DE2622416A1 - PROSTAGLANDIN ANOLOGIST - Google Patents

Description

O: ίο Pharmaceuti nal Co., Ltd. Osaka, Janan

PRO STAGLMDIN ANALOGS

609 850/1106

- ι -

The present invention relates to new prostaglandin analogs.

Prostaglandins are derivatives of prostanoic acid as follows

Formula:

7 5 3

13 15

Various Prostaglandinarten known, inter alia, differ in the constitution, and in the substituents of ali cyclic ring. For example, the alicyclic rings of the prostaglandins E (PGE), F (PGF) and A (PGA) have the constitutions:

(H)

(III)

respectively.

(IV)

The dashed lines in the formulas above and in further formulas in this patent specification mean, according to the generally applicable nomenclature rules, that the relevant Grouping behind the main level of the ring system,

d. H. the grouping has the α-configuration, the thickened

6 0 9 8 5 0/1106

- 2 -

Lines "S" mean that the grouping is in front of the main plane of the system, ie the grouping has the β-configuration, and the wavy line ~~ indicates that the grouping has either the cc or the β-configuration.

Such compounds are further subdivided depending on the position of the double bond (s) in the side chain (s) which are bonded in the 8- and 12-position of the alicyclic ring. Thus PG -, - compounds have a trans double bond between C -, ^ and C, »(trans-Δ) and PGp compounds have a cis double bond between Cc and Cg and a trans double bond between C -, ^ and C-, r (cis-Δ, trans-Δ *). Prostaglandin F. ( ^PGF i _a ) ¹ ^ Prostaglandin E,

For example, -j) are identified by the following Constitutions V or VI:

(V) (VI)

The constitutions of PGF ₂ and PGE ₂ , as members of the PGp group, correspond to those of the formulas V and VI with a cis double bond between the carbon atoms in 5- and 6-

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Position. Compounds in which the double bond between the carbon atoms in the 13- and 14-position is replaced by ethylene in members of the PG - group are known as dihydro-prostaglandins, for example dihydroprostaglandin-F _la (dihydro-PGF _la ) or dihydro -prostaglandin-E ₁ (Dihydro-PGE ₁ ), known.

Will continue to have one or more methylene groups

into those in the 12-position of the alicyclic ring of the prostaglandins Bound aliphatic group switched on or omitted from it, so these compounds are in agreement with the usual organic nomenclature rules as homo-prostaglandins (Methylene group switched on) or nor-prostaglandine (methylene group omitted) known, and at Including or omitting more than one methylene group, the number is indicated by di-, tri- etc. in front of the prefix "homo" or "nor" is displayed.

It is generally known that prostaglandins have pharmacological properties, for example they stimulate smooth muscles and have blood pressure _levels

lowering, diuretic, bronchodilator and antilipolytic Effects, and further inhibit platelet aggregation and gastric acid secretion; accordingly they are suitable for the treatment of high blood pressure, thrombosis, asthma and gastric and intestinal ulcers, for inducing labor and abortions in pregnant female mammals or pregnant women, for the prevention of atherosclerosis and as Diuretics. There are fat-soluble substances that are obtained in very small quantities from various animal tissues

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Secrete prostaglandins in the living organism are available.

For example, PGE and PGA compounds have an inhibitory effect on gastric acid secretion and can accordingly used to treat stomach ulcers. They also inhibit the epinephrine induced Release of free fatty acids, therefore lower the free fatty acid level in the blood and are therefore valuable for the prevention of arteriosclerosis and hyperlipemia. PGE- inhibits the Platelet aggregation and also removes blood clots and prevents thrombosis. Have PGE and PGF compounds a stimulating effect on smooth muscles and increase intestinal peristalsis; a therapeutic use in post-operative hay and as a laxative, these effects are indicated. PGE and PGF compounds can furthermore as a means of stimulating labor, as a means of interrupting pregnancy in the first and second trimester, in the expulsion of the placenta after labor and, since they control the sexual cycle of female mammals, as oral contraceptives Funds are used. Occupy PGE and PGA connections.

vasodilator and diuretic effects and, because they increase cerebral blood flow, are valuable as agents for the amelioration of patients suffering from cerebral vascular disease and also in the treatment of asthmatic patients because of their bronchodilator effects.

Extensive research has been carried out in the last ten years in order to find, among other things, new products that enhance the pharmacological properties of the "naturally occurring ¹ *

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Prostaglandins or one or more of these properties to an increased extent or. Hitherto unknown pharmacological Have properties. Ajifgrund from research and experimentation it has now been found that by introducing a chlorine atom on the carbon atom at the end of the 12-position of the prostaglandins E, F and A as well as certain analogs thereof bound side chain receives new prostaglandin analogs, which, as disclosed below, possess certain advantageous pharmacological properties over the "naturally occurring" prostaglandins.

Thus, the present invention provides new prostaglandin analogs of the general formula:

! 0OR

(VII)

HO R ¹

[where A stands for a grouping of the formula IV as indicated above or a grouping of the formula:

respectively.

(VIIIA) (VIIIB)

R represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 12 (preferably 1 to 4) carbon atoms (advantageously methyl) and η for zero or an integer

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from 1 "to 3 inclusive (preferably 2), R, R, R, R and R can be the same or different and each for one Methyl or ethyl group or preferably a hydrogen atom

"" IO -7

are, and (i) if or more represented by R, R and R one of a methyl or ethyl, X is ethylene, (ie, -CH ₂ CH ₂ -), or preferably cis-vinylene (d _o h -CH = CH. -) and Y is trans-vinylene or X and Y are each ethylene, and (ii) when R, R and R each represent a hydrogen atom, X is ethylene or preferably cis-vinylene, Y is ethylene or preferably trans Vinylene and · η stands for an integer of 1 Ms 3 including (preferably 2)] and cyclodextrin clathrates of such acids and esters and, if R stands for a hydrogen atom, nontoxic salts of such acids are available. The hydroxyl group bonded to the C-15 carbon atom of the formula VII preferably has the α configuration, and the hydroxyl groups bonded in the 11-position of the cyclopentane rings of the formulas VIIIA and VIIIB also have the α configuration.

The present invention relates to all compounds of the general formula VH in the "naturally occurring" Form or the form enantiomeric thereto, or mixtures thereof, in particular in the racemic form, consisting of equimolar Mixtures of the naturally occurring and the enantiomeric form.

As those skilled in the art will readily appreciate, the compounds represented by general formula VII have at least three Chirality centers, which are identified as 8 and 12, group A and alicyclic ring carbon atoms

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on the C-15 carbon atom bearing a hydroxyl group are located. Other centers of chirality emerge when the alicyclic group A on the carbon atom in the 11-position is a hydroxyl group (i.e. when the ring has the formula YEHB has) or hydroxyl groups in the 9- and 11-positions (i.e. when the ring has the formula VHIA.), and further centers of chirality occur in the 16- and 17-positions,

2 "= 5 4 5

when at least one of the symbols R, R, R and R is methyl or Represents ethyl group. It is well known that the existence of chirality leads to the existence of isomerism. All of them Compounds of the general formula VII, however, have such a configuration that those identified as 8 and 12 in FIGS Side chain positions attached to the ring carbon atoms. th are in trans position to each other. Accordingly are all isomers of the general formula VII and mixtures thereof in which these side chains are in the trans configuration on the ring carbon atoms are bonded in the 8- and 12-position and which, as shown, carry a hydroxyl group in the 15-position, as to be considered falling under the framework of general formula VII.

According to a feature of the present invention, the prostaglandin analogs of the general formula VII, wherein A represents a grouping of the formula VIIIA, R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, preferably methyl, X is ethylene or cis-vinylene and Y is trans-vinylene or X and Y are each ethylene and the other symbols have the meanings given above, i.e. compounds of the general formula:

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- 8th -

)H

(VIIA)

HO

(where R stands for a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, preferably methyl, X ^f for ethylene or cis-vinylene and Y 'for trans-vinylene or X' and Y ¹ each stand for ethylene and the other symbols are those given above Have meaning) according to a process which

consists in that the groups -OR in a cyclopentane derivative the general formula:

.7

(ix)

(CH ₂ J _n CH ₂ Cl

wherein R is a 2-tetrahydrofuranyl group, a 1-ethoxyethyl group or preferably a 2-tetrahydropyranyl group which is unsubstituted or substituted by at least one alkyl group and the other symbols are the ones given above

Have meaning hydrolyzed to hydroxyl groups. The -OR groups in compounds of the general formula IX can be by mild hydrolysis with an aqueous solution of an organic Acid, e.g. acetic acid, or with a dilute inorganic one

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Acid, for example hydrochloric acid, for example by treating compounds of the general formula TX with the aqueous solution of an organic acid, for example acetic acid, or with a dilute aqueous inorganic acid, for example hydrochloric acid, in the temperature range from room temperature to 60 ^° C. (preferably at a temperature ' below 45 ° C.) in the presence of a water-miscible organic solvent, for example a lower alkanol or tetrahydrofuran, converted into hydroxyl groups. . - '

Compounds of the general formula IX are from one

Compound of the general formula:

(χ)

(where the various symbols have the meanings given above have) by chlorination for two hours at room temperature with thionyl chloride in an inert organic solvent, for example chloroform, in the presence of a base, for example pyridine, can be prepared «

Compounds of the general formula IX can also be prepared from compounds of the general formula X by tosylation with subsequent chlorination. The tosylation is expediently effected by means of tosyl chloride in an inert organic solvent, for example methylene chloride, in the presence of a base, for example triethylamine, at a temperature between ⁰ ° C. and room temperature. The chlorination can after itself

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known methods, for example with lithium chloride, in Ν, Ν-dimethylformamide can be carried out at room temperature. The term "methods known per se", as used in the present patent specification, means methods which have already been used or described in the chemical literature.

Compounds of the general formula X can be obtained by hydrolysis under alkaline conditions of a compound of general formula:

(XI)

(where R is an alkylcarbonyl group having 2 to 5 carbon atoms, for example an acetyl group, and the rest Symbols have the meaning given above). The hydrolysis under alkaline conditions can be, for example with a 1 molar amount of anhydrous potassium carbonate in an anhydrous alkanol with 1 to 4 carbon atoms, preferably absolute methanol, perform, whereby one compound of the general formula X, in which R is an alkyl group having 1 to 4 carbon atoms, or with one aqueous alkali, e.g. sodium or potassium, hydroxide or carbonate solution in the presence of a water-miscible solvent, e.g. tetrahydrofuran or an alkanol having 1 to .carbon atoms, whereby a compound of the general

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nv formula X, in which R represents a hydrogen atom, is obtained.

Compounds of the general formula XI can be prepared by reacting a compound of the general formula:

(in which the various symbols have the meanings given above) with a dihydropyran, dihydrofuran or ethyl vinyl ether in an inert solvent, e.g. methylene chloride, in the presence of a condensing agent, e.g. p-toluenesulphonic acid, produce.

Compounds of the general formula XII can be obtained by selective acylation of a compound of the general formula:

3 ^COOr6 (XIIIA)

(CH ₂ J _n CH ₂ OH 5

(where the various symbols have the meanings given above) with a corresponding acyl chloride or acid 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, e.g. at -40 C to O C, with the hydroxyl group at the end of the

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- 12 -

side chain bound in the 12-position converted into a group -OR will.

According to a further feature of the invention, the prostaglandin analogs of the general formula VII, wherein A is a grouping of the formula VIIIB, R for a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, X for Ethylene or cis-vinylene and Y stands for trans-vinylene or X and Y each stand for ethylene, i.e. compounds of the general formula:

(VIIB)

(in which the various symbols have the meanings given above) according to the above for the preparation of compounds of general formula VIIA described reaction sequence can be prepared, but one of compounds of the general formula:

(XIIIB)

(CH ₂ ) _n CH ₂ OH

where the various symbols have the meaning given above.

The procedures described above can be carried out by the 609850/1106

- 13 -

Reaction sequence shown schematically in panel A below

reproduce:

TABLE A

OH

(XII)

COOR

CH ₅ J CH ₉ QR

(XIIA)

(XIA)

RO R
(X)

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OR

OOR

(CH ₂ J _n CH ₂ OH

(XA)

2622Λ16

TABLE A (CONTINUED)

(IX)

where Z is C

,-OH

(XA)

X '

COOR

R "

(IXA)

(CH) CH Cl 2 η 2

(VIIB)

or C = O and the other symbols the

have the meaning given above.

The compounds of the general formula XIII used as starting materials in the reaction sequence described above can be obtained by a process which consists in that

one the groups -OR in a cyclopentane derivative of the general Formula:

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- 15 -

(XIV)

wherein R is a 2-tetrahydrofuranyl group, a 1-ethoxyethyl group or preferably a 2-tetrahydropyranyl group which is unsubstituted or substituted by at least one alkyl group and the other symbols have the meanings given above, hydrolyzed to hydroxyl groups and, if desired, the Carboxyl group in an alkoxycarbonyl group with 2 to 5 carbons

converts material atoms. The -OR groups in compounds of the Formula XIV can be prepared by mild hydrolysis, as above for the conversion of compounds of general formula IX into prostaglandin analogs of the general formula VIIA described, convert into hydroxyl groups. The conversion of the carboxyl group to alkoxycarbonyl by treatment with an appropriate diazoalkane in a suitable inert solvent, e.g. Diethyl ether.

Compounds of the general formula XIV, wherein Z

C <L and the remaining symbols have the meaning given above

can be obtained by hydrolysis under alkaline conditions of a compound of the general formula:

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- 16 -

(XV)

wherein R represents a lower alkyl group, preferably having 1 to 4 carbon atoms, and R represents an alkylcarbonyl group to 5 carbon atoms, for example an acetyl group, and the other symbols have the meaning given above. The hydrolysis under alkaline conditions can be carried out, for example, by means of aqueous alkali, e.g. sodium or Potassium, hydroxyl or carbonate solution in the presence of a water-miscible organic solvents, e.g. a lower alkanol or tetrahydrofuran.

If desired, compounds of the general

Formula XIV, in which Z is CX and X ^{1 is} cis-vinylene

and the other symbols have the meanings given above, by reduction into corresponding compounds of the general formula XIV, in which X ^! for ethylene and Y 'stands for trans-vinylene or ethylene, and compounds of the general formula XIV, in which X ^{1 stands} for cis-vinylene and Y' stands for trans-vinylene, can also be converted into corresponding compounds of the general formula XIV, by reduction where both X ^f and Y ¹ stand for ethylene. The reductions are expediently carried out by catalytic hydrogenation in the presence of a hydrogenation catalyst and in the presence of an inert one

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organic solvent, for example a lower alkanol, for example methanol or ethanol, at laboratory temperature and normal or elevated pressure, for example at a hydrogen pressure of atmospheric pressure to 15 kg / cm. If only the cis-vinylene group X ^{1 is to be} reduced and a trans-vinylene group Y ¹ remains unaffected, the hydrogenation catalyst can be, for example, palladium-carbon or palladium black, the hydrogenation being followed closely ^{in order to avoid a reduction in the trans-vinylene group Y 1.} If the cis-vinylene group X ^{1 is to be} reduced and at the same time Y ¹ in the general formula XIV is ethylene, then platinum dioxide can also be used as a hydrogenation catalyst. If X ¹ as cis-vinylene and Y 'as trans-vinylene are to be reduced to compounds of the general formula XIV, in which both X ¹ and Y ^{f are} ethylene, then platinum oxide is a suitable catalyst for this purpose, and the hydrogenation is continued until twice the molar amount of hydrogen has been consumed.

The cyclopentane derivatives of the formula XIV, where Z is C = O and the other symbols have the meaning given above, one sets after for the conversion of a hydroxyl group in the 9-position a prostaglandin compound into an oxo group methods known per se, for example by means of a chromic acid solution (e.g. from chromium trioxide, manganese sulfate, sulfuric acid and Obtained water) or Jones reagent, from compounds of the

^ OH

Formula XIV, in which Z stands for CnT and the remaining symbols

^ H

have the meaning given above.

Compounds of the general formula XV, wherein Y ^{1 is}

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trans-Vinylen stands and the various other symbols the Have the meaning given above are by reacting a compound of the general formula:

.IT

OOR ¹⁰

(CH ₂ ) _n CH ₂ OR ^S 5

(XVI)

(in which the various symbols have the meanings given above) with a dihydropyran, dihydrofuran or ethyl vinyl ether in an inert organic solvent, e.g. methylene chloride, in the presence of a condensing agent, e.g. p-toluenesulphonic acid, manufacturable.

Compounds of the general formula XV, in which X ¹ and Y ¹ each represent ethylene and the various other symbols have the meanings given above, can be prepared by adding a compound of the general formula XVI (in which the various symbols have the meanings given above) a compound of the general formula:

COOR

10

(XVII)

(in which the various symbols have the meaning given above), which is then reduced with a dihydropyran,

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Dihydrofuran or ethyl vinyl ether in an inert organic solvent, for example methylene chloride, in the presence of a condensing agent, for example p-toluenesulfonic acid, to give a compound of the general formula XV, in which X ^! and Y 'each stand for ethylene and the other symbols have the meaning given above, can be implemented.

The reduction of compounds of the general formula XVI is expediently carried out by hydrogenation in the presence a hydrogenation catalyst, for example palladium carbon, palladium black or platinum dioxide, in the presence of a inert organic solvent, for example a lower alkanol, e.g. methanol or ethanol, at laboratory temperature and normal or increased pressure, e.g. with hydrogen pressure

from atmospheric pressure to .15 kg / cm ».

Compounds of the general formula XVI in which R stands for a hydrogen atom and the various other symbols have the meaning given above, can be reduced by reducing a compound of the general formula:

? ^r11

/ Nx ^ 'N / ^ cOOR ¹⁰ (XVIII)

(where the various symbols have the meanings given above), with the carbonyl group in the 15-position in Hydroxymethylene, i.e. -CH- is converted. The reduction will

OH

6 0 9 8 5 0/1 IO J3
- 20 -

zv / eckmäßig with excess sodium borohydride in a lower alkanol, for example methanol, at a low temperature, preferably at -30 ⁰ C to -6O ⁰ C, or zinc borohydride in a suitable inert organic solvent, for example 1,2-dimethoxyethane, at a temperature from -10 C to 10 ⁰ C carried out. The product of the general formula XVI, in which R represents a hydrogen atom, thus obtained by reducing a compound of the formula XVIII, represents a mixture of isomers in which the hydroxyl group in the 15-position has the α- or β-configuration. If desired, the isomer with the hydroxyl group in the α-configuration can be separated from the isomer with the hydroxyl group in the β-configuration by column chromatography of the mixture over silica gel. The separated isomers can be used in the processes described above to obtain cyclopentane derivatives in which the 15-position hydroxyl has the α or β configuration.

Compounds of the general formula XVI (in which R stands for a methyl or ethyl group and the various other symbols have the meanings given above) can be obtained by reacting a compound of the formula XVIII (in which the different symbols have the meanings given above) with a Grignard reagent of the general formula:

R ¹² MgHaI (XIX)

12th
where R stands for a methyl or ethyl group and Hal stands for a bromine or iodine atom, and hydrolysis of the organomagnesium complex formed by treatment with water or an aqueous acid or ammonium chloride solution.

The reaction is preferably in diethyl ether at a

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Temperature from -1O ⁰ C to 10 ⁰ C carried out.

Compounds of the general formula XVIIi can be prepared by reacting a compound of the general formula;

.13

_{χχ)

(wherein X, R and R have the meanings given above and R represents a hydrogen atom or an alkylcarbonyl group with 2 to 5 carbon atoms, for example an acetyl group) with the sodium derivative of a dialkylphosphonate compound the general formula:

R ² R ⁴ .
¹ ^ -C C (CH ₂ J _n CH ₂ OR ⁹ (XXl)

I 3 ς

OOR ^J R ^D

ρ "5 L 5 Q

wherein R, R, R, R, R and η have the meaning given above 14th

and R stands for a lower alkyl group, preferably with 1 to 4 carbon atoms, for example a methyl or ethyl group. The reaction is preferably carried out by suspending sodium hydride in an inert solvent, for example tetrahydrofuran or 1,2-dimethoxyethane, and adding the dialkyl phosphonate of the formula XXI. The resulting sodium derivative of dialkyl phosphonate can then be reacted with the compound of the formula XX for one to five hours at room temperature, the trans-enone compound of the formula XVIII being formed stereospecifically. Adding the appropriate compounds of the formula XVIII, wherein R is a

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Alkylcarbonyl group, you can then obtain the compounds of the formula XX thus obtained, in which R * is a hydrogen atom, with an appropriate acylation agent, for example an acid halide derived from an alkanoic acid having 2 to 5 carbon atoms, for example acetyl chloride, in the presence treat of pyridine in methylene chloride.

The compounds of the general formula XX used as starting materials in the procedures described above, where R ^ stands for a hydrogen atom, R and R the above-

have given meaning and the group OR the α-configuration (as shown below in the general formula XXA) are in turn selected from the known compounds of the formula XXII below [the racemic form of the compound of formula XXII is given in J. Amer. Chem. Soc. £ 1, 5675 - (1969) and the naturally occurring Configuration of the compound of formula XXII in J. Amer. Chem. Soc. 92, »397 (1970)] can be produced by a method the reaction sequence shown below in panel B is represented:

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TABLE B

OAc

(XXII)

OAc

I.
OH

(XXTV)

OH

Or ⁹

(XXVI)

(XXIII)

¹ 9 OR *

(XXV)

+ (C ₆ H _{5) 3} P = CH (CH ₂ J ₃ COOH

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ir

TABLE B (CONTINUED)

(XXVI)

! 0OH

(XXVIII)

\ .. ΛΛ

X '

COOR

10

α in
where R and R have the meaning given above and Ac stands for the acetyl group, ie -COCH ,,.

Compounds of the formula XXIII can be prepared by hydrolysis of compounds of the formula XXII under alkaline conditions produce. Compounds of formula XXIV are acetylated by compounds of formula XXIII under mild conditions obtainable and by reaction with a dihydropyran, dihydrofuran or with ethyl vinyl ether in an inert Solvents such as methylene chloride in the presence of a condensing agent such as p-toluenesulfonic acid in compounds

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- 25 -

transferable to formula XXV. Compounds of formula XXVI can be prepared by diisobutylaluminum hydride in toluene at -60 ⁰ C for about 15 minutes long reduction of compounds of formula XXV. Dimsyl anion previously prepared from sodium hydride and dimethyl sulfoxide is reacted with (4-carboxybutyl) triphenylphosphonium bromide to form (4-carboxybutylidene) triphenylphosphorane. This compound is mixed with a compound of the formula XXVI and the mixture is allowed to react in dimethyl sulfoxide for 2 hours at room temperature, which gives a compound of the formula XXVII.

If desired, compounds of the formula XXVII can be reduced to compounds of the formula XXVIIA. The reduction can expediently be carried out as described above for the reduction of compounds of the formula XVI to compounds of the formula XVII Carry out hydrogenation in the presence of a hydrogenation catalyst. Compounds of the formulas XXVII are then used or XXVIIA with a diazoalkane in a suitable inert solvent, e.g. diethyl ether, to give compounds of the formula XXVIII at. Compounds of the formula XXVIII can be prepared under mild and neutral conditions, e.g. with chromium trioxide / pyridine complex and at moderately low temperature, oxidize to compounds of formula XXA. Such oxidation conditions are preferred for selective formation of the formyl group and avoid excessive oxidation of the secondary alcohol group.

The compounds of the general formula XX used as starting materials in the procedures described above, in which X ^f for cis-vinylene and R ^J for an alkylcarbonyl group having 2 to 5 carbon atoms, for example an acetyl group,

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ο 2.0
and R and R have the meaning given above and the group OR has the α-configuration (as shown below in the general formula XXB) are in turn made up of compounds of the general formula XXVIII, in which X ^{f stands} for cis-vinylene, per se known methods can be prepared by the reaction sequence shown below in Table C:

TABLE C

(XXVIII) (X ¹ = cis vinylene)

COOR

10

COOR

10

(XXXI)

(XXB)

wherein R and R have the meaning given above and R is an alkylcarbonyl group having 2 to 5 carbon atoms, for example an acetyl group.

Compounds of the formula XXIX can be obtained by reacting a compound of the formula XXVIII with trimethylchlorosilane in

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an inert organic solvent, e.g. B. methylene chloride, in the presence of a base, e.g. B. pyridine or a tertiary amine, at low temperature, e.g. B. at -30 ⁰ C to O ⁰ C, produce. Compounds of Formula XXX. are by reacting a trimethylsilyl ether of the formula XXIK with the corresponding acyl chloride or acid anhydride in an inert organic solvent, e.g. B. methylene chloride, in the presence of a base, e.g. B. pyridine or a tertiary amine, at low temperature, e.g. B. at 0 ⁰ C to 30 ⁰ C, can be produced. Compounds of the formula XXXI can be prepared by treating a compound of the formula XXX by methods known per se for splitting off a trimethylsilyl group, for example an acid treatment; preferably one does not use a strong acid to avoid the danger

q
exclude a split of the group R. The compounds of the formula XXXI can be oxidized to compounds of the formula XXB under mild and neutral conditions, for example with chromium trioxide / pyridine complex or Jones reagent and at a moderately low temperature. Such oxidation conditions are preferred for selective formation of the formyl group and avoid excessive oxidation of the secondary alcohol group.

The compounds of the general formula XX which can be used as starting materials in the processes described above, in which X 'is cis-vinylene, R ^, R ¹⁰ and R ¹ ^ are the above

have given meaning and the group OR the ß-configuration can in turn be prepared by the reaction sequences shown in Tables B and C, but under Replacement of the compounds of the formula XXII by compounds of the formula:

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o-v

(XXXII)

OAc

wherein Ac has the meaning given above.

A method for the preparation of the bicyclooctane starting materials of the formula XXXII, in which Ac has the meaning given above using known procedures can be represented by the sequence of reactions shown schematically in Table D below (see, E.J. Corey and Shiro Terashima, Tetrahedron Letters, No. 2, Pp. 111-113, 1972):

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X)

TABLE D.

OH

(XXXIII)

(XXXIV)

NJ /

(XXXV) (XXXVI)

OÄC

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where Ac has the meaning given above and Ts the tosyl group represents. The various reactions shown in Table D above can be carried out using methods known per se. Compounds of the formula XXXV can be prepared by reacting compounds of the formula XXXIV with tetraethylammonium acetate produce.

The compounds of the general formula XXI, in which R,

> 5 L. 5 Q ~ \ L
R, R, R, R, R and η have the meaning given above, can by reacting a compound of the general formula:

R ¹⁶ O ₉ -CC- (CH ₉ ) CH ₀ OR ⁹ (XXXVII)

2 ^ 459
(in which R, R, R, R, R and η have the meaning given above and R stands for a lower alkyl group with preferably 1 to 4 carbon atoms, with the corresponding di-lower alkyl-a-lithiomethylphosphonate in an inert organic solvent, e.g. tetrahydrofuran, at lower Temperature, for example from -78 ° to -50 ⁰ C, are produced.

Compounds of the general formula XXXVIT, wherein the different symbols have the meanings given above, can be converted into a compound of the general formula:

R ² R ⁴

16 IIR ° OC-C — C— (CH) CH.OH (XXXVIIl)

£ * XJl £ *

(in which the various symbols have the meanings given above) with a dihydropyran, dihydrofuran or with ethyl vinyl ether in an inert organic solvent, e.g. .Methylene chloride, in the presence of a condensing agent, e.g.

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p-toluenesulfonic acid.

Compounds of the general formula XXXVIII can be obtained by esterifying a compound of the general formula:

2 4
R ^Z R ⁺

HOC-C G (CH ₀ ) CH ₀ OH (XXXIX)

U ₃ I ₅ ^{2n 2}

OR ^J R ^D

wherein the various symbols have the meaning given above, after for the esterification of the carboxylic acid group Hydroxyalkylcarboxylic acid to produce methods known per se.

The compounds of the general formula XXXIX can be used in the preparation of compounds of the general formula XXXVIII can be used in the racemic or in the optically active form. As compounds of the general formula XXXIX, which can be used according to the present invention, include 4-hydroxy-n-butanoic acid, 5-hydroxy-n-pentanoic acid, 6-hydroxy-n-hexanoic acid, 6-hydroxy-2-methyl-nhexane acid, 6-hydroxy-2-ethyl-n-hexanoic acid, 6-hydroxy-2,2-dimethyl-n-hexanoic acid, 6 ~ hydroxy-3-methyl-n-hexanoic acid, 6 ~ hydroxy-3-ethyl-n-hexanoic acid. and 7-hydroxy-n-heptanoic acid.

The compounds of the general formula XXXIX are known per se for the preparation of hydroxyalkylcarboxylic acids Methods available. For example, you can use 6-hydroxy-2-methyl-n-hexanoic acid prepare according to the reaction sequence shown below in table E:

608850/1106
- 32 -

TABLE E.

+ CH ₃ CH

CH.

^ Br (CH ₃ J ₄ C

0OC ₂ H ₅

COOC _O H

0OH

COOH

HO (CH ₂ J ₄ CHCOOH

The various reaction steps shown in Table E can be carried out according to methods known per se will.

According to a further feature of the present invention

can prostaglandin analogs of the general formula VII,

12 3

wherein R, -R and R ^ each for a hydrogen atom, A for one Grouping of the general formula VIIIA or VIIIB and η stands for an integer from 1 to 3 inclusive and the rest Symbols have the meanings given above, i.e. compounds of the general formula:

■ ⁽ \ AA

COOR

CH ₂ J _n , CH ₂ Cl

(VIIC)

6 0 9 8 5 0/1106

(where n ^{f stands} for an integer from 1 to 3 inclusive and the other symbols have the meanings given above) by mild hydrolysis of a compound of the general formula:

OOR
(CH ₂ ) _n , CH ₂ Cl _(XL)

17th
wherein R stands for an unsubstituted or substituted by at least one alkyl group 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group or a 1-ethoxyethyl group and the other symbols have the meanings given above. The mild hydrolysis can be carried out using the procedure described above for the conversion of compounds of general formula IX to compounds of general formula VIIA.

Compounds of the general formula XL, in which the various symbols have the meanings given above, are by converting a compound of the general formula:

'COOR

(XLI)

OR

(in which the various symbols have the meanings given above) with a compound of the general formula:

609850/1106
- 34 -

M-CHy-C- (CH ₉ ) .CH ₀ Cl (XLII)

4 5
in which R, R and n ^{T have} the meaning given above and M stands for a magnesium halide group, can be prepared. The reaction can be 10 minutes to 2 hours in the presence of an inert organic solvent, for example tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, and preferably at low temperature, eg below ⁰ ° C are performed. The reaction mixture is then hydrolyzed by treatment with water or an aqueous acid or ammonium chloride solution, which gives compounds of the general formula XL.

Compounds of the general formula VIIC can be prepared directly by reacting a compound of the general formula:

(XLIII)

(in which the various symbols have the meanings given above) with a compound of the general formula XLII, such as described above for the preparation of compounds of the general formula XL from compounds of the general formula XLI, and subsequent hydrolysis of the reaction mixture, as for the preparation of compounds of the general formula XL described, produce.

609850 / IJ06

The esters of the prostaglandin analogues of the general formula VII, i.e. compounds of the general formula VII, in which R stands for a straight-chain or branched alkyl group with 1 to 12 carbon atoms and the various other symbols Have the meaning given above, are by reaction of the corresponding acids of the general formula VII, wherein R is represents a hydrogen atom, with (i) the corresponding diazoalkane in a suitable inert solvent, e.g. diethyl ether, (ii) the corresponding alcohol in the presence of dicyclohexylcarbodiimide as a condensing agent or (iii) the corresponding alcohol after formation of a mixed anhydride by adding a tertiary amine and then a pivaloyl halide or an arylsulfonyl or alkylsulfonyl halide (see British Patents Nm. 1,362,956 and 1,364,125 of Applicant) available.

According to a further feature of the present invention, prostaglandin analogs of the general formula VII, in which A stands for a grouping of the formula IV and the other symbols have the meanings given above, produce by a process, which is characterized by the fact that the alicyclic Ring A of a compound of the formula VII in which A stands for a grouping of the formula VIIIB and the remaining symbols have the meaning given above, according to methods known per se, for example by using the compound of the formula VII, in which A stands for a grouping of the formula VIIIB and the other symbols have the meanings given above, using the aqueous solution of an organic or inorganic acid of higher than that for the hydrolysis of compounds of the

609850/1106

- 36 -

concentration used in general formula IX, e.g. in-hydrochloric acid, if desired in the presence of cupric chloride or acetic acid, and with heating to a temperature of 30-60 ° C dehydrated, converted into an alicyclic ring A of the formula IV. . '

If desired, you can make appropriate PGA connections " direct 'to represent the simultaneous hydrolysis and dehydration of compounds of the general formula IXA or XL, where Z stands for C = O and the remaining symbols are those given above Have importance to perform under acidic conditions, as above for the conversion of prostaglandin-analog of the general formula VII, in which A stands for a grouping of the formula VIIIB and the other symbols have the meanings given above have, in a corresponding prostaglandin analogous to the general Formula VII, in which A is a grouping of the formula IV j, specified.

The procedures previously described can be followed by the reaction sequence illustrated in Table F below be reproduced:

609850/1106
- 37 -

TABLE F.

OR ¹⁷ CHO (XLI)

OOR

OR

(XL)

Ohh O

(XLIII)

COOR - '' \ _χ ΛΛ

COOR

_n , CH ₂ Cl

OH

COOR "

(CH ₂ ) _n CH ₂ Cl

(VIIE)

609850/1 106 - 38 -

TABLE F (CONTINUED)

.7
OR

(IXA)

I ^ V

OH R ^J

(VHF)

(XLA)

COOR-

_n , CH ₂ Cl

(VIIG)

Connector genes of the general formula XLI or XLIII,

17th

wherein the group -OR or the hydroxyl group has the α-configuration possesses, i.e. compounds of the general formula:

Zv \

0OR

(XLIV)

ι ίο \

OR CHO

IB
(where R "represents a hydrogen atom or a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group or a 2-tetrahydropyranyl group which is unsubstituted or substituted by at least one alkyl group

609850/1106
- 39 -

l-ethoxyethyl group and Z, X, Y and R are the ones given above Have meaning), can be prepared by adding the grouping -CH = CH-CHpOH of a compound of the general Formula:

COOR

(XLV)

(in which the various symbols have the meanings given above) for the oxidation of an allyl alcohol group to the Formyl radical oxidizes to -CH = CH-CHO, methods known per se, where a compound of the general formula:

COOR

(XLIVA)

L ^ib

(in which the various symbols have the meanings given above), and optionally when X stands for cis-vinylene, the cis-vinylene group to ethylene and optionally the C-i-z-Cn λ-trans-vinylene group reduced to ethylene.

Advantageously, the oxidation of compounds of the formula XLV to compounds of the formula XLIVA with manganese dioxide, for example in an inert organic solvent such as acetone or methylene chloride at room temperature carried out. The oxidation of compounds of the formula XLV in an inert organic solvent, e.g. diethyl ether,

609850/1106

- 40 -

can also be achieved with chromic acid solution, and: d if Z for

. OH
C ', this grouping is simultaneously converted into a carbonyl group with this reagent, a compound of the formula XLIVA, in which Z stands for C = O, being formed.

Compounds of the formula XLIVA, in which X is cis-vinylene, can be prepared by catalytic hydrogenation in the presence of a hydrogenation catalyst, for example palladium carbon, palladium black or platinum dioxide, and in the presence of an inert organic solvent, for example a lower alkanol, for example methanol or ethanol, at laboratory temperature and normal or elevated pressure, for example at a hydrogen pressure of atmospheric pressure to 15 kg / cm2, into corresponding compounds of the formula XLIV, in which X and Y are ethylene. If only the Cc-Cg-cis-vinylene group of a compound of the formula XLIVA is to be reduced and the C ₁ ^ -C-, λ-tr ans-vinylene group remain unaffected, the hydrogenation is preferably carried out in the presence of a weak hydrogenation catalyst, for example palladium on barium sulfate or Lindler catalyst (Pd / CaCO ^ / PbO), carried out in the presence of an inert organic solvent, for example a lower alkanol or ethyl acetate at room temperature.

If X in formula XLIVA stands for cis-vinylene, then compounds of the formula XLIV, in which X for cis-vinylene and Y for Ethylene is available through selective reduction of the carbonyl conjugated Double bond in compounds of the general formula XLIVA by methods known per se, for example by means of lithium pent-1-yne hydrocuprate (LiCuH-CSC-CJHY) [cf. J. Amer. Chem. Soc ,, 96, 3686 (1974)].

609850/1 106
- 41 -

Ί R compounds of the formula XLIV, where R is an unsub-

substituted or by at least one alkyl group substituted 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group or a 1-ethoxyethyl group, ie compounds of the general formula XLI obtained by the above process, can be obtained by mild hydrolysis with an aqueous solution of an organic acid, e.g. acetic acid, or with a dilute inorganic acid, for example hydrochloric acid, advantageously in the presence of a water-miscible organic solvent, for example a lower alkanol or tetrahydrofuran, for example by treating compounds of the formula XLI with the aqueous solution of an organic acid, for example acetic acid, or with a dilute inorganic acid, for example dilute hydrochloric acid, optionally in the presence of tetrahydrofuran or methanol, in the temperature range from room temperature to 60 ⁰ C (preferably at a temperature below 45 ° C), in appropriate

18 compounds of the formula XLIV, in which R stands for a hydrogen atom, i.e. compounds of the general formula XLIII, convict.

Compounds obtained by the above process of the general formula XLIV, in which R represents a hydrogen atom, one can use the above for the conversion of compounds of the general formula VII, in which R stands for a hydrogen atom and the other symbols have the meanings given above, in corresponding compounds of the general formula VII, in which R represents a straight-chain or branched alkyl group with 1 to 12 Carbon atoms, 'methods described in corresponding compounds of the above formula, wherein R is a straight-chain

609850/1106
- 42 -

or branched alkyl group having 1 to 12 carbon atoms stands, convict.

Compounds of the general formula XLIV, wherein Z is

18th
C = O and R represents a hydrogen atom, an unsubstituted or substituted by at least one alkyl radical 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group or a 1 · ethoxyethyl group and R, X and Y have the meaning given above, are prepared by a process which characterized in that a compound of the formula XLIV, wherein Z is a group of the formula CC and Y

> H stands for trans-vinylene, i.e. a compound of the general

Formula:

(XLIVB)

(where R stands for an unsubstituted or by at least one Alkyl radical substituted 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group or a 1-ethoxyethyl group and R and X have the meaning given above) for the conversion a hydroxyl group in the 9-position of a PGF connection in oxidizes an oxo radical per se known methods, a compound of the general formula:

609850/1106

- 43 -

* ^^ COOR (XLIVC)

CHO

(in which R, R and X have the meaning given above),

19 optionally the group OR to form a hydroxyl radical

hydrolyzed, whereby a compound of the general formula:

^C00R (XLIVD)

(in which R and X have the meanings given above), and optionally when X is cis-vinylene, the cis-vinylene group to ethylene and optionally the C-, ^ -C-, .- trans-vinylene group reduced to ethylene.

The oxidation of a compound of Formula XLIVB to convert the 9-position hydroxyl to an oxo group and thereby to obtain a compound of the formula XLIVC is carried out under mild and neutral conditions, for example by means of Collins reagent or Jones reagent performed at a moderately low temperature, e.g. below room temperature.

To obtain a compound of the formula XLIVD, can

19th
the OR group of a compound of the formula XLIVC

mild hydrolysis with the aqueous solution of an organic acid or with a dilute inorganic acid, as above for

609850/1106

- 44 -

the conversion of compounds of the general formula XLIV, in which R has the same meaning as R, into corresponding ones

η ο

Compounds of the formula in which R is a hydrogen atom is, described, convert into a hydroxyl radical.

If X in formula XLIVD stands for cis-vinylene, you can this group and / or the C-, ^ -C-, Λ-trans-vinylene group to the top for the conversion of such groups in compounds of the formula XLIVA to ethylene to ethylene reduce, with compounds of the formula XLIV being formed.

The conversion of compounds of the general formula XLV into compounds of the general formula XLIV is schematic reproduced in panel G:

609850/11 Often

TABLE G

P ^H

_0H (XLVA)

COOR

CHO

OH (XLIVE)

(XLVD)

COOH

, CHO

¹ 19th
OR (XLIVF)

COOR ¹

CHO

OR ¹⁹ (XLIVG)

COOR

OH (XLIVE)

CHO

OH (XLIVH)

609850/1 106 - 46 -

TABLE C- (CONTINUED)

COOH

COOR ¹

COOR

(XLIVL)

CHO

(XLIVM)

wherein R ^{1 stands} for a straight-chain or branched alkyl group having "up to 12 carbon atoms and the various other symbols have the meanings given above.

Compounds of the general formula XLVB are obtained by reacting compounds of the general formula XLVA with (i) Diazoalkane compounds, e.g. diazomethane, (ii) alcohols in the presence of dicyclohexylcarbodiimide as a condensing agent or

609850/1 106 - 47 -

(iii) alcohols after formation of a mixed acid anhydride by the addition of a tertiary amine and then a pivaloyl halide or of an arylsulphonyl or alkylsulphonyl halide (see British patents Nm. 1 362 956 and 1 364 125 of the applicant) available.

Compounds of the general formula XLIVE, in which R represents a straight-chain or branched alkyl group with 1 to 12 Carbon atoms, you can, as above for the conversion of compounds of the general formula XLVA into compounds of the general formula XLVB described, from compounds of the general formula XLIVE, wherein R is hydrogen, through Obtained esterification.

Compounds of the general formula XLIVE in which R is hydrogen or in which R is a straight-chain or branched one Alkyl group with 1 to 12 carbon atoms can be obtained by selective oxidation with manganese dioxide, which is a Allyl alcohol group oxidized to formyl group, for example in an inert solvent, e.g. acetone or methyl chloride, at laboratory temperature, obtained from compounds of the general formulas XLVA or XLVB.

Compounds of the general formulas XLIVF and XLIVG are by oxidation, as above for the conversion of compounds of the general formulas XLVA and XLVB described in compounds of the formula XLIVE, from compounds of the general XLVC or XLVD formulas available.

Compounds of the general formula XLVD can be according to the above for the conversion of compounds of the general Formula XLVA described in compounds of Formula XLVB

609850/1106
- 48 -

2622Λ16

"known methods from compounds of the general formula XLVC obtain.

Compounds of the general formula XLIVH are by selective reduction of the carbonyl-conjugated double bond in Compounds of the general formula XLIVE according to methods known per se, for example by means of lithium pent-1-yne hydrocuprate, can be prepared from compounds of the general formula XLIVE.

Compounds of the general formulas XLVC and XLIVF can be oxidized under mild conditions, e.g. with Collins reagent or Jones reagent at moderately low temperature, e.g. below room temperature, or using a chromic acid solution convert into compounds of the general formula XLIVJ.

Compounds of the general formula XLIVJ can, according to known, above for the esterification of a compound of the formula XLVA described methods are esterified, compounds of the general formula XLIVK being obtained.

Compounds of the general formulas XLIVJ and XLIVK can be obtained by mild hydrolysis with an aqueous solution of an organic acid, for example acetic acid, or with the dilute ~ "~ aqueous solution of an inorganic acid, for example hydrochloric acid, advantageously in the presence of a water-miscible organic solvent, e.g. tetrahydrofuran or an alkanol, converting the temperature range from room temperature to 60 ° C and preferably below 45 ⁰ C in compounds of general formula XLIVL.

If desired, compounds of the general Formula XLIVL by selective reduction of the carbonyl-conjugated double bond in compounds of the general formula XLIVL

609850/1106
- 49 -

methods known per se, for example by means of lithium pent-1-yne hydrocuprate, convert into compounds of the general formula XLIVM.

The compounds of the general formula XLVC used in Table G and other compounds of the general formula XLV can be produced by the reaction sequence shown schematically in Table H:

TABLE H

(LII)

609850/1106 - 50 -

TABLE H (CONTINUED)

(LH)

COOH

(XLVC) '

COOH

(XLVF)

where R has the meaning given above, Ac for the acetyl-20

group, R for a straight-chain or branched alkyl group

OH

with 1 to 4 carbon atoms and R for an unsubstituted or substituted by at least one alkyl group 2-tetrahydro pyranyl group, a 2-tetrahydrofuranyl group or a 1-ethoxyethyl group stands.

609850/1106

- 51 -

The starting compound of the formula XLVI is prepared according to the method described in J. Amer. Chem. Soc., 91, 5675 (1969) and J. Amer. Chem. Soc., 92 , 397 (1970) and can be prepared by reaction with a sodium derivative of the general formula:

ο ρ

(R ²² O) ₂ P-CH-C-OR ²⁰ Na ⁺ - (LV)

(in which R has the meaning given above and R _, represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms) in an inert organic solvent, for example tetrahydrofuran or 1,2-dimethoxyethane, at a temperature from O ⁰ C to 3O ⁰ C, the reaction is usually complete in two hours, stereospecifically converting in high yield into trans-α, ß-unsaturated esters of the general formula XLVII.

The compounds of the general formula XLVII can be obtained by reduction with more than 4 equivalents of diisobutylaluminum hydride in an inert solvent, e.g. toluene, n ~ pentane or η-hexane, at low temperature, e.g. -78 ° C to -20 ° C, convert quantitatively into compounds of formula XLVIII.

A compound of the formula XLVE can be converted into a compound of the general formula XLVIII a compound of the formula:

(C ₆ H ₅ J ₃ PCH ₂ Ch ₂ CH ₂ CH ₂ COOH Br "(LVl)

in the presence of a strong base, for example sodium ethylsulfinylmethylide, under the conditions normally used to achieve the Wittig reaction, e.g. B. for room

609850/1106

- 52 -

S3 2622476

temperature in an inert solvent. The reaction is preferably carried out in dimethyl sulfoxide because the phosphonium compound is practically insoluble in other solvents, e.g. tetrahydrofuran, and because in the Wittig reaction formed a cis double bond stereospecifically must become. For better success of the Wittig reaction, more than three equivalents are those from the compound of the formula LVI produced phosphorane compound, i.e. (4-carboxyb.utylidene) -triphenylphosphorane necessary. The reaction of the compound of the formula XLVIII with the phosphorane is at laboratory temperature usually finished in about one to five hours. The products of the formula XLVE, i.e. the acid component in the reaction mixture can be isolated from the reaction mixture in high yield by customary methods.

Compounds of the general formula XLIX can be prepared by applying the above for the conversion of compounds of the general Formula XLVI in trans-α, ß-unsaturated esters of the general Formula XLVII procedure described stereoselectively converted into trans-α, ß-unsaturated esters of the general formula LI will. Compounds of general formula LI are also selective from compounds of general formula XLVII Deacetylation with an equimolar amount of anhydrous potassium carbonate in absolute methanol and subsequent etherification of the compounds of the general formula L thus obtained with a dihydropyran, dihydrofuran or with ethyl vinyl ether in an inert organic solvent, e.g. methylene chloride, in the presence of a condensing agent, e.g. p-toluenesulphonic acid, manufacturable.

609850/1106
- 53 -

Compounds of the general formula LI can be obtained by reduction with more than 3 molar equivalents of diisobutylaluminum hydride in an inert solvent, e.g. toluene, n-hexane or n-pentane, at low temperature, e.g. -78 ° C to -20 ° C, convert quantitatively into compounds of the general formula LII.

Compounds of the general formula LII are based on the above for the preparation of a compound of the formula XLVE a compound of the formula XLVIII described methods can be converted into compounds of the general XLVC.

If desired, a compound of the general formula XLVE can be converted into a compound of the formula XLVF by etherifying it with a dihydropyran, dihydrofuran or with ethyl vinyl ether in an inert organic solvent, e.g. methylene chloride, in the presence of a condensing agent, e.g. p-toluenesulphonic acid, the resulting triether of the general formula LIII in the presence of a hydrogenation catalyst, for example palladium black or palladium carbon, in the presence of an inert solvent, for example a lower alkanol, for example methanol or ethanol, hydrogenated at laboratory temperature and normal pressure and the triether of the general formula LIV formed by mild hydrolysis with the aqueous solution of an organic acid, for example acetic acid or with dilute aqueous solution of an inorganic acid, for example hydrochloric acid are reacted in the temperature range of 2O ⁰ C to 40 ⁰ C for triol of formula XLVF.

Compounds of the general formula XLIX can be prepared by the reaction sequence shown schematically in Table J:

609850/1106

- 54 -

CH ₂ C ₆ H ₅ IAFEL J γ , \ y k ¹⁹ / J vV ⁰⁸

XLIX

(LVII) (LVIII)

19th
wherein R has the meaning given above. Compounds of the general formula LVIII can be prepared from compounds of the general formula LVII by catalytic reduction in the presence of a hydrogenation catalyst, for example palladium carbon or palladium black, and by oxidation under mild conditions, for example with Collins reagent and at moderately low temperature, in compounds of the general formula XLIX being transformed.

Compounds of the general formula LVII can be prepared by known methods, for example as described in J. Org.

Chem., 37, 2921 (1972) for the preparation of the compound of

19th
general formula LVII, in which R represents the 2-tetrahydropyranyl group.

Compounds of the general formulas XLI or XLIII,

17th

in which the -OR group or the hydroxyl group has the ß-configuration, i.e. compounds of the general formula:

609850 / ^ 106

COOR

(LIX)

CHO

(in which the various symbols have the meanings given above) can be prepared according to the reaction sequence given in Table G, but with replacement of the compounds the general formula XLVA or XLVC by combining the general formulas:

: 00H

(LX)

OH

0OH

(LXI)

Compounds of the general formulas LX and LXI can be prepared according to the reaction sequence shown in Table H, however replacing the compounds of the general formulas XLVI or XLIX with compounds of the general formulas:

- 56 609850/1106

(LXII)

OAc

(LXIII) CHO

19th
wherein Ac and R have the meaning given above.

Compounds of the general formula LXII can be obtained by oxidation of a compound of the general formula XXXII under mild conditions, for example with Collins reagent and at at a moderately low temperature.

Compounds of the general formula LXIII, in which R has the meaning given above, can be obtained by the below in Table K schematically reproduced reaction sequence can be prepared:

609850/1106 - 57 -

TABLE K

OAc

OH (LXV)

OR ¹⁹ (LXVI)

19th

CHO

.19

(LXVII) (LXIII)

where R and Ac have the meaning given above. The different Reactions shown in Table K above can be carried out by known methods. Let compounds of the formula LXV by selective acetylation of compounds of the formula LXIV under mild conditions, for example with an equimolar Prepare the amount of acetyl chloride at a low temperature, e.g. -20 ° to -10 ° C.

4 5 compounds of the general formula XLII, in which R, R,

n ¹ and M have the meaning given above, are by reacting a compound of the general formula:

HaI-CH,

(LXVIIl)

609850/1106 - 58 -

4 5

(in which R, R and η ^{1 have} the meaning given above and Hai stands for a halogen atom) which can be prepared with magnesium by methods known per se for the preparation of a Grignard reagent.

Compounds of the general formula LXVIII can be prepared by the reaction sequence given in Table L below:

TABLE L

! ACO-CH ₂ -C- (CH ₂ J _n , CH ₂ Cl

(LXIX)

Hal-CH ₂ -C- (CH ₂ ), CH ₂ Cl

i ⁵

(LXVIII)

wherein the various symbols have the meanings given above.

Compounds of the general formula LXIX can be prepared from compounds of the general formula LXX by reaction with Acet3? "Oil chloride and zinc chloride according to the method described in Org. Syn., Coll. Vol. 4, 266 (1963).

Compounds of the general formula LXVIII can be prepared from compounds of the general formula LXIX by reaction with hydrobromic acid and sulfuric acid according to the method described in J. Amer. Chem. Soc., 74, 917 (1952) produce.

According to a further feature of the present invention can one compounds of the general formula VIIB, in which the various symbols have the meanings given above, also manufacture according to a method, which is characterized

609850/110 6
- 59 -

is that under particularly mild acidic conditions, the trimethylsilyloxy groups of a compound of the general formula:

(LXXI)

(where TMS stands for the trimethylsilyl group and the other symbols have the meanings given above) to hydroxyl groups hydrolyzed, for example by treating the solution of a compound of the general formula LXXI in an inert organi between solvents, e.g. ethyl acetate, with aqueous oxalic acid solution, preferably at room temperature.

Compounds of the general formula LXXI are obtained by oxidation of a compound of the general formula:

(LXXII)

(CH ₂ J _n CH ₂ Cl "5

TMSO

(in which the various symbols have the meanings given above) can be prepared with Collins reagent (chromium trioxide / pyridine complex) in the presence of an inert organic solvent, for example methylene chloride, preferably at a temperature of approximately ⁰ ° C., or Jones reagent.

Compounds of the general formula LXXII, wherein the

609850/1106 - 60 -

Various symbols have the meanings given above, can be derived from compounds of the general formula VIIA (in which the various symbols have the meanings given above) by reaction with a suitable trimethylsilylating agent, e.g. N-trimethylsilyl diethylamine or N, O-bis (trimethylsilyl) acetamide in acetone, preferably at room temperature.

Compounds of the general formula XI, in which the various symbols have the meanings given above also from a compound of the general formula LXXIII by the below in panel M, wherein the various symbols are those given above Have importance, schematically reproduced reaction sequence can be produced.

6 0 9 8 5 0/1106

- 61 -

2822416

TABLE M

(LXXIII)

(LXXV)

(CH) CH OR ⁸ 2 η 2

R ⁵

OR

(LXXVIA)

(CH ₂ J _n CH ₂ OR _n 5

(LXXVIB)

OR

Compounds of the general formula LXXV can be prepared by Wittig reaction of a compound of the general formula LXXIII with the sodium derivative of a dialkyl phosphonate of the general formula:

609850/1106 - 62 -

(R ¹ ^ O) P-CH ₂ -CCC- (CH ₉ ) CH ₀ OR ⁸ (LXXIV) ² II ² W TT 2 η 2

² Κ *

W ₃ T 2 η 2 O 0 ³

(in which the various symbols have the meanings given above) as above for the conversion of a compound of the general Formula XX is described in a compound of the general formula XVIII.

The conversion of compounds of the general formula LXXV into compounds of the general formula LXXVIA. or LXXVHB can as above for the conversion of compounds of general formula XVIII into compounds of general formula XVI described.

The conversion of compounds of the general formula LXXVIA or LXXVIB into compounds of the general formula XIB can be used as above for the conversion of compounds of the general formula XVI into compounds of the general formula XV as described.

Compounds of the general formula XI, in which X ^{1 is} an ethylene group and Y 'is a trans-vinylene group and the other symbols have the meanings given above, are obtained by reducing compounds of the general formula XIB in which X ^{f is} a cis-vinylene group and the other symbols have the meaning given above. Advantageously, the reduction can be carried out by hydrogenation in the presence of a hydrogenation catalyst, for example palladium carbon or palladium black, in an inert organic solvent, for example a lower alkanol, for example methanol or

60 98 507 1106 - 63 -

Ethanol, at laboratory temperature and normal or elevated pressure, e.g. at a hydrogen pressure from atmospheric pressure to 15 kg / cm.

Compounds of the general formula XI, in which X 'and Y' each represent an ethylene group and the other symbols are Have the meaning given above, by reducing compounds of the general formula XIB, wherein the various Symbols that have the meaning given above can be produced. The reduction is expediently used for the conversion as above of compounds of the general formula XVI described in compounds of the general formula XVII.

The starting materials of the general formula LXXIlI, wherein

the various symbols have the meanings given above and

7th
the group OR has the α-configuration can be prepared from compounds of the general formula XXVIII, in which the various symbols have the meanings given above, by the reaction sequence shown schematically below in Table N, in which the various symbols have the meanings given above.

609850/1106
- 64 -

TABLE N

(LXXIX)

COOR

(LXXIIIA)

Compounds of the general formula LXXVII can by Acetylation of compounds of the general formula XXVIII prepared under mild conditions and by reaction with a dihydropyran, dihydrofuran or with ethyl vinyl ether in an inert organic solvent, e.g. methylene chloride, in the presence of a condensing agent, e.g. p-toluenesulphonic acid, can be converted into compounds of the general formula LXXVIII.

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66 2B22416

Compounds of the general formula LXXIX are through Hydrolysis of a compound of the general formula LXXVIII can be prepared under alkaline conditions. The hydrolysis under alkaline conditions can be (l) by means of an aqueous alkali, e.g. sodium or potassium, hydroxide or carbonate solution in the presence of a water-miscible organic solvent, e.g. tetrahydrofuran or an alkanol with 1 to 4 carbon atoms, using a compound of the general formula LXXIX, wherein R is a hydrogen atom is obtained, or also (2) by means of anhydrous potassium carbonate in an anhydrous alkanol with 1 to 4 carbon atoms, preferably absolute methanol, using a compound of the general formula LXXIX, in which R is an alkyl group with 1 to 4 carbon atoms is obtained.

The conversion of compounds of the general formula LXXIX into those of the general formula LXXIIIA can be carried out as above for the conversion of compounds of the general formula XXVIII into compounds of the general formula XXA carry out.

The starting materials of the general formula LXXIII, wherein

the various symbols have the meanings given above and

7th
the group OR has the ß-configuration, are according to the reaction sequence given above schematically in Table N from compounds of the general formula:

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(LXXX)

Ag
OR

wherein the various symbols have the meaning given above, can be produced.

Compounds of the general formula LXXX, in which the various »symbols have the meanings given above, can from compounds of the general formula XXXII by those for the preparation of compounds of the general formula XXVIII prepared from a compound of the general formula XXII above in Table B schematically reproduced reaction sequence will.

The phosphonate of the general formula LXXIV can be derived from compounds of the general formula:

R ² R *

R ¹⁶ OC-CC- (CH,) CH-OR ⁸ (LXXXI)

i I ₃ 'β

OR ΈΓ

wherein the various symbols have the meanings given above, as above for the preparation of dialkyl phosphonate compounds of the general formula XXI described from compounds of the general formula XXXVII.

Compounds of the general formula LXXXI are obtained from compounds of the general formula XXXVIII by reaction with a corresponding acyl halide or acid anhydride in an inert organic solvent, e.g. methylene chloride, in

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Presence of a base, for example pyridine or a tertiary amine, at low temperature, eg 0 ° to 3O ⁰ C, to produce.

The compounds of the general formula VII in which R represents a hydrogen atom can be used according to known principles Methods, for example by reacting stoichiometric amounts of compounds of the general formula VII, in which R is is a hydrogen atom, with the corresponding base, for Example of an alkali hydroxide or carbonate, ammonium hydroxide, ammonia or an amine, in a suitable solvent Making salts. The salts can be removed by concentrating the solution or, if they are sufficiently insoluble in the reaction medium are isolated by filtration, if necessary after partial removal of the solvent. Preferably the salts are non-toxic salts, i.e. salts whose cations are relatively harmless to the patient when used in therapeutic doses animal organism are so that the wholesome pharmacological Properties of the cyclopentane compounds of the general formula VII not due to side effects attributable to these cations be affected. The salts are preferably water-soluble. Suitable salts include alkali, e.g. sodium and potassium, as well as ammonium salts and pharmaceutically acceptable (i.e. non-toxic) amine salts. For the formation of such salts Amines suitable with carboxylic acids are well known and include, for example, in theory by replacement of one or more Hydrogen atoms of ammonia by groups which are identical or, if more than one hydrogen atom has been replaced, be different can and, for example, under alkyl groups with 1 to 6 carbon atoms and Hydroxy.alkylgruppen with 1 to 3

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Carbon atoms, e.g. triethanolamine, selects derived Amines.

If desired, the prostaglandic acids and esters of the general formula VII can be converted into cyclodextrin clathrates. To produce the clathrates, the cyclodextrin can be dissolved in water and / or a water-miscible organic solvent and the prostaglandin compound can be added to the solution in a water-miscible organic solvent. The mixture is then heated. and isolates the desired cyclodextrin clathrate product by concentrating the mixture under reduced pressure or by cooling and separating the product by filtration or pouring off. The organic solvent / water ratio can be varied depending on the solubility of the starting materials and products. Preferably, the temperature during the preparation of the cyclodextrin to clathrate 70 ⁰ C not exceed. In the preparation of the cyclodextrin clathrates, α-, β- or Y-cyclodextrins or mixtures thereof can be used. The conversion into their cyclodextrin clathrate serves to increase the stability of the prostaglandin analogs.

The prostaglandin analogs of the general formula VII and their cyclodextrin clathrates and, if R is a hydrogen-> ■ atom represents whose non-toxic salts selectively possess the valuable pharmacological properties typical of prostaglandins Properties, in particular an antihypertensive effect, an inhibitory effect on platelet aggregation, an inhibitory effect on gastric acid secretion and gastric ulcer formation, a bronchodilator effect, a stimulating effect

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Effect on uterine contraction as well as an abortive, luteolytic and anti-implantation effects, and are used to treat high blood pressure, to treat peripheral disorders Circulatory system, for the prevention and treatment of brain thrombosis and myocardial infarction, used to treat stomach ulcers, for the treatment of asthma, termination of pregnancy and induction of labor in pregnant female mammals or pregnant women as well as for the treatment of reduced fertility, for controlling the estrous stage, for preventing pregnancy and the regulation of the sexual cycle in female Valuable to mammals and women. For example, one achieves in standardized laboratory tests (i) in the case of intravenous administration on the allobarbital-anesthetized dog with 20-chloro-PGP methyl ester in a dose of 5 or 10 μg / kg body weight of the Animal showed a 16 and 14 minute drop in blood pressure by 10 torr and 26 torr, respectively, with 16 £ -methyl-20-chloro-PGEp-methyl ester at a dose of 0.2 or 0.5 μg / kg body weight of the animal a drop in blood pressure of 18 torr for 18 and 36 minutes, respectively or 32 Torr, with 16 ^ -Methyl-20-chloro-PGE -methylester in one Dose of 0.1 or 0.2 μg / kg body weight of the animal a 9 or Blood pressure drop lasting 25 minutes by 17 Torr or 34 Torr and with 16 ^ -methyl-20-chloro-15-epi-PGEp-methyl ester in one Dose of 20 or 50 μg / kg body weight of the animal a 7 or Blood pressure drop of 26 Torr or 52 Torrj for 30 minutes (ii) when administered orally to the conscious rat with spontaneously increased blood pressure with 20-chloro-PGEp-methyl ester in one dose of 5 mg / kg body weight of the animal 0.5 and 3 hours after administration, a drop in blood pressure of 31 torr and 11 torr, respectively

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Lö ^ -Methyl ^ O-chloro-PGEp-methyl ester in a dose of 0.1 mg / kg body weight of the animal 0.5, 1 and 3 hours after administration, a drop in blood pressure of 40 torr, 27 torr and 15 torr, respectively and with 16C-methyl-20-chloro-PGE ₁ -methylester at a dose of 0.1 mg / kg body weight of the animal 0.5, 1 and 3 hours after administration, a drop in blood pressure of 47 torr, 46 torr and 24, respectively Torr; (iii) in platelet-rich rat or human plasma with 16 ^ -methyl-20-chloro-PGE- _L -methyl ester compared to controls, a 50% inhibition of adinosine diphosphate-induced platelet aggregation at a concentration of 8.2.10 "^ μg / ml or 5.8.10 ~~ μg / ml; (iv) when inhaled as an aerosol of 20-chloro-PGEp-methyl ester in a dose of 1, 3 or 10 μg / ml aerosol in the conscious guinea pig, a delay in the inhalation of a histamine-containing aerosols, which lead to an increase in the time elapsing before a seizure by 60%, 88% and 141%; histamine-induced contraction, with 20-chloro-PGE ^ methyl ester a relaxation effect (PD ₂ ) of 6.70 + 0.23, calculated according to the method of Rossler et al. [Arch, Int. Pharmacodyn. Ther., 143, 299 ( 1963)], whereby the PD ₂ ~ value is the negative logar ithmus of the concentration of the compound in grams which results in a 50% eating tension of the tracheal muscle in 8 of 8 preparations, ie the compound results in a 50% relaxation of the histamine-induced contraction in

- Pi VD 8 of 8 preparations each at a dose of 10 g / ml; (vi) with gastric lavage of 20-chloro-PGE ₂ -methyl ester or 16 ^ -methyl

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20-chloro-PGEp-methyl ester in an amount of 1.9 or 0.1-0.25 μg / animal / minute in 50% pentagastrin-treated rats showed an increase in gastric acid pH of 2.0-2.5 at least 4.0; (vii) in the case of stress-induced gastric ulcer formation in the rat [according to the method of Takagi and Okabe - Jap. J. Pharmac., 18 , 9-18 (1968) - caused by soaking the rat for 6 hours in a water bath at 19 C] with peroral administration of 20-chloro-PGEp-methyl ester at a dose of 2000 μg / kg body weight of the Animal an inhibition of stress-induced ulcer formation by 16.9%, of 16 ^ -methyl-20 »chloro-PGE ₂ -methylester in a dose of 10 and 20 μg / kg body weight of the animal an inhibition of stress-induced ulcer formation 50% or 63%, of 16 ^ -methyl-20-chloro-PGE- _L -methyl ester in a dose of 50 or 100 μg / kg body weight of the animal inhibits stress-induced ulcer formation by 76.33% or 95j 10% as well as 16% methyl-20-chloro-l5-epi ~ PGE ₂ -methylester in a dose of 1000 and 2000 μg / kg body weight of the animal inhibit stress-induced ulcer formation by 40.96% or 53.5%; (viii) with intravenous administration of 20-Cblor-PGEp methyl ester, 20-chloro-PGE ₂ -methyl ester, 16 ^ -Methyl-20-chloro-PGF _{2c (} -methylester, 16 ^ -Methyl-20-chloro-PGE ₂ - methyl ester, Ι6ξ-methyl-20-chloro-PGE-j ^ -methyl ester or l6 ^ -methyl-20-chloro-l5-epi-PGE ₂ -methylester in a dose of 10 - 20, 10, 1 - 2, 0 , 2, 0.5 or 50 - 100 μg / kg body weight of the animal on the 20th day of gestation stimulate uterine contraction in the pregnant female rat; and (ix) with subcutaneous administration of 20-chloro-PGFp-methyl ester or 16 ^ -Methy1-20-chloro-PGFp -methylester in one on the 3rd, 4th and 5th day of the

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2B22416

During pregnancy, doses of 0.5-1.0 or 0.25-0.5 μg / kg body weight of the animal administered daily to the pregnant female rat inhibited implantation. The prostaglandin analogs of the general formula VII, their cyclodextrin clathrates and, if R in formula VII stands for a hydrogen atom, their non-toxic salts have a relatively low effectiveness with regard to causing undesirable side effects, for example diarrhea. The dose of 20-chloro-PGFp methyl ester, 20-chloro-PGE ₂ -methyl ester, 16-methyl-2D-chloro-PGF _2a -methyl ester, 16 £ - required in 50% of mice treated in this way to induce diarrhea. Methyl-20-chloro-PGE ₂ -methyl ester, or 16 £ -methyl-20-chloro- _{15-epi-PGE 2} -methylester amounts to ^ 10, »2.0, 4.5, 0.08, 0.46 or> 20 mg / kg body weight of the animal.

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The following reference examples and examples illustrate the method of the present invention and its Products. In the examples, "IR", "NMR" and "DSC" stand for "infrared absorption spectrum", "nuclear magnetic resonance spectrum" or "thin layer chromatography". When specifying solvent ratios in chromatographic separations, these are Volume ratios.

REFERENCE EXAMPLE 1 Ethy1-6- (2-tetrahydropyranyloxy) hexanoate

66 g (0.412 mol) of ethyl 6-hydroxyhexanoate [according to S.R. Sandler and ¥. Karo, in "Organic Functional Group Preparation", Academic Press, New York and London, Volume 1, page 262 - cf. G.B. Hatch and H. Adkins, J. Amer. Chem. Soc., 59 1694 (1937)] in 400 ml of methylene chloride and the mixture is left Minutes at 25 C with 45 g of dihydropyran and 1 g of p-toluenesulfonic acid react. The reaction mixture is washed with aqueous sodium bicarbonate solution, dried, concentrated and distilled Residue in vacuo, giving 77 g of the title compound with the following physical characteristics; Boiling point: 135 ° C / 3 torr;

IR (liquid film); ν: 2940, 2860, 1740, 1445, 1370, 1350, 1325, 1260, 1160, 1140, 1120, 1080, 1040, 985, 910, 870 and 820 cm "¹;

NMR (CDC1 ₃ solution): δ: 4.70 to 4.35 (IH, m), 4.05 (2H, q), 4.00 to 3.00 (4H, m), 2.24 (2H , t) and 1.20 (3H, t).

REFERENCE EXAMPLE 2 Dimethyl 2-OXO-7- (2-tetrahydropyranyloxy) heptylphosphonate 45 g (0.36 mol) of dimethyl methylphosphonate are dissolved in

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400 ml of absolute tetrahydrofuran and added dropwise 180 ml of a 2n-butyllithium solution in diethyl ether (0.36 mol), keeping the temperature below -50 ⁰ C. Ten minutes later, 37 g (0.15 mol) of ethyl 6- (2-tetrahydropyranyloxy) hexanoate (prepared according to Reference Example 1) in 100 ml of absolute tetrahydrofuran are added dropwise to the solution, and the reaction mixture is at the same temperature for 3 hours and then for 16 hours stirred at 0 ^{° C.}

The reaction mixture is acidified with acetic acid, evaporated, the residue dissolved in a little water, extracted with diethyl ether, the extracts dried over MgSO ^, concentrated and subjects the residue to a distillation at 140 ° C (oil bath temperature) and a pressure of 0.2 torr. There remain 31 g of the title compound, the boiling point of which for a distillation is high and has the following physical characteristics:

IR (liquid film; v: 2950, 2870, 1720, 1455, 1445, 1410, 1375, 1365, 1335, 1275, 1200, 1190, 1140, 1120, 1110-990, 920, 880 and 820 cm "¹;

NMR (CDCl4 solution); δ: 4.75-4.30 (IH, m), 4.15-3.10 (4H, m), 3.75 (6H, d), 3.06 (2H, d) and 2.58 (2H, t).

• REFERENCE EXAMPLE 3

Methyl-9oc-acetoxy-11a, 20-bis (2-tetrahydropyranvloxv) -15-oxoprosta-cis-5, trans-13-dienoate

1.44 g of 55% sodium hydride are suspended in 200 ml absolute tetrahydrofuran, the suspension is added with stirring at room temperature under nitrogen with 11.3 g (0.035 mol) Dimethyl 2-OXO-7- (2-th traphydropyranyloxy) heptylphosphonate

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prepared according to reference example 2) in 100 ml of tetrahydrofuran and stirred for 20 minutes.

One gives 11.6 g (O 0294 ₃ mol) of la-Acetoxy-2cc- (6-methoxycarbonylhex-cis-2-enyl) -3ß-formyl-4a- (2-tetrahydropyranyloxy) cyclopentane in 50 ml tetrahydrofuran was added thereto and stirred the mixture for 1 hour at room temperature. The reaction mixture is then neutralized with acetic acid, filtered, the filtrate is concentrated and the residue is purified by column chromatography over silica gel using benzene / ethyl acetate (4: 1) as the eluent, 16.0 g of the title compound having the following physical characteristics:

IR (liquid film); v: 2950, 2870, 1745, 1700, 1675, 1635, 1455, 1445, 1380, 1360, -1330, 1255, 1200, 1190-1155, 1145, 1130, 1085, 1045, 980, 925, 915, 880, 855 and 825 cm "¹; NMR (CDCl ₃ solution); δ: 6.65 (IH, q), 6.15 (IH, d), 5.60-5.15 (2H, m), 5.15 -4.85 (IH, m), 4.80-4.35 (2H, m), 4.30-3.00 (6H, m), 3.62 (3H, s) and 2.04 (3H , s);
DSC (solvent benzene / ethyl acetate = 2: 1): Rf = 0.54.

The la-acetoxy-2a- (6-methoxycarbonylhex-cis-2-enyl) -3β-formyl-4a- (2-tetrahydropyranyloxy) -cyclopontane used as starting material in the above process becomes from 2-0xa-3-oxo-6-syn-hydroxymethyl-2-anti-acetoxy-cis-bicyclo- [3.3.0] octane [according to E.J. Corey et al., J. Amer. Chem. Soc., 91, 5675 (1969) and ibid., 92, 397, (1970) -produced] as follows:

190 g of 2-oxa-3-oxo-6-syn-hydroxymethyl-7-anti-acetoxy-cis-bicyclo [3 »3» 0] octane are stirred in 1.5 liters of absolute methanol and 130g of potassium carbonate for 1 hour at room temperature, then cools in an ice bath and neutralizes with hydrochloric acid.

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The precipitate is filtered off and the filtrate was concentrated under reduced pressure "is washed with den'Rückstand! Ethanol, followed by ethyl acetate _s and dried completely to give 124 g of 2-Qxa-3-oxo-6-syn-hydroxymethyl-7- anti-hydroxy ~ cis == bicyclo [3,3,0] octane obtained as white crystallites with the following physical characteristics

Melting point; 119 ° Cj

IR (KBr pellet); v? 3350, 2970-288O ₅ 174O ₃ 148O _P 1440 _s 1410, 1380, 1335, 1305 ₉ 1270, 1205, 1100, 1080 _s 1060, 1040, 1020, 1000 and 975 cm ""¹;

NMR (CDCl + Deutero-dimethylsulfoxide solution) j6s 5.10-4.60 '(IH, m), 4.29 (2H, s), 4.13-3.77 (1H _S m) and 3 _S 38 (2H, d) j DSC (mobile phase methylene chloride / methanol = 2OzI) s Rf = 0 _g 2? _a

124 g of 2-0xa-3-oxo-6-syn-hydroxymethyl-7-anti-hydroxy-cis-bicyclo- [3f3.0] octah, prepared as described above, are dissolved in 1.4 liters of absolute pyridine, and the mixture is cooled to -4O ⁰ C, treated dropwise with 74 g of acetic anhydride and the mixture is stirred for 5 hours at '40 to -20 ⁰ C and then for 16 hours at ⁰ ° C., the pyridine removed at reduced pressure, the residue is dissolved in 1 liter of ethyl acetate, stirred Man vigorously with 200 g of sodium bisulfate, filtered, the filtrate is concentrated under reduced pressure and the residue is purified by column chromatography over silica gel using benzene / ethyl acetate (1: 3). as an eluent, 112 g of 2-0xa-3-oxo-6 ~ syn-acetoxymethyl-7-anti-hydroxy-cis-bicyclo [3,3, Q] octane being obtained as colorless needles with the following physilsalioehea:

Melting point: 36-37 ° C;

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^ 2822416

IR (KBr pellet); v. 3450, 2960, 2850 ₉ 1775, 1740, 1420, 1370,

125O ₉ 1190 ,, 112O ₈ 1090 _s 1040 and 980 cm " ¹ 5 NMR (CDC1 ₃ solution) j6: 5.15-4.6 (IH, m), 4.3-3 * 75 (3H, egg) ₁

3.50 (IH, s) and 2.02 (3H, s);

DSC (mobile phase methylene chloride / methanol = 20: 1): Rf = 0.50.

Dissolve 43 g of 2-0xa-

3-oxo-6-syn-acetoxymethyl-7-anti-hydroxy-cis-bicyclo [3.3 » O] octane in 520 ml of methylene chloride and stir the solution for 20 minutes at room temperature with 25 g of dihydropyran and 0.52 g of p -Toluenesulfonic acid. The reaction mixture is neutralized with aqueous sodium bicarbonate solution, diluted with ethyl acetate, washed with water, dried and concentrated under reduced pressure, 56 g of 2-Qxa-3-oxo-6-syn-acetoxymethyl-7-anti-(2-tetrahydropyranyloxy ) -cis-bicyclo [3.3 _s O] octane obtained as a colorless oil with the following physical characteristics: IR (liquid film); v: 2950-2840, 1775, 1740, 1465, 1440, I39O-I34O, 1240, 1180, 1140-1120, 1080, 1040 and 980 cm "* ¹ ; NMR (CDC1 ₃ solution); 5: 5.2-4.72 (IH, m), 4.72-4.30 (IH, m), 4.2-3.2 (5H, m) and 2.01 (3H, s);
DSC (eluent methylene chloride / methanol = 20: 1): Rf = 0.74.

56 g of 2-0xa-3-0x0-6-33, prepared as described above, are dissolved ^^ 06 ^ x3 ^^ 11 ^ 1-7-3 ^ 1- (2-tetrahydropyranyloxy) -cisbicyclo [3,3,0] octane in 900 ml of toluene, cooled to ⁰ C -6O from _s mixed with 456 ml of diisobutylaluminum hydride in toluene (25 $ Gew./Vol.) and the mixture is stirred for 20 minutes. Aqueous meihanol is then added to destroy excess diisobutylaluminum hydride. The precipitate is filtered off, the filtrate is dried and concentrated under reduced pressure, 35.2 g being obtained

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Z-Oxa ^ -hydroxy-e-syn-hydroixymethyl-T-anti- (2-tetrahydropyranyloxy) -cis-bicyclo [3.3 »0] octane obtained as a colorless oil with the following physical characteristics:

IR (liquid film) Jv; 3400, 2940-2860, 1465-1440, 1380, 1355,

1325, 1260, 1200, 1140, 1120, 1075 and 1020 cm "¹; DSC (mobile phase, ethyl acetate): Rf = 0.25.

Suspending 37.6 g 63,5-% sodium hydride in 400 ml of dime thy lsulfoxyd and stirred for 1.5 hours under heating at 70 ⁰ C to obtain Natriummethylsulfinylmethylid. The mixture is left, the reaction mixture cool to room temperature and there is then added dropwise to the solution of 226 g (4-carboxybutyl) triphenylphosphonium bromide in 460 ml of dimethyl sulfoxide while maintaining the reaction temperature in the range 20 to 25 ⁰ C.

A solution of 35.2 g of 2-0xa-3-hydroxy-6-syn-hydroxymethyl-7-anti- (2-t.etrahydropyranyloxy) -cis-bicyclo [3,3,0] is added. 6ktan in 90 ml of dimethylsulfoxide and the mixture is stirred vigorously for 1.5 hours at 35 to 40 ⁰ C. The reaction mixture is poured into ice-water in 6 liters and neutral substances by extraction with ethyl acetate / diethyl ether: distance (1 1). The aqueous layer is acidified to pH 2 with saturated oxalic acid solution, shaken out with diethyl ether / n-pentane (1: 1), the extracts are washed with water, dried over sodium sulfate, concentrated under reduced pressure and the residue is column chromatographed over silica gel using of benzene / methanol (10: 1) as the eluent, 35 g of 2a- (6-carboxyhex-cis-2-enyl) -3ß-hydroxymethyl-4a- (2-tetrahydropyranyloxy) -cyclopentan-la-ol as a colorless oil with the following physical characteristics:

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IR (liquid film); ν: 3400, 2940-2860, -2300, 1710, 1450, 1435, 1400, 1355, 1245, 1200, 1140, 1120, 1075 and 1025 cm ""¹; NMl (CDCl ^ solution); δ: 6.20 (3H, s), 5.50-5.10 (2H, m), 4.75-4.36 (IH, m), 4.24-3.85 (2H, m) and 3.85-3.0 (4H, m); DSC (mobile phase chloroform / tetrahydrofuran / acetic acid = 1 ^r : 2: 1): Rf = 0.53.

The solution of 18.8 g is added as described above prepared 2a- (6-carboxyhex-cis-2-enyl) -3β-hydroxymethyl-4a- (2-tetrahydropyranyloxy) -cyclopentan-la-ol in 130 ml of diethyl ether while cooling in an ice bath with freshly prepared ethereal diazomethane solution until the solution has a pale yellow color shows. The reaction mixture is concentrated in vacuo and column chromatographed the residue on silica gel using cyclohexane / ethyl acetate (2: 1) as the eluent, 15.4 g of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3β-hydroxymethyl-4a- (2-tetrahydr opyranyloxyj-cyclopentan-la-ol as a colorless oil with the following physical characteristics receives:

IR (liquid film); ν: 3450, 2950-2870, 1740, 1440, 1360, 1325, 1250, 1200, 1140, 1120, 1080 and 1025 cm "¹; NMR (CDCl ₃ solution);. Δ: 5, 55-5.00 (2H ₁ m), 4.78-4.30 (IH, m), 4.20-3.06 (6H ₁ m), 3.55 (3H, s) and 2.97 ( 2H, s); DSC (mobile phase methylene chloride / methanol = 19: 1); Rf = 0.43.

Mari dissolves 13.1 g of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3 ß-hydroxymethyl-4a- (2-tetrahydropyranyloxy) -cyclopentan-la-ol prepared as described above in 250 ml of absolute methylene chloride, mixed with 25 ml of pyridine and displaces the air in the apparatus with nitrogen while cooling to -20 ⁰ C. Man

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5.1 ml of trimethylchlorosilane in 30 ml of methylene chloride are added dropwise to the solution, with continued stirring, and the mixture is stirred Continue for 30 minutes at the same temperature. DSC testing of a sample then gives the following Rf value: DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.61.

The reaction mixture is added dropwise with 2.9 ml of acetyl chloride in 20 ml of methylene chloride and stir for 30 minutes at room temperature. Then 2 ml Ethanol added to destroy excess acetyl chloride. To remove the pyridine, 50 g of sodium sulfate are added Reaction mixture, the precipitate formed is filtered off and the filtrate is concentrated under reduced pressure, DSC testing a sample gives the following Rf value: DSC (solvent benzene / ethyl acetate = 2: 1): Rf = 0.82 ..

The residue is diluted with 300 ml of ethyl acetate and stir vigorously at room temperature with 100 ml of aqueous oxalic acid solution. The organic layer is separated off and washed successively with water, aqueous sodium bicarbonate solution, water and aqueous sodium chloride solution, dried with sodium sulfate and concentrated under reduced pressure, 13.7 g of crude product being obtained. The crude product is made using Benzene / ethyl acetate (3: 1) as eluent chromatographed on a column over silica gel, 7.45 g of la-acetoxy-2a- (6-methoxy-carbonylhex-cis-2-enyl) ~ 3ß-hydroxymethyl-4a- (2-tetrahydropyranyloxy) -cyclopentane, 2.40 g of la-hydroxy-2a- (6-methoxycarbonyl-hex-cis-2-enyl) ^ .ß-hydroxymethyl ^ a- (2-tetrahydropyranyloxy) -cyclopentane, 720 mg of la-hydroxy-2a- (6-methoxycarbonylhex-cis-2-enyl) -3β-acetoxymethyl-'4a- (2-tetrahydropyranyloxy) -cyclopentane as

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1.45 g of la-acetoxy-2a- (6-methoxycarbonylhex-cis-2-enyl) -3β-acetoxymethyl-4a- (2-tetrahydropyranyloxy) -cyclopentane receives.

la-acetoxy-2a- (6-methoxycarbonylhex-cis-2-enyl) -3a-hydroxymethyl-4a- (2-tetrahydropyranyloxy) -cyclopentane has the following physical characteristics:

IR (liquid film); ν: 3450, 3000, 2950, 2870, 1740, 1440, 1380, 1330, 1250, 1200, 1160, 1140, 1080, 1030, 980, 920, 875 and 815 cm;

NMR (CDCl ₃ solution) _; 6; 5.45-5.27 (2H, m), 5.16-4.92 (IH, m),

4.76-4.46 (IH, m), 4.27-3.96 (IH, m), 3.67 (3H, s), 2.98-2.64 (IH, m) and 2.05 (3H, s);

DSC (solvent benzene / ethyl acetate = 2: 1): Rf = 0.27.

80 ml of absolute methylene chloride and 4.4 ml of absolute pyridine with 2.88 g of chromium trioxide are stirred under nitrogen " 15 minutes at laboratory temperature. The solution is then added with 12 g Infusor earth and then with 956 mg of la-acetoxy-2a- (6-methoxycarbonyl-hex-cis-2-enyl) -3 prepared as described above ß-hydroxymethyl-4a- (2-tetrahydropyranyloxy) -cyclopentane in 20 ml of methylene chloride are added and the mixture is stirred at laboratory temperature for 10 minutes. "The reaction mixture is then treated with 20 g of sodium bisulfate and stir for a further 10 minutes at laboratory temperature further, filtered and then concentrated the filtrate at reduced pressure and laboratory temperature. . ■ · ·

The residue is column chromatographed over silica gel using benzene / ethyl acetate (5: 1) as eluent, 768 mg of α-acetoxy-2a- (6-methoxycarbonylhex-cis-2-enyl) -3β-formyl-4a- (2-tetrahydropyranyloxy) -cyclopentane obtained as a colorless oil with the following physical characteristics:

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IR (liquid film); v: 3000, 2950, 2860, 2725, 1740, 1440, 1380, 1325, 1255, 1200, 1165, 1140, 1085, 1030, 980, 920, 880

and 820 cm; . ·

NMR (CDCl ₃ solution); δ: 9.85-9.68 (IH, m), 5.45-4.96 (IH, m),

4.68-4.48 (IH, m), 4.48-4.25 (IH, m), 3.67 (3Η, s) and 2.08 (3Η, s);

DSC (eluent benzene / ethyl acetate = 2: 1): Rf = 0 ^ 66.

REFERENCE EXAMPLE 4

Methyl 9a-acetoxy-11a, 20-bis (2-tetrahydropyranyloxy) -15a-hydroxylprosta.-cis-5, trans-13-dienoate and methyl-gct-acetoxy-11a, 20-bis (2-tetrahydropyranyloxy) -15ß-hydroxyprosta -cis-5, trans-13-dienoate . · ■

The solution of 12.3 g of methyl 9a-aoetoxy-11a, 20-bis (2-tetrahydropyranyl oxy) -15-oxo-prosta-cis-5, trans-13-dienoate, prepared according to Reference Example 3, is cooled in 200 ml of methanol with stirring to -30 to -40 ⁰ C, and treated portionwise with 2.7 g of sodium borohydride. The reaction mixture is then stirred for 30 minutes at the same temperature and then neutralized with acetic acid. The solvent is removed, the residue is extracted with ethyl acetate, the extracts are washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, concentrated and the residue is column chromatographed over silica gel using benzene / ethyl acetate (5: 1) as the eluent, whereby one 4.89 g of the 15α-OH title compound, 4.34 g of the 15β-OH title compound and 2.78 g of a mixture of the 15α-OH and 15β-OH title compounds. DSC of the I5a-OH and 15ß-OH title compounds gives the following results: DSC (solvent benzene / ethyl acetate = 1: 1): Rf = 0.53 (I5a-OH- ^-

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Title compound) and Rf = 0.62 (15β-OH title compound).

The 15 (X-OH- or 15β-OH title compounds are identified by testing the biological effectiveness of the 20-hydroxy-PGF _{2a #} The 15 (X-OH- and 15β -OH title compounds have the following additional physical characteristics:

IR (liquid film); v: 3450, 2940, 2860, 1740, 1455, 1445, 1380, 1360, 1330, 1250, 1200, 1140, 1125, 1080, 1035, 980, 925, 910, 875 and 820 cm "¹;

NMR (CDCl ₃ solution); δ: 5.65-5.40 (2H, m), 5.40-5.10 (2H, m), x 5.10-4.80 (IH, m), 4.73-4.30 ( 2H, m), 4.30-3.00 (8H, m), 3.56 (3H, s) and 2.01 (3H, s).

REFERENCE EXAMPLE 5

Methyl-gq-acetoxy-lla, 15α, 20-tris (2-tetrahydropyranyloxy) - . prosta-cis-5, trans-13-dienoate

4.27 g of methyl 9a-acetoxy-11a, 20-bis (2-tetrahydropyranyloxy) -15ahydroxyprosta-cis-5, trans-13-dienoate prepared according to Reference Example 4 are dissolved in 40 ml of methylene chloride and the mixture is left at 25 for 30 minutes ⁰ C react with 1.1 ml of dihydropyran and 20 mg of p-toluenesulfonic acid, giving 4.9 g of the title compound with the following physical characteristics:

IR (liquid film); v: 2950, 2870, 1745, 1460, 1445, 1380, I36O, 1335, 1250, 1200, 1190, 1165, 1140, 1080, 1045, IO30, 980, 925, 915, 880 and 825 cm "¹;

NMR (CDCl ₃ solution); δ: 5.65-5.10 (4H, m), 5.10-4.80 (IH, m), 4.80-4.35 (3H, m), 4.20-3.00 (IOH , m), 3.58 (3H, s) and

- 84 609850/1 106

2.00 (3H, s).

DSC (solvent benzene / ethyl acetate = 1: 1): Rf = 0.80.

REFERENCE EXAMPLE 6

-IIa, 15α, 20-tris (2-tetrahydropyranyloxy) -prostacis-5, trans-13-dienoic acid

4.9 g of methyl ga-acetoxy-llct, 15 a, 20-tris (2-tetrahydropyranyloxy) -prosta-cis-5, trans-13-dienoate, prepared according to Reference Example 5, are added to a mixture of 3 g of potassium hydroxide , 5 ml of water and 20 ml of methanol and the mixture is stirred for 2 hours at room temperature. The reaction mixture is then neutralized with oxalic acid, extracted with ethyl acetate, washed with water, dried with magnesium sulfate and concentrated, and the residue is column chromatographed over silica gel using benzene / ethyl acetate (1: 2) as the eluent, 3.6 g of the title compound being obtained with the following physical characteristics:

IR (liquid film); ν: 3450, 2940, 2860, -2350, 1745, 1715, 1455, 1445, 1380, 1360, 1330, 1250, 1200, 1190, 1140, 1125, 1080, 1040, 1030, 980, 915, 890, 875 and 820 cm ^"1; NMR (CDC1 ₃ solution) δ: 6.50 (2H, s broad), 4.85 to 4.35 (4H ₁ m) and 4.30 to 3.00 (11H, m);
DSC (solvent benzene / ethyl acetate = 1: 2): Rf = 0.12,

REFERENCE EXAMPLE 7 20-Hydroxy-PGF ₂

686 mg of ga-hydraxy-llo :, 15 a, 20-tris (2-th trahydropyranyloxy) -prosta-cis-5, trans-13-dienoic acid prepared according to reference example 6 are dissolved in 11 ml of a mixture of acetic acid, water and tetrahydrofuran (65:35:10) and stirs the resulting one

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Solution vigorously at 40 ° C for 2 hours. The reaction mixture is concentrated under reduced pressure, and the residue is mixed with toluene and the acetic acid removed by azeotropic distillation. After the treatment has ended, the residue is purified Column chromatography over silica gel using ethyl acetate / ethanol (30: 1) as the eluent, 300 mg pure 20-hydroxy-PGFp as a colorless oil with the following physical Characteristic values receives:

IR (liquid film); v: 3350, 3010, 2950, 2860, -2200, 1715, 1460, 1440, 1415, 1250, 1190, 1150, 1120, 1085, 1060, 980, 935 and 890 cm "¹;

NMR (CDCl, - + deuterodimethyl sulfoxide solution); δ: 5.67-5.13 (4H, m), 5.10-4.32 (5H, s broad), 4.16-3.67 (3H, m) and 3.51 (2H, t); "'

DSC (mobile phase ethyl acetate / formic acid = 400: 5): Rf = 0.06.

20-Hydroxy-15-epi-PGFp is prepared according to similar procedures as described in Reference Examples 5, 6 and 7 from methyl-9oc-acetoxy-IIIa, 2Q-bis (2-tetrahydropyranyloxy) -15β-hydroxy-prosta- cis-5, trans-13-dienoate produced. The NMR and IR peaks for 20-hydroxy-15-epi-PGF _2a are essentially the same as those for 20-hydroxy-PGFp. The Rf value of 20-hydroxy-15-epi-PGF _2Q on DSC (mobile phase ethyl acetate / formic acid = 400: 5) is 0.10.

REFERENCE EXAMPLE 8

2Q-Hydroxy-15 2-PGF ₂ methyl ester

983 mg of a mixture of 20-hydroxy-PGF _2a and 2Q-hydroxy-15-epi-PGFp 'prepared according to reference example 7 are dissolved in 5 ml of methylene chloride and 5 ml of ethyl acetate and added

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with freshly prepared diazomethane solution in diethyl ether until a yellow color persists. One narrows the reaction. mixture under reduced pressure and the residue is purified by column chromatography over silica gel using ethyl acetate as the eluent, giving 954 mg of the title compound with the following physical characteristics; IR (liquid film); v: 3600-3050, 1720, 1430, 1243, 1050 and 975 cm '^1;. . .

NMR (CDC1 ₃ solution); "6: 5.8 to 5.1 (4H, m), 4.5 to 3.4 (5H, m), 3.66 (3H, s), 2.53 ( 4H, s) and 2.4-2.1 (2H, m); DSC (mobile phase ethyl acetate / formic acid = 400: 5): Rf = 0.14 (15oc_hydroxyisomer), 0.22 (15β-hydroxy isomer).

REFERENCE EXAMPLE 9 20-Acetoxy-15f-PGF _{2a -methyl ester}

The solution is added of 932 mg in accordance with Reference Example 8 produced 20-hydroxy-L5J-PWF _2a -niethylester and 4 ml of pyridine in 10 ml of methylene chloride was added dropwise under nitrogen at -20 ⁰ C with the solution of 190 mg acetyl chloride in 10 ml of methylene chloride. After stirring for 30 minutes at this temperature, an excess of ethanol and sodium bisulfate monohydrate are quickly added and the reaction mixture is allowed to warm to room temperature while stirring for 15 minutes The filtrates and washing liquids are combined, dried over magnesium sulfate, concentrated under reduced pressure and the residue is purified by column chromatography over silica gel using ethyl acetate / cyclohexane (3Jl)

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as the eluent, 520 mg of the title compound with receives the following physical parameters:

DSC (mobile phase ethyl acetate / formic acid = 400: 5): Rf = 0.24 (15α-hydroxy isomer), 0.36 (15β-hydroxy isomer);

IR (liquid film); v; 3380, 1740, 1248, 1040 and 977 cm "¹; NMR (CDCl ₃ solution); δ: 5.73-5.2 (4H, m), 4.53-3.4 (5H, m), 3 , 64

(3H, s) and 2.23 (3H, s).

REFERENCE EXAMPLE 10

20-acetoxy-9a, lla, 15 ^ -tris (2-tetrahydropyranyloxy) -PGFp methyl ester

The solution of 154 mg of 20-acetoxy-15 ^ -PGF ₂ -methyl ester prepared according to Reference Example 9 and a catalytic amount of p-toluenesulfonic acid monohydrate in 10 ml of methylene chloride are added dropwise under nitrogen at room temperature with 0.2 ml of dihydropyran. After stirring for 30 minutes, the reaction mixture is diluted with 50 ml of ethyl acetate, washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and the organic solution is concentrated under reduced pressure, giving 260 mg of the title compound with the following physical characteristics: DSC ( Mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.64.

REFERENCE EXAMPLE 11

20-Hydroxy-9a, lla, 15 ^ -tris (2-tetrahydropyranyloxy) -PGF2 _a methyl ester

50 mg of potassium carbonate are rapidly added to the solution of 260 mg prepared according to reference example 10 at room temperature 20-acetoxy-9a, lla, 15 | -tris (2-tetrahydropyranyloxy) -PGFp methyl ester in 2 ml of methanol. After stirring for 30 minutes

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The reaction mixture is diluted with 30 ml of ethyl acetate, washed with 0.72 ml of hydrochloric acid, aqueous sodium bicarbonate solution and aqueous common salt solution, dried over magnesium sulfate, concentrated under reduced pressure and the residue is purified by column chromatography over silica gel using ethyl acetate / cyclohexane (1: 1) as eluent, 220 mg of the title compound having the following physical characteristics being obtained: '. DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.21; IR (liquid film); v: 3400, 1740, 1435, 1240, 1080, 1035 and 970 cm " ^1. ■.

■ - EXAMPLE 1

20-chloro-9a, lla, l5? -Tris (2-tetrahydropyranyloxy) -PGF ₂ methyl ester

The solution of 220 mg of 20-hydroxy-9a, 11a, 15 ^ -tris (2-tetrahydropyranyloxy) -PGFp prepared according to Reference Example 11 is added methyl ester and 112 mg of pyridine in 5 ml of chloroform under nitrogen at room temperature dropwise with the Solution of 94 mg of thionyl chloride in 5 ml of chloroform. After stirring for one hour, a solution of 94 mg of thionyl chloride is again added and 112 mg of pyridine in 5 ml of chloroform to this and stirring is continued for one hour at room temperature. The reaction mixture is diluted with 30 ml of ethyl acetate and the excess thionyl chloride destroyed by adding 2 ml of water. The separated organic layer is washed with 3 ml of aqueous sodium bicarbonate solution and 3 ml of aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and cleaned the residue by column chromatography over silica gel under

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Use of benzene / ethyl acetate (3: 1) as eluent, 97 mg of the title compound having the following physical Characteristic values receives:

DSC (mobile solvent benzene / ethyl acetate = 2: 1): Rf = 0.63;

IR (liquid film); v: 1735, 1435, 1350, 1200, 1135, 1080, 1025, 970, 890, 870 and 820 cm " ¹ .

EXAMPLE 2
20-chloro-15 ξ-PGF ^ methyl ester

90 mg of 20-chloro-9a, lla, 15j -tris (2-tetrahydropyranyloxy) -PGF ^ methyl ester prepared according to Example 1 are dissolved in 2 ml of a mixture of acetic acid, water and tetrahydrofuran (65:35:10) and the mixture is stirred reaction mixture for 2 hours at 40 ° to 50 ⁰ C. it is then concentrated the reaction mixture under reduced pressure and the residue diluted with toluene and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel using benzene / ethyl acetate (1: 1) as the eluant, giving 19 mg of the title compound with the following physical characteristics: DSC (mobile phase ethyl acetate / formic acid = 400: 5): Rf = 0, 43 (15α-hydroxy isomer), 0.57 (15β-hydroxy isomer); IR (liquid film); v: 3380, 1740, 1430, 1200, 1020, 880 and 710 cm ""¹;
NMR (CDGU solution); δ: 5.6-5.2 (4H, m), 4.2-3.6 (5H, m) and 3.66 (3H, s).

REFERENCE EXAMPLE 12

2-0xa-3-oxo-6-syn- (2-methoxycarbonyl ~ trans-vinyl) -7-

~ 5,

anti-acetoxy-cis-bicyclo [^

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- 90 -

140 ml of absolute methylene chloride and 16.1 ml of absolute pyridine for 30 minutes with 10 g of chromium trioxide and then treated with 20 g of infusoric earth. After cooling to 0 ⁰ C., then 2.14 g 2-0Jca-3-oxo-6-syn-hydroxymethyl-7-anti-acetoxycis-bicyclo [3,3,0] octane [according to J. Amer. Chem. Soc., 92, 397 (1970)] in 20 ml of methylene chloride and stirred for 15 minutes at 0 ° C. The reaction mixture is then treated with 25 g of sodium bisulfate, ^{stirred for a further 10 minutes at 0} ° C. and filtered through a pad of magnesium sulfate. The filtrate is then concentrated under reduced pressure below ⁰ ° C., 2-0xa-3-oxo-6-syn-formyl-7-anti-acetoxy-cisbicyclo [3.3.0] octane being obtained.

369 mg of 65% strength sodium hydride are suspended in 60 ml of absolute tetrahydrofuran are added to the suspension under nitrogen at room temperature while stirring with 1.82 g Trimethylphosphonoacetate [according to C.R. Acad. May be. Paris. Ser. A, B 262B, 515 (1966)] and stir for 30 minutes.

Adding the above-obtained Formy! Compound in 30 ml of tetrahydrofuran are added, while maintaining the temperature below 15 ° C, and stirred for 2 hours at 15 ⁰ C. Then the reaction mixture with 2 mL of acetic acid to pH made 5, concentrated slightly, with 20 ml of water are added and the mixture is extracted twice with 80 ml of ethyl acetate each time (total volume 160 ml). The organic layer is washed with aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and the residue obtained is purified by column chromatography over silica gel using ethyl acetate / benzoil (1: 4) as the eluent, giving 2.0 g of the title compound with fol-

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the following physical parameters:

IR (liquid film); v: 2970, 1775, 1735, 1710, 1650, 1240, 1160, 1037 and 980 cm "¹;

NMR (CDCl ₃ solution) j6; 6.77 (IH, d), 5.87 (IH, d), 5.00 (2H, m),

3.70 (3H, s), 3.0-1.9 (6H, m) and 2.04 (3H, s); DSC (mobile phase ethyl acetate / benzene = 1: 2); Rf = 0.38.

REFERENCE EXAMPLE 13

2-0xa-3-oxo-6-syn- (2-methoxycarbonyl-trans-vinyl) -7-anti-hydroxy-cis-Mcyclpr 3 »3, θ] octane

2.68 g of 2-0xa-3-oxo-6-syn- (2-methoxycarbonyltrans-vinyl) -7-anti-acetoxy-cis-bicyclo [3.3.0] octane are stirred (prepared according to Reference Example 12) in 30 ml of absolute methanol and 1.38 g of potassium carbonate for 15 minutes at room temperature, then cooled in an ice bath, neutralized with 20 ml of In hydrochloric acid and treated with 260 ml of ethyl acetate and 27 ml of aqueous sodium bicarbonate solution, whereupon the reaction mixture in two layers separate. The organic layer is washed with an aqueous saline solution, dried over magnesium sulfate and concentrated under reduced pressure, giving 1.96 g of the title compound having the following physical characteristics receives:

IR (liquid film) ν: 3430, 1786-1690 (broad) and 1650 cm ^"1; NMR (CDC1 ₃ solution) j6: 6.82 (IH, dd), 5.90 (IH, d), 4 , 95 (IH, m), 3.72 (3H, s), 4.30-3.25 (2H, m) and 2.90-1.70

DSC (mobile solvent methylene chloride / methanol = 19: 1): Rf = 0.38.

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REFERENCE EXAMPLE l4

$ -Oxa-3-oxo-6-syn- (2-methoxycarbo nyl-trans-vinyl) -7-anti- (2- tetrahydroT3yranyloxy) -cis-bicyclo [3>3; oioctane

2.31 g of 2-Qxa-3-oxo-6-syn- (2-methoxycarbonyltrans-vinyl) -T-anti-hydroxy-cis-bicyclo [3 * 3.0joctane (prepared according to reference example 13) are dissolved in 30 ml Methylene chloride, and stirred for 15 minutes at room temperature with 20 mg of p-solenosulfonic acid and 3 ml of dihydropyrans. The reaction mixture is neutralized with aqueous sodium bicarbonate solution, diluted with ethyl acetate _3, washed with aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and the residue is purified by column chromatography over silica gel using ethyl acetate / benzene (IJ3) as Eluiermittelp give 3 ₃ 0 g of the title compound as white crystals having the following physical characteristics erhältι melting point of 85 ⁰ C ^

IR (KBr pellet) jv: 2930, 1770, 171O ₂ 1650, 1343, 1240 and 11.52 cm " ¹ ?....

NMR (CDCl ^ solution) ^; 6 _S 78 (IH, dd) _s 5.84 (IH, d), 4.97- (IH, m), 4 _S 63 (IH, m), 3.71 (3H ₅ s) - and 4 _s 30 -3 _sec 20 (3H, m);

DSC (mobile phase ethyl acetate / benzene = 1: 2) s Rf = 0.34.

. REFERENCE EXAMPLE 13

2 ~ 0xa-3-hydroxy-6-syn- (3-hydroxyprop-trans -l-enyl) -7-anti- (2-tetrahydropyranyloxy) -cis-bicyclo [3,3, 0j ° ^ tan

Dissolve 3? 10 g of 2-0xa-3-oxo-6-syn- (2-methoxycarbonyltrans-vinyl) ~ 7-anti- (2-tetrahydropyranyloxy) -eis-bicyclo- [3j3jO] octane (prepared according to reference example 14) in 100 ml of toluene, after cooling to -65 ⁰ G, the solution is treated with 23 ml

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Biisobutylaluminiumhydridlösung in toluene (25? 6 Gew./Vol.) And stirred for 20 minutes at -60 ⁰ C. In order to destroy excess Diisobutylaluminiumhydrids is then added to aqueous methanol. The precipitate is filtered off, the filtrate is dried and concentrated under reduced pressure, 2.8 g of the title compound having the following physical characteristics being obtained:
IP, (liquid film); v; 3390, 2930, 1350 and 1120 cm "¹;

) C1 ₃ solution); 6s 5.75-5.15 (3H, m) and 4.75-5.34 (8H, m) s

DSC (mobile solvent methylene chloride / methanol = 19: 1)! Rf = 0 _? 23 _o

REFERENCE EXAMPLE '16

2 «- (6-Methoxycarbonylhex-cis-2-enyl) -3 3- (5-hydroxyprop -transl ~ eny1 ) -4a- (2-tetrahydropyranyloxy) -cyclopentan-la-ol

Is suspended 2.94 g of 65 -? & Lges sodium hydride in 40 ml dimethyl sulfoxide and stirred for 40 minutes under heating at 65 ⁰ C to obtain Natriummethylsulfinylmeth'ylid. The mixture is allowed the reaction mixture to cool to room temperature and then dropwise add it to the solution of 18.5 g of (4-carboxybutyl) triphenylphosphonium bromide in 40 ml of dimethyl sulfoxide a _g wherein the reaction temperature in the range is maintained 2C ⁰ C to 25 ⁰ C.

A solution of 2.84 g of 2-0xa-3-hydroxy-6-syn- (3-hydr oxy-pr op-trans-1-enyl) -7-anti-(2-th trahydropyranyloxy) -cis is added bicyclo [3 "3 _J 0] octane (described in reference example · 15hergestellt) in 40 ml dimethyl sulfoxide, the Reaktionsgemiscli stirred vigorously for 1 hour at 25 ⁰ C, pouring it into 500 ml of ice

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water and removes neutral substances by extraction with ethyl acetate / diethyl ether (1: 1). The aqueous layer is ^{acidified to pH 3 with 1} saturated oxalic acid solution and extracted with diethyl ether / ethyl acetate (1: 1). After washing with water, the extracts are dried over magnesium sulfate and concentrated under reduced pressure, crude 2a- (6-carboxyhex-cis-2-enyl) -3ß- (3-hydroxyprop-trans-l-enyl) -4a- (2-tetrahydropyranyloxy) -cyclopentan-la-ol with the following physical characteristics:

IR (liquid film); v: 2930, 1720, 1240 and 1120 cm "¹; NMR (CDC1 ₃ solution); 6: 5.70-5.25 (4H, m) and 4.62 (IH, m) ; DSC (mobile phase methylene chloride / methanol = 19: 1): Rf = 0.23.

The crude acid compound thus obtained is dissolved in 40 ml of methylene chloride, cooled to ⁰ ° C. and mixed with diazomethane solution in diethyl ether until the reaction mixture is pale yellow in color. The reaction mixture is then concentrated under reduced pressure and the residue is column chromatographed over silica gel using ethyl acetate / cyclohexane (1: 1) as the eluent, giving 2.87 g of the title compound with the following physical characteristics: IR (liquid film); ν : 3420, 2930, 1740, 1435 and 1020 cm "¹; NMR (CDCl ₃ solution); δ: 5.75-5.20 (4H, m), 4.67 (IH, m), 4.20- 3.30 (6H, m) and 3.67 (3H, s);

DSC (mobile phase ethyl acetate / cyclohexane = 2: 1): Rf = 0.31.

REFERENCE EXAMPLE 17

2a- (6-Methoxycarbonylhex-cis-2-enyl) -3β- (2-formyl-transvinyl) -4a- (2-tetrahydrot | yranyloxy) -cyclopentan-la-ol

The solution of 382 mg of 2a- (6-methoxy- 6 09850/1106

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earbonylhex-cis-2-enyl) ™ 3β ~ (3-hydroxyprop-trans-1-enyl) ~ 4α- (2-tetrahydropyranyloxy) "cyclopentan-la-ol (prepared according to reference example ίδ) in 30 ml of methylene chloride with 3.8 g active manganese dioxide, stir for 2 hours at room temperature. and filtered off. The precipitate is washed thoroughly with acetone washed, and the filtrate and the washing liquid combined and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel using ethyl acetate / benzene (1: 4) as the eluent, wherein you get 266 mg of the title compound with the following physical Characteristic values receives:

IR (liquid film); v: 3450, 2930, 1737, 1688, 1632, 1435, 1125, 1022 and 977 cm "¹;

NMR (CDC1 ₃ solution), 5: 9.56 (IH, d), 6.82 und.6,79 (each IH, dd), 6.20 and 6.18 (each IH, dd), 5, 36 (2H, m), 4.58 (IH, m), 3.61 (3H, s) and 4.30-3.20 (4H, m);
DSC (mobile phase ethyl acetate / benzene = 1: 2): Rf = 0.27.

EXAMPLE 3
20-chloro-II- (2-tetrahydropyranyloxy) -15 ^ -PCF. "-Methyl ester

380 mg of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3β- (2-formyl-trans-vinyl) -4a- (2-tetrahydropyranyloxy) -cyclopentan-la-ol prepared according to reference example 17 are dissolved in 10 ml of tetrahydrofuran, the solution was added dropwise at -25 C under nitrogen with 6.5 ml 0,33m-5-chloro-n-pentylmagnesiumbromidlösung in tetrahydrofuran and the reaction mixture stirred for 10 minutes at -25 ⁰ C and 2 hours at room temperature. The reaction mixture is then cooled and the reaction is terminated using an excess of aqueous ammonium chloride solution.

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While stirring for 15 minutes, the reaction mixture is allowed to warm to room temperature, shaken out with ethyl acetate, the organic layer is washed with aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and the residue is purified by column chromatography over silica gel using benzene / Ethyl acetate (3: 1) as eluent, 200 mg of the title compound having the following physical characteristics being obtained: i

DSC (mobile solvent benzene / ethyl acetate = 1: 1): Rf = O ₅ 33 (15- • • hydroxy isomer), 0.4 (15 [beta] -hydroxy isomer).

EXAMPLE 4
20-chloro-PGF _2a methyl ester

330 mg of 20-ChlorIII- (2-tetrahydropyranyloxy) -15 | -PGFp prepared according to Example 3 are dissolved methyl ester ■ in 7 ml of one Mixture of acetic acid, water and tetrahydrofuran (65:35:10) and the reaction mixture is stirred at 60 ° to 70 ° C. for 2 hours. Then the reaction mixture is under reduced pressure concentrated and the residue diluted with toluene and concentrated under reduced pressure. The residue is cleaned thoroughly Column chromatography over silica gel using ethyl acetate / cyclohexane (2: 1) as the eluent, giving * 93 mg of the title compound and 109 mg of its 15β-hydroxy isomer. The title compound has the following physical characteristics on:

DSC (mobile phase ethyl acetate / formic acid _F 400: 5): Rf = 0.43; (15β-hydroxy isomer: 0.57);
IR (liquid film); v: 3350, 1735, 1430, 1198 ,. 1020, 880 and 710 cm " ¹

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NMR (CDCly solution); δ: 5.57-5.25 (4Η, m), 4.25-3.7 (3Η, m), 3.65 (3Η, s) and 3.51 '(2H, t).

REFERENCE EXAMPLE 18

2 (x- (6-Carboxyhex-cis-2-enyl) -3β- (2-formyl-trans-vinyl) -4a- (2-tetrahydropyranyloxy) -cyclopentan-1-one

1.0 g of 2a- (6-carboxyhex-cis-2-enyl) -3ß- (3-hydr oxyprop-trans-l-enyl) -4a- (2-tetrahydropyranyloxy) -cyclopentan- la-ol in 47.5 ml of diethyl ether and cool the solution to 0 ° C. 47.5 ml of a 12 g by dissolution of manganese sulfate, 2.5 g of chromium trioxide and 2.75 ml of sulfuric acid in 50 ml ¥ ater prepared chromic acid solution is added thereto and stirred vigorously, the reaction mixture for one hour at -5 ° to 5 ⁰ C. After the aqueous layer has been saturated with sodium sulfate, the reaction mixture is then extracted with diethyl ether. The ether extract is washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and the residue is purified by column chromatography over silica gel using benzene / ethyl acetate (2: 1) as the eluent, 250 mg 2a ~ ( 6-Carboxyhex-cis-2-enyl) -3β ~ (2-formyl-trans-vinyl) -4a- (2-tetrahydropyranyloxy) -cyclopentan-l-one with the following physical characteristics: * NMR (CDC1 ₃ solution) ; δ; 2.5-3.0 (1H, dd), 4.5-4.8 (IH, m), 5.0-5.6 (2H, m), 6.25 (IH, dd), 6, 90 (IH, dd), 7.3-7.8 (IH, m) and 9.62 (IH, d);

IR (liquid film) j ν; 3000, 2930, 2850, 1735, 1685, 1435, 1345, 1155, 1125, 1075, 1035, 975 and 915 cm "¹; DSC (eluent benzene / ethyl acetate = 1: 2): Rf = 0.60.

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. 2622418

REFERENCE EXAMPLE 19

2α- (6-Methoxycarbonylhex-cis-2-enyl) -5β- (2-formyl-trans-vinyl) -4α- (2-tetrahydropyranyloxy) -cyclopentan-1-one

2.0 g of 2a- (6-carboxyhex-cis-2-enyl) -3β- (2-formyl-trans-vinyl) -4a- (2-tetrahydropyranyloxy) -cyclopentan-1-one prepared according to reference example 18 are dissolved in 200 ml of diethyl ether and this solution is added at ⁰ ° C. Freshly prepared diazo, methane solution in diethyl ether. After stirring for 10 minutes at the same temperature, the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography over silica gel using benzene / ethyl acetate (3: 1) as the eluent, whereby 1.65 g of 2a- ( 6-methoxycarbonyl- • hex-cis-2-enyl) -3ß- (2-formyl-trans-vinyl) -4a- (2-tetrahydropyranyloxy) -cyclopentan-l-one with the following physical characteristics:

NMR (CDCl ₃ solution); δ: 3.63 (3H, s), 4.5-4.8 (IH, m), 5.05-5.7 (2H, m), 6.25 (IH, dd), 6.93 (IH, dd) and 7.59 (IH, d); '·

IR (liquid film); v: 2940, 2860, 1740, 1690, 1640, 1440, 1350, 1250, 1200, 1080, 1035 and 975 cm " ¹ .

EXAMPLE 5
20-chloro-II- (2-tetrahydropyranyloxy) -15 t-PGE ₂ methyl ester

1.89 g of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3β- (2-formyl-trans-vinyl) -4a- (2-tetrahydropyranyloxy) -cyclopentan-1-one prepared according to reference example 19 are dissolved in 25 ml of tetrahydrofuran and the solution added dropwise at -78 ⁰ C under nitrogen with 20 ml O ^ mS-chloro-n-pentylmagnesiumbromidlösung in tetrahydrofuran and stir the reaction mixture 15

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Minutes "at -78 C and one hour at room temperature .. Then the reaction is terminated using 10 ml of aqueous ammonium chloride solution. The reaction mixture is extracted with ethyl acetate, Washed with aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and cleaned Residue by column chromatography over silica gel using benzene / ethyl acetate (5: 1) as the eluent, whereby 791 mg of the title compound are obtained with the following physical characteristics:

DSC (solvent benzene / ethyl acetate = 1: 1): Rf = 0.4l (15a-hydroxy isomer), 0.51 (15β-hydroxy isomer).

EXAMPLE 6
20-chloro-PGE ₂ methyl ester

352 mg of 20-Chlorll- (2-tetrahydropyranyloxy) -15 | -PGE2-methyl ester prepared according to Example 5 are dissolved in 6 ml of a mixture of acetic acid, water and tetrahydrofuran (65:35:10) and the reaction mixture is stirred at 45 ° C. for 2 hours. Afterward the reaction mixture is concentrated under reduced pressure, the residue is diluted with toluene and again at reduced pressure Pressure restricted. The residue is purified by column chromatography over silica gel using benzene / ethyl acetate (2: 1) as eluent, 89 mg of the title compound and 96 mg of its 15β-hydroxy isomer being obtained. the Title compound has the following physical characteristics: DSC (mobile solvent benzene / ethyl acetate = 1: 1): Rf = 0.1; (I5β-hydroxy isomer: 0.15);

IR (liquid film); · v: 3380, 1740, 1720, 1438, 1245, ll60, 1075, 975, 760 and 730 cm "¹;

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NMR (CDCl ₃ -LOSiAIg); δ; 5.65-5.5 (2H, m), 5.45-5.35 (2H, ₅ m), 4.25-3.9 (2H, m), 3.68 (3H, s), 3, 55 (2H, t) and 2.75 (IH, dd).

REFERENCE EXAMPLE 20 Ethyl 2 ^ - methyl-6- (2-tetrahydropyranyloxy) hexanoate

The solution of 6.2 ml of diisopropylamine in 50 ml of tetrahydrofuran is added dropwise with stirring at -70 ° C. with 36 ml of 1,37m-n-butyllithium solution in η-hexane and the mixture is stirred for 15 minutes at the same temperature, lithium diisopropylamide being obtained . The amide solution thus obtained is added dropwise at -70 C with the solution of ethyl 6- (2-tetrahydropyranyloxy) hexanoate in ml of tetrahydrofuran, prepared according to Reference Example 1, and the mixture is stirred for 30 minutes at the same temperature. Added to the reaction mixture at -70 ⁰ C was added dropwise the solution of 3 ml of methyl iodide in 20 ml of tetrahydrofuran and stirred for 10 minutes at the same temperature and then for one hour at room temperature. The reaction mixture is poured into water, extracted with ethyl acetate, the extract is washed with water, dried over magnesium sulfate, concentrated under reduced pressure and distilled. residue obtained in vacuo, 6.2 g of the title compound having the following physical characteristics being obtained: boiling point: 129-132 ° C./4 torr;

IR (liquid film); v: 2920, 2850, 1735, 1460, 1380, 1355, 1265, 1205, 1080 and 1040 cm "¹;

NMR (CCl ₄ solution); δι 4.70-4.50 (IH, m), 4.42 (2H, q), 4.40-3.15 (4H, m) and 1.25 (3H, t).

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REFERENCE EXAMPLE 21

Dimethyl 2-oxo-5f> -methyl-7- (2-tetrahydropyranyloxy) heptyl phosphonate

The solution of 12 g of dimethyl methylphosphonate in 140 ml of absolute tetrahydrofuran is added dropwise with 71 ml of 1.37m-n-butyllithium solution in η-hexane, the temperature being kept below -50.degree. Ten minutes later, the solution at -70 ⁰ C is treated dropwise with the solution of 12.4 g in Reference Example 20 prepared ethyl-2j - methyl-6- (2-tetrahydropyranyloxy) hexanoate was added in 70 ml of absolute tetrahydrofuran and the mixture 2 hours stirred at the same temperature and then at 4 ° C for 16 hours. The reaction mixture is acidified with acetic acid, concentrated under reduced pressure, the residue is dissolved in a little water and extracted with diethyl ether. The extract is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is subjected to distillation at 45 to 59 ° C. and a pressure of 2 to 4 torr. The residue is purified by column chromatography over silica gel using ethyl acetate as the eluent, 14.0 g of the title compound having the following physical characteristics: IR (liquid film); .v: 2930, 2850, 1715, 1455, 1445, 1375, 1365, 1330, 1260, 1200, 1180, 1140, 1120, 1035 and 990 cm "¹; NMR (CDC1 ₃ solution); δ: 4.70- 4.40 (IH, m) ·, 4.15-3.10 (4H, m), 3.77 (6H, d) and 3.10 (2H, d).

REFERENCE EXAMPLE 22 Dimethyl 2-oxo-3 ^ -methyl-7-hydroxyheptylphosphonate 'The solution of 19 g according to the reference example is added

21 produced dirnethyl-2-oxo-35-roethyl-7- (2-tetrahydro-

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pyranyloxy) heptylphosphonate in 100 ml of anhydrous methanol with 1.0 g of p-toluenesulfonic acid and the mixture is stirred for one hour Room temperature. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 300 ml of ethyl acetate and the resulting solution washed with aqueous sodium bicarbonate solution and aqueous saline solution over magnesium sulfate dried and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel using ethyl acetate / methanol (10: 1) as • Eluent, with 14.0 g of the title compound with the following physical characteristic values:

NMR (CDCU solution); δ: 3.80 (6H, d), 3.60 (2H, t), 3.25 (IH, s), 3.14 (2H, d), 2.90-2.55 (IH, q), 2.00-1.21 (6H, m) and 1.10 (3H, d).

REFERENCE EXAMPLE 23 Dimethyl 2-oxo-3t-methyl-7-acetoxyheptylphosphonate

The solution of 20 is treated g in Reference Example 22 produced dimethyl ^ -oxo ^ i-methyl-T-hydroxyheptylphosphonat in a mixture of 160 ml methylene chloride and 50 ml of pyridine was added dropwise at 20 ° to 30 ⁰ C with the solution of 8.0 ml Acetyl chloride in 20 ml methylene chloride. The mixture is stirred for 15 minutes at the same temperature and then 10 ml of methanol and 132 g of sodium bisulfate monohydrate are added. A yellow solid is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography over silica gel using ethyl acetate as the eluent, 19 g of the title compound having the following physical characteristics:

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HMR (CDCl ^ solution); δ: 4.08 (2H ₅ t), 3.82 (6H, d), 3.20 (2H, d), 3.00-2.05 (IH, q), 2.05 (3H, s) , 1.80-1.35 (6H, m) and 1.15 (3H, d).

REFERENCE EXAMPLE 24

Methyl-9cc, lla-bis (2-tetrahydropyranyloxy) -15-οχο-Ιβ V-methyl-2Q-acetoxy-prosta-cis-5, trans-13-dienoate

The solution of 19 g of dimethy l-2-oxo-3 "5- ^me " tl ¹ yl-7-acetoxyheptylphosphonate prepared according to the reference example in 20 ml of anhydrous tetrahydrofuran is added dropwise with stirring at room temperature under nitrogen into the suspension of 1.55 g of sodium hydride in 200 ml of anhydrous tetrahydrofuran. When the solution has cleared, it is added dropwise with 9.0 g of 2ce- (6-methoxycarbonylhex-cis-2-enyl) -3β-formyl-la, 4a- bis- (2-tetrahydropyranyloxy) cyclopentane in.10 ml of anhydrous tetrahydrofuran and the mixture is stirred for 2 hours at 20 to 30 ⁰ C. the mixture is acidified with acetic acid, the reaction mixture filtered through a magnesium sulfate pad and the filtrate under reduced pressure, concentrated and purified the residue by column chromatography over silica gel using benzene / ethyl acetate (3: 1) as the eluent, 10 g of the title compound having the following physical characteristics being obtained:

DSC (solvent benzene / ethyl acetate = 3: 1): Rf = 0.50; IR (liquid film); v: 2950, 2850, 1740, 1700, 1670, 163O, 1460, 1440, 1370, 1250, 1150, 1090, 1040 and 1000 cm "¹; NMR (CDCl ₃ -LOSUiIg); δ: 6.95-6.15 (2H, m), 5.70-5.21 (2H, m), 4.75-4.40 (2H, m), 4.05 (2H, t), 3.65 (3H, s) and 4.31-2.10 (6H, m).

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The 2a- (6-methoxycarbonylhex-cis-2-enyl) -3ßformyl-1, 4a-bis (2-tetrahydropyranyloxy) cyclopentane used as starting material in the procedure described above is prepared as follows from 2a- (6-methoxycarbonylhex) prepared according to reference example 3 -cis-2-enyl) -3ß-hydroxymethyl-4a- (2-tetraiiydropyranyloxy) cyclopentan-la-ol produced ι

The solution of 12 g of 2a- (δ-methoxycarbonylhex-cis ^ -enyl) -3ß-hydroxymethyl-4a »(2-tetrahydropyranyloxy) -cyclopentan-la-ol in 60 ml of methylene chloride is added dropwise at -20 -30 ° to ⁰ C with a solution of 3) 2 g of acetyl chloride in 40 ml of anhydrous methylene chloride and the mixture stirred for 45 minutes at -30 ⁰ C. the reaction mixture thus obtained is mixed at 10 ml of methanol and 40 g Natriumbisulf. A yellow solid is filtered off and the filtrate is concentrated under reduced pressure, 15 g of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3β-acetoxymethyl-4a- (2-tetrahydropyranyloxy) cyclopentan-la-ol having the following physical properties Characteristic values receives:

DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.46; IR (liquid film); v: 3500, 2950, 2850, 1740, 1440, 1370, 1250 ujad 1150 cm "¹;

NMR (CDCl ₃ solution); δ: 5.70-5.23 (2H, m), 4.85-4.56 (1H, m), 3.65 (3H, s), 4.40-3.34 (7H, m) and 2.05 (3H, s).

The solution of 15 g of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3ß-acetoxymethyl-4a- (2-tetrahydropyranyloxy) ~ cyclopentan-la-ol, prepared as above, is added in 100 ml of methylene chloride with 81 mg of p-toluenesulfonic acid and 5.0 g of 2,3-dihydropyran. After stirring for 10 minutes at room temperature, the

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Solution with 200 ml of ethyl acetate, washed with aqueous sodium bicarbonate solution and aqueous common salt solution _5, dried over magnesium sulfate and concentrated under reduced pressure., 17 g of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3ß-acetoxymethyl ~ la, 4a-bis (2-tetrahydropyranyloxy) cyclopentane with the following physical characteristics:

DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.67; IR (liquid film); v: 2950, 2850, 1740, 1440, 1380, 1250,

1220, 1140 and 1030 cm * " ¹ .

The solution of 17 g of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3ß-acetoxymethyl-1, 4abis (2-tetrahydropyranyloxy) cyclopentane in 120 ml of methanol at room temperature with 7.3 g of potassium carbonate and stir for 30 minutes at room temperature. The reaction mixture is acidified with acetic acid, diluted with 300 ml of ethyl acetate, washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel using benzene / ethyl acetate (2: 1) as the eluent, 12 g of 2a- (6-methoxycarbonylhex-cis-2-enyl) -3β-hydroxymethyl-1, 4a-bis (2-tetrahydropyranyloxy) -cyclopentane with the following physical characteristics is obtained: DSC (solvent benzene / ethyl acetate --- 2: 1): Rf = 0.38; NMR (CCl ₄ solution); δ: 5.59-5.15 (2H, m), 4.83-4.45 (2H, m), 3.65 (3H, s) and 4.33-2.90 (9H, m).

The solution of 25.9 g of pyridine in 400 ml of methylene chloride is _{mixed with 16}} 4 g of chromium trioxide at room temperature under nitrogen, and the mixture is stirred for 20 minutes

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Room temperature and then add 70 g of infusory soil. The mixture is ^{cooled to 0} ° C. and a solution of 12 g of 2a- (6-methoxycarbonylhex ~ cis-2-enyl) -3β-hydroxymethyl-1, 4oc-bis (2-tetrahydropyranyloxy) cyclopentane in 30 ml of methylene chloride, prepared as above, is added . After stirring at ⁰ ° C. for 30 minutes, 100 g of sodium bisulfate are added, the reaction mixture is stirred for 10 minutes at the same temperature, filtered through a pad of magnesium sulfate and the filtrate is concentrated under reduced pressure, 9 g of 2a- (6-methoxycarbonylhex-cis -2-enyl) - · 3ß-formyl-la, 4a-bis (2-tetrahydropyranyloxy) cyclopentane with the following physical characteristics; DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.65; IR (liquid film); v: 2950, 2850, 1740 (broad), 1440, 1360, 1250, 1210, 1170, 1150, 1090, 1050 and 1000 cm "¹; NMR (CDCIU solution); δ: 9.75 (IH, s broad ), 5.55-5.15 (2H, m), 3.65 (3H, s) and 4.30-3.00 (6H, m).

REFERENCE EXAMPLE 25

Methvl-9a »lla-bis (2-tetrahydropyranyloxy) -15a-hydroxy-16tmethyl ^ O-acetoxyprosta-cis ^, trans-13-dienoate

The procedure is as described in reference example 4, but replacing the methyl ~ 9cc-acetoxy-llcc, 20-bis (2-tetrahydropyranyloxy ) -15-oxoprosta-cis-5, trans-13-dienoate by 10 g prepared according to Reference Example 24 dissolved in 100 ml of methanol Methyl-9oc, 11a-bis (2-tetrahydropyranyloxy) -15-oxol6j-methyl-20 ~ acetoxyprosta-cis-5, trans-13-dienoate and using 2.6 g of sodium borohydride, 4.15 g of the title compound and 3.32 g of its 15β-hydroxy isomer are obtained as well 0.53 g of a mixture of the isomers. The title compound has

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the following physical characteristics on DSC (solvent benzene / ethyl acetate = 2si) % Rf = 0.48; (15β-hydroxy isomer ₅ Rf = 0.56) 5

IR (liquid film); v: 3450, 295O ₅ 285O ₅ 1740, 1440, 1370,

1250, 1150, 1090, IO30 and 980 cm "¹; NMR (CDCl ₇ solution);. Δ: 5.72-5.23 (4H, m), 4.70-4.50 (2H, m), 4.09 (2H, t), 3.67 (3H ₅ s), 4.32-3.23 (8H ₅ m), 2.05 (3H, s) and 0.95 (3H, d).

REFERENCE EXAMPLE 26

Methyl-9 " , Ha , 15a-tris (2-tetrahydropyranyloxy) -16 \ -inethyl-20-acetoxyprosta-cis-5, trans-13-dienoate

Proceeding as described in reference example 5, but replacing the methyl-9cc-acetoxy-lla, 20-bis (2-tetrahydropyranyloxy) -15a-hydroxyprosta-cis-5, trans-13 ~ dienoate through 4.15 g of methyl 9a, 11a-bis (2-tetrahydropyranyloxy) -15ahydroxy-16-methyl-20-acetoxyprosta-cis-5, trans-13-dienoate, dissolved in 40 ml of methylene chloride and prepared according to reference example 25 as well as using 13 mg p-toluenesulfonic acid and 0.86 g 2,3-dihydropyran, this gives 5.0 g of the title compound with the following physical characteristics:

DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.70; IR (liquid film); v: 2950, 2850, 1740, 1450, 1440, 1370, 1250, 1150, 1090, 1050 and 980 cm " ¹ .

BEZUC S EXAMPLE 27

Methvl-9oc »Ha, 15a-tris (2-tetrahydropyranyloxy) -16 s-methyl-20-hydroxyprosta-cis-5> trans-13-dienoate

If one proceeds as described in reference example 11, but with replacement of the methyl-9a, "lla, l5? -Tris (2-tetrahydro-

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pyranyloxy) -20-acetoxyprosta-cis-5 _s trans-13-dienoate [20 ~ acetoxy ~ 9a, llaj, 155-tris (2-tetrahydropyranyloxy) -PGFp -methyl ester] by 5.0 g M 60 ml of methanol, according to the reference example

26 produced methyl-9a _? 11a, 15a-tris (2-tetrahydropyranyloxy) -16-5-ynethyl-20-acetoxyprosta-cis-5, trans-13-dienoate and using 2.8 g of potassium carbonate, 3 * 26 g of the title compound are obtained with the following physical parameters:

DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0 _s 32; IR (liquid film); v: 3450, 2950, 2850, 1740, 1440, 1360, 1210, 1150, 1090, 1040 and 980 cm " ¹ ?

NMR (CDCl ₃ solution); δ: 5.60-5.15 (4H, m), 4.70-4.51 (3H, m), 3.65 (3H, s), 4.20-3.31 (HH, m) and 0.95 (3H, t).

REFERENCE EXAMPLE_28 '

M ethyl-9a> 11 α, 15a-tris (2-tetrahydropyranyloxy) -L6 ^ - me t hyl -20- (p-toluenesulfonyloxy) prosta-cis-5, trans-13-dienoate is added the solution of 3 * 26 g according to the reference example

27 prepared methyl 9a, lla, l5a-tris (2-tetrahydropyranyloxy) -l65-methyl-20-hydroxyprosta ~ cis-5, trans-13 ~ dienoate in 20 ml of methylene chloride at ⁰ ° C. with 1.4 ml of triethylamine and 1 , 43 g tosyl chloride. The mixture is one hour at 0 C and then.

Stirred for 4 hours at room temperature. The reaction mixture is poured into 100 ml of ethyl acetate and the solution is washed with aqueous solution Sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and purifies the residue by column chromatography over silica gel using benzene / ethyl acetate (5: 1) as the eluent, 3.4 g of the title compound having the following physical characteristics are obtained:

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BSC (solvent benzene / ethyl acetate = 5si): Rf = 0.46s NMR (CDClj solution); δ: 7.75 (2H ₅ d), 7.41 (2H, d), 5.70-5.15

(4H, m), 4.78-3.98 (3H ₅ m), 4 _s 02 (2H, t), 3 _S 65 (3H, s), 4 _S 26-3.25 (9H, m), 2.45 (3H, s) and 0.95-0.75 (3H ₅ m).

EXAMPLE 7

Methyl 9 "" 11 " , 15" -tris (2-tetrahydropyranyloxy) -16t-niethyl-20-chloro-prosta-cis-5, trans-13 -dienoate

The solution of 3.5 g of lithium chloride in 100 ml of Ν, Ν-dimethylformamide is mixed with the solution of 3.4 g according to Reference Example 28 prepared methyl 9a, 11a, 15a-tris (2-tetrahydropyranyloxy) -16 | -methyl-20- (p-toluenesulfonyloxy) -prosta-cis-5, trans-13-dienoate in 10 ml Ν, Ν-dimethylformamide and stir the mixture for two hours at room temperature. The reaction mixture is poured in 500 ml of ethyl acetate, the solution is washed with water and aqueous sodium chloride solution and dried over magnesium sulfate and concentrated under reduced pressure, giving 2.0 g of the title compound with the following physical characteristics receives:

DSC (solvent benzene / ethyl acetate = 5: 1): Rf = 0.56; NMR (CDCl ₃ solution); δ .: 5.61-5.15 (4H, m), 4.55-4.42 (3H, m), 3.65 (3H, s), 3.50 (2H, t), 4.30 -3.20 (9H, m) and 0.95-0.70 (3H, m).

EXAMPLE 8

Methyl 9a, Ha, I5a-trihydroxy-16 <-met h yl-20-chloro-p r osta- cis-5, trans-13-dienoate [165-methyl-20-chloro-PGFp _or -methyl ester] is followed as described in Example 2, but with replacement of the methyl 1 · -9α, 11α, 15 | -tris (2-tetrahydropyranyloxy) 20-chloro-prosta-cis-5, trans-13-dienoate [20-chloro-9a, lla, l5t-

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tris (2 ~ tetrahydropyranyloxy) -PGF ₂ -methyl ester] by 1.0 g of methyl Sa, lla, 15a-tris (2- tetrahydropyranyloxy) -l6 ^ -methyl-20-chloro prosta-cis-5, trans-13-dienoate, this gives 241 mg of the title compound with the following physical characteristics: DSC (mobile solvent chloroform / tetrahydrofuran / acetic acid = 10: 2: 1) % Rf = 0.375;

IR (liquid film); v: 3400, 2950, 2850, 1740, 1440, 1380, 1320, 1240, 1170, 1050 and 980 cm "¹;

NMR (CDCl ₃ solution); δ: 5.60-5.26 (4H, m), 4.25-3.76 (3H, m), 3.65 (3H, s), 3.55 (2H, t) and 0.95 ( 3H, t).

EXAMPLE 9

Methyl-9-oxQ-lla, l5a-dihvdroxy-l6? ~ Methyl-20-chloro-prosta cis-5, trans-13-dienoate [16g-methyl-20-chloro-PGE ₂ -methylester]

The solution of 319 mg of methyl ~ 9a, 11a, 15a-trihydroxy ~ 16E-methyl-20-chloro-prosta-cis-5, trans-13-dienoate, prepared according to Example 8 is added in 7 ml of anhydrous acetone under nitrogen with 1.5 ml of N-trimethylsilyl diethylamine, stirred 5 seconds at 30 ° C. and the reaction mixture is concentrated under reduced pressure, giving 530 mg of methyl-9a-hydroxy ~ lla, l5a-bis (trimethylsilyloxy) -l6g-methyl-20-chloro-prosta-cis-5, trans- 13-dienoate receives.

0.91 g of chromium trioxide are introduced under nitrogen into a solution of 1.47 ml of anhydrous pyridine and 25 ml of methylene chloride, the mixture is stirred for 20 minutes at room temperature and then 2.5 g of infusoric earth are added. It is cooled to ⁰ ° C., and the solution of 530 mg as prepared above is added

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Methyl-9a-hydroxy-lla, l5a-bis (trimethylsilyloxy) -l6§-methyl- ' 20-chloro-prosta-cis-5, trans-13-dienoate in 3 ml of methylene chloride and stir the mixture for 15 hours at OC. 3 ml of allyl alcohol are added and the mixture is stirred for 10 minutes at the same temperature and then 6 g of sodium bisulfate are added. After stirring for 10 minutes at this temperature, the reaction mixture is filtered through a pad of magnesium sulfate and concentrated Filtrate under reduced pressure, 515 mg of methyl 9-oxo-11a, 15a-bis (trimethylsilyloxy) -16-methyl-20-chloroprostacis-5, trans-13-dienoate receives.

The solution of 515 mg of methyl 9-oxo-IIIa, 15a-bis (trimethylsilyloxy) -16§-methyl-20-chloroprosta-cis-5, trans-13-dienoate in 10, prepared as described above is added ml of ethyl acetate with 10 ml of saturated aqueous oxalic acid solution and the mixture is stirred for 5 minutes at room temperature. The reaction. mixture is washed with water and aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel using benzene / ethyl acetate (1: 3) as the eluant, giving 95 mg of the title compound with the following physical characteristics: DSC (mobile phase benzene / ethyl acetate = 1: 3): Rf = 0, 29; IR (liquid film); v: .34OO, 2950, 2850, 1740, 1430, 1370, 1310, 1250, 1220, 1160, 1080 and 980 cm "¹; NMR (CDC1 ₃ solution); δ: 5.70-5.55 (2H, m), 5.45-5.32 (2H, m), 4.14-3.80 (2H, m), 3.66 (3H, s), 3.55 (2H, t), 2.23 (IH, dd) and 0.97-0.80 (3H, m).

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EXAMPLE 10

Me thy 1-9α _? 11κ , ΐ5α-ΐΓΐηνάΓθχν-1β " -ΐαΘΪ] ιν1-20- ^ 1θΓ-ρΓθ3Ϊ-tran s-13-enoate [16S ~ methyl-20-chloro- ~ PGF _la -methyl ester]

The solution of 1.09 g of methyl 9a, 11α, 15cc-tris (2-tetrahydropyranyloxy) -166-methyl-20-chloroprosta-cis-5, trans-13-dienoate is hydrogenated in 10 ml of 0, ^ 6 g of 5-% palladium-carbon containing methanol at a Atmosphere pressure. After one equivalent of hydrogen gas has been taken up, the catalyst is filtered off and the filtrate is concentrated at reduced pressure, 1.0 g of methyl 9a, lla, 15atris (2-tetrahydropyranyloxy) -166-methyl-20-chloro-prost-trans-13-enoate receives.

The procedure is as described in Example 2, but with replacement of the methyl-9a, 11a, "15jr-tris (2-tetrahydropyranyloxy) -20-chloro-prosta-cis-5, trans-13-dienoate [20-chlorine -9a, lla, 155-tris (2-tetrahydropyranyloxy) -PGFp -methyl ester] by 1.0 g in a mixture of 16 ml acetic acid, 9 ml water and 3 ml tetrahydrofuran dissolved, prepared as described above, methyl-9a, 11a, 15a-tris (2-tetrahydropyranyloxy) ~ 16 ^ -methy1-20-chloro-prost-trans-13-enoate, 380 mg of the title compound are obtained with the following physical characteristics: DSC (mobile solvent ethyl acetate / benzene = 5: 1): Rf = 0.34; IR (liquid film); v: 3450, 2950, 2850, 1740, 1442, 1380, 1310, 1170, 1050 and 980 cm "¹;

NMR (CDCl ,, solution); δ: 5.71-5.55 (2H, m), 4.23-3.7.1 (3H, m), 3.66 (3H, s), 3.56 (2H, t) and 0.93 (3H, t).

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EXAMPLE 11

Methyl-9-oxo-llo :, 15 <x-dihydroxy-16S -methyl- ^ O-chloroprost trans-13-enoate [16f-methyl-20-chloro-PGE - ^ - methyl ester]

The procedure is as described in Example 9, but replacing the methyl 9a, 11a, 15a-trihydro: xy-16§-methyl-20-chloroprosta-cis-5, trans-13-dienoate with 363 mg according to Example 10 If methyl 9a, lla, l5a-trihydroxy-l6g-methyl-20-chloro-prost-trans-13-enoate is produced, 145 mg of the title compound are obtained with the following physical characteristics: DSC (mobile phase ethyl acetate / benzene = 3: 1) : Rf = 0.325; IR (liquid film); v: 3400, 2950, 2850, 1740, 1430, 1370, 1310, 1250, 1220, 1160, 1030 and 980 cm "¹; NMR (CDCl3 solution); δ: 5.76-5.55 (2H, m ), 3.65 (3H, s), 3.55 (2H, t), 4.30-3.35 (4H, m), 2.88-2.56 (IH, dd) and 0.99- 0.80 (3H, t).

REFERENCE EXAMPLE 29

Methyl-9 ", Uo :, 15β-tris (2-tetrahydropyranyloxy) -165-methyl-20-acetoxyprosta-cis-5, trans-13-dienoate

The procedure is as described in reference example 5, but replacing the methyl 9a-acetoxy-11a, 20-bis (2-tetrahydropyranyloxy) -15a-hydroxyprosta-cis-5, trans-13-dienoate by 3.4 g of methyl-9a, 3.1a-bis (2-tetrahydropyranyloxy) -15, prepared according to reference example 25, dissolved in 40 ml of methylene chloride β-hydroxy-l6 | ~ methyl ~ 20-acetoxyprosta-cis-5, trans-13-dienoate so / ie using 13 mg of p-toluenesulfonic acid and 0.715 g of 2,3-dihydropyran, 4.12 g of the title compound are obtained with the following physical characteristics: DSG (solvent benzene / ethyl acetate = 2: 1): Rf = 0.76;

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IR (liquid film); ν: 2950, 2850, 1740, 1450, 1440, 1370, 1250, 1150, 1090, 1050. and 980 cm " ¹ .

REFERENCE EXAMPLE 30

Methyl 9a, 1 1α, 15β-tris (2-tetrahydropyranyloxy-16% -methyl-20-hydroxyprosta-cis-5, trans-13-dienoate

The procedure is as described in Reference Example 11, but replacing the methyl 9a, 11a, 15a-tris (2-tetrahydropyranyloxy) -20-acetoxyprosta-cis-5, trans-13-dienoate with 4.12 g in 50 ml of methanol dissolved methyl 9a, 11a, 15 ß-tris (2-tetrahydropyranyloxy) -16 | -methy1-20-acetoxyprosta-cis-5, trans-13-dienoate and using 2.3 g of potassium carbonate, this gives 2.88 g of the title compound with the following physical characteristics: DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.20; IR (liquid film); ν: 3450, 2950, 2850, 1740; 1440, 1360, 1210, 1150, 1090, 1040 and 980 cm "¹; *

(CDCIU solution); δ: 5.60-5.15 (4H, m), 4.70-4.51 (3H, m), 3.65 (3H, s), 4.20-3.31 (11H, m) and 0.95 (3H, t).

REFERENCE EXAMPLE 31

Methyl-9oc, 11a _? 15 ß-tris (2-tetrahydropyranyloxy) -Ι6 ~ ξ-methyl-20- (p-toluenesulfonyloxy) prosta-cis-5, trans-13-dienoate

Proceeding as described in reference example 28, but replacing the methyl-9a, lla, l5a-tris (2-tetrahydropyranyloxy) -l6; §-methyl-20-hydroxyprosta-cis-5, trans-13-dienoate by dissolving 2.88 g in 20 ml of methylene chloride, prepared according to reference example 30, methyl-9a, lla, 15ß-tris (2-tetrahydropyranyloxy) -l65-methyl-20-hydroxyprosta-cis-5, trans-13 -dienoat as well as using 1.27 ml of triethylamine and 1.27 g of tosyl

. 609850/1106

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Chloride, 3.23 g of the title compound is obtained with the following physical parameters:

DSC (mobile phase benzene / ethyl acetate = 2: 1): Rf = 0.70; NMR (CDClj solution); δ: 7.75 (2H, d), 7.41 (2H »el)» 5.70-5.15 (4H, m), 4.78-3.98 (3H, m), 4.02 (2H, t), 3.65 (3H, s), 4.26-3.25 (9H, m), 2.45 (3H, s) and 0.95-0.75 (3H, m). .

EXAMPLE 12

Methyl ~ 9a, 11k , 15 ß-tris (2-tetrahydropyranyloxy) -l6> -methyl-20-chloroprosta-cis-5 _? trans-13-dienoate

If you proceed as described in Example 7, .jedoch replacing the methyl 9cc, lla, l5a-tris (2-tetrahydropyranyloxy) -16f-methyl-20- (p-toluenesulfonyloxy) -prosta-cis-5, trans-13-dienoate by methyl-9a, lla, 15ß-tris (2-tetrahydropyranyloxy) -l6 ^ -methyl-20- (p-toluenesulfonyloxy) -prosta-cis-5, trans- dissolved in 10 ml of Ν, Ν-dimethylformamide, prepared according to reference example 31 13-dienoate as well as using a solution of 3.4 g of lithium chloride in 100 ml of Ν, Ν-dimethylformamide, one obtains 5.7 g of the title compound with the following physical parameters:

DSC (mobile solvent benzene / ethyl acetate = 5: 1): Rf = 0.50; NMR (CDCl4 solution); δ: 5.61-5.15 (4H, m), 4.55-4.42 (3H, m), 3.65 (3H, s), 3.50 (2H, t), 4.30-3.20 (9H, m) and 0.95-0.70 (3H, hl).

EXAMPLE 13

Methyl-9a, 11a, 15β-trihydroxy ~ 16 ^ -methyl-20-chloroprosta-cis- . 5, trans-13-dienoate [l65-methyl-20-chloro-15-epi-PGF _2a -methylester]

Proceed as described in Example 2, but with replacement of the methyl-9a, 11a, I5f-tris (2-tetrahydropyranyloxy) -

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20 - chlorprosta-cis-5, trans-13-dlenoats (20-chloro-9a, 11α, 15 £ ~ tris (2-tetrahydropyranyloxy) -PGF2 -methyl ester] by 5.7 g Dissolved in a mixture of 33 ml of acetic acid, 17 ml of water and 5 ml of tetrahydrofuran, prepared according to Example 12 Methyl ~ 9a, 11a, 15β-tris (2-tetrahydropyranyloxy) -165-methyl-20-chloroprostatic-cis ~ 5, trans-13-dienoate, ' this gives 1.179 g of the title compound with the following physical characteristics:

DSC (mobile phase chloroform / tetrahydrofuran / acetic acid = 10: 2: 1):

Rf = 0.36;

IR (liquid film); v: 3400, 2950, 2850, 1740, 1440, 1380, 1320, 1240, 1170, 1050 and 980 cm "¹;

NMR (CDCl4 solution); δ: 5.60-5.26 (4H, m), 4.25-3.76 (3H, m),

3.65 (3H, s), 3.55 (2H, t) and 0.95 (3H, t).

EXAMPLE 14

Methyl- 9 -οχο-ΙΙα, 15 8-dih vdro xy-l6 '^ - methyl -20- chloroprosta-cis- _i 5, trans-13-dienoate [l6f-M3thyl-20 ~ chloro-l5-epi -PGEp> -methylester] The procedure is as described in Example 9, but replacing the methyl ~ 9 «, 11α, lSa ~ trihydroxy-16t-methyl-20-chloroprostacis-5, trans-13-dienoate with one prepared according to Example 13 Methyl ~ 9a. 11a, 15β-trihydroxy ~ 16'§-methyl-20-chloroprosta - cis ~ 5, trans - 13-dienoate, 0.38 g of the title compound is obtained with the following physical characteristics:

DSC (mobile phase chloroform / tetrahydrofuran / acetic acid = 10: 2: 1): Rf = 0.40;

IR (liquid film); v: 3400, 2950, 2850, 1740, 1430, 1370, 1320, 1250, 1220, 1160, 1080, 1000 and 970 cm ^"1; NMR _(CDCl3 -Lo solution ^1); δ: 5.80 to 5.55 (2H, m), 5.55-5.22 (2H, m), 4.38-3.86 (2H, m), - 3.65 (3H, s), 3.55 (2H, t) , 2.90-2.60

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282241 '

- (IH, dd), 2.60 (2H, broad s) and 0.90 (3H, d).

. 609850/1106

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The scope of the present invention further includes pharmaceutical compositions comprising at least one Prostaglandin compound according to the present invention with a pharmaceutical carrier or coating agent. In clinical practice one becomes such novel Compounds usually administer orally, rectally, vaginally or parenterally.

Solid compositions for oral administration

include compressed tablets, pills, dispersible powders and granules. In such solid compositions, one or more of the active compounds is mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, mannitol or lactose. The compositions can also contain, in the usual manner, additional substances in addition to the inert extenders, for example lubricants such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing the inert diluents commonly used in the art, such as water and paraffin oil. In addition to the inert diluents or extenders, such compositions can also contain additives such as wetting agents, suspending agents, and sweeteners, flavorings and aromas and preservatives. Compositions according to the invention for oral administration also comprise capsules made of absorbable material such as gelatin, which contain one or more of the active ingredients with or without the addition of excipients or carriers.

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2622A1S

Solid compositions for vaginal administration include pessaries formulated in a manner known per se and contain one or more of the active compounds. . .

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

Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or suspension media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions can also contain additives such as preservatives, wetting agents, emulsifiers and dispersants. You can for example by germ filtering, by incorporating sterilizing agents into the compositions, or by irradiation sterilize. They can also be obtained in the form of sterile, solid compositions which are then immediately prepared Use dissolved in sterile water or another sterile injectable medium.

The percentage of active ingredient in the compositions of the invention can be varied provided that there is a proportion suitable as a dose for the desired therapeutic effect. Of course you can multiple dosing units can be administered at approximately the same time. In general, the preparations should usually

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contain at least 0.025 % by weight active ingredient if they are intended for administration by injection; for oral administration, the preparations should usually contain at least 0.1% by weight of active ingredient. The dose used depends on the therapeutic effect desired, the route of administration and the duration of the treatment.

The prostaglandin compounds according to the present invention can be used perorally as bronchodilators any methods known per se for administration by. Inhalation of drugs that are not taking yourself gaseous under normal conditions of administration. So you can get a solution of the active ingredient in a suitable pharmaceutically acceptable solvent, for example water, using a mechanical nebulizer, for example a "Wright Nebulizer", using an aerosol of finely divided particles suitable for inhalation receives liquid particles. The solution to be nebulized is advantageously diluted, with aqueous solutions, which contain from 0.001 to 5 mg, preferably 0.01 to 0.5 mg, of active ingredient per ml of solution, are particularly suitable. The solution can contain stabilizers such as sodium bisulfite and, to add to it to give an isotonic character, buffer substances, for example sodium chloride, sodium citrate and citric acid.

The active ingredients can also be administered orally by inhalation in the form of aerosols made from self-propelling pharmaceutical compositions. Useful compositions can be obtained by

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the active ingredients are finely divided, preferably comminuted to an average particle size below 5 microns, in pharmaceutical form. acceptable solvents such as ethanol, to promote as auxiliary solvents · the dissolution of the active ingredients in the below volatile liquid blowing agents described, or pharmaceutically acceptable suspending or dispersing agents, for example, aliphatic alcohols such as oleyl alcohol, dissolved or suspended, and the solutions or suspensions obtained together with pharmaceutically acceptable volatile liquid propellants in known pressure packs which can be made of any suitable material, e.g. metal, plastics or glass, that can withstand the pressures created by the volatile propellant in the pack. Pressurized pharmaceutically acceptable oases such as nitrogen can also be used as the propellant. The pressure pack is preferably equipped with a measuring valve which delivers a controlled amount of the self-propelling aerosol composition as a single dose.

Suitable volatile liquid propellants are known to the person skilled in the art and include fluorochlorinated alkanes having one to four, preferably one or two, carbon atoms, for example dichlorodifluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane, dichloromonofluoromethane and monoehlortrifluoromethane. The vapor pressure of the volatile liquid propellant is preferably between about 1.76 and 4.54 atmospheres (25 and 65 psig), and more particularly between about 2.1 and 3.87 atmospheres (30 and 55 psig) at 21 ⁰ C. As your specialist is familiar

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one can mix volatile liquid propellants of different vapor pressures in different proportions to obtain a propellant whose vapor pressure is adequate to produce a satisfactory aerosol and suitable for the container selected. For example, one can dichlorodifluoromethane (vapor pressure 5.9 atm = 85 psig at 21 ° C) mixed with dichlorotetrafluoroethane (vapor pressure 1.97 atm = 28 psig at 21 ⁰ C) in various ratios to propellant having vapor pressures between those of the two constituents are to obtain, for example, has a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane in the weight ratio 33s62 a vapor pressure of 3.73 atm (53 psig) at 21 ⁰ C.

One can prepare the self-propelling pharmaceutical compositions by adding the required amount dissolves of the active ingredient in the auxiliary solvent or the required amount of active ingredient with a measured

. Amount of suspending or dispersing agent mixed. A measured one Amount of this composition is then placed in an open container used as a pressure pack shall be. The container and its contents are then cooled to below the boiling point of the volatile propellant to be used. The required amount of volatile propellant, cooled below its boiling point, is then added and the contents of the Mixed container. The container is then closed with the required valve seal without the temperature exceeding increases the boiling point of the propellant. The temperature of the closed container is then left at room temperature increase, shaking to full

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Ensure uniformity of content, and being one Receives pressure pack suitable for generating aerosols for inhalation. On the other hand, you can get the solution of the active ingredient, or the mixture of active ingredient and suspending or dispersing agents in the cosolvent Pour into the open container, close the container with a valve and add the liquid propellant Apply pressure.

Devices for making self-propelling compositions for generating aerosols for administration medicaments are described in greater detail in, for example, U.S. Patent Nos. 2,868,691 and 3,095,355.

Preferably contain the "self-propelling pharmaceutical Compositions according to the present invention 0.001 to 5 mg, and most particularly 0.01 to 0.5 mg, of active ingredient per ml Solution or suspension. It is important that the pH of the

according to the invention for the generation of aerosols used solutions and suspensions in the range 3 "to 8 is kept,

and preferably they should be ^{stored at or below 4 °} C. in order to avoid pharmacological deactivation of the active ingredient.

In practicing the present invention, the devices for generating an aerosol for inhalation should be selected according to the physicochemical properties of the active ingredient.

The term "pharmaceutically acceptable" as used in this specification in relation to solvent, suspension or Dispersants, propellants and gases are used,

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means solvents, suspending or dispersing agents, propellants and gases that are used in for the Aerosols suitable for inhalation therapy are not toxic.

It is highly desirable that the aerosols have a particle size less than about 10 microns, preferably less than 5 microns, for example between 0.5 and 3 microns, for effective distribution in the very narrow Ensure bronchioles. The administration is preferably carried out by means that the administration is controlled Allow amounts of active ingredients, for example with the aid of the above-mentioned measuring valves.

In adults, the individual dose is generally between 5 and 5000 μg for oral administration Treatment of high blood pressure, between 5 and 5000 μg peroral Administration for the treatment of disorders of the peripheral circulation, between 0.1 and 50 mg in the case of peroral administration for Prevention and treatment of brain thrombosis and myocardial infarction, between 0.5 and 500 µg when administered orally for treatment gastric ulcer formation, between 5 and 500 μg with aerosol administration for the treatment of asthma and between 0.05 and 5000 μg for peroral, intravaginal, intrauterine, intravenous, intramuscular and extra-ovular administration for termination of pregnancy and induction of labor in pregnant women female mammals or pregnant women as well as .zur Treatment of decreased fertility, oestrus control, contraception and menstrual control in female mammals or women. With female pets such as cows, mares, sows, ewes and bitches this is the case

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Dose generally between 0.01 and 50 mg / animal for intramuscular, subcutaneous, intrauterine, intravaginal and intravenous Administration for the timing of the estrous stage, for the treatment of reduced fertility and for Induction of abortion and labor.

The following example explains the invention pharmacy marriage. Compositions.

EXAMPLE 15

16; §-Methyl "20-chloro-PGE ₂ -methylester (2 mg) is in

Ethanol (10 ml) dissolved, mixed with mannitol (18.5 g), sieved through a sieve with a mesh width of 0.59 mm (30 mesh), dried at 30 ° C for 90 minutes and again forced through a sieve with a mesh size of 0.58 ram (30-mesh). Aerosil (microfine silicon dioxide, 200 mg) is then added and the powder obtained is filled into hundreds by machine Hard gelatine capsules No. 2, whereby capsules with a content of 20 μg each of l6 ^ -methyl-20-chloro-PC-E -methyl ester are obtained, which is released in the stomach after swallowing the capsule.

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Claims (1)

Patent claims
Prostaglandin analogs of the general formula: (VIIIA) (VIIIB) (IV). R stands for a hydrogen atom or a straight-chain or branched alkyl group with 1 "to 12 carbon atoms and η for zero or 12 3 4 is an integer from 1 to 3 inclusive, R, R, R, R and R can be the same or different and each represents a hydrogen atom or a methyl or ethyl group, and (i) 12 "5
if under R, R and R one or more represent the methyl or ethyl group, X represents ethylene or cis-vinylene and Y represents trans-vinylene * or X and Y each represent ethylene, and (ii) if R, R and R each represent a hydrogen atom, X for ethylene or cis -vinylene, Y for ethylene or trans-vinylene and η for an integer from 1 to 3 inclusive 609850/1106 - 127 - stands] and cyclodextrin clathrates of such acids and esters and, if R stands for a hydrogen atom, non-toxic Salts of such acids. 2. prostaglandin analogs according to claim 1, wherein R is a straight-chain or branched alkyl group with 1 to 4 carbon atoms stands. 3. prostaglandin analogs according to claim 1, wherein R stands for a methyl group. 4. prostaglandin analogs according to claim 1, 2 or 3, wherein η is 2. 5. prostaglandin analogs according to any one of the preceding claims, wherein R ¹ , R ² , R ^, R and R each represent a hydrogen atom. 6. prostaglandin analogs according to any one of claims 1 to 4, 12 3 wherein under R, R and R ^ one or more for a methyl or Ethyl group, X for cis-vinylene and Y for trans-vinylene stand. 7. prostaglandin analogs according to any one of claims 1 to 4, 12 3 "
wherein R, R and R each represent a hydrogen atom, X represents cis-vinylene, Y represents trans-vinylene and η represents an integer from 1 to 3 inclusive. 8. Prostaglandin analogs according to any one of the preceding claims, wherein A is in the general shown in claim 1 Formula VII stands for a grouping of the formula VIIIA or VIIIB and which is attached to the carbon atoms in the 11- and 15-positions bonded hydroxyl groups have the α-configuration. 9. Non-toxic salts of a prostaglandin analog after any one of claims 1 and 4 to 8, wherein R is in claim 1 609850/1 106 - 128 - General formula VII shown represents a hydrogen atom. 10. Cyclodextrin clathrates of a prostaglandin analog according to any one of claims 1 to 8. 11. 20-chloro-15 | -PGF _2a -methyl ester. 12.. 20-chloro-PGF _2a methyl ester.
13. ' 20-chloro-PGE ₂ methyl ester. 14. 16 ^ -Methyl-20-chloro-PGF _2a -methyl ester. 15. 16i-methyl-20-chloro-PGE ₂ -methyl ester. 16. 16 £ -Methyl ~ 20-chloro-PGF _la -methyl ester. 17. lof-methyl- ^ O-chloro-PGE-L-methyl ester. 18. 16 ^ -Methyl-20-chloro-15-epi-PGF _2a -methyle ster. 19. lo ^ ethyl ^ O-chloro-IS-epi-PGE ^ methyl ester. 20. A process for the preparation of prostaglandin analogs of the general formula VII shown in claim 1, wherein A is a grouping of the formula VIIIA, R for a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, X for ethylene or cis-vinylene and Y represents trans-vinylene or X and Y each represent Ethylene are · and the other symbols have the meaning given in claim 1, characterized in that the Groups OR in a cyclopentane derivative of the general formula: 7th OR T • *. j / \ 6 1 I. ^/ COOR ι
1 \ A 3 or ' 2 ": R ⁷ O ■ n \ J _{/ (} CH ₂ J _n CH ₂ Cl / ^X R ⁵ (ix) 609850/1106 - 129 - 2622476 where X ^! represents ethylene or cis-vinylene and Y 'represents trans-vinylene or X ¹ and Y' each represent ethylene, R represents a hydrogen atom or an alkyl group with 1 to 4 carbon 7th
atoms and R is a 2-tetrahydrofuranyl group, a 1-ethoxyethyl group or an unsubstituted or substituted by at least one alkyl group 2-tetrahydropyranyl group and the other symbols have the meaning given in claim 1, hydrolyzed to hydroxyl groups. 21. A process for the preparation of prostaglandin analogs of the general formula VII shown in claim 1, wherein A is a grouping of the formula VIIIB, R for a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, X for ethylene or cis-vinylene and Y is trans-vinylene or X and Y are each Ethylene stand and the other symbols have the meaning given in claim 1, characterized in that the 7th
Groups OR in a compound of the general formula: (IXA) IT wherein the various symbols have the meaning given in claim 20 hydrolyzed to hydroxyl groups. 22. A process for the preparation of prostaglandin analogs of the general formula VII shown in claim 1, wherein R, 2 3 R and R each for a hydrogen atom, A for a group 609850/1106 - 130 - of the formula VIIIA or VIIIB and η for an integer from 1 to 3 including stand and the other symbols have the meaning given in claim 1, characterized in that one a compound of the general formula: where Z stands for C or C = O, n ^{1 stands} for an integer from 1 to "^ H ₁₇
3 including and R is an unsubstituted or substituted by at least one alkyl group 2-tetrahydropyraiiyl group, a 2-tetrahydrofuranyl group or a 1-ethoxyethyl group and the other symbols have the meaning given in claim 1, hydrolyzed. 23. The method according to claim 20 or 21, characterized in net that R stands for a ^; n- ^m - '? + rahy'rci; / ranyl group. 24. The method according to claim 22, characterized in that 17th
R represents the 2-tetrahydropyranyl group. 25. The method according to claim 20, 21 or 23, characterized in that that R stands for the methyl group '. 26. The method according to claim 22 or 24, characterized in that R stands for the methyl group. 27. The method according to any one of claims 20 to 26, characterized ■ 7 characterized in that the hydrolysis of the groups OR or the group 17th
OR to hydroxyl groups with an aqueous solution of a +) organic acid or with a dilute one! inorganic acid 609850/1106 ^{+) wässri} s ^s - 131 - BATH ORIGINAL carried out in the temperature range from room temperature to 60 ° C in the presence of a water-miscible organic solvent.
28. Process for the preparation of prostaglandin analogs of the general formula VII shown in claim 1, wherein R, 2 ~ *>
R and R each represent a hydrogen atom, A represents a grouping of the formula VIIIA or VIIIB and η represents an integer from 1 up to and including and the other symbols have the meaning given in claim 1, characterized in that a compound of the general formula : OOR (XLIII) OH where Z stands for C or C = O and the remaining symbols ^ H have the meaning given in claim 1, with a compound of the general formula: i
M — CIL ₅ - G (CH-), CH ₀ Cl (XLII) i. j / L Ii c. where M for a magne s iumhalo genidgroup e and n 'for a whole L 5 is a number from 1 to 3 inclusive and R and R have the meaning given in claim 1, converts and then hydrolyzes the reaction mixture. 29. The method according to claim 28, characterized in that the reaction is carried out at low temperature in an inert carries out organic solvents, 609850/1106
- 132- 30. The method according to claim 28 or 29, characterized in that the hydrolysis of the reaction mixture by treatment with water or an aqueous acid or ammonium chloride solution. 31. A process for the preparation of compounds of the general formula VII shown in claim 1, wherein A is a Grouping of the formula VIIIB, R for a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, X for ethylene or cis-vinylene and Y stands for trans-vinylene or X and Y each stand for ethylene, characterized in that the trimethylsilyloxy groups are obtained under particularly mild acidic conditions a compound of the general formula: . _f R ² R ^{3 Y} x X - (CH ₂ ) _n CH _? Cl (LXXI) rfTMS ^ ¹ wherein TMS stands for the trimethylsilyl group and the other symbols have the meaning given in claim 20, to Hydrolyzed hydroxyl groups. 32. The method according to claim 31, characterized in that the hydrolysis is carried out by treating the solution of a compound of the general formula LXXI in an inert organic solvent with aqueous oxalic acid solution. 33. The method according to claim 32, characterized in that the inert organic solvent is ethyl acetate and the treatment is carried out at ordinary temperature. 609850/1106 - 133 - 34. Process for the preparation of prostaglandin analogs the general formula VII shown in claim 1, where A stands for a grouping of the formula IV and the other symbols have the meaning given in claim 1, characterized in that the alicyclic ring A of a compound of Formula VII, in which A stands for a grouping of the formula VIIIB and the other symbols have the meaning given in claim 1 have converted into the alicyclic ring A of the formula IV by methods known per se. 35. The method according to any one of claims 20 to 34, characterized in that a prostaglandin analogue is subsequently used of the general formula VII shown in claim 1, in which R represents a hydrogen atom, according to methods known per se in a corresponding ester of the formula in which R is an alkyl radical having 1 to 12 carbon atoms. 36. The method according to any one of claims 20 to 35, characterized in that a prostaglandin analogue is subsequently used of the general formula VII shown in claim 1, wherein the various symbols have the meaning given in claim 1 converted into a cyclodextrin clathrate. 37. The method according to any one of claims 20 to 34, characterized in that a prostaglandin analogue is subsequently used of the general formula VII shown in claim 1, wherein R stands for a hydrogen atom and the other symbols are those in Claim 1 have given meaning, converted into a salt. 38. Prostaglandin analogs of the general formula shown in claim 1, and their cyclodextrin clathrates and salts, characterized in that it according to the method of a 609850/1106 - 134 - of claims 20 to 37 were produced. 39. Pharmaceutical compositions, characterized in that they contain at least one prostaglandin analog as the "active ingredient" according to any one of claims 1 to 19 and 38 or a cycle dextrin clathrate or non-toxic salt thereof together with contain a pharmaceutical carrier or coating agent. 40. Compounds of the general formula: OR ⁷ I.
ι T 7th R. '\ X ¹ cooir 2 3
R R I.
s 1 OR ί sK /: > K * R ⁵ O \ t ¹ (ix) wherein the various symbols have the meaning given in claim 20. 41. A compound according to claim 40, characterized in that it is obtained according to Example 1, 7, 10 or 12 as a product became. 42. Compounds of the general formula: (IXA) wherein the various symbols have the meaning given in claim 20. 43. Compounds of the general formula: 609850/1106 - 13 5- 262241g X ^ COOR (XL) OR ΈΓ R- wherein the various symbols have the meanings given in claim 22. 44. A compound according to claim 43, characterized in that it. according to Example 3 or 5 was obtained as a product. 45. Compounds of the general formula: "COOR OTMS (LXXI) OTMS wherein the various symbols are those given in claim 30 Have meaning. 46. A compound according to claim 45, characterized in that it was obtained as a product according to Example 9, 11 or 14. 609850/1 106 - 136 -