DD202010A5 - PROCESS FOR THE PREPARATION OF NEW CARBACYCLINE - Google Patents

Abstract

The aim of the invention is the provision of new Carbacyclinderivaten with extended duration of action and increased selectivity of the efficacy. According to the invention, carbacyclin derivatives of the general formula I are prepared ## STR1 ## in which, for example: R 1 denotes the radical OR 2; R deep2 is hydrogen, alkyl, cycloalkyl, aryl, a heterocyclic radical or others; X is oxygen A is a -CH 2-CH 2 deep, trans-CH = CH- or -C = C group; W is a free or functionally modified hydroxymethylene group or a free or functionally modified CH 3-membered group, where the OH Group may be alpha or beta OH; D is a straight-chain or branched, saturated or unsaturated alkylene group having 1-10 C atoms; E is a -C = C bond or another group; R 4 is an alkyl, cycloalkyl, or optionally substituted aryl or heterocyclic group; R deep 5 is a free or functionally modified hydroxy group and their salts with physiologically acceptable bases.

Description

05/27/1932

AP G 07 G / 235 993/0

60 115/11

Process aar Preparation of Garbacyclin Derivatives Field of application of the invention

The invention relates to a process for the preparation of novel ProstaGyclin derivatives and / or their use as medicaments,

Characteristic of the known technical solutions

DE-OS 2,845,770, 2,900,352, 2,902,442, 2,904,655, 2,909,088 and 2,912,409 describe (5E) and (5Z) -6a-garbaprostaglandin I ₂ analogues. Nomenclature of the compounds according to the invention is based on a proposal by Morton and Brokow (J. Org.Chem.A ±, 2880, 1979) In the synthesis of these compounds, always two double bond isomers are formed, which are characterized by the addition (5Ξ) or (5Z) The two isomers of this prototype are illustrated by the following structural formula:

S ii GO ₂ H \ V HO OH

OH (5E) -6a-0arbaprostaglandih-I ₂ (5Z) -6a ~ Garbaprostaglandin-I ₂

From the very extensive state of the art of prostate cancer

235993 O

-f- 27.5.1982

AP C 07 G / 235 993/0 60 115/11

cycline and its analogues are known to be useful in the treatment of mammals, including humans, due to their biological and pharmacological properties. However, their use as medicines often encounters difficulties because they have too short a duration of action for therapeutic purposes.

Object of the invention

The aim of the invention is the provision of new carboicyclin derivatives with extended duration of action and increased selectivity of activity.

Darlesung the essence of the invention

The invention has for its object to find new Carbacyclinderivate with the desired properties and processes for their preparation.

It has now been found that by substitution of the methylene group in the 3-position of the carbacycline by oxygen a longer duration of action, greater selectivity and better efficacy can be achieved. The compounds according to the invention have a bronchodilator effect and are suitable for inhibiting platelet aggregation for lowering blood pressure via vasodilation and for inhibiting gastric acid secretion.

Carbacyclinderivate of the general formula I

23 5 99 3 O i

05/27/1932

AP G 07 C / 235 993/0

60 115/11

OH ₂ GH

I!

^S 5

manufactured,

in which

R. the radical OR ₂ , where R ₂ may denote hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic radical, or the radical IJHR- with R_ in the meaning of an acid radical or hydrogen atom,

X oxygen,

A is a -CH ₂ -CH ₂ -, trans-CH = CH- or -C = C group,

W is a free or functionally modified hydroxymethylene group or a free or functionally modified

CH,

A group, where the OH group can be £- or--permanently OH,

-P-

D is a straight-chain or branched, saturated or unsaturated alkylene group having 1-10 C atoms, which may optionally be substituted by fluorine atoms,

235 QQl Π η

· - w > j sj ^ j ^ y y _ _t _ 27.5.1982

AP G 07 G / 235 99.3 / 0 60 115/11

E represents a -C ^ C bond or a -CRg = CR "group, where Rg and R" denote a hydrogen atom or an alkyl group having 1-5 C atoms,

R is an alkyl, cycloalkyl, or an optionally substituted aryl or a heterocyclic group,

R ₁ - a free or functionally modified hydroxy group, and if Rp has the meaning of a hydrogen atom, their salts with physiologically compatible bases mean ·

The compounds of the formula I represent both (5E) and (5Z) -isomers "

Suitable alkyl groups Rp are straight-chain or branched-chain alkyl groups having 1-10 C atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, beepentyl, heptyl, hexyl, decyl.

The alkyl groups R ₂ can optionally be monosubstituted to polysubstituted by halogen atoms, C 1 -C -alkoxy groups, optionally substituted C 1 -C ₁₀ -aryl groups, di-C 1 -C ₄ -alkylamines and tri-C.C-alkylammonium , Preferred are those alkyl groups which are monosubstituted ·

Examples of substituents which may be mentioned are fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethyl.

Preferred alkyl groups R ₂ are those having 1-4 C atoms,

3 O - * "" 27.5.1982

AP C 07 C / 235 993/0 60 115/11

such as, for example, methyl, ethyl, propyl, pimethylaminopropyl, isobutyl, butyl. Suitable aryl groups R ₂ are both substituted and unsubstituted aryl groups, for example phenyl, 1-i-naphthyl and 2-haphthyl, each of which may be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each having 1-4C -Atomen, a chloromethyl, Pluormethyl-, trifluoromethyl, carboxyl, hydroxy or alkoxy group having 1-4 C-atoms, Preferably, the substituents in the 3- & η <3 4-position on the phenyl ring, for example by S ¹ IuOr , Chloro, alkoxy or irifluoromethyl or in the 4-position by hydroxy, which may contain 4-10, preferably 5 and 6 carbon atoms in the Hing · The rings may be substituted by alkyl groups having 1-4 carbon atoms. Examples of its derivatives are cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl. Heterocyclic groups R ₂ are embossed with 5-n-heterocyclic heterocycles containing at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. For example, 2-puryl, 3-puryl, 2-thienyl, 3-ethylenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, u, a.

Preferred acids are organic carboxylic acids and sulfonic acids having 1-15 carbon atoms which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsaturated and / or be substituted polybasically and / or in the usual way. As examples of the substituents its C.-C, alkyl, hydroxy, Cj-C ^ alkoxy, oxo or amino groups or halogen atoms (P, Cl, Br) mentioned ,

05/27/1982

AP C 07 G / 235 993/0

60 115/11

Examples which may be mentioned are the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, gapronic acid, enanthic acid, caprylic acid, perlaregonic acid, gaprinsäure, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, Gyolopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanearonic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, with halogeno, irifluoromethyl, hydroxy Alkoxy- or carboxy-Grips substituted benzoic acids, nicotinic acid, isonicotinic acid, uran-2-carboxylic acid, glylopentylpropionic acid. Particularly preferred acyl radicals are considered to be those having up to 10 carbon atoms. Examples of suitable sulfonic acids are methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, isopropanesulfonic acid, β-chloroethanesulfonic acid, butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, H, H-dimethylaminosulfonic acid, K, U-diethylaminosulfonic acid, H, N-bis - (ß-chloroethyl) -aminosulfonic acid, ΐϊ, Ν-Diisobutylaminosulfonaäure, H, H-dibutylaminosulfonic acid, pyrrolidino, piperidino, piperazino, ΪΙ-methylpiperazino and Morpholinosulfonsäure in embossing.

The hydroxy groups R ₁ - and in W may be modified fütktionell, for example, by etherification or esterification, wherein the free or modified hydroxy groups in W may be OC- or ßständig, with free hydroxy groups are preferred.

3 3 U -W- 27Ö.1982

AP.C 07 G / 235 993/0 60 115/11

Suitable ether and acyl radicals are the radicals known to the person skilled in the art. Cleavable ether radicals, such as the tetrahydropyranyl, tetrahydrofuranyl _s ou-Äthoxyäthyl-, trimethylsilyl, dimethyl-tert, butyl-silyl and tri-p-benzyl-silyl group are preferably slightly. As acyl radicals, the same as for iL · called in question; By way of example, mention may be made, for example, of acetyl, propionyl, butyryl, benzoyl.

As the alkyl group R, straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, having 1-10j particular 1-7 C atoms, in question, which may optionally be substituted by optionally substituted aryl. Examples include its methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, hexenyl , Benzyl and p-chlorobenzyl.

The cycloalkyl group R. may contain in the ring 4-10, preferably 5 and 6 carbon atoms. The rings may be substituted by alkyl groups of 1-4 carbon atoms. Examples which may be mentioned are glylopentyl, cyclohexyl, methylcyclohexyl and adamantyl.

Examples of suitable substituted or unsubstituted aryl groups R are phenyl, 1-naphthyl and 2-naphthyl, each of which may be substituted by 1-3 halogen atoms, a phenyl group, and 1-3 alkyl groups each having 1-4 C atoms Chloromethyl- »fluoromethyl-, trifluoromethyl-, carboxyl-, CJ-C-alkoxy- or hydroxy group. The substitution in 3- and 4- position on the phenyl ring is preferred, for example by fluorine, chlorine, C ₁ -G ₄ -alkoxy or irifluoromethyl or in the 4-position by hydroxy. Suitable heterocyclic groups R ₄ are 5- and 6-membered heterocycles, ie at least

Π -44- 27.5.1982

^ AP G 07 G / 235 993/0

SO 115/11

1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples which may be mentioned are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-uryl, 3-ihienyl u _e a.

Suitable alkylene group D are straight-chain or branched-chain, saturated and unsaturated alkylene radicals, preferably saturated with 1-10, in particular 1-5, C atoms, which may be substituted by fluorine atoms, 1,2-methylene or "1,1-trimethylene For example, soaps called: methylene, fluoromethylene, ethylene, 1,2-propylene, ethylethylene, irimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene, 1-methyl-trimethylene

Particularly preferred compounds are those with E ala C-C triple bond and CRg-CR ,, - double bond, wherein the double bond is trisubstituted.

For salt formation with the free acids (R ₂ = H), inorganic and organic bases are suitable, as are known to those skilled in the formation of physiologically acceptable salts. Examples which may be mentioned: alkali hydroxides such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, H-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.

The invention furthermore relates to a process for the preparation of the prism derivatives of the general formula according to the invention, which comprises, in a manner known per se, a compound of the general formula II

 -β- 27.5.1932

AP C 07 G / 235 993/0 60 115/11

CH ₂ OH

CH and

II.

AWDSR ₄

^S 5

wherein R ₄ , R ₁ -, A, W, D and S have the abovementioned meanings, if appropriate after protection of free hydroxy groups present with a haloacetic acid derivative of the general formula III,

Hal-CH ₂ -C III

wherein Hal is a chlorine or bromine atom and Rg is an alkyl radical or an alkali metal etherified in the presence of a base and optionally subsequently in any order isomers isomers and / or releases protected hydroxy groups and / or esterified free hydroxy groups, etherified and / or esterified a free carboxyl group and / or saponifies an esterified carboxyl group or converts a carboxyl group into an amide or with a physiologically compatible base into a salt.

The reaction of the compound of the general Pormel II with a haloacetic acid derivative of general formula III is conducted at temperatures from Q ⁰ C his 100 ⁰ C, preferably 10 ⁰ C to 80 ⁰ C, in an aprotic solvent or solvent mixture, such as dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, etc. , performed. When

Oio

AP C 07 C / 235 993/0 60 115/11

Bases are those known to those skilled in the art for bases, for example, matrium hydride, potassium tert-butoxide, butyllithium, etc.-

The saponification of the irostaglandinester is carried out by the methods known in the art, such as with basic catalysts.

The introduction of the ester group -ORp for R., in which Rp represents an alkyl group having 1-10 C atoms, takes place according to the methods known to the person skilled in the art. The carboxy compounds are reacted, for example, with diazohydrocarbons in a manner known per se. The esterification with diazohydrocarbons is carried out, for example, by mixing a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether with the carboxy compound in the same or in another inert solvent, such as methylene chloride. After completion of the reaction in 1 to 30 minutes, the solvent is removed and the ester purified in a conventional manner. Diazoalkanes are either known or can be prepared by known methods / Urg. Reactions Vol. 8, pages 389-394 (195427.

The introduction of the ester group -OR ₀ for R-, in which R represents a substituted or unsubstituted aryl group, is carried out by the methods known to those skilled in the art. For example, the carboxyl compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform, in question. The reaction is carried out at

Η- 27.5.1982

^ν AP G 07 G / 235 993/0

60 115/11

doors between -30 ⁰ G and +50 ⁰ G, preferably at +10 ⁰ G performed.

The prostaglandin derivatives, the general formula I with R ^ in the meaning of a hydroxy group can be converted with salts of appropriate amounts of the corresponding inorganic bases under iieutralisierung. For example, upon dissolution of the corresponding PG acids in water containing the stoichiometric amount of the base, after evaporation of the water or after addition of a water-miscible solvent, for example, alcohol or acetone, the solid inorganic salt is obtained.

The preparation of the amine salts is carried out in a customary manner. For this purpose, the PG acid is dissolved, for example, in a suitable solvent, such as ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to this solution. The salt usually accumulates in solid form or is isolated by evaporation of the solvent in a conventional manner.

The functional modification of the free QH groups is carried out according to the methods known to those skilled in the art. For the introduction of ether protecting groups, for example, is reacted with dihydropyran in methylene chloride or chloroform using an acid condensing agent such as p-toluene sulfonic acid. The dihydropyran is used in excess, preferably in 4 to 10 times the theoretical requirement. The reaction is normally complete at 0 ^° C. to 30 ^° C. after 15 to 30 minutes.

The introduction of the acyl protecting groups takes place by reacting a compound of general formula 1 in a manner known per se with a carboxylic acid derivative, such as, for example,

OAH

- - ~ - AP C 07 G / 235 993/0

60 115/11

chloride, acid anhydride and the like a., implements ·

The release of a functionally modified OH group to the compounds of the general formula I is carried out by known methods. For example, the removal of ether protecting groups in an aqueous solution of an organic acid, such as acetic acid, propionic acid, among others, or in an aqueous solution of an inorganic acid, such as hydrochloric acid, performed. To improve the solubility, a water-miscible inert organic solvent is expediently added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. The cleavage is preferably at temperature. doors between 20 ⁰ C and 80 ⁰ G »

The splitting off of the silyl ether protective groups takes place, for example, with tetrabutylammonium fluoride. Suitable solvents are, for example, tetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc. The cleavage is preferably carried out at temperatures between 0 ⁰ G and. 80 ⁰ C performed.

The saponification of the acyl groups, for example, with alkali or Erdalkaü-carbonates and hydroxides in an alcohol or the aqueous solution of an alcohol. Suitable alcohols are aliphatic alcohols, such as, for example, methanol, ethanol, butanol, etc., preferably methanol. As alkali metal carbonates and hydroxides, potassium and sodium salts may be mentioned, but the potassium salts are preferred. As alkaline earth metal carbonates and hydroxides are, for example, calcium carbonate, and barium carbonates Galciumhydroxyd The reaction takes place at -10 to 70 ⁰ G G ^0, preferably at 25 ⁰ C..

0 43 - * £ - 27.5.1982

AP G 07 C / 235 993/0 60 115/11

The introduction of. Amide group IiHR ₃ for R ₁ is carried out according to the methods known in the art. The carboxylic acids of the general formula I (R ₂ = H) are first converted into the mixed anhydride in the presence of a tertiary amine, such as, for example, triethylamine, with isobutyl chloroformate The reaction of the mixed anhydride with the alkali metal salt of the corresponding amide or with ammonia (EUeH ) is carried out in an inert solvent or solvent mixture, such as tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric triamide, at temperatures between -30. ⁰ C and +60 ⁰ C, preferably at 0 to 30 ⁰ G ⁰ C.

A v / eitere possibility for the introduction of the amide group JSHR-, for R. consists in the implementation of a 1-carboxylic acid of the general formula I (Rp = H), in which free hydroxyl groups are optionally intermediately protected, with ^ linkages of the general formula IV .

O = C = H-R IV

wherein R- has the meaning given above.

The reaction of the compound of the general formula I (R ₁ = OH) with an isocyanate of the general formula IV is carried out optionally with the addition of a tertiary amine, such as. B, triethylamine or pyridine. The reaction can be carried out without solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80 ⁰ G to 100 ⁰ C, preferably at 0 ⁰ C to 30 C.

y ö ü - *? - 27.5.1982

AP G 07 G / 235 993/0 60 115/11 -

Contains the Ausgangsprodiikt OH ~ groups in Prostanrest, these OH groups are also reacted Finally, final products are desired, containing free hydroxyl groups in Prostanrest, it is expedient from starting products in which these intermediates by preferably easily cleavable ether or acyl radical are protected ·

The compounds of the general formula II which serve as starting material can be prepared, for example, by reacting, in a manner known per se, an aldehyde of the formula V (DE-OS 2,845,770).

Γ I 0 0

OGO -

with a phosphonate of the general formula VI,

· * P-GH ₂ -CDSR ₄ YI CH.O - "**""'

v / orin D, E and R have the abovementioned meaning, in an olefination reaction to give a ketone of general formula VII.

235933 O

27.5.19.82

AP G 07 G / 235 993/0

60 115/11

0

THE,

OCO

VII

Hach reduction of the keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesium bromide or alkyllithium and subsequent epimer separation and optionally hydrogenation of the double bond leads to the compounds of general formula VIII.

VIII

A-W-D-E-R,

OCO

Saponification of the ester group, for example with potassium carbonate in methanol and ketal cleavage with aqueous acetic acid and optionally functional modification of the free hydroxyl groups, for example by etherification with dihydropyran provides the ketone of the general formula IX.

05/27/1982

AP C 07 C / 235 993/0

60 115/11

0 and

IX

AWDSR ₄

^R 5

After olefination reaction with triethyl phosphonoacetate or trimethyl phosphonoacetate and subsequent reduction with lithium aluminum hydride, the compounds of general formula II which are isomeric to the double bond and, if appropriate, can be separated are obtained.

The preparation of the phosphonates of the general formula VI is carried out in a manner known per se by reacting the anion of dimethyl methylphosphonate with an ester of the general formula X.

0 - D - S - R ₄ "Σ,

wherein D, E, R _{4 have} the abovementioned meanings and Rg is an alkyl group having 1-5 C atoms.

The compounds of this invention are hypotensive and brochodilatory. Furthermore, the new prostacyclin derivatives of the formula I are valuable pharmaceutical active ingredients. In addition, they have a higher specificity and, above all, a similar activity spectrum compared to corresponding prostaglandins

235993 O

20-27.5.1982

AP G 07 C / 235 993/0 60 115/11

much longer effectiveness. In comparison to ₂ , they are characterized by greater stability. The high tissue specificity of the novel prostaglandins is shown in a study on glattinuskulären organs such _e B, the guinea pig ileum or on the isolated Iianinchentrachea, where a substantially lower stimulation can be observed than in the administration of natural prostaglandins of front E, A or F -Type, '

The new prostaglandin analogs possess the properties typical of prostacyclin, such as: B, lowering of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure, without at the same time reducing stroke volume and coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary trombosis, cardiac infarction, peripheral arterial disease, arteriosclerosis and thrombosis, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion and cytoprotection of the gastric and intestinal mucosa; hypoallergenic properties, reduction of pulmonary vascular resistance and pulmonary blood pressure, promotion of intracerebral hemorrhage, use in place of heparin or adjuvant in the hemofiltration dialysis, preservation of blood plasma preserves, especially of platelet preserves, inhibition of labor pains, treatment of pregnancy toxicity, increase of cerebral Circulation, cytoprotection in the liver and in the pancreas, etc. In addition, the new prostaglandin analogues have antiproliferative properties »The new prostacyclins can also be used in combination, for. B. with SS blockers or diuretics.

! J - & t- 27.5.1982

AP G 07 C / 235 993/0 60 115/11

The dose of the compounds is 1-1500yUg / kg / day when administered to the human patient. The unit dose for the pharmaceutically acceptable carrier is 0.01 to 100 mg.

When administered intravenously to conscious, hypertensive rats at doses of 5-20 and 100 / ug / kg of body weight, the compounds of the present invention show greater hypotensive and longer lasting activity than PGB ₂ and PGAp without triggering PGS ₂ diarrhea or PGAp cardiac arrhythmias.

When administered intravenously to anesthetized rabbits, the compounds of the invention in comparison to PGS ₂ and PGA _{2 show} a stronger and significantly longer lasting blood pressure reduction, without other smooth muscle organs or organ functions are affected.

For parenteral administration, sterile, injectable, aqueous or oily solutions are used. S ¹ for the oral administration are for example tablets, dragees or capsules suitable.

The invention thus also relates to medicaments based on the compounds of the general formula I and conventional excipients and carriers.

The active compounds according to the invention are intended to be used in conjunction with the auxiliaries known and customary in galenics, for. B. for the production of blood pressure lowering serve.

The unit dose range for the ampoule is 0.1 to 0.5 mg, for the tablet 0.1 to 1 mg *

19 -ag- 27.5.1932

AP G 07 G / 235 993/0 60 115/11

Ausführungabeispiel

The invention will be described in more detail below with reference to some examples

explained.

example 1

(5E) - (i6R8) -i6-methyl-3-oxa-18,18,19,19-tetradehydro-6acarba prostaglandin Io

To a solution of 530 mg of 2-L (E) - (iS, 5S, 6R, 7R) -7- (1-tetrahydropyran-2-yloxy) -6- / TE) - (3S, 4RSJ-4-methyl-3- (Tetrahydropyran-2-yloxy) -oct-1-en-6-yn-7-bicyclo / 3.3 "07octan-3-ylidenj-ethane-1-ol in 3 ml of tetrahydrofuran is added at 10 ⁰ G 0.77 ml of a 1.52 molar butyllithium solution in hexane, stirred for 5 minutes, mixed with 3 ml of dimethylformamide and 4 ml of dimethyl sulfoxide and then added 225 mg of chloroacetic acid lithium salt is stirred for 24 hours at room temperature, poured into ice water, acidified with 10% citric acid solution _{9 is} extracted with ether, the organic extract is washed once with brine, dried over magnesium sulfate and evaporated in vacuo, and the residue is chromatographed on silica gel with ethyl acetate / isopropanol (8 + 2) 290 mg (5E) - (i6RS) -i6 -Methyl-3-oxa-18 _} 18,19,19-tetradehydro-α-carbä-pröstaglandin-Ip-H, 15-bis- (tetrahydropranyl ether) To cleave the protecting groups, 290 mg of the bistetrahydropyranyl ether are stirred into 28 ml of a mixture from acetic acid / water / tetrahydrofuran (65 + 35 + 10) for 16 hours at room temperature and then evaporated in vacuo, the residue is chromatographed with ethyl acetate / acetic acid (99 + 1) on silica gel. This gives 105 mg'der the title compound as a colorless oil.

The starting material for the above title compound will be like

23 5 93 3 Ö -23- 27.5.1982

AP G 07 G / 235 993/0 6p 115/11

follows:

2- ^ (iL ⁱ ) -

(3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) oct-1-en-6-t-inyl7> icyclo> / '3.3.Ü / octaja-3-ylidenj-ethane-1- oil

To a solution of 4.0 g of phosphonoacetic acid triethyl ester in 80 ml of tetrahydrofuran is added at 0 ^° C. 1.73 g of potassium tert-butylate, stirred for 10 minutes, treated with a solution of 4.45 g (iR, 5S, 6R, 7R). -7- (2-tetrahydropyran-2-ylo2: y) -6- / yes) - (3S, 4R-S) -4-methyl-3- (tetrahydropyran-2-yloxy) -oct-1-ene-6-ynyl7 -t> ioyclo / 3 «3» 7-octan-3-one in 45 ml of toluene and stirred for 20 hours at room temperature. It is diluted with 600 ml of ether, shaken once with water, once with 20% sodium hydroxide solution, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo · The residue is filtered with hexane / ether (3 + 2) on silica gel. This gives 3.7 g of the unsaturated ester as a colorless oil. IR: 2945, 2870, 1700, 1655, 970 / cm.

Is added 1.2 g of lithium aluminum hydride portionwise at 0 ⁰ C to a stirred solution of 3.9 g of the ester prepared above in 130 ml of ether and stirred for 30 minutes at 0 ⁰ G. destroying the excess reagent by dropwise addition of acetic water, add 6 ml of water stirred for 2 hours at 20 ⁰ G, filtered and evaporated in vacuo · Ώβη. The residue is chromatographed on silica gel using ether / hexane (3 + 2). 1.05 g of 2-Kz) (iS, 5S, 6R, 7R) -7- (tetrahydropyran-2-ylo2y) are obtained as the less polar compound. 6- / 1B) - (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-ylosy) -oct-1-en-6-yn-7-bicyclo / _i 3'.3.07octan-3-ylidene } -ethan-1-ol and 2.2 g of the title compound as colorless oils. IR: 3605, 3450, * 2940, 2865, 1600, 970 / cm.

05/27/1982

AP C 07 G / 235 993/0

60 115/11

Example 2

(5Z) - (i6RS) -i6-methyl-3-oxa-18,18,19,19-tetrahydro-6acarba-prostaglandin-I ₂

In analogy to. Example 1, from 490 mg of the Z-configured allyl alcohol prepared according to Example 1a 85ng of the title compound as a colorless oil · IR (GHGl _3): 3340 (broad), 2920, 1722, 16oo, 1420, 966 / cm.

Example 3

(5E) - (i6RS) -i6,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-gafba-prostaglandin-I ₂

In analogy to. Example 1 is obtained from 0.5 g of 2 lb (£) - (iS, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / TE) - (3S, 4xHS) -4- Hiethyl 3- (tetrahydropyran-2-yloxy) non-i-en-G-in-1-yl-bicyclo / 3.3,, ootan-3-ylidene-1-ethan-1-ol and 220 mg chloroacetic acid lithium salt 260 mg (5B) - (i6RS) -i6,2O-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I ₂ -11,15-bis- (tetrahydropyranyl ether) _o Kach elimination of the protection groups gives 90 mg the title compound as a colorless oil

 IR; 3400 (wide), 2920, 172.1, 1600, 1420, 966 / cm

The starting material for the title compound above is prepared as follows:

(IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- / TE) - (3S, 4RS) -3-hydroxy-4-methyl-non-1-en-6-inyl7- bicyclo / 3.3.Öjoctan

To a suspension of 1.46 g of sodium hydride (55% suspension)

9 9 3 O -25- 27.5.1982

AP C 07 G / 235 993/0 60 115/11

in oil), in 130 ml of dimethoxyethane (1MB) is added dropwise

0 ⁰ C, a solution of 9.02 g of 3 ~ methyl-2-oxo-oct-5-ynylphosphonic acid dimethyl ester in 67 ml of BME and stirred for 1 hour at 0 ⁰ G. Then, at -20 ⁰ G with a solution of 9.4 g of (iR, 5S, 6R, 7R) -3,3-ethylenedioxy -7-benzyloxy-6 ~ formyibicyclo / 3.3.07-octane in 130 ml DME, stirred for 1.5 hours at -20 ⁰ C., poured to 600 ml of saturated ammonium chloride solution and extracted three times with ether. Clen washed organic extract with water until neutral, dried over magnesium sulfate and evaporated in vacuo Chromatography of the residue on silica gel are obtained with ether / hexane (1 + 1) 9.1 g of e \ ,, ß-unsaturated ketone as an oil ,

To a solution of 9.1 g of the ketone in 300 ml of methanol is added at -40 ⁰ C protionsweise 5.2 g of sodium borohydride and stirred

1 hour at -40 ⁰ C. Then diluted with ether, washed with water until neutral, dried over magnesium sulfate and evaporated in vacuo. Column chromatography on silica gel with ether / hexane (7 + 3) initially gives 3.9 g of the title compound (PG nomenclature: 15% -hydroxy) and, as the polar component, 3.2 g of the isomeric 15β-hydroxy compound.

IR: 3600, 3400 (wide), 2942, 1711, 1603, 1588, 1276, 968, 947 / cm

(1R, 5S, 6R, 7R) -7- (ietrahydropyran-2-yloxy) -6- / TB) - (3S, 4RS) -3- (tetrahydropyrän-2-yloxy) -4-methyl-non-1 en-6-inyl7-bicyc1o / 3.3.07octan-3-one

A mixture of 3.6 g of c <.- alcohol prepared according to Example 3a and 1.4 g of potassium carbonate in 120 ml of methanol

YYYYYY _26_ 27.5 · 1982

AP.C 07 C / 235 993/0 60 115/11

The mixture is stirred under argon at room temperature for 16 hours. The mixture is then concentrated in vacuo, diluted with ether and washed neutral with brine. It is dried over magnesium sulfate and evaporated in vacuo. The binder residue is stirred for 16 hours at room temperature with 75 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + 10) and then evaporated in vacuo. After filtration of the residue over silica gel, acetic acid / hexane (7 + 3) gives 2.2 g of the ketone as an oil.

A solution of 2.2 g of the ketone, 2.4 ml of dihydropyran and 23 mg of p-toluenesulfonic acid in 75 ml of methylene chloride is stirred for 30 minutes at 0 ⁰ G. Then diluted with ether, shaken with dil »sodium bicarbonate solution, washed with Water neutral, dried over magnesium sulfate and evaporated in vacuo. 3 g of the bis-tetrahydropyranyl ether are obtained, which is used without purification. IR: 2960, 2865, 1738, 970 / cm

2 - ^ (E) - (IS, 53,6R, 7H) -7- (tetrahydropyran-2-yloxy) -6- / rs) - (3S, 4RS) -4-methyl-3- (2- Tefrahydropyran yloxy) -non-1-en-ö-

Analogously to Example 1a, from 3 to 3 g of the ketone prepared according to Example 3b are obtained after chromatographic separation of isomers as a more nonpolar compound 720 mg of 2-f_ (Z) - (i3,5S _} 6R, 7R) -7- (tetrahydropyran-2-one) ylo2: y) -6- / TE) - (33,4RS) -4-methyl-3- (tetrahydropyran-2-ylo3: y) -non-1-en-6-in-y_l7-bicyclo / 5 «3 * 07octan-3-ylidene-3-ethane-1-ol and 1.6 g of the title compound as a colorless oil

 IR: 3600, 3430, 2942, 2863, 1600, 972 / cm

23 5 99 3 O. - * ί- 27.5.1982

AP C 07 C / 235 993/0 60 115/11

Example 4

(5Z) - (i6RS) -i6,2Q-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I ₂

In analogy to Example 1, a 0.65 g of the Z-configured allyl alcohol prepared according to Example 3c 120 mg of the title compound is obtained as a colorless oil. IR: 3320 (wide), 2925, 1720, 1600, 1420, 968 / cm

Example 5

(5E) - (i6RS) -i6,20-dimethyl-3-oxa-i9,19,20,20-tetradehydro-6a-cafba-prostaglandin-I ₂

In analogy to Example 1, from 0.75 g of 2-5S, 6R, 7R) -7- (tetrahydropyran-2-ylosy) -6- / Ji _J ') - (3S, 4RS) -4-methyl-3 - (tetrahydropyran-2-yloxy) -non-1-en-7-ynyl.7-bicyclo-Z "3" 3.C [7octan-3-ylidene-1-ethan-1-ol and 330 mg of chloroacetic acid lithium salt 420 mg (5S) - (i6R8) -i6,20-dimethyl-3-oxa-19,19,20, 20-tetradehydro-6a-carba-prostaglandin-I ₂ -11, i5-bis- (tetrahydropyranyl ether) · After cleavage of the protecting groups gives 180 mg of the title compound as a colorless oil, IR: 3410 (broad), 2925, 1722 1601 ', 1420, 965 / cm

The starting material for the title compound above is prepared as follows:

5a-. ,

3-methyl-2-oxo-oct-6-ynyl-phosphonic acid dimethyl ester

109 g of p-toluenesulfonyl chloride are added to a solution of 40 g of 3-pentin-1-ol in 240 ml of pyridine and the mixture is stirred at 0 ^° C. for 48 hours. 30 ml of water are then added and the mixture is stirred

23 5 9 9 3 O ~ ® * ~ 27.5.1982

+ J * J + J% J KJ. APG 07 C / 235 993/0

So 115/11

2 Stir and dilute with ether. Shake successively with 5% sulfuric acid, with water, with 5% sodium bicarbonate solution, wash neutral with water, dry over magnesium sulphate and evaporate in vacuo. The residue is recrystallized from hexane / ether. This gives 80 g of tosylate (Pp. 43 ⁰ G).

To a suspension of 8.7 g of sodium hydride (55% suspension in oil) is added 34 g of ethyl malonate and boiled for 4 hours under reflux. Subsequently, 35 g of 1-tosyloxy-3-pentyne and 130 ml of DME are added at room temperature. It is refluxed for 8 hours. It is neutralized with acetic acid, treated with 130 ml of water, extracted with ether, shaken three times with water, dried over magnesium sulphate and evaporated in vacuo. The residue is purified by vacuum distillation at 12 torr. At 150 to 156 ⁰ C to obtain 24 g of the alkylated methylmalonic, which is refluxed in 16O ml of dimethyl sulfoxide and 1.5 ml of water for 6 h with 7 »5 g of lithium chloride. It is then poured into 400 ml of ice-water, extracted with ether, the organic extract is extracted twice with water, dried over magnesium sulfate and concentrated in vacuo. The distillation of the residue provides at 92 ⁰ C and 12 Torr 14 g of 2-methylhept-5-acid-ethyl ester as a colorless liquid.

To a solution of 18.6 g of dimethyl methanephosphonate in 280 ml of tetrahydrofuran is added dropwise 73 ml of a 1.7 molar butyllithium solution in hexane at -70 ⁰ C, stirred for 15 minutes and slowly adds a solution of 10.5 g of 2-methyl-hept-5 ethyl acetate in 48 ml of tetrahydrofuran. The mixture is stirred for 4 hours at -70 ⁰ G, neutralized with acetic acid and evaporated in vacuo, the distillation of the residue in vacuo at 0.6 Torr and 130 ⁰ G provides 10.8 g of the title compound as a colorless liquid,

O) Jo -89- 27.5.1982

, _ _ - -. , AP G 07 C / 235 993/0

60 115/11

(IR, 5S, 6R, 7R) -3,3-ÄthyIendioxy-7-benzoyloxy-6 / JE) - (3S, 4ß3) -3-hydroxy-4-methyl-non-1-en-7-inyl7-bicyclo /3.3«ö7octan

Analogously to Example 3a, 12.2 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoylo: γ-6-formyl-bicyclo / _> 30.Q7-octane and 11.9 S of the phosphonate prepared according to Example 5a 14.5 g of the unsaturated ketone, which is converted by reduction with 8.2 g of uratriuniborohydride in 5 »3 S of the title compound. IR: 3600, 3410, 2940, 1712, 1602, 1583, 1277, 970, 948 / cm

(IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / TE) - (3S, 4RS) -3- (tetrahydropyrän-2-ylo2: y) -4-niethyl-non- 1-en-7-ihyl7-bi-

In analogy to Example 3b is obtained from 5 »3 g of the qc alcohol prepared according to Example 5b 5.4 g of bis-tetrahydropyranyläthers as a colorless oil. IR: 2963, 2866, 1737, 968 / cm

2-L (E) - (iS, 5S, 6R, 7R) -7- (tetrahydropyran-2-ylo2: y) -6- / Ti) - (33 4RS) -4-methyl-3- (tetrahydropyran-2 -yloxy) -non-1-en-7-inyl7-bicyclo / 3.3.07octan-3-ylidenJ-ethane-1-ol

In analogy to Example 1a, from 5 to 3 g of the ketone prepared according to Example 5c after chromatographic separation of isomers as nonpolar compound 1.4 g of 2-j ^ (Z) - (iS 5S, 6R, 7R) -7- (letrahydropyran- 2-yloxy) -6- / TE) - (3S, 4R3) -4-ethyl-3- (tetrahydropyran-2-ylo2: y) -non-1-en-7-ynyl.7-bicyclo Z 3.3.3 / octan-3-ylideneethane-1-ol and 2.9 g of the title compound as a colorless oil

 IR: 3610, 3400, 2940, 2862, 10000, 970 / cm

5 99 3 O -i- 27.5.1932

AP G 07 C / 235 993/0 60 115/11

Example 6

(5Z) - (16RS) -1β, 20-dimethyl-3-oxa-19,19,20,20-tetradehydro-Sa-carba-prostaglandin-Ip

In analogy to Example 1 is obtained from 810 mg of after. Example 5d prepared Z-configured allyl alcohol 180 mg of the title compound as a colorless oil. IR: 3430 (wide), 2030, 1721, 1600, 1425, 968 / cm

Example 7

C5S) - (i5R3) -15-methyl-3 ~ oxa-18,18, i9, i9-tetradehydro-6acarba prostaglandin Ig

In analogy to Example 1, from 0.45 g of 2-f (-B) - (12, 5S, 6R, 7R) -7- (tetrahydropyran-2-ylozy) -6- / T.iü) - (3H3 ) -3-ethyl-3 - ('i "-etrahydropyran-2-yloxy) -oct-1-en-6-ynyl-7-bicyclo _J / ^< 3» 3.07 octan-3-ylidene-ethane-i- ol and 210 mg chloroacetic acid lithium salt 270mg (5B) - (i5RS) -15-ethyl-3-oxa-18,18,19,19-tetradehydro-öa-carb'a-pröstaglandin-Ig-H, 15-bis- After removal of the protective groups, 108 mg of the title compound are obtained as a colorless oil: IR: 3410 (broad), 2945, 1720, 1600, 968 / cm

The starting material for the title compound above is prepared as follows:

2 - ^ (B) - (iS, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / TE) - (3RS) -3-methyl-3 - (- eetraliydropyran-2-yloxy ) -oct-1-en-6-inyl.7-bicyclo / 3.3.07octan-3-ylidenJ-ethane-1-ol

23 5 99 3 O - # · '^ .5.

AP G 07 G / 235 993/0 60 115/11

In analogy to Example 1a, from 1.7 g of (1R, 5S, 6R, 7R) -7- ( ⁱ -iethy-hydropyran-2-ylozy) -6- / 1E) - (3RS) -3-niethyl-3- ( tetrahydropyran-2-ylo3: y) -oct-1-en-6-ynyl-7-bi-cyclo / '3.3.07 octan-3-one after chromatographic isomer separation as a less polar compound 320 mg 2-jhz) - (iS, 5S, 6R, 7R ) -7- (tetrahydropyran-2-ylo2y) -6 £ TE) - (3R3) -3-mei; hyl-3- (tetrahydropyran-

ethane-1-ol and 950 mg of the title compound as a colorless oil, IR: 3600, 3400 2945, 2865, 1600, 970 / cm

Example 8

(5E) -3-0xa-13,18,19, ^ - tetradehydro-öa-carba-prostaglandin-

In analogy to Example 1, from 0.92 g of 2-jKiä) - (iS, 55, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / TE) -3- (tetrahydropyran-2 -yloxy ') - oct-1-ene-6-yn-7-bicyclo / 3.3 »07octan-3-ylidene] ~ ethane-1-oil and 430 mg chloroacetic acid lithium salt 510 mg (5S) -3-0za-18 , 18.19, ^ - tetradehydro-öa-carba-prostaglandin-Ip-11,15-bis-tetrahydropyranyl ether. After subsequent cleavage of the protective groups, 245 g of the title compound are obtained as a colorless oil

 IR: 3400 (wide), 2225, 1722, I6OO, 972 / cm

The starting material for the title compound above is prepared as follows:

2- £ (E) - (1S, 53,6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / do) -3- (tetrahydropyran-2-yloxy) oct-1-en-6 in-yl-7-bicyclo / 3.3.07 octan-3-ylidene-1-ethane-1-ol

Analogously to Example 1a, from 3.35 g (1R, 5S, 6R,

OO C QQQ Π -3fi-

L · <J J Ό Ό α U ^ _c

27.5.1982 ^ _{c 07 G} 60 115/11

7R) -7- (tetrahydropyran-2-yloxy) -6- / T3) -3-tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl-7-bicyclo / J3.3.07octan-3-one by chro matographic isomer separation as a more non-polar compound 820 mg 2-Rz) - (iS, 5S, 6R, 7R) -7- (Ietrahydropyran-2-yloxy) -6- £ .TS) -3- (tetrahydropyran-2-ylO2: y) -oct-1-en-6-yn-7-bicyclo / 3,3.07octan-3-ylidene-1-ethane-1-ol and 1.9 g of the compound of Ixtel as a colorless oil

 IR: 3600, 3405, 2943, 2865, 1600, 968 / cm

Example 9

(5E) - (i6R3) -i6, i9-1> imethyl-3-oxa-18 _} 19-dideydro-6a-carbaprostaglandin-Ip

In analogy to Example 1, 0.97 g of 2-y5S, 6R, 7a) -7- (tetrahydropyran-2-ylozy) -6- / riE) - (3S, 4fiS) -4,7-dimethyl- 3- (tetrahydropyran-2-yloxy) -oct-1,6-dienyl-7-bicyclo / 3.3-o7-octanyl-3-ylidene-1-ol and 450 mg of lithium chloroacetate 490mg (5S) - (i6RS) -i6 , 19-Dlmethyl-3-oxa-18,19-didehydro-6a-carba-prostaglandin-I ₂ -11,15-bis-tetrahydropyranyl ether. Subsequent deprotection afforded I60 mg of the title compound as an "oil." IR: 3410 (broad), 2925, 1720, 1600, 965 / cm

The starting material for the above compound compound is prepared as follows:

9A_

(IR, 5S, 6R, 7R) -3,3-lthylendioxy-7 benzpyloxy-6 / TiS) - (3S, 4RS) -3-hydroxy-4 '7 <3imethyl-oct-1,6 < äieny _< 17-bicyclo / 3.3, _i 07octane

In analogy to Example 3a, 6.5 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo [ _i ] 3,3'-octane and 6 g of 2 are obtained -Oza-3,6-dimethyl-hept-5-enyl-phosphonic acid dimethyl ester 6.3 g of the unsaturated ketone, which by

235993 O ⁱ⁰

05/27/1982

AP C 07 G / 235 993/0

60 115/11

Reduction with 4 g of sodium borohydride in 2.7 g of the title compound is converted. IR: 3600, 3420, 2945, 1713, 16O2, 1587, 1273, 972, 943 / cm

(iR, 5S, 6R, 7R) -7- (2-tetrahydropyran-2-ylo3: y) -6- / Tia) - (3S, 4RS) -, 4,7-dimethyl-3- (tetrahydropyran-2-ylo): x: y) -OGt ~ 1,6-dienyl7-bicy.clo / 3 · 3 · 07octan-3-one

In analogy to Example 3b, obtained from 2.7 g of the egg alcohol prepared according to Example 9a 2.6 g of the title compound as a colorless oil

 IR: 2965, 2865, 1738, 965 / cm

2 - ^ (E) - (IS, 53,6R, 7R) -7- (tetrahydropyran-2-ylos: y) -6- / ria) -. / \ 33, 4RS) -4 j 7-dimethyl-3- (tetrahydropyran-2-yloxy) -oc t-1,6-dienyl; 7-bicyclo ^ 3 »3, 27octan-3-ylidene-ethane-1 -oil

In analogy to Example 1a, from 2.6 g of the ketone prepared according to Example 9b after chromatographic separation of isomers as a non-polar compound 0.65 g of 2 - ((Z) - (i8,5S, 6R, 7R) -7- (i ' etrahydropyran-2-ylozy) -6- / Ti £) - (3S, 4RS) -4,7-dimethyl-3- (tetrahydropyran-2-yloxy) oct-1,6-dienyl7-bicyclo / 3 "3" 07 ^oc * ' ^t a ⁿ ~ 3-ylidene-3-ethan-1-ol and 1.4 g of the title compound as a colorless oil, IR: 3600, 3400 (broad), 2945, 2860, 1600, 968 / cni

Example 10

(5E) - (i6RS) -i6-methyl-3-oxa-18,18,19, T9-tetradehydro-6acarba-prostaglandin-I ₂ -methyl ester

A solution of 150 mg of the product obtained according to Example 1 is added.

235993 O

- ^ - 27.5.1982

AP G 07 G / 235 993/0 60 115/11

Asked acid in 10 ml of methylene chloride at 0 ⁰ G dropwise with an ethereal diazomethane solution to a permanent yellow color, after evaporation of the solution in vacuo, the residue is filtered through silica gel with methylene chloride / isopropanol (95 + 5) and receives 120 mg of the methyl ester as a colorless oil , IR: 3600, 3400, 2960, 1740, 1600, 972 / cm

Example 11

(5 ^) - Ci6RS) -i6-methyl-3-oxa-18,18,19, i9-tetradehydro-III'-methanesulfonyl-öa-carba-prostaglandin-Ip-carboxamide

A solution of 360 mg of the acid prepared in Example 1 in 8 ml of dimethylformamide is added at 0 ⁰ G with 16O mg of isobutyl chloroformate and 120 mg of triethylamine. Hach 30 minutes, 480 mg of the ITatriumsalzes of methylsulfonamide (prepared from methylsulfonamide and sodium methylate) and 2 ml of hexamethylphosphoric triamide added and stirred for 3 hours at 20 ⁰ G. Then, the reaction mixture on gitrat buffer (pH 5) »extracted several times with ethyl acetate, washed the organic phase with brine, dried over magnesium sulfate and evaporated in vacuo, Hach chromatography of the residue on silica gel with methylene chloride / isopropanol to obtain 16O mg of the title compound as an oil

 IR: 3600, 3400 (wide), 1730, 1600, 970 / cm

Example 12

(5B) - (i6RS) -i6-methyl-3-oxa-18,18,19,19-tetradehydro-6acarba prostaglandin Ip-acetylamide

To a solution of 500 mg (5E) - (i6RS) -i6-methyl-3-oxa-18,

23 5 39 3 υ -a * - 27.5.1982

AP C 07 C / 235 993/0 60 115/11

18,19,19-tetradehydro-6a-carba-prostaglandin-I ₂ -11,15-bis- (tetrahydropyranyl ether) in 15 ml of acetonitrile are added at 25 ⁰ G 130 mg of triethylamine, cooled to 0 ⁰ G and dripping a solution of 95 mg of acetyl isocyanate in 10 ml of acetonitrile. The mixture is stirred for 2 hours at 25 ⁰ G, concentrated in vacuo, diluted with 100 ml of V / asser, by addition of 1'N hydrochloric acid to pH 5, extracted with ether, the organic phase is washed with brine, dried over magnesium sulfate and evaporated in vacuo. To cleave the protective groups, the residue is stirred with 15 ml of acetic acid / water / tetrahydrofuran (65/25/10) overnight at 30 ⁰ G and evaporated to dryness in vacuo. The residue is chromatographed on silica gel with methylene chloride / \% isopropyl alcohol. 205 mg of the compound are obtained as an oil

 IR: 3600, 3400, 1708, 976 / cm

Example 13

_r (5E) - (i6RS) -i6-methyl-3-o2: a-18,18,19,19-tetradehydro-6acarba-prostaglandin-Ig-carboxamide

200 mg (5B) - (i6RS) -methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-Ip are dissolved in 5 ml tetrahydrofuran and at 0 ⁰ G with 80 mg of triethylamine and 90 mg of isobutyl chloroformate is added. After 1 hour 10 minutes, ammonia gas is introduced at 0 ⁰ C, then left for 1 hour at 25 ⁰ O. The mixture is then diluted with 50 ml of water, extracted three times with 30 ml of methylene chloride, shaken the combined extracts with 20 ml of brine, dried over magnesium sulfate and evaporated in vacuo. It is purified by chromatography on silica gel with chloroform / ethyl acetate (8 + 2) to give 150 mg of the title compound as an oil. IR: 3600, 3540, 3410, 2960, 167Ο, 978 / cm

33 • 56-27.5.1982

AP C 07 G / 235 993/0 60 115/11

Example 14

(5E) -Ci6RS) -i6-methyl-3-oza-18,18,19,19-tetr.adehydro-6acarba prostaglandin Io trishydroxymethylaminomethansals

To a solution of 200 mg of (& B) - (i6RS) -i6-methyl-3-oza-18, ^, ^ »^ - tetradehydro-öa-carba-pfostaglandin-Ip in 35 ml of acetonitrile is added at 65 ⁰ G. Dissolve 60 mg of tris- (hydroxymethyl) -aminoinethane in 0.2 ml of water. The mixture is allowed to cool with stirring, decanted after 16 hours from the solvent, and the residue is dried in vacuo. 190 mg of the title compound are isolated as a viscous oil,

Claims (1)

5 9 9 3 O - ^ Berlin, 27.5.1982 AP G 07 C / 235 993/0 60 115/11 Erfindungsansprach 1. A process for the preparation of Garbacyclinderivaten the general Porinel I GH is wherein R. the radical ORp, where Rp Ϋ / asserstoff, alkyl, cycloalkyl »aryl or a heterocyclic radical, or the radical HHR- with R-, in the meaning of an acid radical or hydrogen atom, X oxygen, A is a -CH ₂ -GHp-, trans-CH = CH- or -CS-C group, W is a free or functionally modified hydroxymethylene group or a free or functionally modified H ₃ - C group, where the GH group is C <- or ß-constantly Can be OH 5 99 3 O-t- 27.5.1982 A? C 07 C / 235 993/0 60 115/11 D is a straight-chain or branched, saturated or unsaturated alkylene group having 1-10 G atoms, optionally substituted by. S ¹ I may be substituted by atoms, B represents a -C = C bond or a -CRg = CR ^ group, where Rr and R ^ denote a hydrogen atom or an alkyl group having 1-5 G atoms, R, an alkyl, cycloalkyl, or an optionally substituted aryl or a heterocyclic group, Rc is a free or functionally modified hydroxy group, and, if R ₂ ^ ^{e has the} meaning of a hydrogen atom, their salts having physiologically compatible bases, characterized in that in itself, known teise a compound of the general Pormel II, CH ₂ OH CH II II ^R 5 in which R ₁ , R ₁ -, A, W, D and B have the abovementioned meanings, if appropriate after protection of free hydroxy groups present with a haloacetic acid derivative of the general formula III 23 5 99 3 O -J- 27.5.1982 AP G 07 G / 235 993/0 60 115/11 Hal-GH ₅ -G ^ III -OR ₈ where Hal is a chlorine or bromine atom and Rq is an alkyl radical or an alkali metal etherified in the presence of a base and optionally subsequently in any order isomers isomers and / or releases protected hydroxy groups and / or esterified free hydroxy groups, etherified and / or esterified a free carboxyl group and / or saponifies an esterified carboxyl group or converts a carboxyl group into an amide or with a physiologically acceptable base in a salt.