DD207901A5 - PROCESS FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES - Google Patents

Abstract

1. Carbacyclin derivatives of the general formula I see diagramm : EP0086404,P12,F1 wherein R1 , R2 , R3 and R4 are hydrogen or alkyl of 1-2 C-atoms. R5 is alkyl of 1-2 C-atoms, as well as their salts with pharmaceutically acceptable bases.

Description

The present invention relates to (5E) -13> 14,18 * 18,19,19-hexadehydro-o-aa-prostaglandin-Ig derivatives, their physiologically acceptable salts, processes for their preparation and pharmaceutical compositions containing them

Characteristic of the known technical solutions

In the SiEM) S 2 845 770 Carbacyolinderivate the general formula

COOR,

AWDER ₂

claimed »in the

E>, hydrogen, alkyl, cycloalkyl, aryl or a

heterocyclic Best, A ^[ a -CH ₂ -CH ₂ -J trans -CHsCH or -CSG group,

₂₂

W is a free or functionally modified hydroxy

OH: methylene group or c 3

a free or functionally modified -C group, wherein the OH group < -, D and E together are a direct bond or

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And (b) the submerged or branched saturated or unsaturated alkylene group containing 1 -> 1-o-oxybenzoyl optionally substituted by fluorine atoms

E is an oxygen atom or a -C = C bond or a direct bond,

\. ' :''. ,

Rg is an alkyl, cycloalkyl, or an optionally

substituted aryl or heterocyclic group, ''. ', . · .. '/'':''.','."-.' :,: -. ^ '; .

R ^ is a free or functionally modified hydroxy group, and if R> has the meaning of a hydrogen atom whose salts mean 'with physiologically compatible bases.

The compounds have the properties typical for Prostacycline such. B. Reduction 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 to reduce stroke volume and coronary blood flow, treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, myocardial infarction, peripheral arterial disease, atherosclerosis and thrombosis, shock therapy, bronchoconstriction inhibition, inhibition of gastric acid secretion, gastric and intestinal mucosal cytoprotection, antiallergic properties, reduction of pulmonary vascular resistance and pulmonary blood pressure, promotion of renal blood flow, use instead of heparin or as adjuvant in the hemofiltration dialysis, preservation of blood plasma conserves, especially of platelet preserves, inhibition of labor pains, treatment of pregnancy toxics e. Increase in cerebral blood flow, etc. In addition, the new prostaglandin analogues possess antiproliferative properties.

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-> βν

$ 1 854 11 14.7 · 83

Among the compounds claimed in DK »QS 2,845,770, the (5E) ~ 13 _f 14,18,1β, 19,19-hexadehydro-6a-oarbaprostaglandin I ₂ compounds as antihypertensive agents and platelet aggregation-producing agents showed such outstanding Characteristics that the dosage can be further reduced thereby »which also unwanted side effects are pushed back even more · The (5E) -13 | 14,18,18,19,19-hexadehydoxo-6a-carba-prostaglandin-I ₂ compounds are in D ^ -OS 2 845 770 not described by name. Compounds with A as a -GsC group are not exposed to the other compounds in which A represents an -OH ₂ -GH ₂ or trena-GHaOH group. «

The nomenclature of the compounds is based on a proposal by Morton and Brokaw (J · Org. Chem · 44, 2280 £ ^ 97 ^ 7) * (5E) -6a-0arba-prostaglandin-I ₂ then has the following structure Formally. , - ''. : '; .. "'. ;;- " y _ ':;';; - ^: \. '^ ⁱ ; - ^: ':: '' / '' ν Ä '^ y / ^ ...

OH

OH

2477 2 3 7 - ^ - β-,

14/7/83

Destination of the Erfladung

The aim of the invention is the provision of new Garbooyollnderlyaten with higher Spezlfltät and longer efficacy ^ · /; · ..-; ; ';. . '; _: .....; ..; ''. :. .. '"

Explanation of the essence of the invention

It is an object of the present invention to provide novel carbohydrate derivatives having the desired properties and processes for their preparation.

According to the invention, (5E) -13,14,18,1B, 19,19-fiexade-hydro-6a-carba-prostaglandin-I ₂ derivatives of the general formula I are prepared {'''''-'''''' \ -: 'r ^; . ''-.''.".'-" ^:. : ...'- '.

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-sr -

COOH

wherein

R, R, R, R is a hydrogen atom or an alkyl, .1.2 3 ^

group with 1-5 C atoms,

R_ is an alkyl group having 1 to 5 C atoms,

and their salts with physiologically acceptable. Bases. "/ '·' ..- / · / ' ^: ·. · ....;,.'.,. -. '

Suitable alkyl groups R ', R_, R-, R *, R ₁ * are straight-chain and branched-chain alkyl radicals having 1-5 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl. Preferred radicals are methyl, ethyl, propyl and isopropyl, in particular methyl and ethyl.

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

' ⁷ , for ^V 1 * 7.83

Pharmacologisca particularly valuable are, for example, the following inventively prepared compounds «

dro "6a-oäfba-prostaglandln-X2;

dehydro-6a-oarba-prostaglandtn - l2i,

C5E) - (16RS) -2O-ethyl-.13 ₁ 14 ^ idebydro-16-methyl-18 _i 18 _f 19,19-tetradehydro-6a ~ carba-prostaglandi ~ l2i (5B) -13 »14-dibdebydro -16 _f-16 dtmethyl-18,18,19t19-tötradehydro-6a ~ oarba-prostaglandin l2 * 1

(5E) -13 9 14-Didebydro-18,18,19 »19-tetradehydro-16,16t20-trlmethyl-δ-qarha-prostaglandin-i-Igi

(5E) -13.14-Didehydro - 18 '. _t 18,19,19-tetradehydro-6a-earbaprofltagagtn-Igi

(5E) - (16RS) -13,1M) tdebydro-16 Metayl _i8,18-f 19,19-tetradehydro-6a ~ oarba-prostaslandln-I _2-tris (hydroxymethyl) -aminome-

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The invention further relates to a process for the preparation of Prostacyclinderivate invention of the general formula I, characterized in that a compound of general formula II.

(II)

H = CBr-CH C-C C = C-R_

= 5

ÖTHP ^0THP

wherein R, R, R, R, R_ have the meanings given above and THP is the tetrahydropyranyl radical with a Wittig reagent of the formula III

Ph P = CH- (CH ₂ ) -C ^ <=>. (III)

wherein Ph represents a phenyl group, and then reacts isomers separated, cleaves off protective groups and optionally the carboxyl group with a physiologically acceptable base in a salt.

The reaction of the compound of the general formula II with the Wittig reagent of the formula III, which is prepared from the corresponding Phosphoniutnsalz with Methansulfinylmethylnatrium or Methansulfinylmethylkalium or potassium tert-butoxide in dimethyl sulfoxide or dimethyl sulfoxide-tetrahydrofuran mixtures, at temperatures from 0 ° C to 100 C, preferably 20 ° C to 60 C, in an aprotic solvent or

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Solvent mixture, preferably dimethyl sulfoxide, dimethylformamide or tetrahydrofuran made. The separation of the Z- and E-configured olefins thus obtained is carried out in the usual way, for example by column or layer chromatography. In the Wittig olefination described above, the formation of the 13,1 ^ -acetylene bond takes place simultaneously with elimination of hydrogen bromide.

The deprotection is carried out in an aqueous solution of an organic acid, such as, for example, acetic acid, propionic acid, and the like. or in an aqueous solution of an inorganic acid such as hydrochloric acid. To improve the solubility, a water-miscible inert organic solvent is conveniently 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 carried out at temperatures between 20 C and 30 C.

The carboxylic acids of general formula I can be converted into salts with suitable amounts of the corresponding inorganic bases with neutralization. For example, when the corresponding acids are dissolved in water containing the stoichiometric amount of 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. To prepare an amine salt, the PG acid is dissolved in a suitable solvent, for example 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.

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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 IV (German Offenlegungsschrift No. 2,845,770).

(IV)

OCO

with a phosphonate of the general formula V

OOR ₁ F

v Il Il \ / -

> P-CH "-C" C "

CsC-R.

(V)

wherein R ₁ , Rp, R_, R · and R ₁ . have the meanings given above, in the presence of a deprotonating agent such as sodium hydride or potassium tert-butoxide and a brominating agent such as N-bromosuccinimide, to give a ketone of the general formula VI.

OCO

CH = CBr-C - C C C

(VI)

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4c

After reduction of the keto group with sodium borohydride and optionally epimer separation, saponification of the ester group, for example with potassium carbonate in methanol and ketal cleavage / with aqueous acetic acid and optionally epimer separation, the ketone of general formula VII is obtained

(VII)

CH = CBr-CH-C --- C--

OH OH

The etherification of the hydroxyl groups with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid provides the compounds of general formula II.

The preparation of the phosphonates of the general formula Y is carried out in a manner known per se by reacting an alkyl halide (preparable from the corresponding alcohol by halogenation) of the general formula VIII-

Hal-C-C = C-R (VIII)

with the dianion produced from the phosphonate of general formula IX, "

^X P - CH - C - ^ C - H (IX)

/ 2 CH 0 /

247723 7 -S-

wherein R., R ", R-, R and R have the meanings given above.

Another access to the phosphonates of the general formula V consists in the reaction of the anion of methyl ·; Phosphonsauredimethylester with an ester of the general formula X.

Ο R R R R.

I ^ x / ² \ ³ / ^k

C C CSC-R- (X)

  5 ·. ·

wherein R, R ₀ , R-, R ^ and R- have the meanings given above and Rg is an alkyl group having 1-5 C-atoms, which is obtained from the corresponding malonic acid ester by alkylation with the halide of the general formula VIII and subsequent Decarbalkoxylierung can receive. The ester of the general formula X is also from the carboxylic acid of the general formula XI

0 R ₁ R ₀

Il N ^ / ² HO-C CH (XI)

wherein R and R _{2 have} the meanings given above accessible by alkylation with the halide of the general formula VIII and subsequent esterification.

The compounds of this invention have hypotensive and bronchodilatory effects. They are also suitable for inhibiting platelet aggregation. Consequently, the new prostacyclin derivatives of the formula I are valuable pharmaceutical active ingredients. In addition, they have a similar spectrum of activity, compared with corresponding prostaglandins, a higher specificity and especially a much longer efficacy. in the

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Compared to PGI "they are characterized by greater stability * The high tissue specificity of the new prostaglandins is evident in the examination of smooth muscle organs, such. B, guinea pigile or isolated rabbit trachea, where significantly less stimulation is observed than with V application of natural E, A or F type prostaglandins. '''"'.''' ... V

The new carbacyclin derivatives have the properties typical for Prostacycline, such. B. Reduction of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and resolution of platelet thrombi, myocardial cytoprotection and thus lowering the systemic blood pressure without simultaneously reducing stroke volume and coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, myocardial infarction, peripheral arterial disease, arteriosclerosis and thrombosis, prophylaxis and therapy of ischemic attacks, the CNS system, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion, cytoprotection of gastric and intestinal mucosa, cytoprotection in the liver and pancreas; antiallergic properties, reduction of pulmonary vascular resistance and pulmonary blood pressure, promotion of renal circulation, use instead of heparin or adjuvant in the hemofiltration dialysis, preservation of blood plasma preserves, especially of platelet preserves, inhibition of labor pains, treatment of pregnancy toxcosis, increase of cerebral blood flow etc. In addition, the new carbacyclin derivatives have antiproliferative properties. The carbocyclines of this invention may also be used in combination, e.g. B. with ß-Blockerh or diuretics used. .

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

When injected intravenously in awake, hypertonic rats in doses of 5 »20 and 100 / Ug / kg body weight of the compounds of the invention exhibit a stronger hypotensive and longer lasting effect than PGrE ₂ and PGA _2, without ₂ diarrhea or PGA trigger as PGE ₂ cardiac arrhythmias ,

When administered intravenously to anesthetized rabbits, the compounds of the invention show in comparison to PGE ₂ and PGA ₂ a stronger and significantly longer-lasting blood pressure reduction, without affecting other smooth muscle organs or organ functions.

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

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

The active compounds according to the invention are intended to be used in conjunction with the auxiliaries known and customary in galenics, for. B. serve to produce Blutdruoksenkern.

Implementation objective

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

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Example 1 '

(5E) - (16RS) -13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I ₂

To a solution of 9.4 g of 4-carboxybutyltriphenylphosphonium bromide in 20 ml of dimethyl sulfoxide and 7, δ ml of tetrahydrofuran is added at 5 C within 45 minutes 4.75 g of potassium tert-butoxide and stirred for 45 minutes at 5 ° C after. To the red solution of Ylen is added a solution of 1.83 g (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / 13S, 4RS) -2-bromo-4-methyl-3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl-7-bicyclo / 3 · 3 »07octan-3-one in 3 ml of tetrahydrofuran and stirred for k hours at kO C. The reaction mixture is poured onto ice water, with 35 % citric acid solution acidified to pH 4-5 and dreima'l extracted with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel. Hexane / ethyl acetate (3 + 2) initially gives 18.0 mg of the 5Z-configured olefin and, as the more polar component, 680 mg (5E) - (16RS) -13,14-didehydro-16-methyl -18,18,19,19-tetradehydro-oa-carba-prostaglandin-Ig-i1 j 15-t> is- (tetrahydropyranyl ether) as colorless 01. IR (CH 2 Cl 2): 3500 (wide), 2940, 2860, 2225, 1710, i44O / cm.

For deprotection, 680 mg of the olefination product obtained above are stirred with 25 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) for 20 hours at 25 ° C. Subsequently, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel. With ethyl acetate / acetic acid (99.9 + 0.1) gives 345 mg of the title compound as a colorless oil. 'IR: 3600, 3400 (wide), 2930, 2225, 1710, 16Ο3, 1020 / cm.

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

a) (iR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- / ^i- iRS) -2-bromo-1-methyl-3-oxo-oct-1-ene-6 inyl-7-bicyclo / 3 »3« 07 octane

To a suspension of 1.81 g of sodium hydride in 1 80 ml of dimethoxyethane is added dropwise at 0 C, a solution of 10.5 g of 3-methyl-2-oxo-hept-5-yn-phosphonsäuredime ⁱ methyl ester in 70 ml Dimethoxyäthan, stirred Hour at 0 C and then added 7, ^ g finely powdered N-bromosuccinimide. The mixture is stirred for 30 minutes at 0 C, treated with a solution of 11.4 g (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3 · 3 07-octane in 90 ml of dimethoxyethane and stirred for 2 hours at 0 C. The reaction mixture is poured into saturated ammonium chloride solution and extracted with ether The organic extract is washed neutral with water, dried on magnesium sulfate and concentrated by evaporation in vacuo After chromatography of the residue on silica gel With hexane / ether (3 + 2), 8.2 g of the unsaturated ketone are obtained as a colorless oil.

IR: 2930, 2880, 1712, 1688, 16O2, 1595, 1 ^ 50, 1275, 945 / cm.

b) (iR, 5S, 6R, 7R) -7-hydroxy-6- / r3S, 4tRS) -2-bromo-3-hydroxy

^ · 3.07octan-3-one

To a solution of 5.9 g of the ketone prepared according to Example 1 a) in 1 ^ 0 ml of methanol are added at - portionwise 2.5 g of sodium borohydride ^ O ⁰ G and stirred for 30 minutes at -Ί0 C. Then it is diluted with ether , washed neutral with water, dried over magnesium sulfate and evaporated in vacuo.

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The crude product (15-Epimerengemisch) is dissolved in 200 ml. Methanol, added, 2.5 g of potassium carbonate and stirred for 17 hours at 23 C under argon. Then concentrated in vacuo, diluted with ether and washed with brine neutral. It is dried over magnesium sulfate and evaporated in vacuo.

The evaporation residue is stirred for 16 hours at room temperature with 300 ml of a mixture of acetic acid / water / tetrahydrqfuran (65/35/10) and then evaporated in vacuo. Column chromatography on silica gel with ether / methylene chloride initially gives 1.6 g of the 15β-configured alcohol and, as the more polar component, 2.1 g of the title compound (pG nomenclature 15a-hydroxy) as colorless oils. IR: 3600, 3 ^ 30 (broad), 296O, 2920, 2870, 1738, 1 6OO, 1 OO / cm. ,

c) (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / T3S, ^ RS) 2-bromo - '' i-methyl-3- (tetrahydropyran-2-yloxy) - oct-1-ene-6-ynyl-7-bicyclo / 3x3 -7octan-3-one

A solution of 1.6 g of the α-alcohol prepared according to Example 1 b), 16 mg of p-Toluolsulforisäure and 1.5 g of dihydropyran in 50 ml of methylene chloride is stirred for 35 minutes at 0 C. Then diluted with ether, shaking with dilute Sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel gives, with hexane / ether (7 + 3) 2.17 g of the title compound as a colorless oil

 -IR: .2940, 287O, 1735, 1450, 1120, IO18, 965 / cm.

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Example 2

(5E) - (16RS) -1 3.1 * t ~ didehydro-16, 20-dimethyl-1 8,1 8,19,19-tetradehydro-oa-carba-prostaglandin-I,

In analogy to Example 1, 1.6 g of (iR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / r3S, ^i- lRS) -2-bromo-4-methyl-3 are obtained - (tetrahydropyran-2-yloxy) -non-1-en-6-ynyl-7-bicyclo / 3.3.07octan-3-one 6 ^ 0 mg (5E) - (16RS) -13,1 * i-didehydro-i6, 20-dimethyl-i8, i8,19,19-tetradehydro-6acarba-prostaglandin ~ I _o -11,15-bis (tetrahydropyranyl ether)

in the" ,

as a colorless oil. ^J

IR: 3500 (wide), 29 ^ 2, 2860, 222Ί, 1710 / cm.

After cleavage of the protective groups according to Example 1, 0.3 g of the title compound are obtained as a colorless oil. IR: 3600, 3350 (wide), 2932, 222 * 1, 1710, i6O2 / cm.

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

a) (iR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- / t / tRS, 2-bromo-1-methyl-3-oxo-non-1-en-o-inylZ -bicyclo / ^. 3 · θ7 octane

In analogy to Example la), 3.7 g of N-bromosuccinimide and 5.6 g (1R, 5S, 6R, 7R) are obtained from 6 g of dimethyl 3-methyl-2-oxo-oct-5-ynylphosphonate. 3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3 · 3.07octane Ί, Ο g of the unsaturated ketone as a colorless oil.

IR: 2935, 2883, 1713, 1687, 16O2, 1596, 1275, 9 ** 7 / cm "

b) (1R, 5S, 6R, 7R) -7-hydroxy-6- / 3S, ^ RS) -2-bromo-3-hydroxy k -methyl-non-1-en-6-ynyl-7-bicyclo / 3 · 3 · θ7octan-3-one

In analogy to Example 1b) obtained from 3 g of the ketone prepared according to Example 2 a) after reduction with 1.3 g of sodium borohydride, saponification with 1.2 g of potassium carbonate and subsequent Ketal cleavage with I5O ml of a mixture of acetic acid / water / tetrahydrofuran 1.2 g of the title compound (15 <x-hydroxy) as a colorless oil, IR: 361Ο, 3 * i00 (broad), 296O ₁ 2870, 1739, i600 / cm.

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c) (iR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / r3S _t ^ RS) -2-bromo-4-ethyl-3- (tetrahydropyran-2-yloxy) -none 1-en-6-ynyl-7-bicyclo / 3x3 "octoctan-3-one"

In analogy to Example 1 c), from 0.78 g of the diol prepared according to Example 2b) and 0.7 g of dihydropyran 1.1 g of the title compound as a colorless oil. IR: 2940, 2872, 1736, 1450, 1120, 965 / cm.

Example 3

(5E) - (1 6RS) -20-ethyl-1 3, 14-didehydro-16-methyl-18,1,8,1,19,19-tetradehydro-6a-carba-prostaglandin-Ip

In analogy to Example 1, from 2 g (1R, 5S, 6R, 7R) of 7- (tetrahydropyran-2-yloxy) -6- / Γ3S, 4RS) -2-bromo-4-methyl-3- (tetrahydropyran- 2ryloxy) -dec-1-en-6-ynyl-7-bicyclo / 3x3x7-octan-3-one 900 mg (5E) - (16RS) -20-ethyl-13,14-didehydro-16-methyl- 18,18,19 "19-tetradehydro-6a-carba-prostagl_andin-I ₂ -11,15-bis (tetrahydropyranyl ether) as a colorless oil. IR: 3500 (wide), 2948, 2862, 2220, 1708 / cm.

After removal of the protective groups according to Example 1, 420 mg of the title compound are obtained as a colorless oil. IR :. 3.6.00, 336Ο (wide), 2930, 2858, 2220, 17Ο8, i60i / cm.

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

a) (iR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- / t4RS) -2-bromo-4-methyl-3-oxo-dec-1-en-6-ynyl-7-bicyclo / 3 · 3 · θ7 octane,

In analogy to Example 1 a) is obtained from 6.25 g of 3-methyl-2-oxo-non-5-ynyl-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.6 g (1R, 5S, 6R , 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3.3.07octane 4.5 g of the unsaturated ketone as a colorless oil. IR: 2940, 288Ο, 1712, 1688, 1601, 1592, 1275 »948 / cm.

247723 7 '. £.

b) (iR, 5S, 6R, 7R) -7-hydroxy-6- / 3S, ^i- lRS) -2-bromo-3-hydroxy 4-methyl-dec-1-en-6-ynylbicyclo; ?. 3 "9.7octan-3-one

In analogy to Example 1 b) is obtained from k g of the prepared according to Example 3 a) ketone after reduction with Natriuraborhydrid, saponification with potassium carbonate and subsequent Ketalspaltung with acetic acid / water / tetrahydrofuran (65/35/10) 1.5 g of the title compound (15o r-hydroxy) as a colorless oil

 IR: 361Ο, 3400 (wide), 2955, 2868, 1738, 1601 / ctn.

c) (iR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy-6 / r3S, 4RS) -2-bromo-4-methyl-3- (tetrahydropyran-2-yloxy) -dec-1 -en-6-inyl7-bicyclo / 3 x 3 "07octan-3-one

In analogy to Example 1 c) obtained from 1.2 g of the diol prepared according to Example 3 b) 1.8 g of the title compound as a colorless oil. IR: 29 ^ 2, 2868, 1738, 1 ^ 50, 1125, 960 / cm.

d) 3-methyl-2-oxo-non-5-ynyl-phosphonic acid dimethyl ester

To a solution of 15 8 g of sodium in 340 ml of ethyl alcohol is added dropwise at 20 C 120 g Methylmalonsäurediäthylester. After 30 minutes, added dropwise 135 g of 1-bromo-2-hexyne (prepared from hex-2-in-1 oil with phosphorus tribrotnide in pyridine) and heated under reflux for 16 hours. Then filtered, the residue is washed with methylene chloride and concentrated in vacuo. The residue is dissolved in 500 ml of methylene chloride, shaken twice with 50 ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue is distilled in vacuo at 1 k Torr and 148 - 152 ° C. The distillates of the alkylated methylmalonic acid ester are refluxed for 4.5 hours in 1200 ml of dimethyl sulphoxide and 12 ml of water with 52 g of lithium chloride. It is then poured into 5 1 of ice water, extracted with ether, the extract is extracted with water, dried over magnesium sulfate and concentrated in vacuo.

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The distillation of the residue provides at 94-96 C and 14 Torr 95 g of 2-methyl-oct-4-cyanate as a colorless liquid.

640 ml of a 1.5 M butyllithium solution in hexane are added dropwise at -70 ° C. to a solution of 176 g of dimethyl methanephosphonate in 2 l of tetrahydrofuran. After 15 minutes, slowly add a solution of 90 g of ethyl 2-methyl-oct-4-amino acid in 300 ml of tetrahydrofuran. The mixture is stirred for 4 hours at -70 C, neutralized with acetic acid and evaporated in vacuo. The residue is combined with 200 ml of water, extracted three times with 500 ml of methylene chloride each time, the extract is extracted by shaking with 100 ml of water, dried over magnesium sulphate and concentrated in vacuo. Distillation of the residue at 0.35 Torr and yields 126 to 128 ⁰ C. 80 g of the title compound as a colorless liquid.

Example 4

(5E) -13,14-didehydro-16,16-dimethyl-18,18,19,19-tetradehydro-öa-carba-prostaglandin-I "

In analogy to Example 1 is obtained from 1.5 g (1R, 5S, 6R, 7- (tetrahydropyran-2-yloxy) -6- / r3S) -2-bromo-4,4-dimethyl-3 (tetrahydropyran-2 -yloxy) -oct-1-en-6-ynylZ-bicyclo / ·3 3θ7octan-3-one 610 trig (5E) -13,14-didehydro-16,16-dimethyl-1,8,18,19, 19-tetradehydro-6a-carba-prostaglandin-I _o -11,15-bis- (tetrahydropyran-2-yl-ether) as a colorless oil. IR: 35OÖ (wide), 2944, 2862, 2222, 17O3 / cm.

After removal of the protective groups according to Example 1, 290 mg of the title compound are obtained as a colorless oil. IR: 36ΟΟ, 34ΟΟ (wide), 293o, 2862, 1708, i600 / cm.

477 2 3 7

a) (1R, 5S, β ", 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- (2-bromo ^z l,% -dimethyl-3-oxo-oct-1-en-6-ynyl) -bicyclo / 3.3.07- oc tan

In analogy to Example 1 a) is obtained from 6.25 g of 3, 3 "-Dimeth.yi-2-oxo-hept -5-in-phosphonic acid dimethyl ester, 3.7 g of N-Brotnsuccinimid and 5.6 g (1R ₁ SS ₁ OR ₄ R -3,3-ethylenedioxy-7-benzoyloxy-6-fluoryl-bicyclo / 3x3x7-octane 4.7 g of the unsaturated ketone as a colorless oil IR: 2940, 2878, 1710, 1688 16Ο2, 1594, 1448, 127Ο, 944 / cm.

b) (iR, 5S, 6R, 7R) -7-hydroxy-6- / r3S) -2-bromo-'t, 4-dimethyl-3- <hydroxy-oct-1-en-6-ynyl-7-bicyclo / 3 x 3 "07octan-3-one

In analogy to Example 1 b) is obtained from 4 g of the ketone prepared according to Example 4 a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent Ketalspaltung 1.40 g of the title compound (15a-hydroxy) as a colorless 01

 IR: 36ΟΟ, 3410 (wide), 2958, 2865, 1738, i600 / cm.

c.) (1R, 5S, 6R, 7H) -7- (tetrahydropyran-2-yloxy) -6- / i "3S) -2-bromo-4,4-dimethyl-3- (tetrahydropyran-2-yloxy) oct-1-en-6-inyl7-bicyclo / 3.3.07octan-3-one

In analogy to Example 1c), 1.2 g of the diol prepared according to Example 4 b) with dihydropyran give 1.6 g of the title compound as 01. IR: 2942, 287Ο, 1738, 145Ο, 1132, 960 / cm.

Example 5

(5E) -13,14-didehydro-18,18,19,19-tetradehydro-i6,16,20-trimethyl-6a-carba-prostaglandin-I _o

Analogously to Example 1, from 1 g (1R, 5S, 6R, 7R) of 7- (tetrahydropyran-2-yloxy) -6- / Γ3S) -2-bromo-4,4-dimethy1-3- (tetrahydropyran- 2-yloxy) -non-1-en-6-ynyl-7-bicyclo / 3x3x7-octan-3-one 400 mg (5E) -13,14-didehydro-18,18,19,19-tetra

7 7 23 7

- zer -

dehydro- 1 6, 1 6, 2 O -trimethyl-6a-carba-prostaglandic-12 -11,15-bis- (tetrahydropyranyl ether) as a colorless oil * IR :. 351-0. (wide), 2940, 2858, 2220, 1708 / cm.

After cleavage of the protective group *! According to Example 1, 41O mg of the title compound are obtained as a colorless oil. IR: 36 °, 33 ° 0 (broad), 29 ° 0, 2832, 2220, 17O8, 1600 ° / cm.

The starting material for the above title compound becomes; made as follows:

a) (iR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- (2-bromo-4, V-dimethyl-3-oxo-non-1 -ene-6-ynyl) bicyclo / 3 system. 3 · θ7octane

Analogously to Example 1 a), 12.6 g of 3,3-dimethyl-2-oxo-oct-5-ynylphosphonic acid dimethyl ester give 7.4 g of N-bromosuccinimide and 11.2 g (1R, 5S , 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3 x 3 x θ7- _; octane 8.7 g of the unsaturated ketone as a colorless oil. IR: 29 ^ 6, 288O, 1712, 1687, 1601, 1594, 1272,

b) (iR, 5S, 6R, 7R) -7-hydroxy-6- / C3S) -2-bromo-A, 4-dimethyl-3-hydroxy-non-1-en-6-ynyl-7-bicyclo / 3 · 3 "07octan-3-one

In analogy to Example 1 b), from 5 g of the ketone prepared according to Example 5a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent Ketalspaltung 1.80 g of the title compound (15a-hydroxy) as a colorless oil

 IR: 36ΟΟ, 3404 (mushy), 2958, 2864, 1738, 1601 / cm.

c) (iR, 5S, 6R, 7R) ~7- (tetrahydropyran-2-yloxy) -6- / r3S) -2-bromo-4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -non- 1 enr-6-ynyl-7-bicyclo / 3x3 -7octan-3-one

In analogy to Example 1 c) obtained from 1.5 g of the diol prepared according to Example 5 b), 2.20 g of the title compound as a colorless oil. IR: 2942, 2878, 1738, 1125, 963 / cm.

24 77 23 7

Example 6

(5E) -13,14-didehydro-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I ₂ \

In analogy to Example 1, 400 mg (IR, 5S, 6P, 7R) -7- (tetrahydropyran-2-yloxy) -6- / Γ3S) -2-bromo-3- (tetrahydropyran-2-yloxy) - oct-1-en-6-ynyl-7-bicyclo / 3.3 "-7octan-3-one 130mg (5E) -13 / 1 4-didehydro-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I ₂ -11,15-bis (tetrahydropyranyl ether) as a colorless oil. IR: 3500 (wide), 2948, 2862, 2226, 1708 / cm.

After cleavage of the protecting groups according to Example 1, 62 mg of the title compound are obtained as colorless IR: 361Ο, 335Ο (broad), 2930, 2862, 2226, 17Ο9, 1600 / cm.

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

a) (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6r- (2-bromo-3-oxo-oct-1-en-6-ynyl) bicyclo / 3x3 07octan

In analogy to Example la) is obtained from 5 »8 g of 2-oxo-hept-5-ynyl-phosphonic acid dimethyl ester 3» 7 g of N-bromosuccinimide and 5.6 g (1R, 5S, 6R, 7R) - _; 3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo- / 3 "3" -07octane 4.7 g of the unsaturated ketone as a colorless oil.

IR: 2932, 2380, 1712, 1688, 16ΟΟ, 1592, 1272, 948 / cm.

b) (1R, 5S ₁ 6R, 7R) -7-hydroxy-6- / 3S) -2-bromo-3-hydroxy-oct-1-en-6-ynyl-7-bicyclo / 3.3.07octan-3-one

In analogy to Example 1 b), from 4 g of the ketone prepared according to Example 6 a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent Ketalspaltung 1.35 g of the title compound as a colorless oil

 IR: 36ΟΟ, 3410 (wide), 2962, 2866, 1740, i60i / cm.

l ^L !

c) (IR, 5S, 6R, -R) -7- (tetrahydropyran-2-yloxy) -6- / Γ3S) -2-bromo-3 ~ (tetrahydropyran-2-yloxy) -oct-1-ene o-inyl-bicyclo / 3 «07,7-octan-3-one

In analogy to Example 1 c) obtained from 1.20 g of the diol prepared according to Example 6 b) with dihydropyran 1.6l g of the title compound as a colorless

IR: 29 ^ -5, 2882, 1739, 1125, 968 / cm.

Example 7

(5E) - (16RS) -13, i ^ -Didehydro-io-methyl-he, 18,19,19-tetradehydro-öa-carba-prostaglandin-1p-tris-hydroxyethyl) -aminomethane salt

To a solution of 358 mg of (5E) - (1 ons) -13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-ρrostaglandin-I ₂ in 60 ml of acetonitrile is added 65 C a solution of 121 mg of tris (hydroxymethyl) aminomethane in 0, 1 ml of water. While stirring, allowed to cool, after 16 hours, decanted from the solvent and the residue is dried at 25 C and 0.1 Torr. 310 mg of the title compound are obtained as a waxy mass.

Claims (3)

77 2 3 7 - ²⁵ ~ - ⁶¹ - * & v 14/7/83 Erfindungaanspruoh 1. A process for the preparation of carboylamine derivatives of 00OH 030-Rc vjorln R _-1 , R ₂ , Ε-, R ^ is a hydrogen atom or an alkyl group with 1 to 5 O atoms, Rc is an alkyl group having 1 to 5 C atoms be suggest and their salts with physiologically compatible bases, 7 "* 2 3> 7 14/7/83 characterized in that a compound of general formula II (II) CH = OBI OH OIHP OTHP -worin B ^ ₉ Ep, So »K4.» 'Bc have the meanings given above and THP represents the tetrahydropyranyl radical with a Ittig-Herggens of the formula III '''-" ^i-: -' -ν ⁰ '