HU204268B - Process for producing new apovincaminic-amide derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Novel pharmaceutical apo-vincaminic-acid-amides and acid adduct salts of formula (I) - where R1 is not defined and R2 = 1-6C alkenyl, 1-6C hydroxyalkyl gp. or in this case a substd. aralkyl gp., are prepd by obtaining apo-vincamine-acid-chloride from apovincaminic-acid (II) and Vilsmeier complex. The acid-chloride reacts with amine of formula (III), opt. in the presence of an acid scavenger. Cpd. (I) is formed and opt. converted into the acid adduct salt.

Description

GB 204,268 Β amine - wherein R and _R2 are as defined above - is reacted, optionally in the compound (I) are those compounds apovinkaminsavamid new derivative into an acid addition salt, and optionally in the presence of a separate acid-binding agent.

The compounds of the present invention are useful in the treatment of various brain disorders.

The present invention relates to novel apovincaminamide derivatives of formula (Ί) wherein:

R 1 is hydrogen, C 1-6 alkenyl or C 1-6 hydroxyalkyl,

R ₂ is C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl or phenyl (C 1 -C 6) alkyl, naphthyl (C 1 -C 6) alkyl and their acid addition salts, by reacting the apovincaminic acid of formula (Π) with a Vilsmeier complex and reacting the apovincaminic acid chloride with an amine of formula (ΠΧ) wherein R 1 and R ₂ are as defined above, optionally in the presence of an acid acceptor and optionally converting the novel apovincaminic acid amide derivative of formula (I) into an acid addition salt.

The compounds of the present invention are novel and have valuable pharmacological properties and are well suited for use in cerebrovascular (cerebral haemorrhage, embolism, thrombosis, spasm) and constrictive (tumor, hematoma, hydrocephalus) processes, brain injuries (commotion, contusion, surgery, edema). ), 30 to treat the brain consequences of paralysis and cardiac arrest.

The invention also relates to processes for the preparation of a pharmaceutical composition comprising a compound of formula (I). 35% Effect ·

Various apovincaminamide derivatives are known in the literature.

Belgian Patent No. 797,017 discloses cyclic apovincamic amide derivatives having pharmacological properties. 40

Belgian Patent No. 830,587 discloses cycloalkylamides of apovincaminic acid, which are declared to have antihypoxic activity.

Apovincaminamide derivatives of peripheral and cerebral vasodilator activity described in Hungarian Patent No. 160,367 are closest to structure. According to the disclosure, the compounds are prepared by reacting apovincamic acid with pentachlorophenol for 12 days and reacting it with ammonia, mono and 50 dialkylamines to produce very poor target compounds.

The novel apovincaminamide derivatives of the present invention are prepared by a process not previously used for ebuman skeletal compounds. According to this, apovincaminic acid is prepared from apovincamic acid using the Vilsmeier complex, and the apovincaminic acid of formula (Π) is reacted with amines to give apovincaminic acid amide with very high yield in 60% 86% yield. apovinkamínsavamidokat.

The starting materials are known. Apovincaminic acid (Π) can be prepared, for example, as described in Hungarian Patent No. 160,367 (Example 10). Amines of formula (ΠΙ) are also known, commercially available compounds.

To investigate the oxygen deficiency of the brain, the generally known method is used, whereby the complete deprivation of oxygen in the inhaled air causes the animal to become unconscious and the electrical activity (EEG) of the brain to function as an isoelectrochrome (iEEG). The model is usually used on an anesthetized (anesthetized) animal; measure the time to the appearance of the iEEG (Thin). In the present studies, adult male, adult Hannover-Wistar rats weighing 350-400 g, prepared for chronic EEG, were used at the time of the study. The compounds were administered orally at a dose of 50 mg / kg, and after 30 minutes the animals were individually enclosed in transparent chambers. The chambers were flushed with nitrogen gas (1.67 rpm). T _{i £ E} G was measured and the percentage effect of the compounds (v) relative to control (c) was calculated using the following formula (TjEEGc-TiEEGv) / 46.5 10 -1 100

Flunarizine, commonly used in cerebrovascular disease, reduced TjEEG by 17% and compounds of Formula I by 27-31% in this experiment (Table I a).

Effect of flunarizine and compounds of formula (Γ) on TiEEG relative to control rats (N).

average (Tíeeg) hatsás % control (53) 28.1 flunarizine (6) 24.8 -17 1006050 (5149, l.példa) (6) 22.6 -31 1006069 (5178,2.példa) (6) 23.3 -27 1006144 (5285,6.példa) (6) 22.6 -31

Based on these results, it can be clearly seen that the compounds of formula I are effective and useful in the treatment of cerebral vascular (stroke, embolism, thrombosis, spasm) and constrictive (tumor, hematoma, hydrocephalus), respiratory paralysis and cardiac arrest.

HU 204268 Β

The daily dose of the compounds of formula (I) is 0.8 mg / kg body weight, administered orally or parenterally, once or repeatedly.

The preparation of the compounds of formula I according to the invention is described in detail below.

First, apovincaminic acid chloride is prepared from apovincaminic acid of formula II using the Vilsmeier complex.

1-1.5 moles, preferably 1.1 moles, of Vilsmeier complex are used per mole of apovincaminic acid. Preparation of the complex by known methods [Hepbum-Hudson; Chem. And Ind. 664 (1974); Anderson et al., Et al. Synthesis 1976. 398-399]. Accordingly, a dialkylformamide and a chlorinating agent such as phosgene, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride are combined in a 1: 1 molar ratio, resulting in the Vilsmeier Complex. Preferably, the complex is prepared from dimethylformamide and thionyl chloride in the solution itself. The chlorination of apovincaminic acid is carried out between 0 'C and 40' C, preferably at room temperature. The reaction may also be carried out by preparing a Vilsmeier complex in a chlorinated solvent such as dichloromethane, chloroform, dichloroethane, to which apovincaminic acid is added either in solution or in solid form. Alternatively, the reaction may be carried out by dissolving apovincaminic acid in one of the above-mentioned chlorinated solvents and adding a solution of the Vilsmeier complex in the same solvent. The reaction time, including the addition of the components, is 1 hour at room temperature. After preparation of the apovincaminic chloride, 10-20% of the solvent used in the mixture is atmospherically distilled to remove the by-product sulfur dioxide and the desired amine of formula III is added at room temperature. When the amidation reaction is carried out in a small excess (about 1.1 molar equivalents) of amine (III), a trisubstituted amine, preferably triethylamine, is added as the acid scavenger. Alternatively, a large excess of the amine (III) may be carried out without the need for a separate acid scavenger.

The amidation reaction can be carried out at a temperature ranging from room temperature to the reflux temperature of the reaction mixture. Preferably, the reaction mixture is heated under reflux for about 1 hour at which time the amidation occurs. Extraction of the product can be accomplished in a very simple manner by diluting the reaction mixture with water and extracting it, separating the organic phase and crystallizing the target compound by exchange with the appropriate solvent.

The compounds of formula (I) thus obtained may, if desired, be converted into acid addition salts in known manner.

The acid addition salt formation can be carried out in an inert solvent such as a C 1-6 saturated monovalent aliphatic alcohol or a bipolar aprotic solvent such as ether, by acetone dissolving the compound of formula (I) in the above solvent and the appropriate acid or a solution of the acid in the above solvent is added until the mixture becomes slightly acidic. The precipitated acid addition salt is then isolated from the reaction mixture by any suitable means, such as filtration.

The active ingredient of formula (I) may be formulated in pharmaceutical compositions with non-toxic, inert solid or liquid carriers and / or excipients which are suitable for parenteral or enteral administration. Suitable carriers include, for example, water, gelatin, lactose, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. It can be used. The active ingredient may be in the form of conventional pharmaceutical compositions, in particular solid forms such as round or square tablets, dragees, capsules such as gelatin capsules, pills, suppositories and the like. in the form of. The amount of solid carrier can vary over a wide range, 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, and the like. may also be included. They may be prepared by conventional techniques such as sieving, mixing, granulating and pressing the components in the case of solid compositions. The compositions may also be subjected to other conventional pharmaceutical techniques such as sterilization.

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

Example 1

Apovincaminic acid diallylamide

Dissolve 4.1 g of dimethylformamide in 150 ml of dichloromethane and add 6.7 g of thionyl chloride. To the resulting VIIIsmeier complex was added 16.1 g of apovincamic acid and the mixture was stirred for one hour at room temperature. After stirring, 30 ml of dichloromethane are distilled off under atmospheric conditions, and a solution of 12 g of triethylamine and 6.8 g of diallyl amine in 30 ml of dichloromethane is added. The solution was then heated under reflux for one hour. After cooling to room temperature, water (100 ml) was added, and after separation, the organic layer was extracted with two additional portions of water (100 ml) and brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to a solvent. The residue was crystallized from 15 ml of methanol. Weight: 17.86 g (89.1%).

Melting point: 119-121 ° C.

[?] D 20 -109.8 '(c-1, CHCl 3).

HU 204268 Β

Example 2

Apovincaminic acid allyl amide

All were carried out as in Example 1, but using 4 g of allylamine instead of 6.8 g of diallylamine.

The residue obtained by the method described in Example 1 was crystallized from 15 ml of toluene. Weight: 15.54 g (86.1%).

Melting point 160-163 ° C.

[.alpha.] D @ 20: + 70.4 DEG (c-1, CHCl3).

Example 3

Apovincaminic Monoethanolamide The procedure described in Example 1 was followed except that 4.8g ethanolamine was used instead of 6.8g diallylamine. The residue obtained in Example 1 was crystallized with 20 ml of diisopropyl ether. Weight: 16.69 g (86%).

Melting point: 188-190 ° C.

[α] D 20 = +73.1 '(c = 1, CHCl 3).

Example 4

Apovincaminic acid n-propanolamide In the same manner as in Example 1, the same volume of dichloromethane as the dichloromethane solvent was used, and 5.2 g of 1-propanol was used instead of 6.8 g of diallylamine. as we use it. The evaporation residue from Example 1 was boiled in methanol (20 mL) and filtered at 0 ° C. Yield: 17.85 g (94.2%). Melting point: 200-202 ° C.

[.alpha.] D @ 20: + 22.5 DEG (c-1. OHCl2).

Example 5

Apovincaminic Acid Diethanolamide The procedure of Example 1 was repeated except that 7.4 g of diethanolamine was used instead of 6.8 g of diallyl amine. The residue obtained in Example 1 was crystallized by adding 10 ml of methanol. Yield: 17.58 g (86%). Melting point: 162-165 ° C.

-94,3 '(c-1, CHCl 3). She. example

Apovincaminic Acid Benzyl Amide As in Example 1, except for 7.8 g of benzyl amine instead of 6.8 g of diallyl amine. The residue obtained in Example 1 is crystallized from 15 ml of ethyl alcohol. Yield: 18.90 g (92%).

Melting point: 142-145 ° C.

[a] g>: +24.8 ° (c = 1, _CHCl3).

Example 7

Apovincaminic acid - (+) - α-phenethylamide All the procedures described in Example 1 were repeated except that 8.6 g of (+) - α-phenethylamine were used instead of 6.8 g of diallylamine. The residue obtained as in Example 1 was treated with a mixture of 5 ml of benzene and 15 ml of petroleum ether. Yield: 18.27 g (86%). Melting point: 78-91 ° C. [c $ ° + 74.3 ° (c = 1, CHC1 _3).

Example 8

Apovincaminic acid (-) -? -Phenethylamide The procedure described in Example 1 was repeated except that 8.6 g (-) -? - phenethylamine was used instead of 6.8 g of diallyl amine. The residue obtained as described in Example 1 was treated with 25 ml of diisopropyl ether. Weight: 19.13 g (90%).

Melting point: 214-216 ° C.

[α] 20 D +18.6 ° (c -1, CHCl ₃ ).

Example 9

Apovincaminic Diallylamide Hydrochloride Dissolve 1 g of apovincaminic acid diallylamide in 20 ml of food, acidify to ρΗ-4 with 10 ml of HCl, filter the precipitated crystals at 0 ° C and wash with food.

Yield: 1.05 g (96.2%).

Melting point: 121-124 ° C.

[α] D 20 -97.1 '(c-1, CHCl ₃ ).

Example 10

Preparation of Apovincaminic Acid (H) 2.85 g (0.008 mol) of apovincamine are dissolved in 190 ml of methanol, 4.25 g (0.10 mol) of potassium hydroxide are added and the mixture is refluxed for 2 hours. The cooled mixture was acidified to ρΗ-4 with concentrated hydrochloric acid and the precipitated potassium chloride was filtered off. Water was removed from the solution as a toluene / water azeotropic mixture and the solution was evaporated to dryness. The dry residue was dissolved in a 1: 7 mixture of methanol-chloroform and the insoluble potassium chloride was filtered off. The filtrate is evaporated to dryness and the residue is crystallized from acetone. 2.4 g of apovincamic acid are obtained.

Yield: 87.9%. They would be uniform by layer chromatography.

Claims (6)

A process for the preparation of novel apovincaminamide derivatives of the formula I wherein: R 1 is hydrogen, C 1-6 alkenyl or C 1-6 hydroxyalkyl, R 2 is C 1 -C 6 alkenyl, C 1 -C 6 alkenyl 45 for the preparation of hydroxyalkyl or phenyl (C 1 -C 6) alkyl, naphthyl (C 1 -C 6) alkyl and acid addition salts, characterized in that the apovincaminic acid (Π) is reacted with a Vilsmeier complex and reacting the resulting apovincaminic acid chloride 50 with an amine of formula (III) wherein R 1 and R ₂ are as defined above, optionally in the presence of an acid acceptor, and optionally converting the resulting apovincaminic acid amide slag of formula (I) into an acid addition salt. Process according to claim 1, characterized in that the reaction of apovincaminic acid with the Vilsmeier complex with Vilsmeier complex is in the range of from 1.0 to 1.5 moles, preferably 1.1 moles, of the Vilsmeier complex from 0'C to 40'C. temperature, in a chlorinated organic solvent. HU 204268 Β Process according to claim 1, characterized in that the reaction of apovincaminic acid chloride and the amine of formula (HI) is carried out in the presence of an acid scavenger at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the reflux temperature of the reaction mixture. Process according to claim 3, characterized in that the acid acceptor is a tri-substituted amine, preferably triethylamine. Process according to claim 1, characterized in that the reaction of apovincaminic chloride and the amine of formula (III) without a separate acid acceptor is carried out in excess of the amine of formula (IH) at a temperature ranging from room temperature to the boiling point of the reaction mixture. reaction mixture at reflux temperature. 6. A process for the preparation of a pharmaceutical composition comprising converting a compound of formula (I) according to claim 1, wherein R 1 and R ₂ are as defined in claim 1, or an acid addition salt thereof into a pharmaceutical composition mixed with customary carriers and / or excipients in the pharmaceutical industry. .