CS229917B2 - Production method of 11-hydroxy-13-oxaprostaglandine derivative - Google Patents

Abstract

Stephan GERO, Jeanine CLEOPHAX, Jean-Claude BARRIERE and André CIER HETEROPROSTAGLANDIN DERIVATIVE AND PROCESSES FOR PREPARING THEM of the disclosure Prostanoic acid derivatives represented by the general formula : < IMG > in which X represents hydrogen or hydroxy, X1 represents hydrogen or X and X1, when they are taken together with the carbon atom to which they are attached, represent a carbonyl group and Z represents hydrogen or hydroxy and pharmaceutically acceptable alkali metal salts thereof. They can be used as bronchodilators and/or inhibitors of blood-plateletaggregation.

Description

(54) A method for producing 11-hydroxy-13-oxaprostaglandin derivatives

The present invention relates to a process for the preparation of prostaglandin derivatives of the general formula (I) below, the structure of which is derived from prostanoic acid of the structural formula

which can also be written as follows:

(t) in which:

The novel prostaglandin derivatives according to the invention are substituted 11-hydroxy-13-oxaprostaglandins of the general formula I

X represents a hydrogen atom or a hydroxyl group,

X ^I represents hydrogen, or

X ¹ and X ¹ together with the carbon atom to which they are bound form a catonyl group, and in daily doses. in the range of 0.1 to 40 milligrams per kilogram of oral administration and in the range of 0.3 to 120. mg by aerosol administration.

Compounds of the above general formula. I can be obtained from the novel cyclopentene derivatives of the general formula IIa

Z. Indicates. a.the hydrogen or hydroxyl group.

The invention also relates to a process for the preparation of pharmaceutically acceptable salts of the compounds. of the formula I, for example the salts formed by the action of alkali metal hydroxides, for example sodium hydroxide, on the compounds of the formula I.

Over the past fifteen years, prostaglandins have been an intensively researched and varied research field. Chemical work carried out in this field has resulted. . in the total synthesis of numerous prostaglandins and their analogs.

Since thromboxane (TXAa) and prostacyclin (PGI 2), with physiological properties opposite to each other, have been investigated, a significant amount of research has been carried out on this type of compound, both biosynthesized in a living organism from arachidonic acid via the respective endoperoxide (PGH 2). Thromboxanes are formed in human platelets and induce aggregation of these platelets, while prostacyclin, which is released from the vascular walls, inhibits said aggregation, thus theoretically, the two compounds regulate their formation with one another and impair or disrupt this process of regulation disruption of the TXA2-PGI2 .. balance, resulting in cardiovascular diseases such as thromboses, heart attacks and the like.

Prostanic acid derivatives having a heteroatom at the 13-position of the molecule and showing an inhibitory effect on platelet aggregation have already been described in British Patent Application Publication No. 2,028,305 and in J. Med. Chem. 22, No. 11, pp. 1402-1408, (1979). . ,

The compounds of British Patent Application Publication No. 2,028,805 · A contain a nitrogen atom as the heteroatom, while the compounds of J.Med .. Chepi · have an oxygen atom as the heteroatom and a two-nitrogen bridge located between the, 9 and 11, and it is thus 9,11-mzoderivatives.

The present inventors have now found that. a new series of pro-stannic acid derivatives, in particular 11-hydroxyprostanoic acid derivatives in which the carbon atom at the 13-position is replaced by an oxygen atom, exhibits the pharmacological properties generally found in the prostaglandin series, particularly the inhibitory effect on. platelet aggregation and / or bronchodilator efficacy.

In view of said pharmacological properties, the general formula I can be used therapeutically in the treatment of pathological conditions that affect the respiratory system, in particular in the treatment of asthma. Furthermore, the compounds of the invention may be used as antithrombotic agents. and in the treatment and prevention of cardiovascular diseases; or. pathological. . states like. myocardial infarction.

Compounds manufactured may be used for human therapy. according to the invention

f // áJ in which

R represents a protecting group, · a hydroxyl group of the formula -CH2R1 _wherein R ¹ represents an aryl or aralkyl radical,

B represents a group of the formula

O?

II —CH or _; ζθ ~ Λ

-CH '> ......

and

And it has the following meaning:

- when B is a group. O.

'. · И ·: ·. ·:

—CH

A represents \

CH2 or \ / $ “Ί - when B is a group of formula

A represents a group. of formulas \ _x s _J x ^c - _s J

substituted with methyl in the core,

D ‘denotes a group

or or

In the meaning of the aforementioned R ¹ substituent may be an aryl radical preferably denote a phenyl group optionally substituted by a methyl group, and the aralkyl radical may be, for example benzyl, optionally substituted in the aromatic part with a methyl group.

Benzyl groups are preferably used as substituent R.

Preferred compounds included within the scope of Formula Ia are, in particular, the following:

2-formyl-4 (R) -benzyloxy-2-cyclopetenoneethylenedithioacetal, hereinafter referred to as "Synthon A",

2-formylpropyleneacetal-4 (R) -benzyloxy-2-cyclopentenone-ethylenedithioacetal, hereinafter referred to as "Synthon B", 2-formylpropylenation of tal-4 (R) -benzyloxy-2-cyclopentenone, hereinafter referred to as "Synthon C",

2-formylpropyleneacetal-4 (R) -benzyloxy-2-cyclopentanol, hereinafter referred to as "Synthon D",

1-formyl-3 (R) -benzyloxy-1-cyclopentene, hereinafter referred to as "Synthon E", and

1-Forms propylene acetal-3 (R) -benzyloxy-1-cyclopentenone, hereinafter referred to as "Synthon F".

wherein R is as defined above and

Z 'represents a hydrogen atom or a group of the formula —OR, in which R is as defined above, hydrogenolyses in the presence of platinum on activated carbon or palladium on activated carbon, at room temperature and in acetic acid and ethanol, to the desired 11-hydroxy-13 -oxaprostaglandins in the form of the free acids of the formula I in which X represents a hydrogen atom or a hydroxyl group and X ¹ and Z are as defined above, optionally to (6-carboxyhexyl) -3 (R) -heptyloxy derivatives of the formula

The preparation of a cyclopentene derivative of the general formula IIIa is described and protected by patent no. 229 926.

The process according to the invention for the production of the above-mentioned 11-hydroxy-13-oxaprostaglandin derivatives of the general formula I is characterized in that

COOH (III in which

Z is as defined above, which is deprotected with mercuric chloride in an organic solvent, preferably acetone, and in the presence of boron trifluoride etherate to give the desired 11-hydroxy-13-oxaprostaglandin free acid of formula I wherein X and X ¹ together with the carbon atom to which they are attached denotes a carbonyl group and Z is as defined above, and the free acid thus obtained is optionally further contacted with an appropriate alkali metal hydroxide to form pharmaceutically acceptable alkali metal salts thereof .

Synthon V or synthon F is first reacted with boron hydride in tetrahydrofuran at a temperature ranging from 0 ° C to room temperature, and the obtained borane is oxidized with hydrogen peroxide in the presence of sodium hydroxide, at a temperature ranging from 0 ° C to temperature and a cyclopentane derivative of the general formula III in which

R represents a hydroxyl protecting group of the formula - CHzR ¹ wherein R ¹ represents phenyl optionally substituted by methyl, or benzyl, or

(lil)

in which

D represents a group of the formula

or \

CH2 /

and R ¹ is as defined above.

Different processes are then applied to the compound of formula III thus obtained, depending on the structure of the desired 13-oxaprostaglandins of formula I.

Synthesis of compounds of the general formula I, in which X and X ¹ together with the carbon atom to which they are attached represent a carbonyl group and Z represents a hydrogen atom or a hydroxyl group

a) A compound of formula III wherein D is a group of formula

is reacted in the presence of sodium hydride, preferably at room temperature and in a suitable solvent, for example N, N-dimethylformamide, with a 1-halo-n-heptane derivative of the general formula IV in which:

Z 'and R ¹ are as defined above.

b] The above compound of formula V is hydrolyzed in the presence of trifluoroacetic acid in chloroform or hydrochloric acid in acetone or hydrochloric acid in a mixture of anhydrous chloroform with isopropyl alcohol under an inert atmosphere to give the 2 (S) -formyl-3 [R] -heptyloxy derivative VI

in which

Z 'and R ¹ are as defined above.

c] The compound of formula VI is reacted with dianion of (5-carboxypentyl) triphenylphosphonium bromide under Wittig reaction conditions, in an inert atmosphere, preferably at room temperature and in a suitable anhydrous solvent, for example ethyl ether, to give 2 (S) - [ 6-carboxy-l-hexenyl) -3 (R) -heptyloxyderivát VII / СН _СН Д ^ ^ CH

Ha-t CH CH _Z CH _Z l '

HV) in which

R-H, CO

^ (CHJ ^ COOh (Vid in which

Hal represents a chlorine, bromine or iodine atom and

Z ‘denotes a hydrogen atom or a protected hydroxyl group of the formula —OR, in which R is as defined above, to give a 2 [S] formylpropylene acetal-3 (R) -heptyloxy derivative of the general formula V

Z 'and R ¹ are as defined above.

d) The hydroxyl protecting groups in the compound of formula (VII) are removed by hydrogenolysis in the presence of platinum on charcoal or palladium on charcoal as a catalyst, preferably at room temperature and in a suitable medium, e.g. acetic acid / ethanol, to give 2 ( S) - (6-carboxyhexyl) -3 (R) -heptyloxy derivative of general formula VIII

in which

Z has the same meaning as described above for Formula I.

e) The thioacetal protecting group in the compound of formula VIII is removed by treatment with mercuric chloride in a suitable solvent, for example acetone, in the presence of boron trifluoride etherate to give the 2 '(S) - (6-carboxyhexyl) -3 (R) -heptyloxy derivative formulas

Z is as defined above, and which is the desired 13-oxaprostaglandin of Formula I.

2. Synthesis of compounds of formula I wherein both substituents X а X @ ¹ represents hydrogen and Z represents a hydrogen atom or a hydroxyl group

a) The compound of formula III is reacted with an n-halo-heptane derivative as described in section 1a) above to give aa) when D is a group.

CH ₂ / a 2 (R) -heptyloxycyklopentanu IX

in which

Z 'and R ¹ are as defined above, and ab) when D is a group of the formula

a compound of the above formula V is obtained which, after desulfuration with Raney nickel at the boiling point of the reaction mixture, yields a mixture of non-isolated products of the formulas

in which

Z 'and R ¹ are as defined above; this mixture is further hydrogenated at atmospheric pressure in the presence of an Adams platinum catalyst (platinum oxide prepared from chloroplatinic acid) to give the compound of formula IX above.

b) Hydrolysis of a compound of formula IX in the presence of a suitable acid, for example trifluoroacetic acid or formic acid, affords the 2 (R) -heptyloxy derivative of formula X (R 1 -heptyloxycyclopentane of formula XII

in which

Z 'and R ¹ are as defined above.

c) The latter compound is reacted under a Wittig reaction, under an inert atmosphere, with dianion (5-carboxypentyl) triphenylphosphonium bromide, preferably at room temperature and in a suitable anhydrous solvent, for example ethyl ether or dimethylsulfoxide, to give 1. The (S) - (6-carboxy-1-hexenyl) -2 (R) -heptyl oxy derivative of the general Formula XI wherein:

Z 'and R ¹ are as defined above as starting materials. The compounds are prepared by the following procedures:

Be yourself

a) A compound of formula III wherein D is a group of formula

in which

Z 'and R ¹ are as defined above.

d) The hydroxyl protecting groups in the compound of formula XI are removed by hydrogenolysis in the presence of platinum on charcoal or palladium on charcoal as a catalyst, preferably at room temperature and in a suitable medium, e.g. acetic acid / ethanol, to give 1 ( S] - (6-carboxyhexyl) -2 (R 1 -heptyloxy derivative of formula (I) is reacted with n-halopentane as described in section 1a) above to give a compound of formula (V);

b) removing the thioacetal protecting group from the compound of formula V by treatment with mercuric chloride in a suitable solvent such as acetone and in the presence of boron trifluoride etherate to give the 1-oxo-3 (R) -heptyloxy derivative of formula XIII

in which

2 'and R ¹ are as defined above;

c) reduction of the ketone function in the latter compound using lithium tri-sec-butylborohydride as the reducing agent yields the 3 (R) -heptyloxycyclopentanol derivative of formula XIV

Z has the same meaning as above and is the desired 13-oxaprostaglandin of formula I.

он

3. Synthesis of compounds of formula I in which X represents a hydroxy group, X ¹ represents hydrogen and Z represents a hydrogen atom or a hydroxyl group

The compounds can be prepared using 2 (S) -formylpropylene acetal-3- derivatives.

(XLV) in which

Z 'and R ¹ are as defined above;

d) protecting the free hydroxyl group in the latter compound in such a way; by reacting a compound of formula XIV with a bromide of formula R-Br, in which R is as defined above and preferably denotes a benzyl group, in the presence of sodium hydride and in a suitable aprotic solvent to give a 3 (R) -heptyloxycyclopentane derivative which corresponds to a compound of formula XII

Or be

a] protects the free hydroxyl group in synthon D by treatment with a bromide of the formula R-Br, in which R is as defined above and preferably denotes a benzyl group, in the presence of an alkali metal hydride such as sodium hydride, preferably at 0 ° C and in a suitable aprotic solvent , for example in N, N-dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, to give a 2-formylpropylene acetal-2-cyclopentene derivative of formula XV

in which

R1 is as defined above;

b) reacting a compound of formula XV with boron hydride as described above for synthon B or F to obtain a 2 (S) -formylpropylene acetal-3 (R) -hydroxycyclopentane derivative of formula XVI above in section 1a) to obtain a derivative 2 (S) -formylpropylene acetalcyclopentane, which corresponds to the compound of formula XII.

The compounds of formula (XII) thus obtained are then subjected to the following reactions:

a) Hydrolysis in the presence of a suitable acid, for example trifluoroacetic acid, yields the 2 (S) -formylcyclopentane derivative of formula XVII

t

IKVII) in which

Z Ri and R 1 are as defined above.

b) The compound of formula XVII is reacted with dianion (5-carboxypentyl) triphenylphosphonium bromide at room temperature and in a suitable anhydrous solvent such as ethyl ether under Wittig reaction conditions, under an inert atmosphere, to give derivative 2 ( S) - (6-Carboxy-1-hexenyl) cyclopentane of formula XVIII

in which

Z Ri and R 1 are as defined above.

XVI in which

c) The hydroxyl protecting groups in the compound of formula XVIII are removed by hydrogenolysis using platinum on activated carbon or palladium on activated carbon as a catalyst, preferably at room temperature and in a suitable medium, e.g. acetic acid / ethanol, to give 2. (S) - (6-carboxyhexyl) -3 (R) -heptyloxy derivative of general formula XIX

OH ώ 'но' °

COOH

ÍK / X)

R 1 is as defined above;

OF

c) reacting said compound of general formula XVI with n-halo-heptane derivative 5 as described in which:

Z represents a hydrogen atom or a hydroxyl group which is the desired 13-oxaprostaglandin of formula I.

With respect to the pharmaceutically acceptable salts of the heteroprostaglandins of the formula I, they can be prepared in a conventional manner, preferably by reacting an acid of the formula I with an appropriate alkali metal hydroxide, for example sodium hydroxide.

With respect to the halopentane derivatives of the general formula IV, in which Z ‘denotes the group of the formula —OR, they can be obtained from (S) - (-) -heptane-1,2-diol by the method described by K. Sea in Arg. Biol. Chem. 40, 1617 (1976). In this process, the starting diol is tritylated to give the 1-O-triethyl derivative and the free 2-hydroxyl group is then protected by reaction with a bromide of the formula R-Br, wherein R is as defined above and is preferably a benzyl group; The 1-O-trityl protecting group is then removed, and the resulting free hydroxyl group is substituted with a halogen atom using conventional methods to give a compound of formula IV wherein Z ‘denotes the above -OR group.

The pharmacological properties of the 13-oxaprostaglandins of formula I were evaluated by the following tests:

The bronchodilator efficacy of the compounds was determined by measuring their relaxation efficacy on isolated guinea pig trachea which had previously been contracted by carbachol, i.e. carbamoylcholine hydrochloride. For the test, spiral strips of trachea tissue about 3 mm wide were placed in the nutrient medium and the isometric tension of said guinea pig trachea preparations was continuously recorded. An initial tension of 0.08 N was applied to each preparation. After a rest period of 60 minutes, submaximal contractions were induced by adding carbachol to the bath. When the shrinkage reaction of the preparation became reproducible, - 11 (R) -hydroxy-13-oxaprostanoic acid of formula I was added to the bath, either at a time when the carbachol-induced contraction was at its maximum, so that the relaxation efficacy of the test substance was evaluated. , or when the preparation was completely relaxed, so that the effect of the test acid on baseline tone was evaluated.

Under these conditions, 11 (R) -hydroxy-13-oxaprostanoic acid induced a slight decrease in the basal tone of the diaphragm (preparation). The amplitude of the decrease depended on the dose of the prostanoic acid derivative used.

It has also found a slight effect delaxační acid H (R] -hydiOxy oxaprostanové-13 in concentrations of about 10 -5 and 4.10 ⁵ moles preparations contracted with carbachol at a concentration of 8.10 ^"8. It was also found that this relaxing action is not similar (3 The agonist-stimulating effect, since in the presence of 10 ⁵ propranolol, the relaxation effect of the test substances did not change in any experiment.

Inhibitory activity on platelet aggregation was determined in vitro on citrated human plasma using thrombin as an aggregating agent.

Platelet aggregation was performed after incubation of the platelet-rich blood plasma fraction for 20 minutes at room temperature in the presence of a 5 μΐ solution of 11 (R) -hydroxy-13-oxaprostonic acid of formula I in dimethylsulfoxide at a concentration of 1 mg / ml. Control samples were incubated in a similar manner in the presence of 5 μΐ dimethylsulfoxide. Samples for thromboxane Ba titration were taken after 3 minutes aggregation using 0.4 U / ml thrombin in the presence of 100 ₍ ag / ml indomethacin and 100 µg / ml imidazole (100 µl per 400 μϊ platelet-rich plasma fraction) The thromboxane B was then assayed in the presence of the test substance in an amount of 857 [mu] g / ml in this test, thereby demonstrating that there was a 77% decrease in thromboxane B2 and a 47% inhibition of aggregation in the presence of oxaprostaglandin. platelets.

Therapeutic compositions containing the 13-oxaprostaglandins of formula (I) as an active ingredient can be prepared in any form for their administration in human and veterinary therapy. For ease of administration, the compositions may be prepared in unit dosage forms suitable for the intended mode of administration, for example in the form of compressed tablets for perlingual administration, pills, powders, capsules, syrups and emulsions for oral administration, suspensions for oral or aerosol administration, suppositories for rectal. administration, or in the form of sterile solutions or suspensions for parenteral administration.

Said therapeutic preparations may be prepared by known techniques by admixing at least one compound of formula I with a suitable diluent or excipient and then, if necessary, processing the resulting mixture into the desired dosage form. Suitable diluents and excipients include, for example, distilled water, ethanol, talc, magnesium stearate, starches, sugars and cocoa butter.

The process according to the invention is illustrated in more detail by the following non-limiting examples.

Example 1

11 (R) -Hydroxy-13-oxapranoic acid (a compound of formula I wherein X, X1 and Z are hydrogen)

a) 1 (S) -Formylpropyleneacetal-2 (R) -hydroxy-3 (R) -benzyloxycyclopentane [a compound of formula III wherein D is

0 9 9 16

18 \

CH ₂ /

and R ¹ is phenyl)

Dissolve 1.5 g of synthon F in 20 ml of freshly distilled tetrahydrofuran in a three-necked flask under nitrogen or argon. The solution was cooled to 0 - G and 2 equivalents - M of a commercial solution of boron hydride in tetrahydrofuran were added. The reaction mixture was allowed to stand at 0 ° C and then for 15 minutes at room temperature before oxidation of the reaction product. To this end, the excess diborane is first decomposed by dropwise addition of 1 ml of water at 0 ° C, and then 1.5 ml of 3 N sodium hydroxide solution and 3 ml of hydrogen peroxide are added to the mixture. The reaction mixture was allowed to stand for 4 hours, then potassium carbonate was added, the mixture was diluted with ethyl ether and the ether phase was decanted off. The ether solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product, after separation by preparative thin layer chromatography, afforded 0.950 g of the desired alcohol (the isomer) and 0.190 g of the starting material.

In this way, the desired compound of formula III is obtained.

Elementary analysis:

For C 16 H 22 O 4 (mol. Wt. 278.348) calculated:

% C, 69.04;% H, 7.96;

found:

68.85% C, 7.94% II.

Optical rotation:

[α] D = + 5 ° c = 7.5 mg / ml)

b) 1 (S) -Formylpropyleneacetal-2 (R) -heptyloxy-3 (R) -benzyloxycyclopentane (a compound of formula IX wherein Z ⁴ is hydrogen and R ¹ is phenyl)

A solution of 0.390 g of the compound of formula III obtained as described above in 10 ml of Ν, Ν-dimethylformamide at 0 ° C under a nitrogen atmosphere is added to 0.600 g of an oil-sodium hydride suspension. After the hydrogen evolution had ceased, 0.7 ml of n-iodo-heptane was added and the temperature was allowed to rise to room temperature. The reaction is complete in two hours. The reaction mixture was cooled to 0 ° C, diluted with dichloromethane and the excess hydride was carefully quenched by the addition of methanol.

The solution was poured into an ice saturated sodium chloride solution, the product was taken up in dichloromethane, the organic portion was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is prepared by preparative thin-layer after separation. chromatography 0.350 g of the desired ether.

In this way, the desired compound of formula IX is obtained.

Optical rotation:

[α-D = + 5 ° (in chloroform, c = 1 ° / w / v)

Elementary analysis:

For CkH36O4 (mol. Wt. 376.537) calculated:

C, 73.26; H, 9.63%;

found:

73.18% C, 9.62 ° / o H.

In the same way, 1 (SJ-formopropyleneacetal-2 (R) - [2 (S) -benzyloxyheptyloxy] -3 (R) -benzyloxycyclopentane can be prepared.

Elementary analysis:

For C 29 H 42 O 5 (mol. Wt. 470.650) calculated:

74.00 o / o C, 8.99 θ / ο H;

found:

% C, 73.96;% H, 8.95.

c) 1 (S) -Formyl-2 (R) -heptyloxy-3 (R) -benzyloxycyclopentane (compound of formula X wherein Z ‘denotes hydrogen and R 1 denotes phenyl)

0.740 g of the compound of formula IX prepared as described above was dissolved in 5 ml of anhydrous chloroform under nitrogen and 20 ml of 80% formic acid were added to the solution. The progress of the reaction was monitored by thin layer chromatography using chloroform as the developing system. After 24 hours, an additional 10 ml of formic acid was added and the reaction mixture was left under nitrogen for 24 hours. The solution is cooled, sodium bicarbonate is added to pH 4 and the mixture is poured into ice water saturated with sodium chloride. The product was taken up in dichloromethane, the organic portion was washed with aqueous sodium bicarbonate until neutral and then with water, dried over anhydrous sodium sulfate, and the solvents were distilled off in a colored flask. 0.630 g of the desired compound of formula X is obtained in the form of a clear oil.

IR spectrum:

belt at 1705 cm -1,

Mass spectrum:

M @ + = 318.

In the same way, 1 (S) -formyl-2 (R) - [2 (S) -benzyloxyheptyloxy] -3 (R) -benzyloxycyclopentane was prepared;

Mass spectrum:

424 ⁺ · = 424.

d) 1 (S) - (6-carboxy-1-hexenyl) -2 (R) -heptyloxy-3 (R) -benzyloxycyclopentane (compound of formula XI wherein Z 'is hydrogen and R ¹ is phenyl)

To 0.940 g of sodium hydride, 19.6 ml of freshly distilled dimethylsulphoxide are added and the mixture is heated at 70 ° C for 1 hour. The resulting sodium methylsulfinylmethide solution, which is a gray-green color, was transferred to a three-necked flask containing 4.48 g of (5-carboxypenyl) triphenylphosphonium bromide and the mixture, which immediately turned red, was left under argon at room temperature for one hour. 0.624 g of the compound of formula (X) obtained above, dissolved in 19 ml of dimethylsulfoxide under argon, are slowly added dropwise to the ylide solution. The reaction mixture was allowed to stand for about 8 hours at room temperature, then poured into ice water containing some sodium bicarbonate and the flask was rinsed with ethyl ether / petroleum ether 1: 1. The aqueous portion was separated, acidified with scalic acid to pH 3 and shaken four times. ethyl ether. The ether extracts were combined, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The crude mixture obtained was purified by column chromatography using a 1: 1 mixture of ethyl acetate and petroleum ether as eluent.

In this way, the desired compound of formula XI is obtained in a yield of 33%.

Optical rotation:

[w] _D = -45 ° [in chloroform, c - 0.35% w / v)

Elementary analysis:

For C 26 H 40 O 1 (mol. Wt. 416,600) calculated:

% C, 74.95;% H, 9.68;

found:

75.17 ° C, 9.70% H.

Mass spectrum:

M @ ⁺ = 416.

1 (S) - (6-carboxy-1-hexenyl) -2 (R) - [2 (S) -benzyloxyheptyloxy] -3 (R) -benzyloxycyclopentane can be prepared by the same procedure.

Elementary analysis:

For C 32 H 46 O 5 (mol. Mass 510.715) calculated:

% C, 75.25;% H, 9.07;

found:

% C, 75.19;% H, 9.00.

Mass spectrum:

¹ ' ¹ = - · 510.

e) 11 (R) -Hydroxy-13-oxaprostanoic acid

The compound of formula XI prepared as described above is dissolved in a 1: 1 mixture of acetic acid and ethanol, 10% palladium on carbon is added and the mixture is hydrogenated in a Parr apparatus. After 48 hours, the reaction mixture was filtered through Whatmann filter paper and the product was purified by column chromatography.

11 (R) -hydroxy-13-oxaprostanoic acid was obtained in a yield of 90%.

Optical rotation:

[α] _D = 4- 19 ° (in chloroform, c = 0.73%, w / v)

Elementary analysis:

For C 19 H 36 O 4 (mol. Wt. 328.497) calculated:

% C, 69.47;% H, 11.04;

found:

% C, 69.54;% H, 10.97.

Mass spectrum:

· 328.

In the same way, 11 (R) -hydroxy-13-oxa-15 (S) -hydroxyprostanoic acid can be prepared.

Elementary analysis:

For C 19 H 36 O 5 (mol. Wt. 344.492) calculated:

% C, 66.24;% H, 10.53;

found:

% C, 66.18;% H, 10.60.

Mass spectrum:

M @ ⁺ - 344.

Example 2

II (R) -hydroxy-13-oxaprostanoic acid

a) 2 (S) -formylpropyleneacetal-3 (R) -hydroxy-4 (R) -benzyloxy cyclopentanonethylenedithioacetal (a compound of formula III wherein D is a group of the formula R ¹ -R ¹ is phenyl)

In a 50 ml three-necked flask, dissolve 0,700 g of synthon B, in about 5 ml, under a nitrogen atmosphere.

223917 freshly distilled tetrahydrofuran. To the solution at 0 ° C under a nitrogen atmosphere, 10 ml of a commercial 1 M solution of boron hydride (BH3) in tetrahydrofuran is slowly added via syringe. The reaction mixture was allowed to stand under a gentle stream of nitrogen to the reaction flask for about 15 hours at room temperature. The borane thus prepared is then oxidized. To this end, the excess hydride is decomposed by slowly adding water (about 2 ml) at 0 ° C. Then 2 ml of 3N sodium hydroxide solution and 2 ml of 30% hydrogen peroxide are added at the same temperature and the product is oxidized for 4 hours. The reaction mixture was diluted with dichloromethane, poured into ice water saturated with ammonium chloride and the product was taken up in dichloromethane. The organic portion was washed with water until neutral, dried over sodium sulfate and the solvent was distilled off. The oily residue containing some of the starting compound is separated by preparative thin layer chromatography in a solvent system - ethyl ether - petroleum ether 1: 1, the product having a lower Rf value is isolated.

In this way the desired compound of formula III is obtained in the form of a colorless oil; 35% yield.

Optical rotation:

[Α] D = -40 ° (in CDCl 3, b = 1.27% w / v).

13 C NMR Spectrum (CDCl 3 / TMS):

Elementary analysis:

For C18H24S2O4 (mol. Wt. 368.52) calculated:

% C, 58.66;% H, 6.56;

found:

% C, 58.99;% H, 6.74.

1 H NMR spectrum (at 250 MHz, in CDCl 3 (TMS)):

d (ppm) position H

1.4

2.1

2.37

2.6

2.9

3.21

3.82

3.95

5.18

5.28

5.6

7.35

UU (8c)

H (8a) *

H ₍ 5) + H (2)

H (5b)

OH (disappears when D2O is added)

2H9 + 2H (>) ^H ('7e) ^{+ H} (7e ^- )

H ₍ 3 &gt;)

H _(n)

H (7a) + H (7a)

H (4)

CH 2 [10] phenyl

number C: 1 2 3 δ (ppm): 66.3 60.6 79 number C: 7 ‘ 8 9 δ [ppm]: 66.8 25.7 40.7

4 5 6 7 82.6 49.5 103.8 66.8 9 ‘ 10 39.1 71.7

Mass spectrum:

M @ + = - 368.

b) 2 (S) -Formylpropyleneacetal-3 (R) -heptyloxy-4 (R) -benzyloxycyclopentanetylenedithioacetal (compound of formula V wherein Z 1 is hydrogen and R ¹ is phenyl)

A solution of 0.1 g of the compound of formula III obtained in the above procedure in 5 ml of N, N-dimethylformamide is added under a nitrogen atmosphere to a suspension of 0.04 g of sodium hydride in 5 ml of Ν, Ν-dimethylformamide. After the hydrogen evolution had ceased, 0.7 g of n-iodo-heptane was added and the reaction mixture was allowed to stand at room temperature while monitoring by thin layer chromatography (ethyl ether-petroleum ether 1: 1). When the reaction is complete, the reaction mixture is cooled to 0 ° C, diluted with 10 ml of dichloromethane and the excess hydride is quenched by careful addition of methanol. The solution is then poured into ice water saturated with sodium chloride, the product is taken up in methylene chloride, the organic phase is washed three times with water, dried with anhydrous sodium sulphate and the solvent is distilled off. The oily product obtained is separated by preparative thin layer chromatography in ethyl ether-petroleum ether 1: 1.

In this way, the desired compound of formula (V) is obtained in the form of a colorless oil. 60% yield.

Elementary analysis:

For C 25 H 33 O 4 S 2 (m / m 466.71) calculated:

% C, 64.34;% H, 8.20;

found:

% C, 64.42;% H, 8.05;

Mass spectrum:

M @ + = 466.

¹³ C NMR (CDCl 3 / TMS):

number C: 1 2 3 <$ (ppm): : 67.8 58.6 84.5 number C: 8 9 9 ‘ I (ppm): : 26 39 38.5 number C: 15 Dec 16 17 δ (ppm): : 22,5 13 71.6 1 H NMR (at 250 MHz): ti (ppm) position H 0.9 СНз (16) 1,27 CHz (13-14-15-16) 1.55 CH 2 (12) + Н 2.1 H (8a) 2.4 H (2) + 2 ° (5) 3.2 2 / Н ₍₉₎ +, (О ') 3.5 CHz (11) 3.8 H (7c) + H ( _7e ') ) 4.1 Н (7a) + Н ( _7a) Н Н ₍₄ ), Н (4) 4.6 СН2 (9) 4.95 Н _(6; (doublet)) J / Н ₍₆₎ - Н (2) / = = 10 Hz 7.34 phenyl.

с) 1 (S) -Formylpropyleneacetal-2 (R) -heptyloxy-3 (R) -benzyloxycyclopentane (a compound of formula IX wherein Z 'is hydrogen and R ¹ is phenyl)

A solution of 0.1 g of the compound of formula V, prepared as described above in ethanol, was heated to reflux for about 15 hours in the presence of Raney nickel. Re ¹³ C NMR spectrum (CDCl 3 / TMS):

number С: 1 2 3 δ (ppm): 48.8 815.4 85 number С: 7 ‘ 8 9 <5 (PPm): 67 25.8 69.7 number С: 14 15 Dec 16 5 (ppm): 22.6 14.1 70.9

4-1 NMR spectrum (at 250 MHz):

δ (ppm) position H 7.35 phenyl 4.55 benzyl 4.45 H ₍₆₎ [doublet] J / H ₍₆₎ -H ₍₂₎ / = 6 Hz 4.15 H (7e) 3.75 H (2), H (7) 3.80 multiplet О — CH2 (9) (in branch chain) 2.05 H (t > + H ( _8a ) 1.7 2H (i) 4- 2H (j) + H _(8e , (complex)) 1.45 CH ₂ (9) 1.3 CH 2 (11-12-13-14) 0.9 (15).

4 5 6 7 7 ‘ 84.1 48.2 102.7 66.3 66.5 10 11 12 13 14 70.8 29.7 317 29 25.5

the action mixture was filtered through Celite and the solvent was distilled off. The product obtained is a mixture of two substances, one of which is unsaturated, according to the ¹³ C NMR spectrum and the ¹ H NMR spectrum. The mixture is therefore hydrogenated in the presence of an Adams catalyst at atmospheric pressure to give a single compound.

In this way, a compound of formula III is prepared; yield 67%.

Optical rotation:

(α] D = + 5 ° [in chloroform, c - 10 mg / ml).

Mass spectrum:

M @ + = 376.

Elementary analysis:

For C 23 H 36 O 4 (mol. Wt. 376.537) calculated:

% C, 73.36;% H, 9.63;

found:

% C, 73.18;% H, 9.62.

4 5 6 7 29.9 22.7 103.3 67 10 11 12 13 29.9 31.8 29.2 26.1

d) 1 (S) -Formyl-2 (R) -heptyloxy-3 (R) -benzyloxycyclopentane (compound of formula X wherein R ¹ is phenyl)

To a solution of 15 g of the compound of formula IX prepared as described above in 5 ml of chloroform at 0 ° C was added 3 ml of a 50% aqueous trifluoroacetic acid solution and the reaction mixture was allowed to stand at room temperature for 36 hours. Dichloromethane was added to the solution, the mixture was neutralized with sodium bicarbonate, filtered and the filtrate was shaken with water. The aqueous portion was extracted with dichloromethane, the organics were combined, dried and the solvent was distilled off. The residue obtained contains 50 percent of the desired aldehyde and 40% of the starting material. The aldehyde was separated by preparative thin layer chromatography in a chloroform solvent system. In this way a compound of formula X is obtained.

Mass spectrum:

M @ ⁺ = 318. [227, 155, 129, 107, 92, 91, 83].

67, 65, 57, 55).

¹ H NMR spectrum (at 60 MHz):

Aldehyde proton doublet at 9.2 ppm.

e) 1 (S) - (6-Carboxy-1-hexenyl) -2 (R) -heptyloxy-3 (R) -benzyloxycyclopentane compound of formula XI wherein Z Z is hydrogen)

The title compound was prepared as described in Example 1 above.

f) The acid II (R) -hydroxy-13-enoic acid ^of oxapros

This compound was prepared as described in Example 1 above.

Example 3

9 (S) -hydroxy-11 (R) -hydroxy-13-oxaprostanoic acid

a) 1 [S] -Benzyloxy-2-formylpropyleneacetal-4 (R) -benzyloxy-2-cyclopentene (compound of formula XV wherein R ¹ is phenyl)

To 0.187 g of sodium hydride are added 3 ml of Ν, Ν-dimethylformamide and the temperature is lowered to 0 ^q C. At this temperature under a nitrogen atmosphere, 0.690 g of synthon D, previously dissolved in 15 ml of Ν, dimethyl-dimethylformamide and 0.637 ( 1.5 equivalents) of benzyl bromide. The progress of the reaction was monitored by thin-layer chromatography in chloroform-ethyl ether 3: 1. After standing at room temperature for 3 hours, the reaction mixture was cooled and the excess hydride was quenched by careful addition of methanol. The reaction solution was added dropwise to ice water and the product was taken up in dichloromethane. The organic portion was dried over sodium sulfate, filtered and the solvent was distilled off.

The title compound (XV) is obtained as a colorless oil in a yield of 90%.

Optical rotation:

[α] D = 4-46 ° (in chloroform, c = 1.17 percent w / v).

Elementary analysis:

For C 23 H 26 O 4 (mol. Wt. 366.461) calculated:

% C, 75.38;% H, 7.15;

found:

% C, 75.35;% H, 7.18.

Mass spectrum:

(Μ + · -1) = 365.

b) 1 (S) -Benzyloxy-2 (S) -methylpropyleneacetal-3 (R) -hydroxy-4 (R) -benzyloxycyclopentane (compound of formula XVI wherein R ¹ is phenyl)

The entire subsequent reaction was carried out under a nitrogen atmosphere and in the apparatus previously dried at 150 ° C.

To a solution of 3.7 g of the compound of formula XV prepared as described above in 50 ml of freshly distilled tetrahydrofuran at 0 ° C was added dropwise 1 equivalent of a commercial 1 M solution of boron hydride in tetrahydrofuran. The reaction mixture was left for 2 hours at 0 ° C and then at room temperature overnight. Excess hydride is decomposed at 0 ° C by the slow addition of a minimum amount of water. The resulting intermediate is then oxidized to an alcohol by adding, at 0 ° C, 2 ml of 6 N sodium hydroxide solution and 1.8 ml of 30% hydrogen peroxide. The reaction mixture was allowed to stand at room temperature for 4 hours, potassium carbonate was added, the mixture was filtered, and the filter was washed extensively with ethyl ether. The ether was dried over anhydrous sodium sulfate, filtered, and the solvents were distilled off. The crude alcohol was recrystallized from aqueous ethanol, and the resulting mother liquors were separated by column chromatography on silica gel using ethyl acetate / petroleum ether (1: 2) to elute the compounds.

In this way, the desired compound of formula XVI is obtained in a total yield of 45%. Mp 76-77 ° C (from ethanol to water), [α] _D = + 48 ° (in chloroform, c = 0.83% w / v).

Elementary analysis:

For С2.3Ы23О5 (mol. Wt. 384,477) calculated:

% C, 71.85;% H, 7.34;

found-:

% C, 71.86;% H, 7.33.

c) 1 [S] -henzyloxy-2 (S) -phenylpropyl-lenacetal-3 (R) -heptyloxy-4 (R) -benzyloxy-cyclopentane (a compound of formula XII wherein Z 1 is hydrogen and R ¹ is phenyl group)

3 equivalents of an oil slurry of sodium hydride are charged to a three-necked flask under nitrogen. After washing the suspension with dry hexane, 5 ml of Ν, Ν-dimethylformamide are added, the temperature of the mixture is lowered to 0 ° C, and a solution of 1 g of the compound of formula XVI, prepared as described above, is added.

29 Я 17 ml of Ν, Ν-dimethylformamide. After hydrogen evolution had ceased, 1.4 ml of n-iodo-heptane (mol, mass 229, h = 1.37) was added and the mixture was allowed to stand for about 8 hours at room temperature, then cooled to 0 ° C, diluted with dichloromethane and The solution is poured into ice water saturated with sodium chloride, the product is taken up in dichloromethane and the solution is dried over anhydrous sodium sulphate. ratio of 1: 2 to elute the substances.

In this way the desired compound of formula XII is obtained in the form of a colorless oil; yield 75%.

Elementary analysis:

For C 30 H 42 O 5 (mol. Wt. 4-2, V 6) calculated:

% C, 74.65;% H, 8.77;

found:

74.59% C, 8.82% H.

Optical rotation:

[α] _D = 0 ° (in chloroform, c = 1.7% w / v).

In the same way, prepare 1 (S) -benzyloxy-2 (S) -formylpropyleneacetal-3 (R) - [2 (S) -benzyloxyheptyloxy] -4 (R) -benzyloxycyclopentane:

Elementary analysis:

For СзбШаОб (mol. Mass 576,774) calculated:

% C, 74.96;% H, 8.38;

found:

% C, 74.89;% H, 8.40.

d) 1 (S) -Benzyloxy-2 (S) -forms 1-3 (R) -heptyloxy-4 (R) -benzyloxycyclopentane (a compound of formula XVII wherein Z 1 is hydrogen and R ¹ is phenyl)

To 0.085 g (0.176 mmol) of the compound of formula (XII) obtained above, 1.5 ml of 80% aqueous formic acid was added under argon, and the reaction mixture was allowed to stand at room temperature for about 8 hours. The solution was diluted with dry dichloromethane and adjusted to pH 4 with sodium bicarbonate. The mixture was taken up in anhydrous chloroform, washed with water to neutral pH, dried over anhydrous sodium sulfate, filtered and the solvents were distilled off.

In this way 0.063 g of the desired compound of formula XVII is obtained in the form of an oil 28 which is colored yellow when deposited. Yield 90%.

IR spectrum:

CHO group at 1720 cm ^-1 .

Elementary analysis:

For С.37НЗ6О4 (m-ol. Mass 424,581) calculated:

76.38 O / o C, 8.54% H;

found:

% C, 75.98;% H, 8.49.

In the same manner, 1 (S) -benzyloxy-2 (S) -formy-1-3 (R) - [2 (S) -benzyloxyheptyloxy] -4 (R) -benzyloxy-cyclopentane was prepared:

Elementary analysis:

For C 31 H 42 O 5 (mol. Wt. 530.705) calculated:

% C, 76.94;% H, 7.97;

found:

% C, 77.0;% H, 8.01.

e) 1 (S) -Benzyloxy-2 (S) - (6-barboxy-1-hexenyl) -3 (R) -heptyloxy-4 (R) -benzyloxycyclopentane (compound of formula XVIII wherein Z 'is hydrogen) and R ¹ is phenyl)

The compound is prepared as described in Example 1 above:

Elementary analysis:

For СззШбОз (mol. Mass 522,726) calculated:

% C, 75.82;% H, 8.87;

found:

75.60% C, 8.91% H.

In the same manner were prepared 1 (S) -benzyloxy-2 (S) - (6-carboxy-1-hexenyl) -3 (R) - [2 (S) -benzyloxyheptyloxy] -4 (R) -benzyloxycyclopentane:

Elementary analysis:

For C10H52O6 (m / m 628.85) calculated:

C, 76.39; H, 35.35;

found:

76.10% C, 8.39% H.

(f) 9 (S) -hydroxy-11 (R) -hydroxy-13-oxaprostanoic acid

The title compound was prepared as described in Example 1 above:

Elementary analysis:

For C19H36O5 (mw 344,492)

Elementary analysis:

For С19Н36О6 (mol. Wt. 360.491) calculated:

63.30% C, 10.06% II;

found:

63.33% C, 9.85% IT.

Mass spectrum:

M @ ⁺ = 360.

calculated ·:

66.24% С, 10.53% Η;

found:

65.95% С, 10.80% Η.

Mass Spectrum: M @ + = 344.

In the same way, 9 (S) -hydroxy-11 (R) -hydroxy-13-oxa-15 (S) -hydroxyprostanoic acid is prepared:

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of 11-hydroxy-13-oxaprostaglandin derivatives of the general formula I in which X represents a hydrogen atom or a hydroxyl group, X ^I represents hydrogen, or X ¹ and X ¹ together with the carbon atom to which they are attached form a carbonyl group, and Z represents a hydrogen atom or a hydroxyl group, and is a pharmaceutically acceptable alkali metal salt thereof, characterized in that the compound of formula (II): R represents a hydroxyl protecting group of the formula -CH ² R ¹ in which R ¹ represents phenyl, optionally substituted with methyl, or benzyl, optionally substituted in the core with methyl, D ‘denotes a group or β-S-i wherein R is as defined above, and Z 'represents a hydrogen atom or a group of the formula —OR, in which R is as defined above, hydrogenolyses in the presence of platinum on activated carbon or palladium on activated carbon, at room temperature and in acetic acid and ethanol, to the desired 11-hydroxy-13 -oxaprostaglandins in the form of the free acids of the formula I in which X represents a hydrogen atom or a hydroxyl group and X ¹ and Z are as defined above, optionally to the (6-carboxyhexyl) -3 (R) -heptyloxy derivative of the formula Z is as defined above, which is deprotected by the action of mercuric chloride in an organic solvent, preferably acetone, in the presence of boron trifluoride etherate to provide the desired 11-hydroxy-13-oxaprostaglandin free acid of formula I wherein X а X ¹ together with the carbon atom to which they are attached represent a carbonyl group and Z is as defined above, and the free acid obtained is optionally brought further to reaction with the appropriate alkali metal hydroxide to form pharmaceutically acceptable salts with alkali metal. Z represents a hydrogen atom or a hydroxy group, characterized in that a compound of the above formula (II) in which D ‘denotes a group \ h |||| OR is hydrogenolyzed 229317 2. Method of claim 1 к production of 11-hydroxy-13-oxaprostaglandinů of formula I wherein X ¹ а X are individually a hydrogen atom and Z represents a hydrogen atom or a hydroxyl radical, characterized in that the hydrogenolysis of a compound of the formula II wherein D 'is -CH 2 - and R and Z' are as defined above. 3. The method of claim 1 к production of 11-hydroxy-13-oxaprostaglandinů of formula I in which X represents OH, X ¹