DD154295A5 - PROCESS FOR PREPARING 7-OXO-PGI LOW 2-DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of new 7-oxo-PGI 2-derivatives of the general formula I, wherein Q is hydrogen, or a physiologically acceptable cation or lower alkyl, X is cis- or trans-CH = CH, - CC- or -CH 2-CH deep 2-, R is high 13 for hydrogen, alkanoyl of 1-4 carbon atoms or a protecting group of formula R high 7 R high 8 R high 9 Si, R high 11-CH deep 2 CR high 10 - CR high 12, where R is high 7, R is high 8 and R 9 are the same or different and represent straight-chain or branched alkyl groups with 1-4 carbon atoms and R 10 and R 11 are identical or different and R 12 is hydrogen or methyl and R 12 is methyl or ethyl and is a tetrahydro-pyran-2-yl protecting group, R 4 is hydrogen or lower alkyl in alpha or beta steric configuration, R is high 1, R is high 2 is hydrogen or lower alkyl, Y is methylene, oxygen or NH and R 3 is lower alkyl, optionally monosubstituted phenyl or substituted heteroaryl, for example of 7-oxo-PGI 2-methyl deep ester or of 7-oxo-15-epi-16, 16-dimethyl-17, 18, 19, 20- tetranor-PGI 2-methyl ester deep. The substances are practically a stabilized analog of the natural PGI deep 2.

Description

14 232 55

225 132

Process for the preparation of new 7-oxo-PGI ₀ derivatives

Scope of the invention :

The invention relates to a process for the preparation of novel optically active or racemic 7-oxo-PGIo derivatives of general formula I, wherein

Q is hydrogen, a physiologically acceptable cation or lower alkyl,

X _{0 0} -CH for cis or trans-CH = CH-, -CC- or -CH - group,

13 ~

R ^ is hydrogen, alkanoyl of 1-4 carbon atoms,

7 8 9 or for a protective group of the formula RR R ^ Si,

R ¹¹ -CH ₂ -CR ¹⁰ -OR ¹² - wherein R ⁷ , R ⁸ , R ^{9 are} identical or different groups and denote straight-chain or branched alkyl groups having 1-4 carbon atoms and R and R are identical or different groups and hydrogen or methyl and

· - 2 - 2 25 132

-ip

R is methyl or ethyl - or is a tetrahydro-pyran-2-yl protective group, R is hydrogen or lower alkyl in & - or ß-steric configuration,

R, R is hydrogen or lower alkyl,

Υ methylene, oxygen or a -UH group and R · ^ is lower alkyl, optionally mono-substituted phenyl, or substituted heteroaryl.

Characteristic of the known technical solutions:

The novel compounds of the general formula I are biologically active substances which can be considered as a stabilized analogue of the extremely effective natural PGI ₂ . PGI ₂ (prostacyclin) was first described in Nature, 26J3, 663 (1976). The substance is one of the most important chain members of arachidonic acid metabolism, which is effective even in a very small amount, and among the remarkable pharmacological effects, especially the aggregation-reducing and hypotensive effect can be mentioned. PGI ₂ inhibits aggregation of platelets in a few nanograms and has a thrombolytic effect on the aggregated thrombus. "Because of its pervasive pharmacological activity, PGIp is a very valuable drug for the treatment of the disease of the century: thrombosis and abnormal hamostasis A large number of articles have already been published on the clinical use of the substance.

The biggest problem with using PGI ₅ as a drug

C.

Medium represents the great instability of the substance. In its acidic or neutral medium PGIp decomposes to form 6-keto-PGF in equilibrium with the hemiketal form. PGIo contains a highly reactive enol-ether structural unit that reacts equally strongly with the external or internal proton source. PGIp does not exist

- 3 «.

- 3 - 2 25 132

in the form of free acid but esters are used in pharmacological and clinical studies.

Object of the invention:

The aim of the invention is the preparation of such new stable PGI ₂ analogues which do not have a pharmaceutical use of the natural PGI ₂ inhibiting lability, but at the same time have its advantageous pharmaceutical, especially a thrombocyte aggregation inhibiting and thrombolytic action.

Explanation of the essence of the invention ·:

It has been found that the optically active or racemic 7-0xo-PGI ₂ derivatives of general formula I according to the invention over the known PGI ₂ derivatives have greater stability and at the same time exert valuable PGI ₂ pharmaceutical activity.

In the meaning of Q, the physiologically compatible cation is any organic or inorganic cation which does not exert any damaging (toxic) effect in the doses used. As such inorganic cations, e.g. Alkali metal - e.g. Sodium, potassium, alkaline earth metal, e.g. Calcium or magnesium ions in question. As a suitable cation is also the unsubstituted or by organic, preferably alkyl substituted ammonium ion mentioned. The substituents of the substituted ammonium ions may be used to favor the solubility properties and crystallization properties of the salts, other substituents e.g. Wear hydroxy groups or amino groups. As an example of such cation tris-hydroxymethylammonium is mentioned.

- 4 - 225 132

The lower alkyl groups may be straight-chain or branched groups having 1-6 carbon atoms. "Examples which may be mentioned are methyl, ethyl and iso-propyl, n-, see. and tert. and iso-butyl and various pentyl and hexyl groups. The preferred alkyl groups contain 1-4 carbon atoms.

The R hydroxyl-protecting groups are protective groups known in prostaglandin chemistry. The introduction of the protective groups into the hydroxyl group and their removal can be carried out by methods known from the literature. The introduction of the protective groups is important in order to oxidize only the hydroxyl group in the 7-position in the oxidation of the compounds of general formula VI.

The protecting group can be removed after oxidation and after elimination.

Monosubstituted phenyl and substituted heteroaryl groups in place of R may contain one or more of the following same or different groups: lower alkyl optionally substituted by one or more halogen atoms, hydroxyl, sulfhydryl, lower alkanoyloxy, benzoyloxy, amino, mono or di (lower) Alkylamino, halogen, lower alkoxy, or lower alkylthio. The heteroaryl groups may consist of a 6-membered ring containing one or more identical or different heteroatoms, which may optionally be condensed with a benzene ring.

The compounds of general formula I can e.g. out

1 2

the compounds of general formula III, wherein R, R,

3 R, X, Y and Q are as defined above and Ac is acetyl. The compounds of general formula III are known / J. Am _e . Soc., 100, ^6, 56 (1978) 7, or can be prepared from the corresponding starting materials by the above known method.

"5 - 225 1 32

The compounds of general formula III are reacted according to the invention with a lower alcohol, preferably methanol, in the presence of a catalytic amount of an acid catalyst at -78 ⁰ C to +25 ⁰ C. As the acid catalyst, mineral acids, sulfonic acids or Lewis acids can be used. Boron trifluoride etherate is preferably used.

The isomeric ketals of the general formula IV formed in the above reactions, wherein in the formula IV R is lower alkyl and the remaining substituents are as defined above, may be used in the form of any of their mixtures or separated by chromatography in the next reaction ,

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

According to a further feature of the invention, the compounds of general formula IV can be reacted with reagents resulting from protective groups corresponding to the above requirements. In the reaction may be preferred

a) silylating agent of general formula VII, wherein R, 8 Q

R and R "are identical or different straight-chain or branched alkyl groups having 1-4 carbon atoms or

b) enol ether of the general formula VIII wherein R ¹⁰ and R

are the same or different and are hydrogen or methyl

12

and R is methyl or ethyl, or

_ ₆ _ 225 1 32

c) 3j4-dihydro-2H-pyran can be used.

As Silylierungsmittel of general formula VII can Trialkyl chi or silanes, such as dimethyl-tert.butyl-ehlorsilan, trimethylchlorosilane, use and the Dirnethyltert.butylchlorsilan is in aprotic solvents, preferably in dimethylformamide in the presence of catalysts, preferably imidazole used. The trimethylchlorosilane is used in pyridine or in aprotic solvents, preferably in the presence of tertiary amines. The reaction temperature can be varied in a wider range, between -20 ⁰ C - +60 ⁰ C.

Preferred enol ethers of the general formula VIII are X-ethylvinyl ether, iso-propenyl methyl ether in aprotic solvents, preferably in dichloromethane in the presence of a catalytic amount of acid. Possible catalysts are mineral acids, phosphoryl chloride, sulfonic acids, preferably p-toluenesulfonic acid. The reaction temperature can be varied within a wider range between -78 ⁰ C- + 50 ⁰ C.

As with the enol ethers of the general formula VIII, it is also possible to work with 3,4-dihydro-2H-pyran.

The protected hydroxyl-containing compounds obtained by the above reactions of the general formula V · wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y, Ac and Q are as above

6V 8

and R is a silyl group of the formula ER R ^y Si or a ck alkoxyalkyl group of the formula R -CH ₀ -CR-

OR or a tetrahydropyra-2-yl group, in which

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above, can be hydrolyzed in a.basischen medium to compounds of general formula VI. The acetyl group may be in lower alkanols, preferably in methanol, in the presence of mild bases, preferably of potassium carbonate ₅ or with

- 7 - 225 1 32

aqueous solutions of alkali or alkaline earth metal hydroxides are hydrolyzed. In the latter case, the carboxylic acids isolated from the reaction mixture are converted back into lower alkyl esters, preferably (by using diazoalkane) in methyl ester. The reaction temperature can vary between 0 ⁰ C and the boiling point of the solvent used, preferably working at room temperature. For longer reaction times and in a strong basic reaction medium, the alkyl group R can be replaced by hydrogen. The oxidation of the hydroxyl group of the compounds of general formula VI which contain hydrogen or lower alkyl in place of R can be oxidized with any oxidizing agent which is capable of oxidizing a secondary hydroxyl group to oxo group (eg Jones-Reagent, Collins Reagent, thioanizol-chloro complex, Pyridiniumchlorch.romat etc.) in aprotic solvents, preferably in chlorinated hydrocarbons, are performed. The reaction temperature can be changed between -40 ⁰ C - +50 ⁰ C as desired.

It is also possible to oxidize those compounds of general formula VI in which R is hydrogen. In this case, the hydroxyl group is selectively oxidized, and obtained hemiketal derivatives of the general formula II, which contain hydrogen as R, which can be further reacted or, if desired, in R lower alkyl-containing compounds of general formula II can be recycled.

The protecting group R of the compounds of general formula II obtained by oxidation can be cleaved, if desired, and the free hydroxyl groups can be acylated with an alkanoyl group having 1-4 carbon atoms. Namely, in the last elimination reaction, compounds of general formula II protected by R group and acylated and containing free hydroxyl groups can be used.

- -β - Z 2 B 1 3 2

7-oxo-PGI derivatives of the general formula I are obtained from the 7-oxo derivatives of the general formula. II obtained by eliminating from the 7-Οζο-derivatives of general formula II, the compound of the general formula R-OH.

By the elimination of the alcohol of the general formula R-OH, compounds of general formula I,

TO

where R is hydrogen, from compounds of the formula 6 UU, wherein R "^ lower alkyl and R is hydrogen, can be prepared." The elimination of the alcohol can be carried out by heating in various dipolar aprotic solvents, such as dimethylformamide, dimethyl sulfoxide or hexamethyl-phosphite triamide, are made. the reaction temperature can be varied between 70 ⁰ C and 180 ⁰ C. the elimination can be accelerated by use of Alkansäureanhydriden having 1-4 carbon atoms in the alkyl moiety benzene or toluene. When using acid anhydrides are also formed compounds of the

general formula I wherein R ₅ is acyl, the enf desired, alls be removed by base catalyzed alcoholysis *

The lower alkyl-containing compounds of general formula I which are lower than Q may be e.g. be isolated by column chromatography.

• jo C.

The instead of R, R-protected hydroxyl-containing compounds of general formula I may instead of

6 5

R is a hydroxyl-protecting group and R lower alkyl-containing compounds of general formula II - obtained by the above elimination reaction.

R can be used for the hydroxyl protecting groups described above, such as

13 e.g. Trialkyl-silyl, alkoxy-alkyl. The instead of R, R protective group-containing compounds of the general

- 9 -

- 9 - 225 1 32

Formula I can be isolated after purification by column chromatography and, if desired, after removal of the protective

13 *

groups in instead of R hydrogen-containing compounds of the general formula I converted v / earth. Trialkyl silyl-protecting groups are preferred Tatrabutyl-ammonium fluoride in solvents of ether type, preferably in tetrahydrofuran, at a temperature of -20 ⁰ C to +50 ⁰ C, preferably at room temperature, removed.

From the compounds of the general formula II which contain hydrogen instead of R and the protective group described above instead of R, the 7-0xo-PGI derivatives of the general formula I can be prepared by elimination of the elements of water. Namely, the above compounds can be prepared by boiling in aromatic hydrocarbons in the presence of water-binding agents in place of

R ^ the compounds of the general formula I containing the above protecting group are converted!

13

Formula I wherein R 1 is Yfoserstoff and Q is lower alkyl, e.g. purified by chromatography.

The compounds of the general formula I which contain Q as a physiologically compatible cation are obtained from Q-lower alkyl-containing ester compounds of the general formula I by aqueous alkaline hydrolysis. For hydrolysis, aqueous solutions of alkali metal and alkaline earth metal hydroxides can be used, which at 0 - 100 are used ⁰ C, and the salts are isolated, for example by lyophilization. From the aqueous solutions of the salts, the carboxylic acids can be released by careful acidification and dissolved in organic solvents and converted with aliphatic and aromatic amines into further salts.

- 10 -

- ίο - 2 2 5 13 2

The compounds of the general formula I according to the invention inhibit the aggregation of the thrombocytes and have a thrombolytic action like the natural PGIg. The new compounds inhibit the synthesis of thromboxane A ₂ and the action of thromboxane A ^ and gastric acid secretion and affect some processes of the circulation. The compounds can be used to cure asthma, myocardial infarction, thrombosis, gastric ulcers, and vascular irregularities in mammals, particularly humans. "

The pharmaceutical preparations containing the 7-oxo-PGI derivatives as active ingredient have a thrombolytic effect and at the same time can eliminate the risk of the thrombi developing. This is of particular importance in the production of preserved blood, in the perfusion of organs, tissues and in the removal of the risk of thrombosis after surgery »

Platelet-enriched human blood-isolated plasma (PRP) in the case of ADP or collagen-induced aggregation gave the following IDc ₀ concentrations:

Platelet aggregation-inhibiting effect:

Aggregation-causing substance PGIP-sodium salt 7-oxo-PGI ₂ -Natriums alz 7-oxo-PGI ₂ methyl ester

^ro 50 ng / ml ADP collagen 1-2 1-2 15 80 100-200 50

It is very important that the gastric fundus contracting action of PGI _{2 is} 0.1 times greater than the same effect. Other information indicates that the

- 11 -

- ii - 2 2 5 13 2

According to the invention compounds with respect to the thrombocyte aggregation-inhibiting Wirlcung not reach the effect of the natural PGI ₂ , however, the compounds of the invention are very stable and still show a strong effect, whereby the compounds used as active ingredients in pharmaceutical preparations v / ground can.

The dose of the 7-0xo-PGI derivatives of the general formula I per day - 'is 100 ng-100 mg and depends on the degree of action to be achieved, the type of application, the sensitivity of the patient or the animal or of the organs and tissues. In the case of continuous infusion, a dose of 1-10 mg per day is generally sufficient «

The single dose may be determined by the physician based on the intensity of the patient's response.

The compounds of the formula I prepared according to the invention can be administered in the form of medicaments.

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

As liquid preparations, solutions, emulsions or injectable solutions, infusion solutions, drops and as solid preparations tablets, capsules, dragees, powders, boluses and powder ampoules may be mentioned. The usual diluents, diluents, additives for influencing the osmotic pressure, the pH, the taste or aroma, lubricants, wetting agents, solution-releasing agents can be added.

- 12 -

- 12 - 2 2 5 13 2

Ausführungsbeispie lejl

Further details of the invention can be found in the following examples without limiting the invention to the examples.

example 1

7β-acetoxy-6-keto-PGK-methylester-methyl-ketal (Formula IV wherein R ⁵ and Q are methyl, R ¹ , R ^{2 is} hydrogen, X is trans-vinyl, R 1 is β-Yfesserstoff, Y is methylene , R- ^{5 is} propyl.)

1 g of the compound of formula III - wherein the substituents are given as in the title product - is dissolved in 10 ml of methanol. To the solution is added a catalytic amount of boron trifluoride etherate. The reaction mixture is stirred for 20 minutes. After addition of a small amount of solid sodium hydrogen carbonate, the methanol is distilled off in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution is washed with water, with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, filtered and the solvent is distilled off. The residual oil is eluted on 120 g of silica gel with 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

exo-IV: R _f : 0.31 * Eluent: ethyl acetate

HNI ^ ¹ [R: 3.64 (3H _S COOCH _3), 3.24 (3H, OCH ₃₎ endo-IV: R _f: 0.26, eluent: ethyl acetate ¹ HNlIR: 3.57 (3H, COOCH ₃ ), 3.14 (3H, OCH ₃ ).

- 13 -

- 13 - 2 2 5 13 2

Example 2

7β-Acetoxy-6-keto-PGF ₁ -methylester-methyl-ketal-11,15-bis- (tert-butyl-dimethyl-silyl) -ether

(Pormel V, wherein R is tert-butyl-dimethyl-silyl and the remaining substituents are as defined in Example 1).

700 mg (1.52 mmol) of the methyl ketal of Pormel IV, which was obtained according to Example 1, is dissolved in 1.4 ml of anhydrous dimethylformamide. To the solution are added 517 mg (7.6 mmol) of imidazole and 552 mg (3.6 mmol) of t-butyl-dimethyl-chlorosilane. The reaction mixture is stirred for 4 hours at 35-40 ⁰ C and poured into 30 ml of water. The aqueous solution is extracted with 3x50 ml of dichloromethane, the combined dichloroethane extract is washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and then the solvent is distilled off. The residual oil is chromatographed on 120 g of silica gel and eluted with an 8: 1 mixture of hexane-ethyl acetate. 788 mg (75 %) of the title product are obtained in the form of a colorless oil.

R ": 0.42, eluent: a 7: 1 mixture of hexane and ethyl acetate. ¹ H BMR: 2.05 (3H, OAc), 0.88 (6H, t-butyl)

At game 3

7β-hydroxy-6-keto-PGF ₁ -methylester-methylketal-11,15-bis- (tert-butyl-dimethyl-silyl) -ether

(Pormel VI, wherein the substituents are defined as in Example 2.)

200 mg (0.29 mmol) of the obtained according to Example 2 Silyläthers the Pormel V are dissolved in 2 ml of methanol. A catalytic amount of freshly calcined potassium carbonate is added.

- 14

225 132

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

Rf ' 0.5 »Eluent: a 4: 1 mixture of hexane and ethyl acetate

IR (film): 335 0 cm ^-1 , (OH).

Example 4

7β-hydroxy-6-keto-PGF, methyl ester hemiketal II bis (tert-butyl-dimethyl-silyl) ether

(Formula YI = R = hydrogen, the other substituents are as in Example 2) _e

200 mg (0.29 mmol) of the Silyläthers of formula V prepared according to Example 2 are dissolved in 2 ml of methanol and is added to the solution 50 mg of freshly calcined potassium carbonate * The reaction mixture is stirred for 48 hours at room temperature. The reaction mixture is worked up according to Example 3. 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 the product are obtained in the form of a colorless oil.

R ^: 0.1, eluent: a 4: 1 mixture of hexane and ethyl acetate

¹ HNMR: 3.67 (3H, COOCH ₃ ).

- 15 -

_ 2 2 5 13 2

Example 5

7-Oxo-6-keto-PGF, methyl ester methyl ketal-II-bis (tert-butyl-dimethyl-silyl) -ether

(Formula II - wherein R = methyl and the other substituents are as defined in Example 2).

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

The reaction mixture is treated with a sodium acetate buffer and then stirred for five 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 with a 12: 1 mixture of hexane and hexyl acetate. 56 mg (75 %) of the product are obtained in the form of a colorless oil. Rfi 0.59, eluent: 7: 1 mixture of hexane and ethyl acetate. IR (Film): 1735 cm * " ¹ (C = O), 1000-1250 cm"" ¹ (0-CO).

Example 6

7-Oxo-6-keto-PGF, methyl ester hemiketalyl-bis (tert-butyldimethylsilyl) ether

(Formula II - wherein R = hydrogen and the remaining substituents are as defined in Example 2).

50 mg (0.08 mol) of the silyl ether of the formula V prepared according to Example 4, in which R is hydrogen, are dissolved in 0.5 ml of dichloromethane. To the solution are added 45 mg (0.21 mmol) of pyridinium chlorocarbonate. The reaction mixture is stirred for six hours at room temperature. The reaction mixture is worked up according to Example 5 and the crude product is purified on 10 g of silica gel with a 1: 1 mixture of ethyl

- 16 -

- 16 - 2 2 5 13 2

acetate-hexane eluted. 37 mg (75 %) of the title product are obtained in the form of a colorless oil.

Rfi 0.55, eluent: 1: 1 mixture, of ethyl acetate and hexane. IR (PiIm): 3300 cm ^-1 (OH), 1730 cm ^-1 (C = O).

Example 7

7β-Acetoxy-6-keto-PGP ₁ -methylester-methylketal-11,15-bis- (tetrahydropyran-2-yl) -ether

(Formula V wherein R is tetrahydro-pyran-2-yl and the remaining substituents are as defined 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. Are added to the solution 1.13 ml (12.4 mmol) of anhydrous 3s4-dihydro-2H-pyran and a catalytic amount of p-toluene-sulfonic acid. The reaction mixture is stirred at room temperature for 10 minutes and diluted with 50 ml of ethyl acetate. The ethyl acetate solution is washed with saturated aqueous sodium bicarbonate solution with water and saturated sodium chloride solution, dried over sodium sulfate and filtered. The solvent is distilled off. This gives 831 mg (crude product) of the product in the form of a pale yellow oil.

Rf .: 0.53, eluent: 1: 1 mixture of benzene and ethyl acetate. IR (film): 1740 cm ^-1 (C = O), 1000-1200 cm ^-1 (O-CH-0),

The product obtained can be used without purification in further processing.

- 17 -

_ ₁₇ _ 2 2 5 13 2

Example 8

7β-Hydroxy-6-keto-PGF- _L -methyl ester methyl ketal-11,15-bis- (tetrahydropyran-2-yl) ether

(Formula VI - the substituents are as defined in Example 7).

831 mg (1.32 ml) of the compound of formula V prepared according to Example 7 are dissolved in 8 ml of methanol. 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 worked up according to Example 3. The residual oil is chromatographed on 40 g of silica gel with a 1: 1 mixture of benzene and ethyl acetate as eluent. 471 mg (65 %) of the title product are obtained in the form of a colorless oil. R ^: 0.35, eluent: 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).

Beispi el 9

7-oxo-6-keto-PGF ₁ -methylester-methylketal-11-yl-S-bis (tetrahydropyran-2-yl) -ether

(Formula II, the substituents are as defined in Example 7.)

344 mg (0.59 mmol) of the compound of formula VI prepared according to Example 8 are dissolved in 3 _S 5 ml of dichloromethane, and 254 mg (1.18 mmol) of pyridinium chlorochromate are added to the solution. The reaction mixture is treated with a sodium acetate buffer and stirred for five hours at room temperature. The reaction mixture is worked up according to Example 5. The crude product is chromatographed on 30 g of silica gel with a 1: 1 mixture of benzene and ethyl acetate as eluent.

- 18 -

225 132

This gives 275 mg (80 %) of the title product as a colorless oil.

R _f ! 0.57, eluent: 1: 1 mixture of benzene and ethyl acetate

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

Example 10

7-Oxo-6-keto-PGF, methyl ester methyl ketal (Formula II - wherein R = hydrogen and the other substituents are as defined in Example 1.)

194 mg (0.33 mmol) of the obtained according to Example 9 Methylketals of formula II, wherein R is tetrahydropyranyl and the other substituents are as defined in the product are dissolved in Io ml of methanol, and the reaction mixture is a catalytic amount of p-toluene-sulfonic acid. The solution is stirred for one 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 a saturated sodium bicarbonate solution, with water and then with aqueous sodium chloride solution, dried over sodium sulphate, filtered and the solvent is distilled off. *

The residual oil is chromatographed on 15 g of silica gel with 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, eluent: ethyl acetate.

¹ HMiR (CDCl ₃ ): 3.67 (COOCH ₃ ), 317 (OCH ₃ ) IR (Film): 3350 cm ^-1 (OH), 1735 cm ^-1 (C = O).

By using appropriately substituted starting materials of the general formula III, the following intermediate steps are obtained according to process steps of Examples 1-10.

- 19 -

- I ₉ - 2 2 5 13 2

products of general formula II:

Hemiketal of 7-oxo-6 ~ keto-l6-methyl-PGF ₁ -methyl-, ethyl, propyl and butyl ester and methyl, ethyl, propyl and Butylketal thereof.

Hemiketal of 7-0xo-6-keto-l6, l6-dimethyl-PGF- _L- methyl, ethyl, propyl and 'butyl ester and methyl, ethyl, propyl and Butylketal thereof.

Hemiketal of 7-0xo-6-keto-l6-phenoxy-17,18,19,20-tetranor-PGF ₁ -methyl, ethyl, propyl and butyl ester and methyl, ethyl, propyl and butyl ketal thereof ,

Hemiketal of 7-oxo-6-keto-20-methyl PGF, methyl, ethyl, propyl and butyl ester and methyl, ethyl, propyl and Butylketal thereof.

Hemiketal of 7-oxo-6-keto-13,14-didehydro-PGF- _L- methyl, ethyl, propyl and butyl ester and methyl, ethyl, propyl and Butylketal thereof.

Hemiketal of 7-oxo-6-keto-15-methyl-PGF _{] L} -methyl, ethyl, propyl and butyl ester and methyl, ethyl, propyl and butyl ketal thereof.

Hemiketal of 7-oxo-6-keto-15-epi-PGF ₁ -methyl, ethyl, propyl and butyl ester and methyl, ethyl, propyl and butyl ketal thereof.

Hemiketal of 7-oxo-6-keto-15-epi-l6, l6-dimethyl-PGF, methyl, ethyl, propyl and butyl ester and methyl, ethyl, propyl and butyl ketal thereof.

Hemiketal of 7-0xo-6-keto-15-epi-l6-phenoxy ~ 17,18,19,20-tetranor-PGF.-methyl, ethyl, propyl and butyl ester and methyl, ethyl, Propyl and Butylketal the same.

Hemiketal of 7-oxo-6-keto-15-epi-20-methyl-PGF ₁ -methyläthyl-, propyl and butyl ester and methyl, ethyl, propyl, and Butylketal thereof.

If the protective group of Example 10 is not removed during the synthesis, the 11,15-bis-silyloxy, II, 15-bis (tetrahydrocyran-2-yloxy) and II ₉ 15-bis0 <-alkoxyalkyl) derivatives of the above enumerated compounds.

- 20 -

O 9 ζ 1 * 3 O

Qa '<ζ) 4βΐ ^ & I <3 * ^ fjj

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

By "epi" derivative is meant a derivative in which the carbon atom identified by the number preceding "epi" carries a substituent whose configuration is reversed, such as the configuration of the substituent on the corresponding carbon atom of the natural prostaglandins. , , -

Example 11.

7-OxO-PGI ₂ -methyl ester

(Formula I, where Q is methyl, R ¹ , R ² , R ^{13 is} hydrogen, X is trans-vinyl, R is β-hydrogen, Y is methylene and R 1 is propyl.)

20 mg (0.31 mmol) of a compound of the formula II

5 6

represents according to Example 5 _S in which R is methyl and R is dimethyl-tert, butyl-silyl and the remaining substituents as defined in the productm are dissolved in 5 ml of hexamethylphosphoric acid triamide. The reaction mixture is stirred for three hours at 150-160 ⁰ C and poured onto 18 ml of water. The aqueous phase is extracted with 3x15 ml of ethyl acetate and the combined Äthylacetat-Estrakt is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and filtered. The solvent is distilled off. The remaining product (250 mg) is dissolved in 5 ml of tetrahydrofuran, and after adding 2 equivalents of the 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 and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and filtered The solvent is aMestilliert .The remaining .0 * 1 to 10 g silica gel chromatographed with ethyl acetate,

• - 21 -

- 21 - 2 2 5 13 2

62 mg (50 %) of the title product are obtained in the form of a colorless oil,

Rf! 0.44, eluent: ethyl acetate,

¹ : 5.37 (IH, t, O-C = CH), 3.76 (3H, s, -COOCH ₃ )

Example 12 7-OxO-PGI ₂ -methylester

200 mg (0.31 mmol) of the compound of general formula II prepared according to Example 6, wherein R "is hydrogen and R is dimethyl-tert-butyl-silyl and the remaining substituents are as defined in Example 11, are in 30 The anhydrous benzene and Soxhlet extractor containing anhydrous magnesium sulphate are boiled for 2 hours, dried with water and then with saturated aqueous sodium chloride solution, washed with anhydrous sodium sulphate and filtered in tetrahydrofuran with 2 equivalents of tetrabutylammonium fluoride, and the reaction mixture is worked up in accordance with Example 11. The mixture is chromatographed on silica gel with ethyl acetate to give 52 mg (45 %) of the title product as a colorless oil Constants of the product are the same as in Example 11.

Example 13 7-Oxo-PGI ₉ -methylester

C.

90 mg (0.215 mmol) of the prepared according to Example 10 7-0xo- ~ 6-keto-PGF, methyl ester methylketal (formula II, wherein R is hydrogen) are dissolved in 0.8 ml of hexamethyl-phosphorous acid triamide. The mixture is stirred at I4O-I5O ⁰ C for 2 hours. The reaction mixture is as in

- 22 -

- 22 - 2 2 5 13 2

The reaction mixture is chromatographed on 10 g of silica gel with ethyl acetate. 40 mg (47 %) of the title product are obtained in the form of a colorless oil. The physical constants of the product are the same as in Example 11.

Example 14

7 "Oxo-PGI ₂ -methylester-II, 15-diacetate -

(Formula I, in which Q is methyl, R ¹ , R ^{2 is} hydrogen, R 1 -β-reactant, Z is trans -vinylene and Y is methylene)

100 mg of 7-oxo-6-keto ~ PGF ₁ -methylester-methylketal-11,15-diacetate are dissolved in 3 ml of hexamethyl-phosphoric acid triamide and stirred in the presence of 0.05 ml of acetic anhydride for 2 hours at 8OrIOO ⁰ G. The reaction mixture is worked up as in Example 11. The crude product is chromatographed on 15 g of silica gel with a 1: 1 mixture of ethyl acetate and hexane.

This gives 70 mg (72 %) of a product in the form of a colorless oil. '· R ^ s 0.65, eluent; 1: 1 mixture of ethyl acetate and hexane.

Example 15

16,16-dimethyl-7-oxo-PGI ₀ -methylester

1 2 (Formula I wherein R and R are methyl and the other substituents are as defined in Example 11).

90 mg (0.21 mmol) 16, 16-dimethyl-7-oxo-6-keto ~ PGF., -Methyl-

e.ster-methyl ketal, wherein R and R are methyl, be triamide hexamethyl-phosphoric acid dissolved in 1 ml, -and the reaction mixture for 2 hours at 140-150 ⁰ C stirred "

- 23 - 2 2 5 13 2

The procedure continues in Example 13.

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

R = 0.52 (in ethyl acetate).

Example 16

7-oxo-PGI ₂ sodium salt

(Formula I wherein Q is sodium and the remaining sub-substituents are as defined in the product of Example 11).

50 mg (0.13 mmol) of 7-oxo-PGI ₂ methyl ester are dissolved in 0.1 ml of methanol. After addition of 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.

Following the reactions of Examples 11-16, the following compounds are prepared from the compounds of formula II prepared according to Example 1-10: 7-oxo-1,6-phenoxy-17,18,19,20-tetranor PGIp and its alkyl ester with 1 -4 carbon atoms (R ~ of methyl ester in ethyl acetate: 0.57):

7-oxo-l6-methyl-PGIp and its alkyl ester with 1-4 carbon atoms (R _f of methyl ester in ethyl acetate: 0.49)> 7-oxo-20-methyl-PGI ₂ and its alkyl ester with 1-4 carbon atoms ( R _f of methyl ester in ethyl acetate: '0.51), 7-O-Ox-13,14-didehydro-PGI ₂ and its alkyl ester of 1-4 carbon atoms (Ro, of methyl ester in ethyl acetate: 0.47), 7-oxo 15-methyl-PGI ₂ and its alkyl ester with 1-4 carbon atoms (R _f of methyl ester in ethyl acetate: 0.53), 7-0xo 15-epi-PGI ₂ and its alkyl ester with 1-4 carbon atoms (R _f of methyl ester in ethyl acetate: O ₅ 50),

- 24 ~

_ ₂₄ . 225132

7-Ozo-15-epi-16,66-d-yl-PGl2 and its alkyl ester of 1-4 carbon atoms (R- of methyl ester in ethyl acetate: 0.58),.

T-oxo-lS-epi-lS-phenoxy-lTjlS ^ SjSO-tetranor PGIp and its alkyl ester with 1-4 carbon atoms (R ^ of methyl ester in ethyl acetate: 0.63),

7-oxo-15-epi-20-methyl-PGIo and its alkyl ester with 1-4 carbon atoms (R, of methyl ester in ethyl acetate: 0.55).

The free acids can be prepared by the specified in Example 16 Saponification of alkali metal salt, for _e B _e Uatriumsalz, by acidifying the aqueous solution with a strong organic or inorganic acid. The free acid separates from the solution.

- 25 -

, - 29 -

COOQ

-R ³

RO '

OR *

COOQ

XCCYR R ^€ 0 R * I. R ²

COOQ cm).

COOQ

^ X - ^ - CY HO k ^u i

QST).

I ψ-

OR ⁵

COOQ

OAc

R ¹

XCC -Υ-R ³

'RM ²

^0R

R ⁶ O

^C00Q

R ⁷

R - Si - Cl

(ST).

(SD.

Claims (10)

₂₅ . · 2 2 5 13 2 Invention claim: A process for the preparation of optically active or racemic 7-OzO-PGIp derivatives of general formula I, wherein Q for hydrogen, a physiologically acceptable X is cis- or trans -CH = CH-, C 1 -C 3 or -CH ₂ -CH ₂ -, 13 R ^{J is} hydrogen, alkanoyl of 1-4 carbon atoms 7 8 9 or for a protective group of the formula R .RR ^ Si, R ^{i: L} -CH ₂ -CR ^lo -OR ¹² , wherein R ⁷ , R ⁸ and R ^{9 are} identical or different and represent straight-chain or branched alkyl groups with 1 -4 carbon atoms and R and R are the same or different and for 12 are hydrogen or methyl and R is methyl or Ethyl and represents a tetrahydro-pyran-2-yl protective group,
R is hydrogen or lower alkyl in <k or ß sterischer configuration means _s 1 2 R and R are hydrogen or lower alkyl, Y is methylene, oxygen, or -HH- and R ^ is lower alkyl, or if desired mono-substituted phenyl or substituted heteroaryl, characterized in that a compound of general formula III, wherein R ¹ , R ² , R 1, R ⁴ , X, Y and Q are as defined above and Ac is acetyl, is reacted with a lower alkanol in the presence of a catalytic amount of an acid catalyst and the obtained T 2 * Ketals of the general formula IV, wherein R, R, R, R, X, Y, .Q and Ac are as defined above and R ^ is lower alkyl, with silylating agents of the general formula VII, or enol ethers of the general • 7 OQ Formula VIII, wherein R ', R, R ^ are the same or different and represent straight-chain or branched alkyl groups having 1-4 carbon atoms and R and R equal - 26 - 225 132 or are different and are hydrogen or methyl   12 ·· and R is methyl or ethyl - or with 3,4-dihydro-2H-pyran protects · and the ge obtained 1 2 protected ketals of general formula V wherein R, R, R, R, R, Σ, Y, Q and Ac are as defined above and C 7 f \ Q R is a silyl group of the formula RR R Si or an & -alkoxyalkyl or i-tetrahydropyran-2-yl group, deacetylated in a basic medium, the resulting, free hydroxy-containing protected ketals of the general formula VI, wherein R ¹ , R ² , R ³ , R ⁴ ", R ⁵ , R ⁶ , X, Y and Q are as defined above, if desired after removal of the R 1 alkyl group by hydrolysis, oxidized in aprotic solvents and from the resulting 7-oxo derivatives of the general formula (II) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R, Xj, Y and Q are as defined above and R 1 is hydrogen or lower alkyl, if desired, deprotecting R and optionally after acylation the free hydroxyl groups with lower alkanoyl'acylated and a compound of general formula R OH, wherein R is hydrogen or lower alkyl, eliminated, and  ίο · if desired, the protecting group R ^J cleaves off and / or saponifies the ester groups and liberates a salt or an ester from the free acid. 2. The method according to item 1, characterized in that as starting material a compound of the general formula 'III, IV, V, VI or II, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y, Q and Ac are as defined above. 3. The method according to item 1, characterized in that • in the implementation of the compounds of the general For- 12 3 mel III, wherein R, R, R ^, J, Y, Q "and Ac, as defined above, with lower alkanols as acid catalyst • Bortrifluoridätherat used.  · '. - 27 - 225 1 32 Method according to item 1, characterized in that 12 is ketals of the general formula IV, wherein R, R, R, R, X, Y, Q and Ac are as defined above and R · is lower alkyl, with tert-butyl-dimethyl-chlorosilane. 5. .Method according to item 1, characterized in that one P 2 3 A ketals of general formula IV, wherein R ', R, R, R, X, Y, Q and Ac are as defined above, and R is lower alkyl, with 3> 4-dihydro-2H-pyran implements. 6. The method according to item 1, characterized in that the deacetylation of the protected ketals of the general formula V, wherein R ¹ , R ² , R ³ , R ⁴ , R, X, Y, Q and Ac are as defined above and Ac is lower alkyl, carried out with potassium carbonate. 7. The method according to item 1, characterized in that the free hydroxy group-containing protected ketals of the general formula VI, wherein R ¹ , R ² , R ³ , R ^, R ^, R, X, Y and Q are as defined above are oxidized with pyridinium chlorochromate. 8. The method according to item 1, characterized in that the alcohol of the general formula R-OH, wherein R · ^ is lower alkyl, from 7-0xo derivatives of the general formula II, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , X, Y and Q are as defined above and R ^{5 is} lower alkyl, eliminated by heating in hexamethylphosphoric triamide. 9. The method according to item 8, characterized in that the mixture is heated at 80-160 ⁰ C. - 28 - '- 28 - 2 2 5 13 2 10. The method according to item 1, characterized in that the water from the 7-oxo derivatives of the general formula II, wherein R ¹ , R ² , R ⁵ , R ⁴ ", R, X, Y.und.Q as defined above, and R 1 is hydrogen, split off by azeotropic distillation. He method according to item 10, characterized in that one carries out the azeotropic distillation in benzene in the presence of anhydrous magnesium sulphate. 12. The method according to item 1, characterized in that 7-0xo-PGI ₂ ~ methyl ester,
7-oxo-PGIg-methylester-11,15-diacetate, l6, l6-dimethyl ~ 7-oxo-PGI ₂ methyl ester, 7-oxo-PGI ₂ sodium salt, 7-oxo-1,6-phenoxy-17,18,19,20-tetranor-PGI _2- methyl ester, 7-oxo-16 methyl-PGP-methyl ester,
7-0xo ~ 20-methyl ~ PGI ₂ ~ methyl ester,
7-oxo-13,14-didehydro-PGIp-methyl ester, 7-oxo-15-methyl-PGI ₂ -methyl ester,
7-0xo ~ 15-epi PGI ₂ methyl ester, 7-0xo-15-e'pi-lβ, l6 ·-dimethyl-17,18,19,20-tetranόr-PGI _o -methyl ester or 7-oxo-15-epi-20-methyl-PGI ₂ -methylester, "