FI69305C - FRAMEWORK FOR THE PREPARATION OF THERAPEUTIC THERAPEUTIC 7-OXO-PGI2 DERIVATIVES - Google Patents

Description

69305

The present invention relates to a process for the preparation of novel therapeutically useful optically active and racemic 7-oxo-PGI2 derivatives of the formula

10 - COOQ

15 I> = o T

p <,

'X-C-C-Y-R

20 R O 1 o / \ u L

RORR1 wherein Q is hydrogen, a physiologically acceptable cation or lower alkyl, X is cis- or trans-CH = CH- or -C = C-, 13 R is hydrogen, an alkanoyl having 1 to 4 carbon atoms or a protecting group which the formula is R 1, R 2, R 2, S 2, R 2, - CH 9 -C (R 2) -, OR 2, wherein R, R and R are the same or different 3a denotes a straight-chain or branched alkyl group having. 10 to 1 to 4 carbon atoms, and R and R are the same or different 12 groups and represent hydrogen or methyl 3a R is methyl 13 or ethyl, or R is a tetrahydropyran-2-yl protecting group, 4. .

R is hydrogen or lower alkyl having a steric configuration of CX or A, 12.

R and R represent hydrogen or lower alkyl, Y is methylene or oxygen, 3 R is lower alkyl or phenyl which may be monosubstituted by halogen.

2 69305

The novel compounds of the formula I are biologically active substances which can be considered as a stabilized analogue of the highly potent natural PGI2. PGI2 (Pros-Tacycline) was first described in Na-5 ture 263, (1976), p. 663. The substance is one of the major chain members of arachidonic acid metabolism, acting in very small amounts, and considerable pharmacological effects are particularly noteworthy. anti-platelet aggregation (antiplatelet) and antihypertensive effect, PGI2 inhibits platelet aggregation even in nanograms and has a thrombolytic effect on aggregated thrombosis. ) and abnormal haemostasis (suppression of bleeding) Numerous articles have been written on the clinical use of the substance.

The main problem with the use of PGI2 as a drug is its very high volatility. In acidic or neutral medium, PGI2 degrades to form 6-keto-PGFQf in equilibrium with the hemiketal form. PGI2 contains a highly reactive enol-ether moiety that reacts immediately with an external or internal proton source. Thus, PGI2 does not exist as a free acid, but its salts and esters are used in pharmacological and clinical studies.

It is an object of the invention to provide novel stable PGI2 analogs which do not show the inhibitory lability of native PGI2 and which at the same time retain its advantageous pharmaceutical, above all antiplatelet and thrombolytic activity.

It has now been found that the optically active and racemic 7-oxo-PGI2 derivatives of the formula I have better stability compared to the known PGI2 derivatives and at the same time have valuable PGI2-pharmaceutical activity.

II

3 69305

The 7-oxo-PG12 derivatives of formula I can be prepared by reacting a compound of formula

5 i / V

'' OAC (III) I1 3

XX-C-C-Y-R

10 / \ „U

HO R R

12 3 4 · wherein R, R, R, R, X, Y and Q are as defined above and Ac is acetyl, is reacted with a lower alcohol in the presence of a catalytic amount of an acid catalyst and the free hydroxyl groups in the resulting ketal of formula OR5

\ ^ COOQ

/ k / ^^ OAc K f.

25 // X - C - C - Y - R3 HO / \ 2

HO R R

12 3 4 30 wherein R, R, R, R, X, Y, Q and Ac are as defined above and R 1 is lower alkyl are protected by a silylating agent of formula R 7 8 * oc R-Si-Cl (VII ) I q Ra or an enol ether of formula 4 to 69305 η (VIII) R12 R10 7 8 9 5 in which R, R, R are the same or different and represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and and R 1 are the same or different and represent hydrogen or methyl 12 and R is methyl or ethyl, or 3,4-dihydro-2-H-pyran-10 and the resulting protected ketal has the formula CX 'r 20 r 6 / X / VP "Y" R3 r60 / r2 wherein R1, R2, R3, R * 1, R5, X, Y, Q and Ac are as defined above and R is a protecting group of formula R7R8R9Si or R11 -CH 2 -C (R 10) -OR 12, wherein R 7, R 8, R 9, R 10 and R 1 are as defined above, or R is a tetrahydropyran-2-yl group, are deacetylated in a basic medium, and the resulting protected hydroxyl group containing a free hydroxyl group is deacetylated. li with the formula 69305 5

0R}> <^ s ^^ C00Q

5 0H (VI) X ~ \ t 3

Jo S X-C-C-Y-R

R ° / \ I

6 '' M- I 2 R O R R

Wherein R 1, R 2, R 2, R 2, R 2, R 2, X, and Y and Q are as defined above, are oxidized - if desired after removal of the alkyl group R 1 by hydrolysis - to aprotic mixtures. in a solvent, and the resulting 7-oxo derivative of the formula

“L / N / n / C00Q

20 i ^> = 0 (ID

Cl f,

/ 'X-C-C-Y-R

25 RO g / \ 4 I 2

R ° 0 R R

wherein R, R, R, R, R, R 0, X, Y and Q are as defined above and R 1 is hydrogen or lower alkyl is optionally cleaved by protecting groups R and if desired the compound is acylated at the 11- and / or 15-position with lower alkanoyl after acylation of the free hydroxyl groups and eliminating R 5 where R is hydrogen or lower alkyl, and if desired the protecting groups R 1 are cleaved and / or the ester groups are saponified and, if desired, the free acid is converted into a salt or ester.

69305

In formula I, the meaning of the substituent Q, physiologically acceptable cation, means any organic or inorganic cation which, at the doses used, has no deleterious (toxic) effect. Suitable such inorganic cations are, for example, alkali metal ions, e.g. sodium, potassium, alkaline earth metal ions, e.g. calcium or magnesium ions. As a suitable cation, an unsubstituted or organic, preferably alkyl-substituted, ammonium ion can also be mentioned. Substituents for substituted ammonium ions may contain - in order to advantageously affect the solubility properties and the crystallization properties of the salts - other substituents, e.g. hydroxy groups, or amino groups. An example of such a cation is tris-hydroxymethylammonium.

Lower alkyl groups may be straight-chain or branched groups having 1 to 6 carbon atoms. Examples are methyl, ethyl, and isopropyl, n, sec, and tert, and isobutyl, and various pentyl and hexyl groups. Alkyl groups preferably contain 1 to 4 carbon atoms.

g R hydroxyl protecting groups are protecting groups known in prostaglandin chemistry. The addition and removal of protecting groups to the hydroxyl group can be performed according to methods known in the literature. The addition of protecting groups is important in order to oxidize only the hydroxyl group in the 7-position in the oxidation of the compounds of formula VI. The protecting group can be removed after oxidation as well as elimination.

The compounds of formula III are known {J.

Am. Chem. Soc. , 100, (1978), p. 675, or can be prepared from the corresponding starting materials by the methods described in the above publication.

The compound of formula III is reacted with a lower alkanol, preferably methanol, in the presence of a catalytic amount of acid catalyst at -78 to + 25 ° C.

69305 7

Mineral acids, sulfonic acids or Lewis acids can be used as acid catalysts. Preferably a boron trifluoride etherate is used.

The resulting ketal of formula IV can be used as a mixture of isomers or chromatographically separated for the next reaction.

In order to selectively deacetylate the 7-acetoxy group and selectively oxidize the hydroxyl group formed, the free hydroxyl groups of the compound of formula IV are temporarily protected in an alkaline or basic medium with stable protecting groups.

Trialkylchlorosilanes, such as dimethyl-tert-b-style-chlorosilane, and trimethylchlorosilane, can be used as silylating agents of formula VII. Di-15-methyl-tert-butyl-chlorosilane is used in aprotic solvents, preferably dimethylformamide in the presence of catalysts, preferably imidazole, and trimethylchlorosilane is used in pyridine or aprotic solvents, preferably in the presence of tertiary amines. The reaction temperature can vary widely; between -20 ° C and + 60 ° C.

Suitable enol ethers of the formula VIII are preferably ethyl vinyl ether, isopropenyl methyl ether in aprotic solvents, preferably dichloromethane, in the presence of a catalytic amount of acid. The reaction temperature can vary widely; in the range of -78 ° C to + 50 ° C. 3,4-Dihydro-2H-pyran can also be used for protection.

A compound of formula V containing protected hydroxyl groups can be hydrolyzed in a basic medium to a compound of formula VI. The acetyl group can be hydrolysed in lower alcohols, preferably methanol, in the presence of weak bases, preferably potassium carbonate, or with aqueous solutions of alkali or alkaline earth metal hydroxides. In the latter case, the carboxylic acid isolated from the reaction mixture is again converted to the lower alkyl ester, preferably the methyl ester, using a diazoalkane in the methyl ester. The reaction temperature may vary between 0 ° C and the boiling point of the solvent used, preferably at room temperature. By using longer reaction times and a strongly basic reaction medium, the alkyl group in place of R can be replaced by hydrogen. Oxidation of the hydroxyl group in a compound of formula VI wherein R is hydrogen or lower alkyl can be performed with any oxidant capable of oxidizing the secondary hydroxyl group to an oxo group, e.g. in aprotic solvents, preferably chlorinated hydrocarbons. The reaction temperature can range from -40 ° C to + 50 ° C.

A compound of formula VI wherein R 5 is hydrogen can also be oxidized. In this case, the hydroxyl group is selectively oxidized to give a hemi-ketal derivative of formula II wherein R is hydrogen.

If desired, the protecting groups R of the compound g of the compound of formula II obtained by oxidation can be cleaved, and the free hydroxyl groups can be acylated with an alkanoyl group if there are 1 to 4 carbon atoms. Namely, in the last elimination reaction g, a compound of formula II protected by an R group, acylated or containing free hydroxyl groups can be used.

The 7-oxo-PGI2 derivative of formula I is obtained from the 7-oxo derivative of formula II by eliminating R1-OH from the 7-oxo derivative of formula II.

Elimination of R-OH from a compound of formula II wherein R is lower alkyl and R is hydrogen gives a compound of formula I wherein R is hydrogen. Elimination of the alcohol can be accomplished by heating in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide, or hexamethylphosphoric acid triamine. The reaction temperature can vary widely between 70 and 180 ° C. Elimination can be promoted by using an alkanoic anhydride having 1 to 4 carbon atoms in the alkyl moiety, benzene or toluene. When an acid anhydride is used, a compound of formula I is also formed in which R is acyl, which can optionally be removed by catalyzed alcohololysis.

The compound of formula I wherein Q is alkyl can be isolated, for example, by column chromatography.

A compound of formula I wherein R is a protecting group is obtained from a compound of formula II wherein R is a protecting group and R 5 is lower alkyl using the elimination reaction described above.

13 6

When R is an R protecting group, the compound of formula I can be isolated by column chromatography and converted to a compound wherein R is hydrogen. The alkyl-silyl protecting groups are preferably removed with tetrabutylammonium fluoride in ether-type solvents, preferably tetrahydrofuran at a temperature of -20 ° C to + 50 ° C, preferably at room temperature.

From a compound of formula II wherein R 1 is hydrogen and R is a protecting group, water can be eliminated by boiling in an aromatic hydrocarbon in the presence of a water-binding agent to give a compound of formula I wherein R 13 is said protecting group. After deprotection, the compound of formula I in which R is hydrogen and Q is lower alkyl is purified, e.g. by chromatography.

Compounds of the formula I in which Q is a physiologically acceptable cation can be prepared from ester compounds of the formula I in which Q is lower alkyl by aqueous alkaline hydrolysis. An aqueous solution of an alkali or alkaline earth metal hydroxide at a temperature of 0 to 100 ° C can be used in the hydrolysis, and the salts are isolated, for example, after lyophilization. The carboxylic acid can be liberated from the second solution of the aqueous salt of the salt by careful acidification and can be dissolved in an organic solvent and converted to another salt with an aliphatic or aromatic amine.

69305 10

The compounds of formula I inhibit platelet aggregation and have a thrombolytic effect as with natural PGI2. The new compounds inhibit the action of thromboxane A2 as well as gastric acid secretion and affect some circulatory processes. The compounds can be used to ameliorate asthma, myocardial infarction, thrombosis (thrombosis), gastric ulcer and vascular irregularities in mammals, especially humans.

Pharmaceutical preparations containing the 7-oxo-PGI2 derivative as an active ingredient have a thrombolytic effect and at the same time can eliminate the risk of thrombus formation. This is particularly important in preserving blood, perfusing organs and tissues, and eliminating the risk of thrombosis after surgery.

In the case of platelet-concentrated plasma (PRP) isolated from human blood, the following ID, -q concentrations were obtained in the case of ADP- or collagen-induced aggregation: 20

Platelet aggregation inhibitory effect: ID5q ng / ml aggregation agent ADP collagen 25 PGI2 sodium salt 1-2 1-2 7-oxo-PGI2 sodium salt 15 80 7-oxo-PGI2-methyl ester 100-200 50 PGI2 subsoil constricting effect is 0.1-fold to 30-fold greater than the same effect of natural PGI2. The antiplatelet activity of the compounds of formula I does not achieve the effect of natural PGI2 *, but the compounds of formula I are very stable and nevertheless have a substantial effect, as a result of which the compounds 35 can be used as active ingredients in pharmaceutical preparations.

11 69305

The 7-oxo-PGI derivatives of formula I may be administered in doses ranging from 100 ng to 100 mg per day, depending on the desired effect, the route of administration and the sensitivity of the individual or animal and the organs and tissues treated. In the case of 5 continuous infusions, a dose of 1 to 10 mg per day is usually sufficient.

The preparations may be in liquid or semi-liquid form, in the form of ointments or pastes.

Liquid form preparations include solutions, emulsions or injectable solutions, infusion solutions and drops. Solid form preparations include tablets, capsules, granules, powders, boluses, and powder ampoules. Conventional lubricants, diluents, additives for regulating the osmotic pressure and pH, flavoring or flavoring agents, lubricants, wetting agents and dissolution retardants may also be added.

The following examples illustrate the invention.

Example 1 7β-Acetoxy-6-keto-PGFβ-methyl ester-methyl ketal (Formula IV wherein and Q represent methyl, 12. 4 and R, R are hydrogen, X is trans-vinyl, R is / N -hydrogen, 3 Y is methylene, R is propyl).

no.

“1 g of a compound of formula III, in which the substituents have the same meaning as indicated in the title product, are dissolved in 10 ml of methanol and a catalytic amount of boron trifluoride etherate is added to the solution. The reaction mixture is stirred for 20 min. I drive. is · · ·

After the addition of a small amount of solid sodium bicarbonate, the methanol is distilled off in vacuo and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, filtered and the solvent is distilled off.

li ...__ 6 9305 12 The residual oil is eluted with 120 g of silica gel using ethyl acetate. 240 mg (22%) of exo-methyl ketal and 680 mg (63%) of endo-methyl ketal are obtained in the form of a colorless oil.

5 exo-IV: Rf: 0.31 flux: ethyl acetate NMR 3.64 (3H, COOCHg) 3.24 (3H OCHg) endo-IV: Rf: 0.26 flux: ethyl acetate NMR 3.57 (3H, COOCHg) ), 3.14 (3H, OCH 3).

Example 2 10-Acetoxy-6-keto-PGF 4 -methyl ester-methyl-ketal-11,15-bis (tert-butyl-dimethyl-silyl) -ether

C

(Formula V wherein R is tert-butyl-dimethyl-silyl and the other substituents have the same meaning as in Example 1).

15,700 mg (1.52 m mol) of the methyl ketal of the formula IV obtained according to Example 1 are dissolved in 1.4 ml of anhydrous dimethylformamide and 517 mg (7.6 m mol) of imidazole and 552 mg ( 3.6 m mol) tert-butyl-dimethylchlorosilane.

The reaction mixture is stirred for 4 hours at 35-40 ° C and poured into 30 ml of water. The aqueous solution is extracted with 3 x 50 ml of dichloromethane, the combined dichloromethane extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the solvent is distilled off. The residual oil is chromatographed on 120 g of silica gel and eluted with 8: 1 hexane-ethyl acetate. 788 mg (75%) of the title product are obtained in the form of a colorless oil.

Rf: 0.42, flux: hexane / ethyl acetate 7: 1 NMR: 2.05 (3H, OAc), 0.88 (6H, tert-butyl).

13 69305

Example 3 7-Hydroxy-6-keto-PGF-β-methyl ester different methyl ketal 11,15-bis (tert-butyl-dimethylsilyl) ether 5 (Formula VI wherein the substituents have the same meaning as in Example 2) was announced).

200 mg (0.29 m mol) of the silyl ether of the formula V obtained according to Example 2 are dissolved in 2 ml of methanol and a catalytic amount of freshly calcined calcium carbonate is added to the solution.

The reaction mixture is stirred for 1 hour at room temperature. The solvent is distilled off in vacuo and the residue is dissolved in ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the solvent is distilled off. The residual oil is chromatographed on 20 g of silica gel and eluted with a mixture of 4: 1 hexane and ethyl acetate. 150 mg (80%) of product are obtained in the form of a colorless oil.

20 Κ ^: 0.5 flux: 4: 1 mixture of hexane and ethyl acetate IR (film) 335 0 cm -1, (OH).

Example 4 7-Hydroxy-6-keto-PGF 4 -methyl ester-hemi-25 ketal-11,15-bis (tert-butyldimethyl-silyl) ether (Formula VI = 5S = hydrogen, other substituents have the same meaning as in Example 2).

200 mg (0.29 m mol) of the silyl ether of the formula V prepared according to Example 2 are dissolved in 2 ml of methanol and 50 mg of freshly calcined potassium carbonate are added to the solution. The reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is further treated according to Example 3.

+ 14 69305

The crude product is chromatographed on 20 g of silica gel and eluted with a 2: 1 mixture of hexane and ethyl acetate. 113 mg (60%) of product are obtained in the form of a colorless oil.

Rf: 0.1 flux: hexane / ethyl acetate 4: 1 NMR: 3.67 (3H, COOCH2).

Example 5 7-Oxo-6-keto-PGF-β-methyl ester-methylketa-10β-11,15-bis (tert-butyldimethylsilyl) ether 5 (Formula II where R = methyl, other substituents mean the same as reported in Example 2).

75 mg (0.11 m mol) of the compound of formula VI (Example 3) are dissolved in 0.7 ml of dichloromethane and 63 mg (0.29 m mol) of pyridine chlorochromate are added to the solution.

The reaction mixture is treated with sodium acetate buffer and then stirred for 5 hours at room temperature. The reaction mixture is filtered, washed with dichloromethane, and the combined phases are concentrated.

The residue is chromatographed on 10 g of silica gel using a 12: 1 mixture of hexane and hexyl acetate.

56 mg (75%) of product are obtained in the form of a colorless oil.

Rf: 0.59 flux: a 7: 1 mixture of hexane and ethyl acetate. IR (film): 1735 cm -1 (C = O) 1000-1250 cm -1 (0-C-O).

Example 6 7-Oxo-6-keto-PGF-N-methyl ester hemiketate-30β-11,15-bis (tert-butyldimethylsilyl) ether Formula II wherein R 1 = hydrogen and other sbustuents have the same meaning as in Example 2 were reported).

50 mg (0.08 mol) of the silyl ether of the formula V prepared according to Example 4, in which 5 R = hydrogen, are dissolved in 0.5 ml of dichloromethane.

To this solution is added 45 mg (0.21 m mol) of pyridine chlorocarbonate. The reaction mixture is stirred for 6 hours at room temperature. The reaction mixture is further treated as in Example 5. and the crude product is chromatographed on 10 g of silica gel using a 1: 1 mixture of ethyl acetate and hexane. 37 mg (75%) of the title product are obtained in the form of a colorless oil. Rf: 0.55 flux: 1: 1 mixture of ethyl acetate and hexane.

IR (film) 3300 cm -1 (OH) 1730 cm -1 (C = O).

Example 7 7β-Acetoxy-6-keto-PGF 4 -methyl ester-methyl ketal-11,15-bis (tetrahydropyran-2-yl) ether g (Formula V wherein R = tetrahydropyran-2-yl) and others the substituents have the same meaning as reported in Example 1.

570 mg (1.24 mmol) of the compound of formula IV prepared according to Example 1 are dissolved in 5 ml of anhydrous dichloromethane and 1.13 ml (12.4 m mol) of anhydrous 3,4-dihydro-2H-pyran are added to solution 20. and a catalytic amount of p-toluenesulfonic acid. The reaction mixture is stirred at room temperature for 10 min. and diluted with 50 ml of ethyl acetate. The ethyl acetate solution is washed with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate, filtered and the solvent is distilled off. 831 mg (crude) of product are obtained in the form of a pale yellow oil.

30 E ^ .: 0.53 flux: a 1: 1 mixture of benzene and ethyl acetate.

IR (film: 1740 cm -1 (C = O), 1000-1200 cm -1 (0-CH-O).

The obtained product can be used without purification for the next reaction.

16 69305

Example 8 N, N-Hydroxy-6-keto-PGF 4 -methylmethyl ketal-11,15-bis (tetrahydropyran-2-yl) ether 5 (The substituents of formula VI are the same as in the example). 7. reported) 831 mg (1.32 m mol) of the compound of formula V prepared in Example 7 are dissolved in 8 ml of methanol and a catalytic amount of freshly calcined potassium carbonate is added to the solution.

The reaction mixture is stirred for 1 hour at room temperature and further worked up according to Example 3. The residual oil is chromatographed on 40 g of silica gel using a 1: 1 mixture of benzene and ethyl acetate as eluent. 471 mg (65%) of 15 partial products are obtained in the form of a colorless oil.

Rf: 0.35 flux: 1: 1 mixture of benzene and ethyl acetate.

IR (film): 3350 cm-1 (OH), 1735 cm-1 (C = O).

1000-1200 cm -1 (0-CH-O).

Example 9 7-Oxo-6-keto-PGFβ-methyl ester-methyl ketal-11,15-bis (tetrahydropyran-2-yl) ether (Formula II, substituents as reported in Example 7).

344 mg (0.59 m mol) of the compound of formula VI prepared according to Example 8 are dissolved in 3.5 ml of dichloromethane and 254 mg (1.18 m mol) of pyridine chlorochromate are added to the solution. The reaction mixture is treated with sodium acetate buffer and stirred for 5 hours at room temperature. The reaction mixture is further treated as described in Example 5. The crude product is chromatographed on 30 g of silica gel using a 1: 1 mixture of benzene and ethyl acetate as eluent.

17 69305

275 mg (0%) of the title product are obtained in the form of a colorless oil.

0.57 flow agent: a 1: 1 mixture of benzene and ethyl acetate.

Δ IR (film): 1730-1740 cm -1 (C = O), 1000-1200 cm -1 (0-CH-O).

Example 10 7-Oxo-6-keto-PGF 4 -methyl ester-methyl ketal (Formula II wherein R 1 = hydrogen and other substituents as reported in Example 1).

194 mg (0.33 m mol) of the methyl ketal of the formula II obtained according to Example 9, in which g R is tetrahydropyranyl and the other substituents as indicated in the product, are dissolved in 10 ml of methanol and a catalytic amount of p is added to the reaction mixture. -toluene-sulfonic acid. The solution is stirred for 1 hour at room temperature and the solvent is distilled off in vacuo. The residue is dissolved in ethyl acetate, the ethyl acetate solution is washed with saturated sodium bicarbonate solution, water and then aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent is distilled off.

The residual oil is chromatographed on 15 g of silica gel using a 2: 1 mixture of benzene and ethyl acetate. 117 mg (85%) of the title product are obtained in the form of a colorless oil.

Rf: 0.34 flux: ethyl acetate λΗ NMR (CDCl3): 3.67 (C00CH3), 317 (OCH2) IR (film): 3350 cm -1 (OH), 1735 cm -1 (C = O).

Using correspondingly substituted starting materials of general formula III, Examples 1-10 are obtained. according to process steps, the following intermediates of general formula II: 69305 18 7-oxo-6-keto-16-methyl-PGF 4 -methyl, ethyl, propyl and butyl ester hemiketal and the same methyl, ethyl, propyl and butyl ketal . 7-Oxo-6-keto-16,16-dimethyl-PGF-N, N-methyl, ethyl, S-propyl and butyl ester hemiketal and the above methyl, ethyl, propyl and butyl ketal.

The hemiketal of 7-oxo-6-keto-16-phenoxy-17,18,19,2 O-tetranor-PGF 4 -methyl, ethyl, propyl and butyl ester and the methyl, ethyl, propyl and 10 butyl ketal.

7-oxo-6-keto-20-methyl-PGF 4 -methyl, ethyl, propyl and butyl ester hemiketal and the above methyl, ethyl, propyl and butyl ketal. 7-oxo-6-keto-13,14-didehydro-PGF 4 -methyl, ethyl, propyl and butyl ester hemiketal and the above methyl, ethyl, propyl and butyl ketal. 7-oxo-6-keto-15-methyl-PFF 4 -methyl, ethyl, propyl and butyl ester hemiketal and the above methyl, ethyl, propyl and butyl ketal.

7-oxo-6-keto-15-epi-PGF1β-methyl, ethyl, propyl and butyl ester hemiketal and the above methyl, ethyl, propyl and butyl ketals.

7-oxo-6-keto-15-epi-16,16-dimethyl-PGF-N, N-methyl, ethyl, propyl and butyl ester hemiketal and the above methyl, ethyl, propyl and butyl ketals.

7-Oxo-6-keto-15-epi-16-phenoxy-17,18,19,20-tetranor-PGFlephmethyl, ethyl, propyl and butyl ester hemiketal and the above methyl, ethyl, prop-30-methyl and butyl ketal.

7-oxo-6-keto-15-epi-20-methyl-PGF1β, methyl, ethyl, propyl and butyl ester hemiketal and the above methyl, ethyl, propyl, and butyl ketal.

Il 19 69305

If no deprotection is carried out during the synthesis according to Example 19, then the 11,15-bis-silyloxy-, 11,15-bis (tetrahydropyran-2-yloxy) - and 11,15-bis-5 (U-alkoxyalkyl) derivatives.

E (R = silyl, tetrahydropyran-2-yl, alkoxyalkyl).

By "epi" derivative is meant a derivative in which a carbon atom known from the number preceding "epin" contains a substituent having a configuration opposite to that of a substituent on the corresponding carbon atom of natural prostaglandins.

Example 11 7-Oxo-PGI9-methyl ester 1 1 2 13 15 (Formula I where Q = methyl, R, R, R =

B

hydrogen, X = trans-vinyl, R = beta-hydrogen, Y = methylene, R = propyl).

20 mg (0.31 m mol) of a compound of formula II - prepared according to Example 5 - in which R5 = g of methyl, R = dimethyl-tert-butylsilyl and other substituents are indicated in the product - are dissolved in 5 ml of hexamethyl-phosphoric acid triamide. The reaction mixture is stirred for 3 hours at 150-160 ° C and poured into 18 ml of water. The aqueous phase is extracted with 3 x 15 ml of ethyl acetate and the combined ethyl acetate extract is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent is distilled off. The remaining 250 mg of product is dissolved in 5 ml of tetrahydrofuran and, after adding 2 equivalents of tetrabutylammonium fluoride, the mixture is stirred at room temperature for 3 hours. The solvent is distilled off in vacuo and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, saturated aqueous sodium chloride solution + 4 69305, dried over anhydrous sodium sulfate, filtered and the solvent is distilled off. The residual oil is chromatographed on 10 g of silica gel using ethyl acetate. 62 mg of 5 (50%) of the title product are obtained in the form of a colorless oil.

Rf: 0.44 flux: ethyl acetate NMR: 5.37 (1H, t, O-C = CH-), 3.76 (3H, s - COOCH3).

Example 12 7-Oxo-PGI2-methyl ester 200 mg (0.31 m mol) of a compound of general formula II prepared according to Example 6, wherein R is hydrogen and R is dimethyl-tert-butylsilyl and other substituents are the same as indicated in Example 11. are boiled in 30 ml of a Soxhlet extractor containing anhydrous benzene and anhydrous magnesium sulfate for 2 hours. The organic phase is washed with water, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent is distilled off. The crude product is treated with 2 equivalents of tetrabutylammonium fluoride in tetrahydrofuran and the reaction mixture is further treated as in Example 11. The mixture is chromatographed on 10 g of silica gel using ethyl acetate. 52 mg (25%) of the title product are obtained in the form of a colorless oil. The physical constants of the product are the same as reported in Example 11.

Il 21 69305

Example 13 7-Oxo-PGI2-methyl ester 90 mg (0.215 m mol) of V-oxo-O-keto-PGF-β-methyl ester-methyl-5-ketal prepared according to Example 10 (formula II where = hydrogen) are dissolved in 0.8 ml. to hexamethyl-phosphoric acid triamide and the mixture is stirred for 2 hours at 140-150 ° C. The reaction mixture is further treated as described in Example 11. The residual oil is chromatographed on 10 g of silica gel using ethyl acetate. HO mg (47%) of the title product is obtained in the form of a colorless oil. The physical constants of the product are the same as reported in Example 11.

Example 14 7-Oxo-PGI 8 -methyl ester-11,15-diacetate * 12 (Formula I wherein Q = methyl, R, R = hydrogen, R = γ-hydrogen, X = trans-vinylene and Y = methylene ).

100 mg of 7-oxo-6-keto-PGF-β-methyl ester methyl ketal-11,15-diacetate are dissolved in 3 ml of hexa-20-methyl-phosphoric acid triamide and stirred in the presence of 0.05 ml of acetic anhydride. for one hour at 80-100 ° C. The reaction mixture is further worked up as described in Example 11. The crude product is chromatographed on 15 g of silica gel using a 1: 1 mixture of ethyl acetate and hexane.

70 mg (72%) of product are obtained in the form of a colorless oil. Rf: 0.65 flux: 1: 1 mixture of ethyl acetate and hexane.

1 H-NMR: 5.55 (1H, t, J = 8Hz), 5.40 (2H, m), 5.34 (1H, m), 4.87 (1H, m), 4.59 (1H , m), 3.45 (3H, s, C 10 CH 3), 1.81, 1.73 (3-3H, s).

22 69305

Example 15 16,16-Dimethyl-7-oxo-PGI, methyl ester 1. 2 1 (Formula I wherein R and R = methyl and other substituents are the same as reported in Example 11).

90 mg (0.21 mmol) of 16,16-dimethyl-7-oxo-6-keto-1 2 PGF 4 -methyl ester methyl ketal, - in which R and R denote methyl are dissolved in 1 ml of hexamethyl-phosphoric acid triamide and the reaction mixture is stirred For 2 hours at 140-150 ° C.

The procedure is further as described in Example 13.

50 mg (56%) of the title compound are obtained in the form of a colorless oil.

Rj. = 0.52 (in ethyl acetate) 1 H-NMR: 5.60 (2H, m, -CH = CH-), 5.29 (1H, t, O-C = CH), δ 3.72 (3H, s, COOCH3), 0.95 (9H, s, CH3).

Example 16 7-Oxo-PG12-sodium salt (Formula I where Q = sodium and other substituents are the same as in the product of Example 11).

50 mg (0.13 mmol) of 7-oxo-PG12-ethyl ester are dissolved in 0.1 ml of methanol, and after adding 1.4 ml of 0.1 aqueous sodium hydroxide solution, the mixture is stirred at room temperature for 24 hours. The solution is lyophilized.

55 mg of the title product are obtained in the form of a white mass.

According to the reactions of Examples 11-16, from the compounds of formula II prepared according to Examples 1-10, the following compounds are prepared: 7-oxo-16-phenoxy-17,18,19,20-tetranor-PF12 and its alkyl ester having 1 to 4 carbon atoms (methyl ester in R 2 ethyl acetate: 0.57); 7-oxo-16-methyl-PGI2 and its alkyl ester having 1 to 4 carbon atoms (methyl ester in R1: ethyl acetate: 0.49); 7-oxo-20-methyl-PGI2 and its alkyl ester having 1 to 4 carbon atoms (methyl ester in R1 ethyl acetate: 0.51);

II

23 69305 7-oxo-13,14-didehydro-PG12 and its alkyl ester having 1 to 4 carbon atoms (methyl ester in ethyl acetate: 0.47); 7-oxo-15-methyl-PG12 and its alkyl ester having 5 to 4 carbon atoms (methyl ester in R1 ethyl acetate: 0.53); 7-oxo-15-epi-PG12 and an alkyl ester thereof having 1 to 4 carbon atoms (methyl ester in R1 ethyl acetate: 0.50); 7-oxo-15-epi-16,16-dimethyl-PGI2 and its alkyl ester having 1 to 4 carbon atoms (methyl ester in R 1 ethyl-10 acetate: 0.58); 7-oxo-15-epi-16-phenoxy-17,18,19,2-tetranor-PG12 and its alkyl ester having 1 to 4 carbon atoms (methyl ester in R1 ethyl acetate: 0.63); 7-oxo-15-epi-20-methyl-PG12 and an alkyl ester thereof having 1 to 4 carbon atoms (methyl ester in R1 ethyl acetate: 0.55).

The free acids can be prepared as described in Example 16 by saponification from an alkali metal salt, e.g. a sodium salt, so that its aqueous solution is acidified with a strong organic or inorganic acid. The free acid separates from the solution.

Example 17 7-Oxo-16-phenoxy-17,18,19,20-tetranor-PG12 methyl ester (Formula I wherein R 1 and R 2 = hydrogen, Q = methyl, R * 4 = hydrogen, X = trans -CH = CH-, Y = oxygen, R 3 = phenyl and R 13 = hydrogen) 50 mg (0.11 mmol) of a compound of formula II,. ^. . .

wherein R is methyl and the other substituents have the same meaning as above, are dissolved in 3 ml of hexamethylphosphoric acid triamide and the reaction mixture is stirred for 2 hours at 140-150 ° C. The reaction mixture is then treated as described in Example 13 to give 30 mg (64%) of the title compound as a colorless oil.

1 H-NMR: 6.68-7.4 (5H, m, phenyl), 5.6 (2H, m, -CH = CH), 5.34 (1H, m, O-C = CH), δ , 67 (3H, s, C 10 CH 3).

24 69305

Example 18 7-Oxo-13,14-didehyro-PGI9-methyl ester. i2 ^ 4 (Formula I wherein R and R = hydrogen, Q = methyl, R = 3 13 hydrogen, X = -C = C-, Y = methylene, R = propyl and R = 5 hydrogen) 100 mg (0, 24 mmol) of 7-oxo-13,14-didehydro-6-keto-PGF-β-methyl ester are dissolved in 3 ml of hexamethylphosphoric triamide and stirred for 2 hours at 140-150 ° C. The reaction mixture is then treated as described in Example 13 to give 55 mg (60%) of the title compound as a colorless oil.

1 H-NMR: 5.32 (1H, t, O-C = CH), 3.67 (3H, s, C 10 CH 3). Example 19 20-Methyl-7-oxo-PG12-ethyl ester-11,15-diacetate (Formula I wherein R "*" and R 1 = hydrogen, R 3 = butyl, R 4 = 13 hydrogen, X = trans -CH = CH-, Y = methylene, Q = methyl and R = acetyl) 100 mg (0.2 mmol) of 20-methyl-7-oxo-6-keto-PGI, -L © 0 20 methyl ester-11, 15-Diacetate is dissolved in 15 ml of anhydrous benzene and the solution is boiled for 2 hours in an anhydrous "Soxhlet" extractor. The procedure is then as described in Example 12 to give 72 mg (75%) of the title compound as a colorless oil.

1 H-NMR: 5.52 (2H, m, -CH = CH-), 5.40 (1H, t, O-C = CH), 5.25, 4.97, 4.86, 3.67 (3H, s, C 10 CH 3), 2.05, 1.97 (3-3H, s, -oco-ch 3).

Example 20 7-Oxo-16- (m-chloro-phenoxy) -17,18,19,20-tetranor-30 PGI 4 -methyl ester (Formula I wherein R 1, R 3, R 4 and R 3 = hydrogen, X = 3 -CH = CH-, Y = oxygen, R = 3-chlorophenyl and Q-methyl) 120 mg (0.25 mmol) 7-oxo-16- (m-chlorophenoxy) -17,18,19 The 20-tetranor-6-keto-PGF 4 -methyl ester-methyl-35 ketal is dissolved in 3 ml of hexamethyl-phosphoric acid triamide and the solution is stirred for 2 hours at 140-150 ° C.

69305 25

The procedure is then as described in Example 13 to give 71 mg (63%) of the title compound as a colorless oil.

1 H-NMR: 6.65-7.3 (4H, m, phenyl), 5.55 (2H, m, -CH = CH-), δ 5.39 (1H, t, O-C-CH), 3.67 (3H, s, C 10 CH 3).

Example 21 7-oxo-PGL ·,

To a solution of 378 mg (1 mol) of 7-oxo-PGI2-methyl ester and 10 ml of methanol are added 3 ml (3 mol, 10 IM) of aqueous sodium hydroxide solution, and the reaction mixture is stirred for 3 hours at room temperature. The methanol is then removed under reduced pressure. 20 ml of water are added to the residue and the pH is adjusted to 3-4 at 0 [deg.] C. with 4 ml (about 4 mol) of sodium hydrogen sulphate solution, followed by extraction with 3 * 50 ml of diethyl ether. The combined organic phases are washed with 30 ml of saturated brine and dried over magnesium sulfate. After evaporation, 183 g of 7-oxo-PG12 are obtained in the form of white crystals.

Thin layer chromatography: R f (benzene / dioxane-1-acetic acid 20/10): 0.35.

Melting point: 57-60 ° C.

Claims (7)

1. A process for the preparation of therapeutically usable optically active and racemic V-oxo-PGI deriv derivatives of the formula -C00Q io 1 o- (I) in Vo 15 ^ - \ 15 f pi3n / nx-ccy- where Q is hydrogen or a physiologically acceptable cation or lower alkyl, X is cis- or trans -CH = CH-, or -C = C-, 13 R is hydrogen, alkanoyl of 1-4 carbon atoms or a protecting group of the formula R 7 R 2 R 9 Si or R 2 -CHO-C (R 1 R, R and R are the same or different and represent a straight-chain or branched alkyl group having 1-4 carbon atoms and R 11 and R are the same or different and represent hydrogen or methyl 12 13 and R is methyl or ethyl, or R is a tetrahydropyran-2-yl protecting group, 14 R is hydrogen or lower alkyl, whose steric configuration is Ct or / b configuration, R 2 is hydrogen and lower alkyl, Y is methylene or oxygen and 3 R is lower alkyl or phenyl which may be monosubstituted. row of halogen, characterized in that a compound of formula 32 Λ 69305 ο _ / V ^ COOQ ί / / * OAc (HI). X - C-C-Y-R 3 / U 2 H RR 12 12 where R, R, R, X, Y and Q are the same as above and Ac Sr acetyl is reacted with a lower alkanol in the presence of a catalytic amount of an acid catalyst, and the free hydroxyl groups of the obtained ketal of the formula: XCCYR HO / HO 4 R, R, R, X, Y, Q and Ac are the same as above and R is lower alkyl, protected by a silylene agent of the formula 3 ° R q I R-Si-Cl (VII) I 9 RS 35 or with an enol ether of formula 33 69305 η (Vili) R12 R10 7 8 9 5 wherein R, R and R are the same or different or represent a straight-chain or branched alkyl group having 1-4 carbon atoms and R and R Mr are the same or different and represents hydrogen or 12 methyl or R 1 methyl or ethyl, or with 3,4-dihydro-2H-pyran, and the resulting protected ketal of the formula o Wherein R, R, R, R, R, X, Y, Q and Ac represent the same 7 8 9 25 as above and R 1 represents a protecting group of the formula RRR Si or R 11 -CH 2 -C (R 10) -R 12, where R 7, R 8, R 9, R 10, R 11 and R 12 the ketal containing a free hydroxyl group and having the formula of 6 S-Sf '0H (VI) X-K i1 3 p6n ^ X-C-C-Y-R R U | R, R, R, R, R, R, R, X, Y and Q denote the same as above, oxidized - possibly after removal of the alkyl group R5 by hydrolysis - in an aprotic solvent and from the obtained 7-oxo derivative of the formula C00 O (II) Χχ f '/' X - C-C-Y-R 3 2. R q / 6 4 2 Rö0 RR 1 2 3 4 5 6 van R, R, R, F., R, R, X, Y and Q denote the same as above and R Sr vSte or lower alkyl is split off, if desired, the protecting groups R and, if desired, the compound 11 and / or 15 position is acylated with lower alkanoyl after acyl 5. 5, where R is hydrogen or lower alkyl, is eliminated and, if desired, the protecting groups R and / or saponified the ester groups are split off and, if desired, the free acid is converted til one site or ester.