DE3909329A1 - 20-ALKYL-13,14,18,18,19,19-HEXADEHYDRO-3-OXA-ISOCARBACYCLIN DERIVATIVES AND THEIR PHARMACEUTICAL USE - Google Patents

Abstract

The invention concerns 20-alkyl-3-oxa-isocarbacyclines of formula(I), in which p = 1 to 3, R<1> is a hydrogen atom or an alkyl group with 1 to 5 C atoms, R<2> is an alkyl group with 2 to 5 C atoms, their salts with physiologically acceptable bases and their cyclodextrine derivatives.

Description

The present invention relates to 13,14,18,18,19,19-hexadehydro-3-oxa-isocarb acycline derivatives, their physiologically acceptable salts and cyclodextrin thrate, processes for their preparation and their pharmaceutical use.

European patent EP 1 36 779 describes isocarbacyclin derivatives of general formula

wherein
R¹ is a group of the formula -A (CH₂) _m -R⁵ (wherein A represents an -O-CH₂ group, R⁵ represents a carboxy group and m is 0 or an integer from 1 to 4);
R² and R³ are the same or different and each represents a hydrogen atom or a hydroxy protecting group;
R⁴ represents a C _3-12 alkynyl group;
B represents the C≡C group;
n is an integer from 1 to 6; and
the dashed line represents a double bond between the 2 and 3 positions or between the 3 and 4 positions and a simple bond between the others of that position;
and their pharmaceutically acceptable salts, in addition to many other isocarbacyclin derivatives.

The compounds have the properties typical of the isocarbacyclins, such as e.g. B. Inhibition of platelet aggregation and dissolution of platelet thrombus ben, myocardial cytoprotection and thus lowering systemic blood pressure.

Among these compounds claimed in EP 1 36 779, the compounds in particular showed 13,14,18,18,19,19-Hexadehydro-3-oxa-isocarbacycline with extended lower Side chain as antihypertensive agent and antiplatelet agent Such outstanding properties mean that the dosage continues can be reduced.  

This can also suppress unwanted side effects even further the. The 13,14,18,18,19,19-hexadehydro-3-oxa-isocarbacycline with 20-alkyl groups are neither described by name in EP 1 36 779, nor are they compared the other connections exposed.

The invention thus relates to 13,14,18,18,19,19-hexadehydro-3-oxa-isocarbacy clin derivatives of formula I.

wherein p is 1 to 3,
R¹ is a hydrogen atom or an alkyl group with 1-5 C atoms and
R² is an alkyl group with 2-5 C atoms, as well as their salts with physiologically compatible bases and their cyclodextrin derivatives.

As alkyl groups R¹ and R² come straight and branched chain alkyl radicals 1-5 carbon atoms, such as methyl, ethyl, propyl, Butyl, isopropyl, isobutyl, pentyl. Preferred radicals R 1 are methyl, ethyl, Propyl and isopropyl, especially methyl and ethyl. Preferred radicals are R² Ethyl and propyl, especially ethyl.

Inorganic and organic bases such as that are suitable for salt formation Are skilled in the art of forming physiologically acceptable salts. Example Alkaline hydroxides, such as sodium and potassium hydroxide, alkaline earth, may be mentioned Hydroxide such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanola min, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methyl amine etc.

Α -, β -, γ- cyclodextrin are particularly suitable for clathrate formation.

The invention further relates to a method for producing the invention essen isocarbacyclin derivatives of formula I, which is characterized in that a compound of the formula II,

wherein R¹ and R² have the meanings given above, with potassium tert-buty lat isomerized in THF, reduced with LiAlH₄ and then with a bromine compounds of formula III

Br- (CH₂) _p -R³ (III)

wherein p has the meaning given above and R³ is the radicals -COOtert.-butyl or -C (OCH₃) ₃, is reacted and then cleaves the silyl ether with an acetic acid / water / THF mixture and saponifies the ester with alkali metal hydroxide. The reaction of the alcohols obtained from a compound of formula II with a bromine compound of formula III is preferably in organic solvents such as toluene with 25-50% sodium hydroxide solution and sodium hydroxide solution and tetrabutylammonium hydrogen sulfate in about 20 hours at 20-30 ° C under argon carried out. The saponification of the isocarbacyclin esters is carried out by the methods known to the person skilled in the art.

The isocarbacyclins obtained by the above process can be with chromatographic methods, such as the HPLC method in the Separate 2 (3) - and 3 (4) -isocarbacyclins.

The deprotection is carried out in an aqueous solution of an organic Acid such as acetic acid, propionic acid and the like. a. or in an aqueous  Solution of an organic acid, such as hydrochloric acid. To Improving the solubility is expediently a water-miscible one added inert organic solvent. Suitable organic solvents are, for example, alcohols such as methanol and ethanol, and ethers such as dimethoxy ethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferred. The cleavage is preferably carried out at temperatures between 20 ° and 30 ° C. guided.

The carboxylic acids of formula I can with suitable amounts of the corresponding inorganic bases are converted into salts with neutralization. Example wise you get when you dissolve the corresponding acid in water, which the contains stoichiometric amount of base after evaporation of the water or after Zuga be a water-miscible solvent, for example alcohol or ace ton, the solid organic salt. To produce an amine salt, the Iso carbacyclic acid in a suitable solvent, for example ethanol, Acetone, diethyl ether or benzene dissolved and at least the stoichiometric Amount of amine added to this solution. The salt usually falls in solid form or after evaporation of the solvent in the usual way isolated.

The dose of the compound is 1-1500 µg // kg / day when used on human pati ducks are administered. The unit dose for the pharmaceutical accept Blen carrier is 0.01-100 mg.

For parenteral administration, sterile, injectable, aqueous or oily solutions used. For oral application, for example, are tablets ten, drag'es or capsules.

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

The active compounds according to the invention are intended to be used in conjunction with those used in galenics usual auxiliaries, e.g. B. for the preparation of agents against platelet thrombi serve.

Example 1 5 - <(1S, 5S / 5R, 6R, 7R) -7-hydroxy-6 - [(3S, 4S) -3-hydroxy-4-methyl-non-1,6 - diinyl] - bicyclo [3.3.0] oct-2 (3) -en-3-yl <-3-oxapentanoic acid (16S) -13,14-Didehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-- Δ 6,6a / Δ 6,7-isocarbacyclin

To a solution of 26 g of 2 - <(E, Z) - (1S, 5S, 6S, 7S) -7-tert-butyl-dimethylsilyl- oxy-6 - [(3S, 4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiiny-l] -bicy clo [3.3.0] oct-3-ylidene <-acetic acid ethyl ester (see DOS 33 06 123 and J.Med. Chemistry 29, 313 (1986)) in 4.2 liters. Tetrahydrofuran is added 2.6 g of potassium tert-butoxide and stirred for 24 hours at room temperature under argon. Subsequently diluted with 6.5 ltr. Ether, washes neutral with water and constricts in a vacuum a. The residue is chromatographed on silica gel. With hexane / ether gemi (9 + 1 - <7 + 3) 12 g of the corresponding isomerized ester are obtained as colorless oil.

To reduce the ester group, dissolve 12 g of the pro prepared above duktes in 650 ml of ether and adds 5.6 g of Lithi in portions at 0 ° C with stirring umaluminiumhydrid and stirred for 30 minutes at 0 ° C. You destroy the reagent Excess by dropwise addition of ethyl acetate, add 40 ml of water, stir 3 hours at 20 ° C, filtered and evaporated in vacuo. The residue chromato graphed with ether / hexane (3 + 2) on silica gel. This gives 8.0 g of desired primary alcohol as a colorless oil.

To a solution of 8 g of the alcohol described above in 100 ml of toluene 14.3 g of tert-butyl bromoacetate, 44.5 ml of 25% sodium hydroxide solution and 214 mg of tetrabutylammonium hydrogen sulfate and stirred for 20 hours at 25 ° C under Ar gon. Then diluted with 100 ml of ether, acidified at 0 ° C with 20% Zi tronic acid to pH 6, extracted 3 × with 200 ml ether, washed with water, dries over sodium sulfate and evaporates in vacuo. After chromatography on Silica gel is obtained with hexane / ethyl acetate (95 + 5) 8.7 g of the tert-butyl ester of the corresponding isocarbacyclin as a colorless oil.  

8.7 g of the ester 18 prepared above are stirred for silyl ether cleavage Hours with 600 ml acetic acid / water / tetrahydrofuran 65/35/10 at 25 ° C. Man evaporates in vacuo with the addition of toluene and chromatographs the back stood on silica gel with hexane / acetic acid (4 + 6). This gives 4.5 g of 11,15-diols as a colorless oil.

For saponification, 4.5 g of the diol prepared above are stirred in 42 ml of Me thanol with 28 ml of a 0.5 N sodium hydroxide solution and 14 ml of water for 5 hours at room temperature under argon. It is diluted with 25 ml of water and acidified with 20% Zi tronic acid to pH 1-2, extracted 4 × with 100 ml of methylene chloride, washed the organic phase with brine, dries over sodium sulfate and evaporates in vacuo a. The residue is chromatographed on silica gel. With ethyl acetate / vinegar Acid (95 + 5) gives 3.1 g of the title compound as a colorless oil.

IR: (CHCl₃): 3600, 3430 (broad), 2970, 2930, 2915, 2230, 1735, 1605, 1160, 1030 cm ^-1

Example 2 7 - <(1S, 5S / 5R, 6R, 7R) -7-hydroxy-6 - [(3S, 4S) -3-hydroxy-4-methyl-non-1,6-diynyl] - bicyclo [3.3. 0] oct-Δ ² / Δ ³-octen-3-yl <-5-oxa-heptanoic acid (16S) -13,14-Didehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-1a, 1b-dihomo- Δ 6,6a / Δ 6,7-isocarbicyclin

To a solution of 8.5 g of 2 - <(E, Z) - (1S, 5S, 6S, 7R) -7-tert-butyl-dimethylsilyl oxy-6 - [(3S, 4S)) - 3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiyn-yl] bicy clo [3.3.0] oct-3-ylidene <-acetic acid ethyl ester (see DOS 33 06 123 and J.Med. Chemistry 29, 313 (1986)) in 1.3 liters. Tetrahydrofuran is added 950 mg of potassium tert-butoxide and stirred for 24 hours at room temperature under argon. Subsequently diluted with 2 ltr. Ether, washes neutral with water and constricts in a vacuum a. The residue is chromatographed on silica gel. With hexane / ether gemi (9 + 1 → 7 + 3), 4.3 g of the corresponding isomerized ester are obtained as colorless oil.  

To reduce the ester group, 4.3 g of the pro prepared above are dissolved duktes in 215 ml of ether and adds 1.43 g of Li in portions at 0 ° C with stirring thiumaluminiumhydrid and stirred for 30 minutes at 0 ° C. You destroy the rea excess by dropwise addition of ethyl acetate, adds 9.6 ml of water, stirred for 3 hours at 20 ° C, filtered and evaporated in vacuo. The backlog chromatographed on ether / hexane (3 + 2) on silica gel. This gives 3 g the desired primary alcohol as a colorless oil.

Add to a solution of 3 g of the alcohol described above in toluene 4.8 g of trimethyl ortho-4-bromobutyrate, 7.2 ml of 50% sodium hydroxide solution and 150 mg Tetrabutylammonium hydrogen sulfate and stirred for 20 hours at 25 ° C under argon. Then diluted with 200 ml of water, extracted 3 × with 200 ml of ether, washes the organic phase neutral with water, dries over sodium sulfate and evaporates in a vacuum. After chromatography on silica gel with hexane / Ethyl acetate (9 + 1) 2.3 g of the corresponding methyl ester as a colorless oil.

For silyl ether cleavage, 2.3 g of the ester 18 prepared above are stirred Hours with 150 ml acetic acid / water / tetrahydrofuran (65/35/10) at 25 ° C. Man evaporates in vacuo with the addition of toluene and chromatographs the back stood on silica gel with hexane / ethyl acetate (4 + 6). This gives 0.85 g of 11,15-diols as a colorless oil.

For saponification, 0.85 g of the diol prepared above is stirred with 23 ml an ethanolic potassium hydroxide solution (preparation: dissolve 5 g of potassium hydroxide in 188 ml Ethanol and 63 ml water). Then diluted with water, acidified with 10% citric acid to pH 4, extracted with methylene chloride, washes the organic phase with brine, dries over sodium sulfate and evaporates in vacuo a. The residue is chromatographed on silica gel. With ethyl acetate / vinegar Acid (95 + 5) gives 0.6 g of the title compound as a colorless oil.

IR (CHCl₃): 3600, 3400 (broad), 2960, 2930, 2875, 1713, 1602, 1450, 1375, 1320, 1110 cm ^-1

Claims (2)

1. 13,14,18,18,19,19-hexadehydro-3-oxa-isocarbacyclin derivatives of formula I. wherein p is 1 to 3,
R¹ is a hydrogen atom or an alkyl group with 1-5 C atoms and
R² is an alkyl group with 2-5 C atoms, as well as their salts with physiologically compatible bases and their cyclodextrin derivatives. 2. Medicament consisting of one or more compounds of claim 1 and usual auxiliaries and carriers.