HU187454B - Process for production of pharmaceutical composition with specifical peripherial vasodilitant activity - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to (a) -la - [(2'-alkoxycarbonyl-2'-hydroxyimino) ethyl] -1β-ethyl-1,2,3,4,6,7,12,12ba-octahydroindole. From the [2,3-a] quinolizine or acid addition salts thereof, a (+) -transparovamic acid ester derivative of the formula (I) obtained by treatment with an inert volatile acid in an inert organic solvent, wherein R 1 is C 1-4 alkyl and R2 is for the preparation of pharmaceutical compositions having a specific peripheral vasodilatory activity comprising ethyl or - or a pharmaceutically acceptable acid addition salt thereof, such that the (+) -trans-apovincinnamic acid ester derivative wherein R1 and R2 are as defined above - or a pharmaceutically acceptable salt thereof; acid addition salts are mixed with pharmaceutical excipients and / or excipients and converted into pharmaceutical compositions. An advantage of the composition according to the invention is that it has a peripheral vasodilator effect against the cerebral vasodilator composition comprising the known cis isomer active agent and this effect is specific; another advantage is that they are hardly influenced by heart rate and blood pressure. -1-

Description

The present invention relates to a process for the preparation of (-) - 1α - [(2'-alkoxycarbonyl-2'-hydroxyimono) ethyl] -1 β-ethyl-1,2,3,4,6,7,12,12b-octahydroindole [ 2,3-a] quinolizine or acid addition salts thereof with a (+) - trans-apovincaminic acid ester of formula (I) prepared by treatment with a concentrated, non-volatile acid in an inert organic solvent, wherein R ¹ is C 1 -C 4 alkyl and R ² is for the preparation of a specific peripheral vasodilator pharmaceutical composition containing an ethyl group, or a pharmaceutically acceptable acid addition salt thereof, wherein the resulting (+) - trans-apovincaminic acid ester derivative wherein R ¹ and R ² are as defined above or mixed with customary carriers and / or excipients and formulated in a pharmaceutical composition.

In the general formula ^1, R ^{1 as a C} 1-4 alkyl group is any linear or branched alkyl group such as methyl, ethyl, η-propyl, ipropyl, η-butyl, sec-butyl, tert-butyl groups.

Pharmaceutically acceptable acid addition salts of the compounds of formula I include, for example, the salts prepared with the acids listed below. Inorganic acids such as hydrogen halides such as hydrochloric acid, hydrobromic acid, etc., sulfuric acid, phosphoric acid; organic carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, benzoic acid, cinnamic acid; alkylsulfonic acids such as methanesulfonic acid: arylsulfonic acids such as p-toluenesulfonic acid; cyclohexylsulfonic acids; aspartic acid, glutamic acid, N-acetyl aspartic acid, N-acetylglutamic acid, and the like.

The novel compounds of Formula I can be prepared from the corresponding, also novel trans-hydroxyimino-octahydro-indolo [2,3-a] quinolizine derivative as described in Hungarian Patent Application Publication No. T / 32825 by treatment with a concentrated non-volatile acid in an inert organic solvent. By this method, leftover trans-apovincaminic acid esters containing a 16α-ethyl group can also be prepared which exhibit anti-inflammatory, anticonvulsant, antiparkinson and anti-arteriosclerotic activity.

It is known that the corresponding cis-apovinic acid esters, in particular the right-rotating cis-apovinic acid ethyl ester, have a valuable cerebral vasodilator activity, but with some degree of limb vasodilator activity. (Hungarian Patent No. 163,434).

Surprisingly, it has now been found that, in anesthetized dog studies, the novel compounds of Formula I exhibit a significant vasodilator effect, which is manifested mainly by a marked increase in limb blood flow and, in addition, by a significantly smaller increase in cerebral blood flow. This effect is unexpected and substantially different from the biological activity of the cis-apovincaminic acid ethyl ester, which causes mainly cerebral vasodilation and increased blood flow.

The studies were performed on dogs anesthetized with chloralose-urethane. Limb blood flow was measured on the femoral artery, and cerebral blood flow was measured on the carotid artery by electromagnetic flowmeters. Changes in blood pressure and heart rate were also evaluated. To demonstrate a different effect, cis-apovincaminic acid ethyl ester was also administered to all animals. The treatments were given intravenously. The mean values of the results obtained from studies in 10-13 animals per dose are shown in Table I below, as well as their statistical standard deviations and percent changes.

Table I

Right rotating trans apovincaminic acid ethyl ester

After dose treatment% change after mg / kg

femoral flow 0.3 43.4 ± 9.7 77.7 ± 15.9 + 79.0 ml / min 1.0 35.6 ± 8.4 82.5 ± 18.3 + 131.7 carotid flow 0.3 31.9 ± 5.2 34.7 ± 5.8 + 8.8 ml / min 1.0 32.0 ± 3.9 39.6 ± 6.0 ± 23.8 blood pressure 0.3 151.5 ± 6.7 138.5 ± 7.3 - 8.6 Hg 1.0 143.5 ± 7.3 132.3 ± 5.8 - 7.8 heart rate 0.3 159.0 ± 11.0 I61, O ± 11.0 + 1.0 1 minute 1.0 160.0 ± 9.2 175.0 ± 10.0 + 9.4

The results of the comparative studies are shown in Table II below. Table.

II. spreadsheet

Right rotating cis-apovincaminic acid ethyl ester (1.0 mg / kg dose).

treatment %-ancestor change before after femoral flow m / min 26.9 ± 3.5 34.7 ± 5.1 29.0 carotid flow in m / min 25.1 ± 3.8 35.3 ± 5.7 ± 40.6 blood pressure Hgmm 151.0 ± 3.8 129.0 ± 5.6 - 14.2 heart rate l / min 178.0 ± 4.8 173.0 ± 5.0 - 2.8

From the above data, it is clear that the compounds of Formula I have surprising and valuable specific limb (peripheral) vasodilating activity. Another significant benefit is that they have little effect on blood pressure and heart rate.

The compounds of Formula I may be administered orally or parenterally in a dosage of 0.1 to 2.0 mg / kg body weight.

In the process of converting to a pharmaceutical composition, the active compound-22

No. 187,454 is formulated with pharmaceutical inert, non-toxic, inert, solid or liquid carriers and / or excipients, suitable for parenteral or enteral administration, to form pharmaceutical compositions. Suitable carriers include, for example, water, gelatin, lactose, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil, etc., gum arabic, polyalkylene glycols, petroleum jelly, and the like. It can be used.

The active ingredient may be in the form of standard pharmaceutical compositions, for example solid (round or square tablets, dragees, capsules such as hard gelatin capsules, pills, suppositories, etc.) or liquid (e.g., oily or aqueous solution, suspension, emulsion, syrup, capsules, injectable oily or aqueous solutions or suspensions, etc.) for rectal administration may be prepared in the form of suppositories. The amount of solid carrier can vary widely, preferably from about 25 mg to about 1 g.

The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffering agents, flavoring agents, coloring agents, perfumes, and the like. may also be included.

Preferably, the composition is formulated in dosage units appropriate to the desired route of administration.

The pharmaceutical compositions may be prepared by conventional techniques, which include, for example, sizing, homogenizing, mixing, granulating and compressing or dissolving the ingredients in the appropriate compositions.

The compositions may be subjected to other conventional pharmaceutical operations (e.g., sterilization).

The invention is further illustrated by the following non-limiting examples.

!. EXAMPLE 1 Preparation of (+) - Trans-apovincaminic acid ethyl ester (3α, 16β).

4.75 g (0.025 mol) of p-toluenesulfonic acid monohydrate is dehydrated at reflux temperature with toluene using a Marcusson plug, then made up to 70 ml and 4.2 g (0.01 mol) of (-) -la - [(2'-ethoxycarbonyl-2'-hydroxyimoni) -ethyl] -1-β-ethyl-1,2,3,4,6,7,12,12ba-ocahydro-indyl-2,3--a] quinolizine hydrogen chloride is added. The reaction mixture was refluxed for 1.5 hours, then water (30 mL) was added at room temperature and basified to pH 9 with aqueous ammonium hydroxide. After separation, the toluene phase is dried, filtered, and the filtrate is clarified with activated carbon and concentrated under reduced pressure to an oil. The residue was boiled with ethanol (5 mL), filtered at 0 ° C.

Weight: 3.14 g.

Yield 90%.

Melting point: 120-122 ° C.

(a) 20: + 144.4 '(c = 1, chloroform).

D

Example 2 Tablet containing (+) - trans-apovincaminic acid ethyl ester (3α, 16β) (+) - trans-apovincaminic acid ethyl ester (3a, 163) 5 mg gelatin 3 mg magnesium stearate 2 mg talc 5 mg potato starch 40 mg lactose 95 mg

The active ingredient is mixed with 3/4 of the potato starch and the milk sugar. The resulting homogeneous mixture is kneaded with an aqueous solution of gelatin, granulated and the wet granulate dried at 30-50 ° C. To the dried granules obtained were added talc, the remaining 1/4 of the potato starch and magnesium stearate, and the resulting mixture was compressed into tablets. Optionally, the tablet is provided with a notch to facilitate dosing.

Example 3 Injection of ethyl (+) - trans-apovincaminic acid ester (3α, 16β) in ml of sterile water for injection at 25 ° C is dissolved in 400 mg of tartaric acid and 3600 mg of sorbitol and 800 mg of benzyl alcohol is added. The solution is then made up to 80 ml with sterile water for injection, carefully homogenized, filtered and filled into sterile ampoules. The air was expelled from the vials with nitrogen gas, the vials were sealed and sterilized by heat treatment at 100 ° C for 30 minutes.

The contents of the ampoules are suitable for dissolution by the physician of the ethyl ester of apovincaminic acid.

Dissolve in 2 ml of the above solvent 10 mg of ethyl (+) -transapovinc (3α, 16β) ethyl ester for parenteral injection, for example by intramuscular injection.

EXAMPLE 4 Ethyl (+) - trans-apovincaminic acid ethyl ester (3α, β6β) t

Dissolve 76.8 mg of sodium hydroxide in 187,454 ml of sterile water for injection and add successively 96 mg of concentrated acetic acid, 32 ml of propylene glycol and 800 mg of benzyl alcohol. The pH of the solution θ is 3.8 ± 0.1. The volume of the solution is then made up to 80 ml with sterile water for injection and proceeded as in Example 3 below.

Example 5 Preparation of (+) - Trans-apovincaminic acid methyl ester (3a, 16 µ) -hydrogen chloride

3.5 g of (+) - trans-apovincaminic acid methyl ester are suspended in 50 ml of methanol and hydrochloric acid methanol is added to pH 5.

The solution was evaporated to dryness in vacuo, the residue was boiled with diisopropyl ether (15 mL) and cooled to room temperature. The precipitated white crystals were filtered off, washed twice with 5 ml of diisopropyl ether and dried.

3.75 g of the expected product are obtained.

Yield: 97%. 25

Melting point; 195-196 'C.

[α] 20 = + 120.8 (¢ = 1, methanol).

Claims (1)

Procedure for the preparation of (-) - la - [2'-alkoxycarbonyl-2'-hydroxyimino) ethyl] -1-β-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo [2,3, - a) quinolizine or acid addition salts thereof with (+) - trans-apovincaminic acid ester of the general formula (I) prepared by treatment with a concentrated non-volatile acid in an inert organic solvent, wherein n 'R ¹ is C 1 -C 4 alkyl and K is or a pharmaceutically acceptable acid addition salt thereof with a pharmaceutically acceptable acid addition salt thereof, characterized in that the (+) - trans-apovincaminic acid ester derivative of the Formula I wherein R ¹ and R ² are as defined above - or a pharmaceutically acceptable their acid addition salts with adjuvants and / or excipients which are customary in the pharmaceutical art and converted into a pharmaceutical composition.