040 and 820cm-1.    



  Example 7:
 Acetoxy-9a (tetrahydropyrannyl-2 oxy) -lla hydroxy-lSa ethyl
   17E, w-dihomoprostadiene-2 trans-13 methyl transoate
 Proceeding as described in Example 2, but replacing acetoxy-9a (tetrahydropyrannyl-2 oxy) -l oxo-15 dimethyl-16,16 prostadiene-2 trans-13 methyl transoate by 2.3 g acetoxy-9a (tetrahydropyrannyl-2 oxy) -lla oxo-15 ethyl-17; o) -dihomoprostadiene-2 trans-13 methyl transoate prepared in Example 6, 720 mg of the desired compound are obtained, 740 mg of its isomer hydroxy-15ss and 500 mg of a mixture of the two. 

  The sought-after compound has the following physical characteristics:
 TLC (developing solvent: benzene / ethyl acetate = 2/1): Rf = 0.40, (hydroxy-15 isomer: Rf = 0.47);
   IR (liquid film): 3450, 1730, 1660, 1440, 1030, 980 cm-1;
 NMR (solution in CDCl3): 7.20-6.70 (1H, m), 6.10-4.90 (4H, m), 4.80-4.50 (1H, m), 3.72 ( 3H, s), 2.06 (3H, s), 1.10-0.70 (6H, m). 



  Example 8:
 Acetoxy-9a bis (tetrahydropyrannyl-2 oxy) -I la, ISa ethyl-17E,
 w-dihomoprostadien-2 trans-13 methyl transoate
 By proceeding as described in Example 3, but replacing acetoxy-9a (tetrahydropyrannyl-2 oxy) - 1 hydroxy- 1 Sa dimethyl-16,16 prostadiene-2 trans-13 methyl transoate by 720 mg of the hydroxy-15a isomer prepared in Example 7, dissolved in 13 ml of methylene chloride, and using 5 mg of p-toluenesulfonic acid and 0.3 ml of 2,3-dihydro-pyran, 870 are obtained mg of the sought compound having the following physical characteristics:
 TLC (developing solvent: benzene / ethyl acetate = 2/1): Rf = 0.64;
 IR (liquid film):

   1730, 1660, 1440, 1030, 980 cm-1;
 NMR (solution in CDCl3): 7.20-6.70 (1H, m), 6.10-4.90 (4H, m), 4.80-4.50 (2H, m), 3.72 ( 3H, s), 2.06 (3H, s), 1.10-0.70 (6H, m). 



  Example 9:
   Hydroxy-9a bis (tetrahydropyrannyl-2 oxy) -lla, lSa ethyl-175
 o-dihomoprostadien-2 trans-13 methyl transoate
 Proceeding as described in Example 4, but replacing acetoxy-9a bis (tetrahydropyrannyl-2 oxy) -lla, 15a dimethyl-16,16 prostadiene-2 trans-13 methyl transoate with the 870 mg of the prepared product in Example 8, dissolved in 11 ml of methanol, and using 380 mg of potassium carbonate, 700 mg of the sought compound is obtained having the following physical characteristics:
 TLC (developing solvent: benzene / ethyl acetate = 2/1): Rf = 0.46;
   IR (liquid film):

   3450, 1730, 1660, 1440, 1030,980cm-1;
 NMR (solution in CDCl3): 7.20-6.70 (1H, m), 6.10-5.30 (3H, m), 4.80-4.50 (2H, m), 3.72 ( 3H, s), 1.10-0.70 (6H, m). 



  Example 10:
 Hydroxy-9-oxo-l la, lSa ethyl-17E o-dihomoprostadiene-2
 trans-13 methyl transoate [or 'ethyl- 1 ## methyl ester (o-dihomo'A2trnns-PGE1J
 Proceeding as described in Example 5, but replacing it with hydroxy-9a bis (tetrahydropyrannyl-2 oxy) -l la, 15a dimethyl-16,16 prostadiene-2 trans-13 methyl transoate with 700 mg of product prepared in Example 9, dissolved in 21 ml of diethyl ether, and using 21 ml of a chromic acid solution (prepared as described in Example 5),

   oxo-9 bis (tetrahydropyrannyl-2 oxy) -lla, 15a ethyl-174 co-dihomoprostadiene-2 trans-13 methyl transoate having the following physical characteristic is obtained:
 TLC (development solvent: benzene / ethyl acetate = 2/1): Rf = 0.68. 

 

   Proceeding as described in Example 5, the compound thus obtained is then dissolved in 1.8 ml of tetrahydrofuran, and using 18 ml of an aqueous solution of acetic acid at 65% by volume, 99 mg of the sought compound having the following physical characteristics:
 TLC (development solvent: chloroform / tetrahydrofuran / acetic acid = 10/2/1); Rf = 0.33;
   IR (liquid film): 3470, 2920, 2840, 1735, 1720, 1650, 1450,
 1430, 1270, 1165, 1080 and 980 cm-1;
 NMR (solution in CDCl3): 6.93 (1H, dt), 5.79 (1H, d), 5.67-5.40 (2H, m), 4.37-3.83 (2H, m) , 3.71 (3H, s), 2.92-2.53 (1H, dd), 1.06-0.65 (6H, m).  


    

Claims (6)

 CLAIMS  1. Process for the preparation of new prostaglandin analogues of general formula: EMI1.1  in which R3 represents the dimethyl-l, l pentyl or the ethyl-2S heptyl group, the zigzag line indicates the attachment of the hydroxy group to the carbon atom according to the a or ss configuration, and the double bonds between the atoms of carbon 2-3 and 13-14 are trans, and non-toxic salts of these acids, characterized in that a compound of general formula is reacted: : EMI1.2  wherein R4 represents a tetrahydropyrannyl-2 group unsubstituted or substituted by at least one alkyl radical, or represents a tetrahydrofurannyl-2 or ethoxy-1 ethyl group, Rs represents a straight or branched alkyl group containing from 1 to 4 atoms carbonate, R6 represents an alkylcarbonyl group containing from 2 to 5 carbon atoms, and the double bond represented is trans, with the sodium derivative of a dialkyl phosphonate of general formula: EMI1.3  in which R7 represents an alkyl group containing from 1 to 4 carbon atoms and R3 is as defined above, to obtain a compound of general formula: : EMI1.4  in which R3, R4, R5 and R6 are as defined above and the carbon-carbon double bonds shown are trans, the oxo-l 5 group of the resulting compound is reduced to hydroxy group to obtain a compound of general formula: EMI1.5  in which the various symbols are as defined above, the zigzag line rrw indicates the attachment of the hydroxy group to the carbon atom according to the configuration a or ss, and the double bonds represented are trans, the compound is reacted obtained with dihydropyran unsubstituted or substituted by at least one alkyl radical, or with dihydrofuran or ethyl vinyl ether, to obtain a compound of general formula: : EMI1.6  in which the various symbols and, are as defined above and the double bonds shown are trans, the resulting compound is subjected to alkaline hydrolysis to obtain a compound of general formula: EMI1.7  in which the symbols and are as defined above and the double bonds shown are trans, the hydroxy-9z group of the compound of general formula (XII) is oxidized to the oxo group, and the OR4 groups of the resulting compound are hydrolyzed,  of for EMI1.8 <tb> general <SEP> mule <tb> <SEP> 0 <tb> <SEP> / k (, \ <SEP> (XIII) <tb> <SEP> R3 <tb> <SEP> CRq <tb> <SEP> 4 <SEP> 4 <tb> in which R3, Rq and M are as defined above and the carbon-carbon double bonds shown are trans, into hydroxy groups to obtain a compound of the general formula (VI) above, after which we transform or not the product obtained in a salt, by reaction with a base.  2. Method for preparing the methyl ester of a prostaglandin analog of formula VI, characterized in that a prostaglandin analog of formula VI is prepared by the method according to claim 1 and that, by esterification, this is transformed produced in its methyl ester.  3. Process for the preparation of cyclodextrin clathrate of a prostaglandin analog of formula VI, characterized in that a prostaglandin analog of formula VI is prepared by the method according to claim 1 and the product is reacted with cyclodextrin.  4. Method for preparing the cyclodextrin clathrate of the methyl ester of a prostaglandin analog of formula VI, characterized in that the methyl ester of prostaglandin analog of formula VI is prepared by the method according to claim 2 and reacting the product with cyclodextrin.  5. Process for the preparation of prostaglandin analogs of general formula: EMI2.1  in which R3 represents the dimethyl-l, l pentyl or the ethyl-24 heptyl group, the zigzag line indicates the attachment of the hydroxy group to the carbon atom according to the configuration x or '3, and the double bonds between carbon atoms 2-3 and 13-14 are trans, characterized in that a compound of general formula is reacted: : EMI2.2  in which Rq represents a tetrahydropyrannyl-2 group unsubstituted or substituted by at least one alkyl radical, or represents a tetrahydrofurannyl-2 or ethoxy-1 ethyl group, Rs represents a straight or branched alkyl group containing from 1 to 4 atoms carbon, R6 represents an alkylcarbonyl group containing from 2 to 5 carbon atoms, and the double bond represented is trans, with the sodium derivative of a dialkyl phosphonate of general formula: EMI2.3  in which R7 represents an alkyl group containing from 1 to 4 carbon atoms and R3 is as defined above, to obtain a compound of general formula: : EMI2.4  in which R3, R4, R5 and R6 are as defined above and the carbon-carbon double bonds shown are trans, the oxo-15 group of the resulting compound is reduced to hydroxy group to obtain a compound of general formula: EMI2.5  in which the various symbols are as defined above, the zigzag line ho indicates the attachment of the hydroxy group to the carbon atom according to the configuration or ss, and the double bonds shown are trans, the compound obtained is reacted with dihydropyran unsubstituted or substituted by at least one alkyl radical, or with dihydrofuran or ethyl vinyl ether, to obtain a compound of general formula: : EMI2.6  in which the various symbols and symbols are defined above and the double bonds shown are trans, the resulting compound is reacted with methanol in an alkaline medium to obtain a compound of general formula: EMI2.7  in which the symbols and are as defined above and the double bonds shown are trans, the hydroxy-9x group of the compound of general formula (XII ') is oxidized to the oxo group, and the OR4 groups of the resulting compound are hydrolyzed, of general formula: : EMI2.8  wherein R3, R4 and are as defined above and the carbon-carbon double bonds shown are trans, into hydroxy groups to obtain a compound of the general formula (VI ') above.    6. A method of preparing cyclodextrin clathrate of a prostaglandin analog of formula (VI '), characterized in that a prostaglandin analog of formula (VI') is prepared by the method according to claim 5 and that reacts the product with cyclodextrin.  The present invention relates to a process for the preparation of new prostaglandin analogs.  In Belgian patent No. 809169, analogs of A2transprostaglandins having the general formula have been described and claimed, among others. ** ATTENTION ** end of the CLMS field may contain start of DESC **.