CZ281347B6 - 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine salts and process for preparing thereof - Google Patents

Abstract

This invention involves new chemically produced substances, salts of 9-amino-7-methoxy-1, 2, 3, 4-tetrahydroacridine of the general formula I, where X' means an anion from the group which includes Cl<->, Br<->, 1/2 SO4<2->, CH3COO<->, C4H5O6, 1/2 C4H4O6<2->, C3H5O3<->, C6H7O7<->, 1/2 C6H6O7<2->. The nature of the method of producing these salts consists of the neutralization of 9-amino-7-methoxy-1,2,3,4-tetrahydroxyacridine by acid in a molar ratio given by the composition of the salt. The substance obtained is separated by filtration or evaporation. The substances are used for the preparation of therapeutic drugs with a reversible inhibitory effect on cholinesterase.

Description

The invention relates to novel chemically produced substances, 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine salts, and a process for their preparation. The substances are particularly useful in the pharmaceutical industry for the preparation of medicaments and for reversible cholinergic activity.

9-Amino-7-methoxy-1,2,3,4-tetrahydroacridine, e.g. 3,232,945, is a highly basic, water-insoluble substance. This feature makes it impossible to use it in practice.

These drawbacks are overcome according to the invention by the formation of the salts of 9-amino-7-methoxy-tetrahydroacridine of formula I

X (I) wherein X represents an anion selected from the group consisting of Cl, Br ^- , 1/2 SO ² ₄ , ch ₃ coo ~, c ₄ h ₅ o " ₆ , c ₃ h ₅ o" ₃ , c ₆ h ₆ o ^{2 -} ₇ .

The essence of the preparation of the salts according to the invention is characterized in that the solution of the base of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in a suitable solvent is neutralized with hydrochloric, hydrobromic, sulfuric, acetic, tartaric, lactic or citric acid. the molar ratio given by the stoichiometry of said formula, wherein the obtained substance is isolated by filtration or by evaporation of the solvent.

Advantages of the new solution are that the basic character of the substance will be weakened, and the salts with organic acids will significantly improve the water solubility, which will enable practical use of the substance.

The process for producing salts according to the novel solution is explained in the following examples.

Example 1

9-Amino-7-methoxy-1,2,3,4-tetrahydroacridine hydrochloride monohydrate.

A solution of 22.8 g of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in 500 ml of absolute ethanol is mixed with 10 ml of concentrated hydrochloric acid and then evaporated to a volume of 100 ml. The precipitate is isolated by suction. 22 g of a colorless substance are obtained, m.p. 263-268 ° C with decomposition.

Example 2

9-Amino-7-methoxy-1,2,3,4-tetrahydroacridinium sulfate

-1GB 281347 B6

By mixing a solution of 22.8 g of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in 500 ml of absolute ethanol and 5 g of concentrated sulfuric acid, dissolved in 50 ml of absolute ethanol, followed by treatment as in Example 1, A colorless substance with a melting point of 298-303 ° C with decomposition was obtained.

Example 3

9-Amino-7-methoxy-1,2,3,4-tetrahydroacridinium acetate

Reaction of 22.8 g of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in 500 ml of absolute ethanol with 6 g of acetic acid gave a temperature of 100 ml after evaporation of the reaction mixture and addition of 500 ml of ether. 214-215 ° C.

Example 4

9-Amino-7-methoxy-1,2,3,4-tetrahydroacridinium hydrogen tartrate

Reaction of 22.8 g of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in 500 ml of absolute ethanol with 15 g of tartaric acid and treatment of the reaction mixture as in Example 3 gave a melting point of 222-226 ° C. with decomposition.

Example 5

9-Amino-7-methoxy-1,2,3,4-tetrahydroacridinium tartrate

Reaction of 22.8 g of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in 500 ml of absolute ethanol with 7.5 g of tartaric acid followed by evaporation of the reaction mixture gave a melting point of 258-265 ° C. with decomposition.

Example 6

9-Amino-7-methoxy-1,2,3,4-tetrahydroacridinium lactate

Reaction of 22.8 g of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in 500 ml of absolute ethanol with 9 g of lactic acid followed by treatment of the reaction mixture as in Example 3 gave a melting point of 198 - 201. Deň: 32 ° C.

Example 7

9-Amino-7-methoxy-1,2,3,4-tetrahydroacridinium dihydrogen citrate

Reaction of 22.8 g of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in 500 ml of absolute ethanol with 21 g of citric acid monohydrate followed by treatment of the reaction mixture as in Example 5 gave a melting point of 194- 196 ° C dec.

-2GB 281347 B6

Example 8

9-Amino-7-methosy-1,2,3,4-tetrahydroacridinium hydrogen citrate

Reaction of 22.8 g of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in 500 ml of absolute ethanol with 10.5 g of citric acid monohydrate followed by treatment of the reaction mixture as in Example 3 gave a melting point. 224 - 227 C with decomposition.

Example 9

The example illustrates the antiacetylcholinesterase activity of the compounds of the invention.

When measuring the inhibitory effect of the compounds of the invention, it was found, for example, that the compound of Example 4 has anticholinesterase activity on rat potential acetylcholinesterase expressed as PI50 = 5.44 (10 minutes incubation, pH 8, temperature 25 ° C) and equine plasma butyrylcholinesterase pI ₅₀ = 6.36 under the same conditions. For Example 6, _p150 = 5.44 (rat brain acetylcholinesterase) and 6.42 (horse plasma butyrylcholinesterase) were found.

Claims (6)

PATENT CLAIMS 1. Salts of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine of formula (I +) wherein X is an anion selected from the group consisting of Cl, Br, 1/2 ^ SO _4, CH ³ COO, C4H5O6, C4H5O 01.02 ^2_ 6, C ₃ H ₅ O ₃ C ₆ H ₇ O _7, 2.1 ΟθΗθΟ ² ^. A process for the production of a salt according to claim 1, characterized in that a solution of the base of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine in a solvent from the group of water, methanol, ethanol, propanol, isopropanol or mixtures thereof These solvents are neutralized with hydrochloric, hydrobromic, sulfuric, acetic, tartaric, lactic or citric acid in the molar ratio given by the stoichiometry of the general formula (I) and the isolation of the obtained salt is carried out. A process for producing salts according to claim 2, characterized in that the isolation of the salt is carried out by filtration. -3GB 281347 B6 4. A process for the production of salts according to claim 2, characterized in that the isolation of the salt is carried out by evaporation of the solvent. A process for the production of salts according to claim 2, characterized in that the isolation of the salt is carried out by partial evaporation of the solvent and filtration. A process for the production of salt according to claim 2, characterized in that the isolation of the salt is carried out by addition of diethyl ether and filtration.