CS235329B2 - Method of 3-oxa-6a-carbaprostaglandine i 2 derivatives production - Google Patents

Abstract

Carbacylin derivatives of the general formula I <IMAGE> in which R1 denotes a hydrogen atom or the radical OR2, in which R2 can denote hydrogen, alkyl, cycloalkyl, aryl, the radical <IMAGE> or a heterocyclic radical, or R1 can denote the radical NHR3 where R3 denotes an acid radical or the radical R2, n can denote the number 2, 3, 4 or 5, X denotes a hydrogen atom or a fluorine atom, A denotes a -CH2-CH2-, a trans -CH=CH- or -C IDENTICAL C- group, W denotes a free or functionally modified hydroxymethylene group or a free or functionally modified <IMAGE> group, in which the OH group can be in the alpha or beta position, D denotes the group <IMAGE> a straight-chain, saturated alkylene group having 1-5 C atoms, a branched saturated or a straight-chain or branched unsaturated alkylene group having 2-5 C atoms, which may be substituted by fluorine atoms, m can denote the number 1, 2 or 3, E represents a direct bond, a -C IDENTICAL C- group or a -CR6=CR7- group, in which R6 denotes a hydrogen atom or an alkyl group having 1-5 C atoms and R7 denotes a hydrogen atom, an alkyl group having 1-5 C atoms or a halogen atom, R4 denotes an alkyl, cycloalkyl or a substituted or unsubstituted aryl group or a heterocyclic group, R5 denotes a free or functionally modified hydroxyl group, and, if R2 denotes a hydrogen atom, the salts thereof with physiologically acceptable bases, a process for their preparation and their use as pharmaceuticals.

Description

A process for the preparation of 3-oxa-6a-kerbaprostaglendine I ₂ derivatives of the general formula I

O

I (CH, ln -c -R-!

I o

Even the esterified carboxyl group is saponified or the carboxyl group is converted into an amide or by treatment with a physiologically acceptable base into a salt.

CH ₂ x (I)

and when IU is hydrogen, a salt thereof with a physiologically acceptable base, wherein the compound of formula II is etherified, optionally after protection of the hydroxyl groups present, with a haloketal of formula III in the presence of a base, and the resulting ketal is cleaved with acid; in any order, the formed isomers are separated and / or the protected hydroxyl groups are released and / or the free hydroxyl groups are esterified or etherified and / or the aldehyde group is oxidized and / or the resulting free carboxyl group is esterified and / or

The present invention relates to a process for the preparation of novel 3-oxa-6e-carb8proataglandin Ig derivatives as well as their salts with physiologically acceptable bases. The novel compounds can advantageously be used as medicaments.

No. 2,845,770, 2,900,352, 2,902,442, 2,904,655, 2,909,088, 3,048,906, and 2,912,409 disclose analogs of (5E) - and (5Z) -6α-carbaprostaglandin 1g. The name of the compounds prepared by the process according to the invention is based on the suggestion of Morton and Brokow (J. Org. Chem., 44, p.280 (1979)). In the synthesis of these compounds, two isomers arise due to the double bond. Both isomers of this prototype are represented by the following structural formulas:

(5Z) -6a-Carbaprooteglandin Ig

It is known from the very broad state of the art of prostaglandins and their analogs that this class of compounds is suitable for use in mammals, including humans, because of its biological and pharmacological properties. However, the use of these compounds as medicaments encounters difficulties because they exhibit too short a duration of action for therapeutic purposes. The purpose of any changes in their structure is to increase their duration and selectivity of their efficacy. .

It has now been found that by homooising the upper chain of 3-oxa-kerbaprostaglandins, longer duration of action, greater selectivity and improved efficacy can be achieved. The compounds produced by the process of the invention have a blood pressure lowering effect and a bronchodilator effect.

In addition, they are suitable for vasodilation, inhibition of platelet aggregation and gastric acid secretion.

More particularly, the invention relates to a process for the preparation of carbaprostaglandin Ig derivatives of formula I from ^w

_-O-CH2-C ^ ÍCHjJn

I Ri

CX

and * 5 (I), wherein - represents a hydrogen atom or an O 1 K> residue, wherein R 8 represents hydrogen, an alkyl group having 1 to carbon atoms, or a residue. / - \ \, · or * - CH ₂ -CO

K, represents a radical NM- *, wherein it represents hydrogen or a 2,3-dhhydrojyropropyl group, n represents 3 or 2,

X represents a hydrogen atom or a fluorine atom,

A represents a group -CHg-ClN- »trans -CH = CH- or -C = C-, represents a free or functionally converted CH group

-cOH or a free or functionally converted hydroxymethylene group, wherein the hydroxyl group may be attached at the alpha or beta position, represents a group

or a straight or branched alkyl. a group having 1 to 5 carbon atoms, mi is 1, 2 or 3,

E represents a direct bond, -C = C- or -CR &lt; = &gt;

and Ry, which is different from each other, is hydrogen or C 1 -C 5 alkyl, C 1 -C 4 alkyl,

K- represents a free or functionally converted hydroxyl group and, when Rg represents an hydrogen atom, their salts with physiologically acceptable bases.

The compounds of formula I exist both in the isomer (5E) and in the isomer (52).

Suitable alkyl groups for the meaning of the symbol J <2 are straight-chain or branched alkyl groups having 1 to 4 carbon atoms, for example the reyeyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl groups.

Hyddoxyl groups in the meaning of R? and W may be functionally converted,. for example, by etherifiooating or esterifying, wherein the free or transformed W-groups may be bonded at the alpha or beta position; free hydroxyl groups are preferred.

Suitable ether and acyl radicals are those known to the person skilled in the art, for example tetrachloride, alpha-ethoxyethyl, tetrahydrofuran, trimethylsilyl, dimethyl-taributylsilyl and tribizylsilyl. Suitable acyl radicals are, in particular, the acetyl, propiol, butyryl and benzoyl radicals.

As alkyl groups in the meaning of R? linear and branched alkyl radicals having 1 to 4 carbon atoms are suitable. Examples are methyl, ethyl, propyl, butyl, isobutyl and tert-butyl.

Suitable alkylene groups for the meaning of the symbol D are straight or branched alkylene radicals having 1 to 5 carbon atoms. Examples are methylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentameeylene, 1-methyltetramethyl and 1-methyltrimethylene.

Alkyl groups in the meaning of R? and R? are linear or branched alkyl groups having 1 to 5 carbon atoms. Examples are methyl, ethyl, propyl, butyl, isobutyl, tert-butyl and pentyl.

Inorganic and organic bases such as those known to those skilled in the art for the formation of physiologically acceptable salts are suitable for the formation of the free acid salts of formula I (R 2 = H). . Examples include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethyltin- _3- dimethoxylamine, triethanolamine, N-methylglucamine, roorphinoin, tris-hydroxydimide and the like. .

The process according to the invention for the preparation of the 3-oxa-68-carbeprosteglindine Ig derivatives of the formula I is carried out by reacting a compound of the formula II

CX-CH2OH

(II) where

X, R, R 1, A, W, D 0 E have the meanings given above, etherify, optionally after protection of the hydroxyl groups present, halogen ketalmm of the general formula III hal, ORn - (CH ₂ IN -).

OR ₉ (III) where

hal represents a chlorine, bromine or iodine atom and each of Rg and Rg represents an alkyl group having 1 to 10 carbon atoms or R and Rg together represent a ring-forming group having 2 to 10 carbon atoms n has the above meaning,

in the presence of a base and the resulting ketal is cleaved with an acid, and optionally the resulting isomers are separated from each other in arbitrary order with / or liberated protected hydroxyl groups and / or free hydroxyl groups are esterified or esterified and / or the aldehyde group is oxidized and or the resulting free carboxyl group is esterified and / or the esterified carboxyl group is separated or converted into an amide group or by reaction with a physiologically acceptable base into a salt.

The reaction of a compound of formula II with a haloketal of formula III is carried ^d s at 'temperature 0 to Ю0 ° C, preferably 10 to 80 ° C, v ^p rotikkém rozpoučit ^ le or Smee rozpouutědel, does not give the eimeeylsulfoxtei, of dimethylformamide, tltгalψerof uranium etc. As such, suitable bases are those known to those skilled in the art for etherification, for example sodium hydride, potassium tert-buylate, butyllituurn, etc.

The cleavage of the ketal group leading to the formation of the compounds of formula (I) following the etherification is carried out by known methods. For example, the cleavage of the ketel group is carried out in an aqueous solution of an organic acid such as acetic acid, propionic acid, etc., or in an aqueous solution of an inorganic acid such as hydrochloric acid. In order to improve the dissolution, an inert organic solvent mixed with water is expediently added. , Suitable organic solvents are alcohols such as methanol and ethane-l, A, ^E tlry ^{as-methoxy-ethane,} dioxane and the ^t ^ ^ye ltrah rsfurθo. Preferably, use ^and tetrahydro-ofuranu. Scaling ^the eta] .ov ^E n ^to u ^{when y} is preferably conducted at ²⁰ to ⁸⁰ ° C.

The oxidation of the aldehyde group is carried out by known methods. Examples of suitable oxidizing agents are pyridinium dichromate (Tetrahedron Letters, 1979 p. 399), Jones reagent (J. Chem. Soc., P. 2555) or the platinum / oxygen system (Adv. In

Chem., 17, p. 169 (1962).

The oxidation with pyridinium dichromate is carried out at a temperature of 0 to 00 ° C, preferably 20 to 40 ° C, in a solvent inert to the oxidizing agent used, for example dimethylformamide.

The oxidation with Jones reagent is carried out at a temperature of -40 to +40 ° C, preferably at 0 to ° C, in acetone as solvent. The platinum / oxygen oxidation is carried out at a temperature of 0 to 60 ° C, preferably 20 to 40 ° C, in a solvent inert to the oxidizing agent used, such as ethyl acetate.

The saponification of carbacycline esters is carried out by known methods, for example using basic catalysts.

The OR ₂ ester group in which R ₂ is a C 1 -C ₆ alkyl group is introduced by known methods. For example, the carboxyl compounds are reacted with die carbohydrates. The esterification using diazocarbon is carried out, for example, by mixing a solution of the diazocarbon in an inert solvent, preferably diethyl ether, with the carboxylic compound in the same or another inert solvent, for example methylene chloride. After completion of the reaction for 1-3 minutes, the solvent is removed and the resulting ester is purified by conventional means. Diazoelkans are known or can be prepared by known methods (Org. Reactions, vol. 8, pp. 389-394 (1954)).

The introduction of the ester group -OR ₂ in the meaning of the symbol R 1, in which R 1 is a group of the formula -CH ₂ -CO-C 1 H 4 -C 4 H-, is carried out by known methods. For example, the carboxyl compounds and the corresponding arylhydroxyl compounds are reacted with dicyclohexylcarbodiimide in an inert solvent in the presence of a suitable base, for example pyridine or triethylamine. As the solvent, methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform, can be used. The reaction is carried out at a temperature of -30 to +50 ° C, preferably at +10 ° C.

The introduction of the ester group -OR ^ in place of the symbol R ^ can also be achieved by reaction of the carboxylate anion with the corresponding alkyl halide or omega-haloketone (hal-CHg-C-ar,

Wherein ar represents a diphenyl radical which may be substituted by C 1 -C 2 alkoxy or by chlorine or bromine.

The carbaprostaglandin I ₂ derivatives of formula I wherein R 1 is a hydroxyl group (R ₂ = H) can be converted by neutralization with an appropriate amount of the appropriate inorganic bases in the salt. For example, by dissolving the appropriate acids in water that contains a stoichiometric amount of a base, evaporating the water or adding a water-miscible solvent such as an alcohol or acetone yields the corresponding solid inorganic salt.

The amine salts are prepared in a conventional manner. To this end, the carbacyclinic acid is dissolved, for example, in a suitable solvent, such as ethanol, acetone, diethyl ether or benzene, and at least an etechiometric amount of the amine is added to the resulting solution. The salt usually precipitates out in solid form or is isolated in a conventional manner by evaporation of the solvent.

The functional conversion of the free hydroxyl groups is carried out by known methods. To introduce the ether protecting groups, the reaction is carried out, for example, with β dihydropyrene in methylene chloride or chloroform using an acidic condensing agent such as p-toluenesulfonic acid. The dihydropyran is used in excess, preferably in a quantity of four to ten times the theoretical need. At 0 to 30 ° C, the reaction is generally complete after 15 to 30 minutes.

The introduction of acyl groups as protective groups is carried out by reacting a compound of the formula I in a known manner with a carbonic acid derivative, for example its chloride or epode anhydride. '

The release of the functionally converted hydrooryl group to produce the compounds of formula I is accomplished by known methods. For example, the ether protecting group is cleaved in an aqueous solution of an organic acid, such as acetic acid, propionic acid, etc., or in an aqueous solution of an inorganic acid, such as hydrochloric acid. Water-miscible inert organic solvents are expediently added to improve solubility. Suitable organic solvents are, for example, alcohols such as methanol and ethenol, and ethers. such as dimethanol, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. Cleavage is an advantage. carried out at 'a temperature of 20 e ⁸⁰ ° C.

The cleavage of the silyether protecting groups is carried out, for example, with tetrabutylammonium fluoride. Suitable solvents are, for example tetrahydesfurao, diethyl ether, dioxane, tneyl ^ chloro ^ s ^p o ^{d. O} ° ^d I ^p measurement is preferably ^performed from ⁰ s at ^{- 80} ° C.

The weekly acyl groups are carried out, for example, with alkali metal or alkaline earth metal carbonates or hydroxides in an alcohol or an aqueous alcohol solution. Suitable alcohols are aliphatic alcohols, preferably meeancell, ethanol, butanol, etc., especially metainl. Alkali metal carbonates and hydroxides include potassium and sodium salts, but potassium salts are preferred. Of the alkaline earth metal carbonates and hydroxides, e.g. calcium, calcium hydroxide and barium carbonate. Reaction with ^{p R6} Adi ^p s t ^ep L EŽ ^about the -10 to +70 ° C, ^Vol yh ^{of the} d u ^p s 25 ° C.

The introduction of the amide group HNR4 as R @ 1 is carried out according to known methods. The carbooyl acids of the formula I (Rg = H) are first converted in the presence of an tertiary amine, such as triethylamine, for example, by treatment with β-methyl chloroformate in mixed arihydride. Reaction of the mixed ankyedride with an alkali salt of the corresponding. . amide or with ammonia (R = H) is carried out in an inert eozpouStěšle or - a mixture rszpouStWšl such as tetrθlydrsfsrao, dimethyl tor ethane, dirnatylforaamid - triamide líexame ^e yl ^f S8 ^f see ^c o ^E, at temperatures ^ a ^ -30 to ^{+ 60} ° C with an outlet at 0 to ³⁰ ° C.

A further moiety to introduce the HNR amide moiety in place of R ^ is to react a 1-carboxylic acid of formula I (Rg = H, in which free hydrodyl groups are optionally temporarily protected, with compounds of formula IV

O C = N - R i (IV), where

R 1 is as defined above.

The reaction of a compound of formula I (R 1 = OH) with an isocyanate of formula IV is optionally carried out with the addition of a tertiary amine, such as triethylamine or pyridine. The reaction can be carried out without or in an inert rszpouStěšll - rszpouStědle, preferably tetrelyšrsfsraos, acetone šimetyllcetlmids, meeylenchloridu, diethyl ether, tslseos ^at a temperature of -80 ^F and ¹⁰⁰ C St. ^{characterized} him during ou ^d 0 ^{and 30} ° C.

If the starting material contains the hydryl groups in the peoat residue, then the reagent is formed. also these - hydroxy groups. If the purpose is to prepare the final compounds containing the free hydryl groups in the free radical, it is expedient to start from the starting materials in which the latter are temporarily protected, preferably by slightly cleaved ester or acyl residues. .

The compounds of formula (II) used as starting materials can be prepared, for example, by treating the aldehyde of formula (V) in a manner known per se (cf. DOS No. 2,845,770).

(V) react with a phosphonate of formula VI

CH ₃ O _S ? ?

p-ch _{2 -} cder ₄

CH ₃ O (VI), where

D, E and R are as defined above, in the presence of a deprotonating agent such as sodium hydride or potassium tert-butoxide to form the ketone of formula VII (X = H) or in addition in the presence of a brominating agent such as N- bromosuccinimide, to form the ketone of formula VII

(VII), where

D, E and are as defined above; and

X is bromine.

Reduction of the keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesium bromide or alkyl lithium followed by separation of the epimers gives compounds of formula VIII

where

W, D, E, X and R ₄ are as defined above.

(VIII),

Quenching an ester group such as potassium carbonate in methanol and optionally hydrogenating the double bond or optionally etherifying with dihydropyran followed by cleavage of hydrogen bromide such as potassium tert-butylate in dirneeyl sulfoxide, cleavage of the ketel with aqueous acetic acid such as, for example, dihydropyran gives the ketone of formula IX

O

* 5 (IX) where

A, W, D, E, R-, and Kg have the above meanings.

After the olefinination reaction in triethylbeeerone phosphonoacetic acid or with trimethyl phosphonoacetic acid and subsequent reduction with lithium aluminum hydride, compounds of the formula II are obtained, isomeric with respect to the double bond, which can then optionally be separated from each other.

The preparation of the phosphonates of the general formula (VI) is carried out according to a known method by reacting the anion of the dineeyl ester of meeyliosonic acid with an ester of the general formula (X)

D-E (X), where

D, E, R4 are as defined above and

R 8 represents an alkyl group having 1 to 5 carbon atoms, which may optionally be prepared from the corresponding malonyl ester by a halide of formula XI hal-E-R ₄ (XI), wherein -hal is chlorine or bromine and

E and H ₄ have the above meanings, followed by decarbaakkoyllac. The ester of formula (X) is also available, optionally, from a carboxylic acid of formula (XII)

HO-C-D (XII)

II o 'where

D - is as defined above, by elution with a halide of formula XI and subsequent esterification.

The compounds of the formula (III) used as starting materials can be prepared, for example, by reducing, in a manner known per se, the TNF-halogeno-carbooxylic acid ester of the formula (XIII hal - XCH ₂ ) n - coor _q (XIII), and as defined above; and

Rq represents a C1-C5 alkyl group, di (isopropyl) -butyl, [eta] < 1 &gt; and then ketalized in a known manner with alcohol.

The compounds produced by the process of the invention exert a blood pressure lowering effect and have an ironing effect. They are also useful for inhibiting platelet aggregation. Therefore, these novel carbacycline derivatives of formula I are valuable pharmaceutical active ingredients. In addition, they show a higher specificity and, in particular, a considerably longer duration of activity, with a spectrum similar to that of the respective prostamines. Compared to prostaglandin Ig, they have greater stability. The high tissue specificity of these new prostaglandins is manifested when examining smooth muscle organs, such as urine ileum or isolated rabbit trachea, where significantly less stimulation is observed than with natural E, A or F prostaglandins.

The new carbaprootaglandin analogs have properties typical of prostacyclin, such as lowering peripheral arterial and coronary vascular resistance, inhibiting platelet aggregation and dissolving platelet aggregates, protecting myocardial cells and thereby lowering systolic blood pressure without simultaneously reducing pulse volume and coronary blood flow; treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, heart attack, peripheral arterial disease, arteriosclerosis and thrombosis, prophylaxis and therapy of central nervous system ischemic seizures, shock therapy, inhibition of cardiac arrest £ cc inhibiting gastric k ^ ^s ^ ^{<^^} Li ^ NY, cytoprotection for gastric and intestinal mucosa, cytoprotection of the liver and pancreas, lntialergicOě vlastnooti, reduction of pulmonary vascular resistance and ^^ í · pulmonary blood pressure, promotion of kidney blood flow, use instead of Heparin or as an aid in dialysis with haemophilia, preservation of blood plasma cans, especially platelet cans, inhibition of labor, pregnancy toxicity, increased cerebral blood flow, etc. In addition, the novel carbacycline derivatives produced by the method of the invention have intolerance and pro-diarrhea. vIisSíooSÍ. The carboprootaglandes according to the invention can also be used in the treatment of, for example, blockers or diuretics. .

The daily dose of these compounds when administered to patients is 1 to 100 .mu.g / g.

The unit dose for a pharmaceutically acceptable carrier is 0.01 to 100 µg.

In irritable intravenous injection to uncontrolled hypertonic rats at doses of 5, 20 and 100 (&lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; kg), the compounds of the present invention exhibit a strong and longer lasting blood pressure lowering effect than prostaglansin. or cardiac arrhythmia such as rrostiggidia Ag.

When intrevemzní Inje-born and appear ^on otisovетlýe toáHkům elephant * ^p ccording to the invention in comparison to the ^p-Ag rrostaglaidiiy Eg stronger and lasts longer · ^ or reduction of blood pressure without affecting other organs smooth svals ^^ ME or their function.

For parenteral administration, sterile, non-aqueous, aqueous or oily solutions are used. For example, tablets, coated tablets or capsules are suitable for oral administration.

The invention also relates to medicaments based on the compounds of the formula I and the usual auxiliaries and carriers.

The active substances produced by the process according to the invention are intended to serve together with the usual auxiliaries known for the production of galenic medicaments, for example for the preparation of blood pressure lowering agents.

Example 1 (5E) - (16R) -2-decarboxy-1α, 1b-dihomo 2 -formy-16-methyl-3-oxe-1 ', 8,18,19,19-tetradehydro-6e-carbaprostaglandin Ig

To a solution of 700 mg of 2 - [(E) -11S, 5S, 6R, 7R) -7- (tertalyalydropyran-2-yloxy) -6- (E) - (3S., RS) -4-methyl-3 - (tetr ahydropyridin-2-yloxy) ok-1- (6,6-1,13) bicyclo [(10,10-octan-1-ylidene) ethen-1-ol in 15 ml of tetrahydrofuran at 0 ° C is added 77 mg 55 # of a suspension of sodium hydride in mineral oil and the mixture is stirred under argon for 30 minutes at 24 ° C. Then a solution of 1.15 g of 2- (3-benzonoyl-1,3-dioxolane in 7 ml of tetralydr) is added dropwise. After completion of the heating, the mixture was diluted with ether, washed with water until neutral, magnesium sulfate and evaporated under reduced pressure. Chromatography residue no tilikrgtlu with - the použžtí sheaf with hexane - ether (7 + 3) gave 480 mg of the oxa-compound, which was stirred for 16 - ^hours at s te ^p Lot ^with 24 ° C 4 ⁰ ml of SM ° Book of acetic acid in ^d ou and tetreltydrofuran ( ⁶ 5 + 35- + 10). The residue was chromatographed on silica gel using a mixture of hexane (4 + 1) to give 270 mg of the title compound as a colorless oil.

IR (CHCj): ^{- 3600,} 3420 (and ^the ^ ^{iy, 2970, 2,} 86 ^ ^{2730, 1725, 1-603,} ЭТ0 · c '.

The 2- (3-bromo-piperidin) -ΉЗ-dioxolro used for the above-described synthesis is prepared as follows:

To a solution of 9.6 g of bromo-butyric acid in 595 ml of toluene was added dropwise at -70 ° C 50 ml of a 1.2 M solution of di-butylbutyl ammonium monohydride in toluene, stirred at -70 ° C for 15 minutes, followed by dropwise addition of 10 ml. isopropyl alcohol; and - 25 ml of water. Reekůní mixture was stirred for 2 hours at -oíítnosti then filtered, the filtrate is dried over magnesium sulfate and angulation of sn ^iz t ^ n ^ ^EE button at a temperature of ²⁵ ° C. Dissolve the residue in 500 ml of toluene, add 10 ml of β-toluene and 100 mg of p-tolueO8U10onic acid to the solution and heat the mixture to reflux and a water trap. Then dilute the reaction mixture with 500 ml. - the organic extract is dried over magnesium sulphate and concentrated under reduced pressure at 30 ° C; by de-distillation of the residue from a pressure of 80 Pa at a temperature of 43 to 45 ° C; 8 g of 2- (3-btoopPtppУ) -1,3 dioxolene as a colorless liquid.

Example - 2 (5)) - (16R) -1θ, 1b-dieomo-166motylo-oxaa | 8 _> 18,19,19-tetrahydro-6a-carbtpt08taglrodio Ig

To a solution of 500 mg of the aldehyde prepared according to Example 1 in 5 -. ml of pyridine are added with 2 ml of acetic anhydride and the mixture is left to stand for 18 hours at room temperature. Then it is concentrated under reduced pressure, the resulting N, N-diacetate is dissolved in 25 ml of acetone and added dropwise at 0 ° C. 1 ml of Jones reagent. The mixture is stirred at 0 ° C for 30 minutes, 2 ml of isoproproleol are added, the mixture is diluted with ether, shaken with water three times, dried over magnesium sulphate and removed under reduced pressure. Treatment of the remainder of the gel using hexane with ethyl acetate (1 + 1) afforded 410 m (5E) - (16W) - 1a, 1b11.

-dihomo-10o-methyl-3-oxa-1 8,18,19,19-tetrodehydro-6α-carbaprostaglandin Ig-11,15-diacetate as a colorless oil.

IR: 3650, 3400 (broad), 2960, 1730, 1600, 1245, 968 cm ^- '.

In order to cleave the protecting groups, 410 mg of the above 11,15-diacetate are stirred in 520 ml of potassium carbonate in ml of methanol at 24 DEG C. for 16 hours. The reaction mixture was concentrated under reduced pressure, acidified to pH 4 with 10% citric acid solution, extracted three times with methylene chloride, washed twice with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel using ethyl acetate / acetic acid (99.5 + 0.5). This afforded 305 mg of the title compound as a colorless oil.

IH spectrum: 3590, 3420 (broad), 2960, 2930, 2865, 1720, 1600, 970 cm ^-1 .

Example 3 (52) - (16RS) -2-decarboxy-1α, 1β-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6α-carbaprostaglandin Ig

From 320 mg of 2 - / (Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (E) - (3S, 4RS) - 4-Methyl-3- (tetrahydropyran-2-yloxy) oct-1-en-6-ynyl-bicyclo [3.3.0] octan-3-ylidene / ethan-1-ol gives 125 mg of the title compound in in the form of a colorless oil.

IR: 3600, 3400 (broad), 2965, 2860, 2730, 1726, 1660, 968 cm &lt; -1 &gt;.

Example 4 (5Z) - (16RS) -1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin Ig

In analogy to Example 2, 90 mg of (52) - (16RS) -1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,19 was obtained from 125 mg of the aldehyde prepared according to Example 3. -tetradehydro-6e-carbaprostaglandin Ig-11,15-diacetate. After deprotection, 57 mg of the title compound is obtained as a colorless oil.

IR: 3600, 3410 (broad), 2960, 2870, 1718, 1600, 968 cm @ -1.

Example 5 (5E) - (16RS) -2-decarboxy-1α, 1b-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-. -e-carbaprostaglandin Ig

From 1.35 g of 2 - [(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6-f (E) - (3S, 4RS) ) -4-Methyl-3- (tetrahydropyran-2-yloxy) non-1-en-6-ynyl-bicyclo [3.3.03 octan-3-ylidene] ethan-1-ol yields 610 mg of the title compound in the form of a colorless oil.

IR: 3600, 3410 (broad), 2967, 2862, 2731, 1725, 1601, 970 cm @ -1.

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

5) (1R, 5S) 6R, 7R-3,3-ethylene IOX ^{d y} -7-benzoyloxy-6 - [\ E) - (3S, ^4S) -3-h ^dr ooxy-4-methyl-non-1 ^{en-6-ynyl] bicyclo]} 3.3, an Oo ^kt

To a suspension of 1.46 g of sodium hydride (55% suspension in oil) in 130 ml dimetoxyéOeru at ^{t l} OTE EP 0 ° ^C at ^the e and ^p mites ^to 9.02 ^g dimetylestoru tysBliny. ³ -methyl ^-2-ethyl oxooott - dimethyl ester in ⁶⁷ ml ^of Dimethoxytricyclo purpose and the mixture míctó one ^h <Odin at ⁰ ° C. Then at -20 ° ^C at ^d thaw ^to 9.4 ^g of (1R ,, 5S, ⁶ R, ⁷ R) - ^- ^ -ethyl ^ nd ^ x ^ oo benzo ^^ ^^ ^{formyl-bis YKL 3} c, 3 ° octane in ¹³⁰ ml Hmetoxyetanu mixture was about ^{1.5 hours} mícM ^di n ^y toploto at - ²⁰ ° C, then poured into saturated ammonium chloride solution and extracted three times with ether. The organic extract is ^p rom ^y is neutral with water, dried over magnesium sulfate and evaporated under reduced pressure. By recrystallization of the residue on SiLkKe, the residue is started. using ether-hexane (1 + 1) gave 9.1 g of elf, betolyl unsaturated ketone as an oil.

К solution 9 ^{1 GT} o n ^t o -ketone in ³⁰⁰ ml mmtanolu at toploto ° C -to ^ ^p stoch chloride ^and 5.2 ^{g. b} laOrium or ^{hydroxylamine} hydrochloride and the mixture was stirred for one hour ječlnu ^p s toploto -4 ⁰ ° C. It is then diluted with ether, neutralized with water, dried over magnesium sulphate and evaporated under reduced pressure. Chromatography on a silica gel column using ether / hexane yielded first 3.9 g of the title compound (according to PG-13a-hydroxya as a more polar component, 3.2 g of isomeric 15-beta-hydroxyisomer).

Ιδ spectrum ^3600, 3400 (broad), · ^2942, 1711 ,, ^- 1 60 ³ 1 ⁵⁸⁸ 1 2 ^ ^96Θ, 947 ™ ^{- '5-b) (1} R, ⁵ 3', R ⁷ 6RJ ) - ⁷ - ^(o ^ etre ^yd ro ^p yren- ² - ^yl oo ^yl) -6- ^[(E) n ^{(3 3, 4R3)} - ³ - ^(o etreh ropyraal ^{yd -} yloxy) - ⁴ -meO ^y lnon-1 - ^ - ⁶ -1 ^ 1] - ^{b y y} klo [3 ·, 3, ^{o k k} tan-3-on

A mixture of 3.6 g .alpha.-alcohol prepared as described in Example 5a and 1.4 g. Potassium carbonate in 120 ml. Of methanol was stirred for 16 hours in an argon atmosphere at room temperature. The mixture was then concentrated under reduced pressure, diluted with ether, washed neutral with brine, dried (MgSO 4) and removed under reduced pressure. The evaporation residue is stirred for 16 hours at 75 ml of a mixture of acetic acid, water and ethyl acetate

Oetrahydrofuran (65 + 35 * 10) and evaporated under reduced pressure. After filtering the residue through silica gel, using a mixture of ethyl ether and hexane (7 + 3) yielded 2.2 g of the ketone as an oil.

Solution - 2.2 g of this ketone - 2.4 ml of dihydropyran and 23 mg of p-toluenesulfonic acid in ⁷⁵ ml- toluelзulfonuvé mt L ^{L t} ^ en ^ l ^ J ^ ^l or ^even chloride is stirred ^and toploto at 0 ° C ^{for 30} min, and the ^P .- diluted with ^{et Erem,} for ^sorting e ^p e dil - hydrogenlUličitenu sodium bicarbonate, washed with water until neutral, dried over huřtčlatým and evaporated under reduced pressure. 3.4 g ^b is-dru eotrlh ^{y py y} lettre ren that použžje without additional purification.

^IR: - R 2 9 ^{6 6} 5 2 8 ^{1 7 38} 9 ⁷⁰ cm ''.

^5c) 2 - / (^) - 0, 3S, 6R, ^7R) - ⁷ - ^(t ttre ^l ydro ^pp гanl2-ylluχ) - ^{- 6) [E)} - (ЗS, 4th ^R) - ^- - -et-Зз ^{t l) (etre-) pyridine} hydro yaal - yl ^χ s) ^LON) --nl ^- 6 ^- I ^l l ^l -bicyкlu ^{[з, 3, and} thin-0Ju ^- з ^- lidt] l ^{/ u} ttenn - ^1-ol

К solution of 8.1 GT ^^ ^ y ^ you phosphonoacetate in 170 ml - ^^ Ο Ι ι ^ ^^^^ ^p s is 0 ° C was added ^{and 3} 5 ^{g l} l Oerc.buOytoto drest ^el for the ^mixture was stirred for ¹⁰ minutes and then to it - is added a solution of 9 g of the ketone obtained according to Example 5b, in 90 ml of toluene and then stirred at atmooféře argon for 16 hours at místnoosi. It is then diluted with 1000 ml of ether, shaken with water until neutral, and dried over magnesium sulphate and dried under reduced pressure. The residue was filtered through silica gel with a 3: 2 mixture of hexane and ether. 8.2 g of unsaturated ester are obtained in the form of a colorless oil.

Spδ mm ^ 2 950 ^, 2 870, 1 700 ^{, -} 1 655 ^, 968 cm ''.

While stirring, to a solution of 8 g of the above ester in 280 ml of ether was added portionwise 2.2 g of tetrahydrofuran anhydride, and the mixture was stirred at 0 ° C for 30 minutes. The reagent was destroyed with ethyl acetate, 12 mL of water was added, stirred for 2 hours at 22 ° C, filtered and evaporated under reduced pressure. The residue was chromatographed on silica gel using ether-hexane (3 + 2). 2.8 g of 2 - / (Z) - ((S, 5S, 6R, 7R) -7-thetoehydro-2,2'-propoxy-2-yl-oxo) -> - [(E) - (3-, 4I) are obtained as the less polar compound. (4-Butel-3- (thetoehyddoopyen-2-yloxy) nono-1-ene-6-ynyl-bicyclo [3.0.0.0 &lt; 2,7 &gt; ^octene -1-enu) and 4.2 g of the title compound as an oil.

IS - ^PE ktru ^m: 3 60 () 3 ^4-0, 2 ^942, 2 86) 1 60 () 972 cm @ ^(.

Example 6 (5E) - ((6R) -1a, (b-dihumo16,22-dimethyl-3-ouaal) 18,18, (9, (9-tetradelydro-6a-carbaprostaglandin * 2).

In a similar manner to Example 2, from the 380 mg of aldehyde prepared by the procedure of Example 5, 305 mg of (5E) - ((6)) - 1a, 1b-dihoou-16,20-dimmet-3-ooa-18, 18 were obtained. 19,9,9-Tetredelydro-6α-carbonylpropionine-4- (1,1-diacetate).

After deprotection, 2 (0 mg of the title compound is obtained as a colorless oil).

IR sp ^e ktru ^m: 3600, 3400 (broad), 2962, 2865, 1720, 1 60 (, 970 ^c m ^(.

EXAMPLE 7 (5E) -2-Decarbo: [beta] - (e, ([beta] -Dihoulo2-functional-20-mutyl-3-uxe- [6, (6-trimethylene)] - [9], (9-tetradethydro-6a)] carbaproostaglandin I ^

In a similar manner as in Example 1 (and 5, from 0.9 g of 2- / (E) - ((S, 5S, 6R, 7R) --- (thetoe-proxy-yloxy)) -6-? (E) - (3H) --- (tetyahydropyyan-yloxp) -4,4,14,17,14,12,10- (-en-6-ynyl) -bicyclo [-, -, o] octene-- -ylidene / ethene - (- ulu (prepared according to Examples 5e and 15c from 2-oxo-2-oxo-1-triethylene-mono-5-in-f8080one dimethyl ester)) gave 0.4 g of the title compound as a colorless oil.

I ^S ^ 3 6 3400 (br), ^{2968, 2864, 2,} 7 ^ ^{(725, '602,} 970 сш ^{_ (.}

the compound for the above compound is prepared as follows:

7e ') 2 - / ()) - ((S, 5S, 6R, 7R) -7- (2-tetrahydroppyoa ylloy) -, 4-'triueeyleImoo-1-ee-661iní] ^{-blcyklojj, -, u} ] uktan Yli-3-ene ^d / eten- ^(-ol

In a similar manner to Example 5c, 3 g of ((R, 5S, 6R, 7R) -7- (tetropyridyen-2-yluxy) -6- (E) - (- R) -— (tetyehyduryl) - 2-Yloxy) -4,4-triethylenenone - (- en-6-yl] -bicyclo- (> - &gt; 0)] octanone after the chromeaphonic separation of the isomers as a less polar compound yields 470 mg of 2- (Z) - (1S, 5S _| 6R, 7R) -7- (2-et0eelУf dooryren-yluxy) -4,4-TRJ ^ -methyl] ^ e ^of nnon- (-eh 6-inl | bicyclo [- o-o-o-octenide-ethene - (- ulu and 690 mg v. the title compound as a colorless oil).

I ^S ^ SJ ktri®: ^3600, 3400 (broad) ^2945, the second ⁸⁶² (602, 972 ^{cm (.}

Example 8 (5E) -1a, 1b-Dihomo-20-methyl-3-oxo-16,16-trimethylene-18,18,19,19-tetrddehydro-6a-carbaprosteglsindine Ig

In a similar manner to Example 2, from the 400 mg of the aldehyde prepared in Example 7, 295 mg of (5E) -1 e, 1,1b-dihomO20-, methyl-3-oxa-16,16-trimethylene-18,18 were obtained, 19,19-tetaBdehydro-6e-carbeprostaglandin Ig-1H-diacetate.

After. The deprotection afforded 220 mg of the title compound as a colorless oil.

IC spectrum: 3634.400 (Wide) 2996 () 2864 1721 ^, 1600 ^, 970 cm -1.

EXAMPLE 9 (5E, N-D-Carbonyloxy, 1b-Dihomo-16,16-dimethyl-O-photol-3-oxa-18,18,19,19-tetradehydro-6α-carbaprostaglendine

JEKO manner similar to Example 1 and 5 from 0.5 g of 2 - / ()) - (18,58,6R, 7R) - ⁷ 7 (2-tetrahyddtspУθn ylosy) -6 - (e)) (ЗR ) -4,4-dimeeyl-3- (tetretydrspyytn - oylosylokt-1-ene - 6inll] -biclkls _[з) 3, o] sktθn-3-ylidene / tttn 1-service afforded 0.28 g in said header Compounds in the form of a colorless oil.

IC Spectrum: 3600 ^, 3400. (wide) 2,965 ^, 2,730 ^, 1,724, 1,600 ^, 970 cm -1.

Example. lo (5E) -1a, 1b-dihomo-16,16-dimethyl-3-oya-18,18,19,19-tetrodedehyde-6t-carbapro-thaglandin Ig ''

In the same manner as in Example 2, from 0.27 g of the aldehyde prepared in Example 9, 180 mg of (5E) -le, 1b-dihso-16,16-dimethyl-3-sxa-18,18,19 were obtained. 19-Tetradehydrs-6-carbaprostaglandin Ig-11,15-diacetate. The deprotection afforded 120 mg of the title compound as a colorless oil.

IR sp ^{e ktrum: 3600,} 3400 (br ^ ^{2960, 2865, 1700, 1600,} 971 cm.

He did! (5E) -O-deca, tbO 2 -yl-1α, 1b-dihomoo2-fortyl-3-oya-16,16,20-? 5? 1-18,18,19,1-tetradehydro-6? carbaprostaglandin

In analogy to Examples 1 and 5, from 1.1 g of O - (E) -11S, 5S, 6R, 7R) -7- (tetrahydro-spyran-2-olyl-6 - [(E) - ( (R) 4,4-Dimethyl-3- (tetrahydro-3-yl-o-looyl) -o-1-et-66-naphthalen-bicyclo [3.3.0] oct-3-yl] ethane-1-thiol gives 0 1.6 g of the title compound as a colorless oil;

^Infrared spectrum ^{3 6} ^ ^{3 420 (Širský) 2 9} 64 ^{2 7 30, 1 725, 1 972 cm} OOR '.

Example 12 (5E) -1ε, 1b-dihomo-3-οχε Ι6,1ó 20 ^{ycimet-yl-18,18,19,19-tetr8dehydro-Ø8-Ig} k6rb8prost8glQndin

In analogy to Example 2, from 0.4 g of the aldehyde prepared in Example 11, 0.3 g of (5E) -1α, 1,1b-dihomo-3-oxa-16,16,2-trimethyl-18-ol was obtained. 18,19,19-tetradehydrco-o-carb-pirstaglindin Ig-11 _; Of di-acetate. After cleavage of the protecting groups, 0.22 g of the title compound is obtained as a colorless oil.

IR ^PE kt ^r jr 3 3400 (Si ^{to C ij)} 2 9 «4 ^2864, 1721, 1 60 (0972 cm ^-1.

Example 13 '(5E) - (16RR) -2-Decarboxy-18,19-didehydro-1, 1b-dihomo-16,19-dimethyl-2-f-rayl-3 - X 8-6a-crbapro-taglsindine Ig

Same manner as in Example 1 and 5 from 0.7 g of 2 - / (E) -1S, 5S, 6R, 7R) -77 (tetraЬ ^ уор гусп- ^ ² - ^^ ^^ £ ^ ¹⁾ - (3 ^ 4 ^) - 4) ⁷ 7 ^di mt ^y ^ L-17 (^ trahi thiopyran ^ - ^^ ^ oxy kt- ^ a ^ lj-die-bicycloQ ^^ octane-ylidene / ethane J -ol ^ ka of ^0, 4 ^{g of} the title ^E oučenin ^{l y} as a colorless oil.

IR: 3 60 (0 3 400 (Simko) ^{2966, 2732, 1725,} 1 60Ц 972 cm ^'1.

P-říkled 14 (5E) -1a, _{1b-dihcmo-16,19-dimeeyl-18>} 19-didehydro-3 - Ig xa7Óa7karbapгosttglandin

JEKO manner similar to Example 2, from 0.2 g of the aldehyde, prepared in Example 13, gave 0.14 g of (5E)) (1a, 1b-dihomo-16,19-dimethyl-18,197didehldyo- ^yl (3- -xa-6a-cecbaprostaglendine Ig-11,15-diacetyl After deprotection, 90 mg of the title compound is obtained as a colorless oil.

IR ektrum with ^{p: 3600,} 3410 (Si -k · ^{c ij),} 2960 _y ^{2860, 1720,} 1,601,972 ^cm "k

EXAMPLE 15 (5E) - (16BS) -2-Decerboxy-13,14-didehydro-1,16-dihomoyl-6-methyl-3-xa-18,18,19,197teade γ ydr-76α7carbaprostaglandin Ig

Same manner as in Example 1 and 5 from 0.6 g of 2 - / (E) - (1S, 5S, 6S, 7R) -7- ^(l tetceh ylгa ^the DDC-2-y ^l l> oy) -6 - £ (3 S, 4 ^R S - ^ - ^l πmty -7- ^(s etrah ^LD ropyym- ^{- yl} oxy) ^o tУa1 ^{l l} 66diinylJ7 -bic kl- ^[3, 3, ^about the ^y-З an -3-yl en ^{id /} e ^{t 1} tn 7 ^l uz ^ ka ^{0.29 g} header Uve ^d ene ^{No L} ou en ⁱ n ^g as a colorless oil.

IR ^ 3 6 3410 (SI ^No. OK ^{y), 2966,} 2 ^{^, 2225,} 725- 1 ^{cm '1.}

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

15a) 2 - / (E) -11S, 5S, ⁶ S, 7 ^R) -7- (tert tre ^HLD RP ^y yan-2- ^{yl l -x)} - ⁶ - £ (3 ^S, 4 ^R) -4 -Me ^YY1 - ³ - ^{(^} ^ trahi rop ^y ran-2- (lx ^{y y)} - ^k Уa ^- ^ J ^ -diin ^bi-3] o okttn- ³ - ylidene ^l / tn e ^{t 1} - ^l

JEKO manner similar to Example 5 * 'from 1.8 g of (1R, 5S, 6S, 7R) -77 (eeΓahlldCropyran-2- ^{l l} lx) - ⁶ - £ (3 S, 4 ^R) -4- (mt ^y ll ³ -teУгah ^l <idc ^-y rвn-2- ^y lo: ^{oχ (1-} d ^l ) - ^- ii ^cl lo - 3,3,03235329

of octan-3-one after chromatography by isomer as a less polar compound gives 380 mg of 2 - / (Z) - (1S, 5S, 6S, 7R) -7- (tetrehydropyran-2-yloxy) -6- (3S) 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) octa-1,6-diinyl] -bicyclo [3.3.0] octan-3-ylidene / ethan-1-ol and 610 mg in the title said compounds in the form of oil ·

IR: 3600, 3400 (broad), 2945, 2860, 2225 cm ^- '.

Example 16 (5E) - (16β) -13,14-didehydro-1α, 1β-dihomo-16-methyl-3-oxa-18,18,19,19-tetredehydro-6β-carbaprostaglandin

In a similar manner to that described in Example 2, 0.4 g of the aldehyde prepared by the process were used. from Example 15, obtaining 0.21 g of (5E) - (16RS) -13,14-didehydro-1, 1b-dihomo-16-methyl-3-oxe-18,18,19,19-tetradehydro-6α-carbaprostaglandin I ₂ -11,15-diacetate.

After deprotection, 150 mg of the title compound is obtained as a colorless oil.

IR: 3600, 3410 (Wide), 2960, 2864, 2226, 1718 cm ^{@ -1} .

Example 17 (5E) - (16BS) -2-decarboxy-13 ', 14-didehydro-1?, 1? -Dihydro-1, 6,20-dimethyl-2-formyl-3-oxa- 18,18, -

19,19-tetradehydro-6α-carbaprostaglandin

From 0.8 g of 2 - [(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S, 4RS) - 4-Methyl-3- (tetrahydro-pyran-2-yloxy) -pyrid-1,6-diinyl] -bicyclo [3.3.0] octen-3-ylidene / ethan-1-olefinic 0.42 g in the title compound colorless oil.

IR: 3600, 3400 (broad), 2969, 2732, 2227, 1724 cm @ ^-1 .

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

17a) 2 - [(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy)] Nona-1,6-diinyl] -bicyclo [3.3.0] octan-3-ylidene / ethan-1-ol

In analogy to Example 5c, from 2.1 g of (1R, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6-L (3S, 4RS) -4-methyl-3- ( tetrahydropyren-2-yloxy) nona-1,6-diinyl] -bicyclo [3.3.0] octan-3-one yields 450 mg of 2 - / (Z) - (1S, 5S) as a less polar compound after isomer separation of the isomers 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) nona-1,6-diinyl] -bicyclo [3.1.1.0 &lt; 2,7 &gt; 3, ooctan-3-ylidene / ethan-1-ol and 740 mg of the title compound as a colorless oil.

IR: 3600, 3420 (Wide), 2947, 2862, 2223 cm @ ^-1 .

Example (5E) - (16RS) -13,14-didehydro-1α, 1b-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6α-carbaprostaglandin Ig

In analogy to Example 2, 620 mg of the aldehyde prepared according to Example 17 yielded 340 mg of (5E) - (16RS) -13,14-didehydro-1, 1b-dihonio-16,20-dimethyl-3-oxa-. 18 _l 18.19, L9-tetradehydro-6a-Ig-11,15-diacetate.

After deprotection, 260 mg of the title compound is obtained as a colorless oil.

IR: 3,610, 3,400 (Wide), 2,962, 2,865, 2,225, 1,720 on.

Example 19 (5E) -2-decarboxy-13,14-didehydro-1, 1b-dihomo-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-10,16-trimethylene- δ-carbaprostaglandin Xg

In analogy to Examples 1 and 5, from 0.41 g of 2 - [(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- [3S] - ( tetrahydropyran-2-yloxy) -4,4-trimethylennona-1,1'-diinyl-4'-bicyclo [3.3.0] octan-3-ylidene / ethan-1-ol yields 0.18 g of the title compound as colorless oils.

IR: 3400, 3400 (broad), 2996, 2732, 2227, 1724 cm ^-1 .

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

19a) 2 - [(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- (3S) -3- (tetrahydropyran-2-yloxy) -4,4- trimethylennona-1,6-diinyl] -bicyclo [3.3.0] octan-3-ylidene / ethan-1-ol

In analogy to Example 5c, from 3.1 g of (1R, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- [3S] -3- (tetrahydropyran-2-yloxy) -4 4-trimethyl ^of nona-1,6-diinyl] -bicyclo [3.3.0] octan-3-one after chromatographic separation of the isomers as a less polar compound yields 890 mg of 2 - / (Z) - (1S, 5S, 6S, 7R) ) -7- (tetrahydropyran-2-yloxy) -6- (3RS) -3- (tetrshydropyran-2-yloxy) -4,4-trimethyl ^from n-nona-1,6-diinyl] bicyclo [3. 3,0] octan-3-ylidene / ethan-1-ol and 1.3 g of the title compound as a colorless oil.

IR-spectrum: 3610, 3420 (broad), 2945, 2862, 2226 cm ^-1 .

Example 8 d 20 (5E) -13,14-didehydro-1α, 1b-dihomo-20-methyl-3-oxa-18,18,19,19-tetredehydro-16,16-trimethylene-6a -carbaprostaglandin Ig

In the same manner as in Example 2, from 0.42 g of the aldehyde prepared according to Example 19, 0.32 g of (5E) -13,14-didehydro-1, 1b-dihomo-20-methyl-3-oxa- is obtained. 18,18,19,19-tetradehydro-16,16-trimethylene-6α-carbaprostaglandin Ig-11,15-diacetate.

After deprotection, 210 mg of the title compound is obtained as a colorless oil.

IC spectrum: 3600, 3400 (wide), 2963, 2865, 2225, 1720 cm @ -1.

Example 21 (5E) -2-decarboxy-13,14-didehydro-1, 1b-dihomo-16,16-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradethydro-6α-carbaprostaglandin Ig

From 0.9 g of 2 - / (E) - (1S, 5S, 6S, 7R) -7- (eetrahydropyran-22yloxy) -6-. 4-d: Methyl-3- (ethoxydropyran-22-yoxx) octaal-4-yl-1-bicyclol-3,3,0-octen-3-yliene / ethan-1-ol yields 0.47 g of the title compound as a colorless oil. .

spektrδ spectrum 3 600, 3 410 (broad), 2 966 ^, 2 730, 2 225, 1 725 сш “ ¹ . .

The starting material for the above compound is prepared (if (by:

a) 2 / (E) -1lD, 5S, 6S, 7R) -7- (-t etrahydtopxy ^^ - ^ ox ^^ - j 3S) ^ N-dimethyl-2-1-3PXran xloxx) of ^{the EA-1, 6} - ^and iin ^yl] LC -bic ^{yk - 3,} 0 ^c o ^k · tan ^- - ^{yl and} day / ^{1-ol L} enan-

Analogously to Example 5c ', from 2.5 g of (1R, 5S, 6S, 7R) -7- ^{(eetrahydtopytan-2-yl} ox ^y) - ⁶ -Q 3 ^S) -4-Dime ^ ^ -HttUa oopyran ^ lo ^ oHa- ^{1, 6} - ^{and iinyi]} -bic ^YK LC ^{(- 3,} 0] octan-3-one after separation chtommtografickém Isomet as the less polar compound obtained 625 mg of 2 - / (Z) - ((S , 5S, 6S, 7R) -7- ^(s eetгaayitop YTA ---- Уoxχ ^ - [((JS) -4,4-diie ^y 1 t -3- (tetaahxdropytan-2-yloxy) okea-1 ' 6-ethynyl-bicyclo [-, -, 0] octan- ^3- yl-ean-1-ol and 1.1 g of the title compound as an oil.

Ιδ ektru ^m with ^{p: 3600,} 3400 (Si ^ KY) ^{2946, 2865,} 2225 c ^m_1.

Example 22 (5E) -13 ~ 14 iiiehydro-1, 6.16 ^1-yl iioét --- cxn- (8,18,19,19-tetnθdehyiro-6n-kaybn ^{osta-amino-Ig x}

Analogously to Example 2, from 0.31 g of aldehyde, p-i-ptaveného procedure of Example 21, 0.21 g of (5E) ^-1-3, 14-iiiehyiУO-1N-1b dihcmo- (6 ( 6-iiiityl-oxn-18, (8 ', (9,19-tetadadehyiro-6a-knoboronatagine) Ig- (1', (5-iince).

After cleavage of the protecting groups, 0.14 g of the title compound is obtained as a colorless oil.

IR ektru ^m with ^{p: 3600,} 3410 (Si ^{TCK s) 2964, 2865, 2225,} 1720 cm "*.

EXAMPLE 23 (5E) -2-Decarbonyl- (3,14-didehydroc-1?, 1? -Dimino-phenoxy-1-x8e) [8,18,19,19-ethoxycarbonyl- (6,16) , 20-tyiieeyl668-kθУbaotcseaglaniin Ig »

From 0.8 g of 2 - (()) - ((1S, 5S, 6S, 7 ^) --- te (taaydyo)^ppytn-2-^ylox^y ) -⁶- (((3)) - 4,4-ⁱⁱшθtyl -³-^(eE^tnal ·^yidУO^pytan-2-^ylox^y) nona-^{1, 6}- (1-yl)] -whip^yklcf³,³, 0^OoOten-³l^-Унern'etnn - [- cL.u z ^^ká 0^,3 ^^{1 g} in the uve header^den^E compound.

in the form of a fixed oil.

Ιδ with ^p ektru ^{m 3} 6-3420 (br ^ 2 730¼ 2965 ^2226, 1724 cm ^'1.

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

a) 2 / (E) - (IS, 5S, 6S, 7R) -7- (tert tsahydropyran-2-yloxy) -o - / (3S) -4,4-dimethyl-butyl 3- (tetrahydro ^{p pyran-2-yl ylnx)} nona-1, a-diynyl] ^y -bit clones / 3.3 okitan JO ^ - ^ - ^ iDEN / ^ethane-1-ol '.

Analogously to Example 5t, was prepared from (3 g ((R, 5S, 6S, 7R) -7- (2- ettrehydrophtan ^hl ox ^y) -ύ - ((ЗS) 44 ^- -dimetylзЗ- ^{(tetra y} ydro ^Py tA - 2-yloxy) п-п - 1 ^{(6 -} 11 ^- hj-bityklo [3, ^3, θ] octan-3-one chrumatografickém after separation of isomers as less polar compound gave 300 mg of 2- / ^) - (^, 55,63,7 ^) - 7- (tedatydro rran ^ - ^ - ^yloxy) -6 ^- £ ^(3S) -4 · ^4-azetidinyl dimethyl-3- ^(tetrahydro ^ ro ^ dihydrofuran-2-yloxy ^s) nona-- ^{(^} -di.irtylj-bteykter. ^3,3 ^ j ^ otean -YH-day-ute and 43 ⁰ mg of the title compound as an oil.

IR: dtrur: 3 610, 3 400 (wide) 2 945, 2 365, 2 225 cm @ -1 ⁽ .

Example 24 (5E) -13,14-didehydro-1α, (b-dihomouЗ-oxa- (r, 1r, 19 '), (9-tetrodecylhdr-16), (6,20-trimethyl-6', 18'-capapetidine) Ig

In a similar manner to that described in Example 2, from O, (6 g of the aldehyde prepared by the procedure of Example 23) there was obtained O, (g, E, N, didehydro) -8,1b-dihydro-8,8b, (9,19-). tetrodedehyde-16, (6-20-trimethl-oa-carbaprostagle-di-Ig-1 (, 15-diatetate).

After deprotection, 60 mg of the title compound is obtained as a colorless oil.

IR apekctiw 3 600 ⁶ 3 400 (wide) 2 965 ⁶ 2 Г64 ⁶ 2 224 ⁶ (7 (8 cm 2).

Example 25 (5Σ) - (16R) -2-dek8aboπ ^y H18, ^{(b-dihπmOπ-5-fluoro-2-yl} fπгm h-1 O ^y Mee-H-3-πx8-1r, ιr 19.1 9 tetredeh ^y dro - κ.-carbεpptπS (зgle-din Ig

To a 420 mg ² - / ( ^z) - (1

RME ^-4-yl] .- 3- ^(t etrαh ^h drπ ^pH te.n-2- ^yl πx ^{h) kt} - ^ ^{(-en-ь-: ш} у ^1]} -Ь ^.с у11 п ^{[3 , 3)]} π ^{to thin-3} - ^{yl i} de] - ^'/ - ² ^ -t uoretan- ^(-ote in ^r ^ RUF ml tetrch uranium ^p s' ^t e ^p lo ^t of 0 ° C was added 42 mg of a 55% ^p sus Enzo tydrteu sits ^on UV mineráteím ε oil ^and the mixture was stirred for ^{30 minutes} at a temperature between approximately ²⁴ ° s C ^ e atoooí argon. Then moats Solutions of _630 mg of 2- (3-brompropyX) - (^ dioxolane in 8 ml of tetrahydrofuran and refluxed in an argon atmosphere for 20 hours, then diluted with ether, neutralized, dried (MgSO4) and evaporated under reduced pressure. hexane ^é tere (3+ ²⁾ ZTE ^ 3 ⁴⁰ mg ^No oxaslou ei ^{of GTP Ter} PA ^to stir ^{(6 hours} Odin teptotě ^p s 24 ° C 30 ml kyselily Smee, acetic, science and tetrahydrnfuranu (65 + 35 +10) After evaporation from the reduced pressure and chromatography of the residue on silica gel, using a mixture of ethyl acetate and hexane (4+) yields 280 mg of the title compound as a colorless oil.

IR 3600 ⁶ 3420 (broad) 2960 ⁶ 2930 ⁶ 2870 ⁶ 2730 ^{6 (6} 730 (603 ^{6970 c} m ^{- (.}

EXAMPLE 26 (5Z) - (1R) -1-E, 1,1b-Dihorno-5-fluoro-16-methyl-3-oxa-18,18,1,9-tetradehydro-6e-carbaprostaglandin Ig

In analogy to Example 2, 110 mg of (5Z) - (16R) -1s, 1b-dihomoyl55-fluoro-16-oeyl-3-oxa-18-ol is obtained after 205 mg of the aldehyde prepared according to Example 25. , 19,195terredelydro-6a5carbaprostagland: in Ig-11,15-diacetate.

After deprotection, 78 mg of the title compound is obtained as a colorless oil.

Example 27 (5Z) - (16RS) -2-decarboxi-1α, 1b-dihomo-16,20-diineeyl-5-fluoro-25-formyl-3-oxa-18,18,19,19-Уθθredehidone- 6a-carbapro8Уaglandin Ig

Analogously to Example 25, from 610 mg of 2 - / ((E) -1 l)> 5 R)> 6 ^R ^ i ^ 7R) -7- ^(, ^ et ^ i ^? Ydropyran-2-lo ^ QT) - ⁶ - [(3S, 4RS-4-methyl-I- ³ - ^ šaayydrop ^ n ^ - ^ OX ^ non- ^1-en--iiylJ -HC-pyrazolo [l ^ iOjoktan-l-ylidene ^ - fluoroethane-l-ol CIS З plated ^{to 70} mg RP ^and the head of said ^E of compound ¹ as a colorless oil.

Ιδ ^epektrum: 3610, 3400 (orphans) ^2963, ₁ 2930, ^2868, 2731, ^{1630,, 1602,} 971 cm ^1st

Example 28 (5Z) - (16R) -11a, 1b-dihomo-16,20-dihydro-5-fluoro-3-oxa-18,18,19,19-tetradehidro-6a-carbaprosteglandin Ig

In analogy to Example 2, from 125 mg of the aldehyde prepared in Example 27, 125 mg of (5Z) - (16RS) -1a, 1b-dihomo-16,20-dihydro-5-fluoro-3- oxa-18,18 CZK

19,19-tetradlyl-6,6-carbonyltarazoline-12,2,15-diacetate.

After deprotection, 85 mg of the title compound is obtained as a colorless oil.

Ep ^δ epectrom ^: 3. ^600, 3410 (8i ^r mesh), ^{2965, 2930, 2870, 1720, 1602,} 970 ^c m ^_1.

Example. 29, (5Z) -2-decarboxy-1α, 1b-dihomo-55-fluoro-2-photyl-20-ol-3-ol-18,18,19,19-tetrahydro-dtO5 -16,16-УrimeУlen-б8- ^k arbaptostaglandin Ig

Posyupem manner similar to Example 25 from 390 mg of 2 - / (Z) - (1S, 5S, 6R, 7R) -7- (aetralydropyrθn- ^- -yloo ^χ r) - ⁶ - ^[(E) - ^(ЗR) - 3- ^(L tan ettr8Уydrop-2- ^{l l OX)} -4,4- rimθ ^t y ^l e ^{and Z} Inlon-1-bicyclo ^ 3 ^ 0] okУan-5з ^- 1idβIn' ^{fluotatan-2-l-15O} u ZIS ¹⁶⁵ mg ^ka mod ^N ^ la: £ Uve ^d en ^{Star No.} enyne compound ^Y as a colorless oil.

4δ 4pectram ^: 3 600 ^, 3 410 (Orphans), 2 965, 2 93 ^ 2 2870 ^, 2 730 ^, 1 630 ^, 1. 601,970 cm ¹ .

Example 30 (5Z) -1a, 1b-dihdmOd55fljor-20-meth ^{yl-3-18,18,19,19-dУj} tet.radθh ^{lrrd18,18-y-trioeeylén} 6э-karbaprdstaglaodio

Analogously to Example 2, from 190 · mg of the aldehyde prepared according to Example 29, 105 mg of (5Z) -1a, 1b-dihdmOd55 ^{ljor-mot-20-yl} 3-oУЭ-18,18,19, 19-terradehydride-16,16-trioethylene-6α-carbodiilaodo Ig-11,1 5-discetate.

After deprotection, 70 mg of the title compound is obtained as a colorless oil.

IC ^SPE ktru ^m: 3600, 3400 (broad), ^{2965, 2930,} 2870, 1'718, ^1602, 970 cm ^1st

Example 31 (5Z) -2-decarbooyl-1a, 1b-dihomo-16,16-dleetl15 -fluoro-2-fd: 1-ml-2-ox8a18,18,19,1 9-tetredelhydro-6e-carbappoditglaodin Ig

From 0.6 g of 2 - / (Z) - (1S, 5S, 6R, 7R) -7- (tert -hydrodan- ^1- yl) -6 - [E] - ( 3R) -4, 4--1 ο ^ ^ 1-3- ^(totrah ^ ro ^ healing - ^ - yloy ¹⁾ of ^kt -1 -eo- ⁶ - ⁱ O ^{y O]} - ^b ic ^yk pyrazolo [3, 3,0] oOk8aoЗ- УOdden ^y / 2 · fOjdretao-1-DLJ gave 0.27 g of title compound as a colorless oil.

Ιδ докИнт; 3,610, 3,420 (wide), 2,966 ^, 2,930, 2,868, 2,732 ^, 1,730, 1,660, 971 ^cm -1.

Example 32.

(5Z) -1a, 1b-dihomo-16,16-dioethyl-5-fludr-3-dxe-18,18,19,19-tetradehydride-6a-kerbairos tagland ^ Ig

In the same manner as in Example 2, 120 mg of (5Z) -1a, 1b-dihdmo-16,16-diolyl-5-trans-3-dxa-18,18 are obtained from 220 mg of the aldehyde prepared according to Example 31, 19,19-tetraddicydro-ba-carhappootaglandin II-11,15-discetate.

After deprotection, 92 mg of the title compound is obtained as a colorless oil.

IR 3,600 ^, 3,410 (broad) 2,964, 2,931, 2,870, 1,720 ^, 1,601, 971.

EXAMPLE 1 'and d 33 ^(5Z) -J-de ARBO ^to IL8 ^{and y} 1 Ъ-dihomo-55f ^{f f 2-fluoro-3-ol} dihydro dxe- ¹ 8 ¹ 8 ^19.1 ^ tetoadetydrd -l ^6, 6 ^1, 2 ⁰ -trioetyl 6.alpha.-Ig ^to 8rbairdstagljodio

Analogously to Example 25, from 0.7 g of 2 - / (Z) - (1S, 5S, 6R, 7R) -7- ^(pl terr8dydrd wounds --- ^y lΰx ^yl-б- £ ^(E) - ^{(3R) -4,} 4-d ⁱ OEt ^{yl-3- (R} T1 aah DRD ^{iy y} 8 N-2- ^yl LD yl) oon-18eeo6- ^- ιn ¹⁰ -bic ^yk pyrazolo ^{[3, 3, 0]} dk1eo-3- ^{ylidene /} -2-fjuc) lip Jo-1-d is ^{already about 0.38 g kA} header Uve ^ Ne ^ oin compound ¹ as a colorless oil.

iC e-k-trum: 3 610, 3 400 (wide) 2 965 ^, 2 930, 2 870, 2 730 ^, 1 730, 1 601, 970 cm ^-1 .

Example 34 (5Z) -1c, 1b-dihomo-5-fluoro-3-oxo-18,18,19,19-tetrBdehydro-16,16,20-trimethyl-6e-carbaprosteglandin Ig

Analogously to Example 2, from 0.3 g of the aldehyde prepared according to Example 33, 0.16 g (5 £) _{-1o> 1b-dihomo-5-fluoor3-18,18,19-l} OOA 18- Ethyletro-16,16,20-trimethyl-6E-carbamaprostegine Ig-11,1 5-diacetamide.

After deprotection, 0.12 g of the title compound is obtained as a colorless oil.

IR with ^p ektru ^m 3 6Ю, 3400 (Si ^ KY) ^2965, 2868, ^1720, 1602, 971 cm ^-1.

EXAMPLE 35 (S) - (16H) -2-Decaroxo-o13,14-didehydro-1, 11b-dihomo-fluoro-2-formyl-16-ethyl-3-oxa-18,18, 19, 19-ethoxy-ydro-6a-kerbapгoseanglutin Ig.

Analogously to Example 25, from 0.41 g of 2 - / (Z) - (1S.5S, 6S, 7R) -7- (2- ^{tetreУydoopyran-y} lox ^y) -6- [33S, 41?) - OEt ^{4-yl-3- t} e ^et aeУydro tθn ^{pyridine-2- y} lox ^y) octene-1, 6- ίι ^ ^ 1] ^y -bic bicyclo ^{[3, 3,} 0] ^oktanз-y з lideIV'- 5-floottean-1-ol yields 0.2 g of the title compound as a colorless oil.

IR 3 ° C: 4 600, 3 410 (wide ^- 2 966, 2 731 »2 22 ^ 1 727 ^cm ").

Example 36 (5) - (16 RS) -13,14-didhydro-! a, 1b-Dihomoo-5-fluoro-16-meteo-3-oxa-18,18,19,19-tetradehydro-6e-carbaprostaglandin I ₂

In a similar manner to that described in Example 2, from 0.2 aldehyde prepared by the method of Example 1, the reaction was carried out in a manner similar to Example 2. Example 35 0.1 g of (52) - (16H) -13,14-didθleddto1 _θ, l1bdiheoo 5-ffuor - ^6-yl mot - зooe - 8, 8.1 t _1, 19- tetdade6ydko-6a-ptrbaprostaglendine Ig-11,15-diaceea. .

After deprotection, 70 mg of the title compound is obtained as a colorless oil.

8ρΛ1ϊ4 ° IR: 3620, 3400 (Si ^ cal ^{- 2965,} 2870, 2225, 1620 cm ^1st

EXAMPLE 1 ad 37 (5Z) - (164S) -2-decarboxy ^y -13,14-di-carbaldehyde] ^ (^ - 1 e, 1-b-16,20-dihomo-5-diteetl fluot- ^2-yl form of one-3-ox8-18,18,19,19 tetaθdeeyrdto-6-I ₂ katbaprostaglandin

Analogously to Example 25, 0.7 g and 2 - / (2) -11S, 5S, 6S, 74) -7- (tetaelyfdto rθn ^{pyridine-2- yloxy) -} 6 - ^[(ЗS, 4S) · meeyl -4-3- ^{(t> t} d ^y être rppyгθn-2- ^yloxy) but ^to - ^1, 6-diynyl] bicyclo [3,3, o] -3-okean ylidtn / o2ofluottttno1-olo yield 0 38 g of the title compound as a colorless oil. · Δδ spectrum: ³ 6 ^ ^{34 (} wide), 2 9 ^ 2 ⁷ 30 ^, 2 225 ^, 1 728 cm ¹ .

Example 1 a d 38.

(51) - (1 ° C) -1,14-didehydro-1?, 1? -Dihydro-16,20-? 1-methyl-5-thiophen-3-ol-1 8,18,19,1 9 ' Tetredehyde O-6a-carbaprostaglandin Tg

In analogy to Example 2, from 0.35 g of the aldehyde prepared according to Example 37, 0.18 g of (5Z) - (1 H) -1,3,14-didehidro-1 and β-dihydro-10-ol-SO 2 -dimethyl was obtained. .-5-11-ω-3-εχ8-18,18,19,19-tetradecidoo-6α-kaobaprostaglandin Ig-diecetate.

After deprotection, 0.14 g of the title compound is obtained as a colorless oil.

Sδ ^s pe ' ^k tr ^u ° ^: 3 600 ^, 3 420 (Si ^Ooc ) ^, 2 966 ,. 2,870 ^, 2,226, 1,718 c ^m_1 .

Example 39 (52) -2-dekaoboxy-13,14-di-Deh ^ ^{<^} i ^ r ^ -1s, 1-b dihomoo - fluoro-2-fooom1-20 oeeyl-3-oxa-18.1 8,19,19-teradradidoo-16,16-triethyyne-6a-krrbaprostaglandin Ig

Analogously to Example 25 from 1.2 g of 2 - / (Z) - (1S, 5S, 6S, 7R) -7- (tetгadyIoop ^{y ran-2-yl} ox ^y) - ⁶ - ^{£ (3} S) -3- ^(t e ^t ^ 2 ^ e ^ h ^ ^yd oo ^p ^ 3 ^ i ^ i ^^ ^- ^ - ^^ ^{l 1} OX) ^{-4, 4} tri ^those lermona- ¹ 6 ^ 1 ^ 1 ^ 1) c 1 ⁱ 1o [d ^ n ^ JOJO-3- ^yl ejV ^ ^ ^ -fluooe nl-ol.uz: IS ^{0.7 g ka} header Uve en ^d ^ ^é reunited as a colorless oils.

Ιδ Spectra ™: ^{3620, 3420,} (conditioner conditioning ^{- Y) 2970,} 2731, 2224, 1 .730 "и ^-1.

Example 40 (5Z) -13,14-diIeh1 (Iro-1, b-1 Iihomoo - ^Fluo-20-yl oot --- oxa-1-8,18,19,1 9 tetradehydro-16,16- trioethylene-6θ-kaгbapoosta ^g 1a-l-Ig.

Analogously to Example 2, 0.6 g of the aldehyde prepared according to Example 39 to give 0,31'g (5Z) -13,14-Iidehlddгo1a, 1-b dihornoo - fluoro-20-l- ^y Mee 3-oxa-18,1 8

19,19-teadedidooro-16,16-trioethylene-6α-arbapdosta ^g- l-din Ig-11,15-diecetate.

After deprotection, 0.25 g of the title compound is obtained as a colorless oil.

IR Speke: ^ i ^ ^{m: 3620,} 3425 (Shiro ^{- Y)} 2 ⁹⁶⁸ 2 ^{.870, 2225,} 1720 cm ^1st

EXAMPLE 41 (5Z) ^-2-yl dekaobox -13,14-didehyddo-1a-1b-16166 didomo of unit in ^{y-1-5-fluod-2-oxa-foomo1-3} 18,18,19,1t- tetгsd1dr0ro-ύ - гbгbεprostθgeenein Tg;

Analogously to Example 25, from 1.4 g г - /)) -!) ^^, ^ ⁷ - ⁷ - ^^ !!! ™ ^y p ^ran-2-y lox ^y) -bJ (3S) - 4,4-Iioee ^yl --- (--- wounds teΓradydoop ^{y y} 1ooχ) oO-t-1166 Ile ^{d y} LJ -bicykloΓз _ι - ^Ojo-tan-3-yl liIen / fluooetae -2-1- This yields 0.65 g of the title compound as a colorless oil.

^Ic PEK: tru ^{m: 3600,} 3420 (broad) 2 97o ² 9Ж ^2865, 7 ^ 2 ^2225, 1730 cm ^-1.

Example 42 (5Z) -13,14-didehydro-1e, 1b-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradahydro-6a-carbaprostaglandin Ig

In analogy to Example 2, from 0.4 g of the aldehyde prepared according to Example 41, 0.22 g of (5Z) -13,14-didehidro-1a, 1b-dihomo-16,16-dimethyl-5-fluoro was obtained. -3-oxa-18,18,19,19-tetradehydro-6α-carbaprostaglandin Ig-didacetate.

After deprotection, 0.18 g of the title compound is obtained as a colorless oil.

Δδ δurnurn: 3 600, 3 420 (δit) ^, 2 970, 2 870 ^, 2 224, 1 718 c ^m_1 .

Example 43 (5Z) -2-Decerboxy-13,14-didehldro-1, 1b-dihomo-5-fluoro-2-photyl-3-oxa-18,18,19,19-tetradiol-16,16,20-trimethyl -6a-catbaptostaglandin Ig ·

Analogously to Example 25, from 0.7 g · 2 - / (Z) - (1S, 5S, 6S, 7Ю-7- (tetaθh1dto ^{pyran-2R y} lox ^y) - ⁶ - ^£ (3S) -4- 4- ^d IMET ^y 1-3- ( ^'T-1 etrah drop ^y healing - ^^ ^ ox nona- ^1, O-diisopropyl-l] bi ^y c ^ clones, 3, ⁰ O] oktвn 3- lide ^y n ^/ - ² -FL · uoteten- ^{1-ol l} získiá at ^0, 3 ^g, Vz ^and a head of said compound ^é ^ Kny as a colorless oil.

Ιδ ^ ectrum ·. ^3600, 3420 (Si ^T O ^{'y), 2968, 2932, 2864, 2730, 2225,} 1730 cm ^-'.

EXAMPLE 44 (5Z) -13,14-Didehydto-1?, 1? -Dihomoo-5-fluoro-3-oxa-18,18,19,1? -α-carbaprostaglandin Ig

Analogously to Example 2, from 0.3 g of the aldehyde prepared according to Example 43, ·, yielding 0.14 g of (5Z) -13,14-dihydro dideh ^gamma-lb, lb-5- dihomoo · luort-- oxaa18,118,19,19-tetradehydro-11,16,20,20-trimethyl-11-octaptoataglandin Ig-11,15-diacetate.

After deprotection, 0.1 g of the title compound is obtained as a colorless oil. ³

Ιδ ^ ktru ^ 3 605 ^, 3 · 420 ^ wide), 2 970, 2 870 ^, 2 225 ^, 1 720 cm ^- 1.

Example 45

Meters ter (5E) - (16R) -1,11,11-Dihydro-16'-methyl-3-oxa-18,18,19,19-tetrahydro-6α-catbaprostaglandin Ig

· To a solution of 60 mg of (5E) - (16RS) ^{-18,1b-dihomo-yl} l16met - з-oetl8,18,19,19-tetredeh1dro ^6ε-cat-b apro8ta Landin ^{Ig g} in 10 ml ^ is chloraetanu at 0 ° C, ^eg IKA ^p ^ e éteric · ^the organic solution of diazomethane until a permanent yellow coloration ·. After 5 minutes the mixture was evaporated · under vacuum and ZB ^y Tek chromaaoogrlfujt to ailikagtlu. Use of ethyl acetate / hexane (4 + 1) to give 40 mg of the title compound as a colorless oil.

Ιδ ^ dktrum: ^3600, 3400 ^(t δi ^mesh), 2960, ^1740, 974 cm ^- '.

Example 46 (5E) - (1S, 5S) -1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetrahydro-o-carbaprostaglandin

-carboxamide

105 mg of (5E) - (16RS) -1e, 1b-dihomo-1-methyl-3-oxa-1 8,18,19,19-tetradehydro-88-carbaprostaglandin I was dissolved in 3 ml of tetrahydrofuran and the resulting solution 40 mg of triethylamine and 45 mg of isobutyl chloroformate were added at 0 ° C. After 1 hour, ammonia gas was introduced at 0 ° C for 10 minutes, and the reaction mixture was allowed to stand at 24 ° C for 1 hour. It is then diluted with 30 ml of water, extracted three times with 30 ml of methylene chloride each time, the combined organic extracts are shaken with 20 ml of sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. Chromatography of the residue on silica gel using methylene chloride / isopropanol (9 + 1) afforded 78 mg of the title compound as an oil.

ΐδ spectrum; 3,610, 3,540, 3,400 (wide), 2,960, 1,670, 975 cm \

EXAMPLE 47 (52) - (16KS) -1a, 1b-Dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin 1- (2,3-dihydroxypropyl) ) amide

195 mg of (52) - (16RS) -1a, 1b-dihomo-5-fluoro-1b-methyl-3-oxa-18,18,19,1 9-tetradehydro-6α-carbaprostaglandin Tg dissolve in 5 ml of acetone and 60 mg of triethylamine and 75 mg of isobutyl chloroformate were added at 0 ° C. After 20 min, a solution of 260 mg of 1-amino-2,3-dihydroxypropane in 8 ml of acetone and 8 ml of acetonitrile was added and the mixture was stirred at 20 ° C for 2 hours. It is then evaporated under reduced pressure, diluted with methylene chloride, shaken with a small amount of sodium chloride solution, the organic phase is dried over magnesium sulphate and evaporated under reduced pressure. Chromatography on silica gel using methylene chloride / isopropanol (8 + 2) afforded 160 mg of the title compound as a colorless oil.

IR: 3600, 3400 (broad), 2935, 1645, 974 cm ^{@ -1} .

Example 48 (52) - (16HS) -1α, 1,1b-Dihomo-5-fluoro-1-methyl-3-oxa-18,18,19,1 9-tetradehydro-6α-carbaprostaglandin (4-phenyl-4-phenylacetate) Tg

120 mg of (52) - (16RS) -1α, 1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6α-carbaprostaglandin Tg are dissolved in 3 ml of acetone and 90 mg of n-bromo-4-phenylacetophenone and 1 ml of triethylamine were added to the obtained solution. The mixture was allowed to stand overnight at room temperature. 100 ml of ether are then added, the mixture is shaken twice with 10 ml of water each time, dried over magnesium sulphate and evaporated under reduced pressure. Purification was by preparative thin layer chromatography on silica gel plates elicited with ethyl acetate. 128 ml of the title compound are obtained.

iC spectrum: 3,610, 2940, 1,740, 1,703, 1,660, 974 cm @ -1.

Example 49

(5E) - (16RS) -1a, 1b-Dihomo-16-methyl-3-oxa-1, 8,18,19,19-tetradehydro-6a-carbaprostaglandin tris-rox-hydroxymethyl) aminomethane salt

To a solution of 185 mg of (5E) - (16RS) -1α, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6α-kerbaprostaglandin in 35 mL of acetonitrile is added at 70 ° C solution of 60 mg of tris- (hydroxymethyl) aminomethane in 0.2 ml of water. The mixture was allowed to cool with stirring, after 16 hours the solvent was decanted and the residue was dried under reduced pressure. 160 mg of the title compound are obtained as a waxy mass.

Claims (1)

Process for the preparation of 3-oxa-oa-carbaprostaglandin I ₂ of the formula I wherein (CH ₂₎ η - С R · I ¹ (I) is hydrogen or alkyl radical or a radical OR _2> where H ₂ is hydrogen, (1-4C) alkyl; - CH ₂ - represents represents a radical NHR ^, where 3 or 2, R is hydrogen or a 2,3-dihydroxypropyl group, is hydrogen or fluorine, represents represents -CH ₂ -CH ₂ -, trans -CH * CH- or -C = C-, free or functionally modified CH3 or free or functionally přemě- OH with ^a new Neno hydroxymethyl group, the hydroxyl group may be attached at the alpha or beta position, represents a group -C-CH = - or a straight or branched alkylene group having 1 to 5 carbon чснр> _т atoms, m. means 1, 2 or 3, a direct bond, a -C = C- group, or a -CR 1 = CR y group, wherein each of R 1 and a is Ry, which is different from each other, represents a hydrogen atom or a C 1 -C 5 alkyl group, _{4 4} represents a C 1 -C ₄ alkyl group, represents a free or functionally converted hydroxyl group, and when R 6 represents an atom hydrogen, their salts with physiologically acceptable bases, characterized in that the compound of the general formula II CH ₂ OH cx (II) »in which X, R, V, O, E are as hereinbefore defined, etherify, optionally after protection of the hydroxyl groups present, with a halogen ketel of formula III (III) wherein hal is chlorine, bromine or iodine, each of Rq and is alkyl a group having 1 to 10 carbon atoms or βθ; and R 2 together represent a C 2 -C 10 ring-forming group, as defined above, in the presence of a base and the resulting ketal is cleaved by acid, and optionally the resulting isomers are separated and / or the hydroxyl groups are liberated in any order; and / or the aldehyde group is oxidized and / or the resulting free carboxyl group is esterified and / or the esterified carboxyl group is saponified or the kerboxyl group is converted into an amide group or by reaction with a physiologically acceptable base into a salt.