DD224318A1 - PROCESS FOR PREPARING NEW 2- (2-GUANIDINOETHYL) -6,7-DIMETHOXY-1,2,3,4-TETRAHYDROISOCHINOLINE - Google Patents

Abstract

The target products according to the invention, including their acid addition products, are best prepared by reacting 2- (2-aminoethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or derivatives thereof in water or ethanol or in their mixtures with S -Methylisothiourea sulfate obtained. Because of their valuable pharmacological properties, they have an antihypertensive and spasmolytic effect and they inhibit the adrenaline or ADP-induced platelet aggregation, they are suitable for the preparation of medicines.

Description

N-CH ₂ -CH ₂ -NH-C

in which R is hydrogen, an alkyl group having 1 to 3 C atoms or a benzyl or 3,4-dimethoxybenzyl group, and their acid addition products, characterized in that amines of the general formula II

CH ₃ O, CH ₃ O "

N-CH ₂ -CH ₂ NH C _n

NH ₂

in which R has the abovementioned meanings, with S-methylisothiourea sulfate

Field of application of the invention

The invention relates to a process for the preparation of novel 2- (2-guanidinoethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolms of the general formula I

T R

NHY

in which R is hydrogen, an alkyl group having 1 to 3 C atoms or a benzyl or 3,4-dimethoxybenzyl group, and their acid addition products.

The erfmdungsgemaßen target products are suitable because of their valuable pharmacological properties for the preparation of medicaments.

Characteristic of the known technical solutions

It is known that substituted guanidines can be obtained by reaction of amines with both S-alkylisothiourea and cyanamide (WP 80124). From DE-AS 1917225 the preparation of 8-hydroxy-i, 2,3,4-tetrahydroisoquinoline-amidine is known, which is obtained by reacting 8-hydroxy-1,2,3,4-tetrahydroisoquinoline with S-Wiethylisothiohamstoff ,

The preparation of 2-guanidinoethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives has hitherto not become known.

Object of the invention

It is the object of the invention to develop a process for the preparation of novel guamdinotetrahydroisochmoline derivatives

Explanation of the essence of the invention

The object of the invention is achieved by reacting nurses of the general formula II,

N-CH ₂ -CH ₂ -NH

in which R has the abovementioned meanings, reacted with S-methylisoihiourea sulfate. This reaction is best carried out in water or ethanol or in their mixtures, preferably under reflux conditions. After completion

-2- 261 894 1

the reaction is cooled, the solution is adjusted slightly acidic with sulfuric acid. The solvent is vacuumed off to dryness in vacuo, the residue is recrystallized from ethanol. The bases of the compounds are advantageously liberated via an ion exchanger or converted into another salt. Suitable acids are both inorganic acids, such as hydrohalic acids or sulfuric acid, and organic acids, such as acetic acid, tartaric acid, citric acid and the like., Suitable. Purification of the acid addition products is conveniently carried out by recrystallization from an alcohol, optionally with the addition of ether or ethyl acetate to increase the recrystallization rate. The new guanidinoethyltetrahydroisoquinolines have valuable pharmacological properties. They have a hypotensive and spasmolytic effect. The adrenaline or ADP-induced aggregation of the platelet is inhibited by them.

embodiments example 1

20 g of 2-aminoethyl-1,2,3,4-tetrahydropapaverine hydrochloride are dissolved in 50 ml of water. By addition of 10N NaOH, the base is liberated and extracted with 2 × 20 ml of benzene. The base is obtained as a viscous-thick mass after distilling off the benzene completely in vacuo. 15.5 g of 2-aminoethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are dissolved in 20 ml of ethanol and a solution of 5.7 g of S-methylisothiourea sulfate in 20 ml of water is added. It is heated for 2 hours on the reflux condenser to boiling, acidified after cooling with sulfuric acid to a pH of 4 to 5 and sucks the solvent mixture in vacuo completely. The residue is dissolved in 25 ml of hot water and to the still hot solution also hot i-propanol (200 ml) was added. On slow cooling, the 2- (2-guanidinoethyl) -1,2,3,4-tetrahydropapaverine sulfate crystallizes in an amount of 19.3 g as white crystals, mp 160-162 ⁰ C.

Example 2

31.7 g of 2- (2-aminoethyl) -1-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are boiled with 19 g of S-methylisothiourea sulfate in 60 ml of ethanol and 60 ml of water for 2 hours heated. After adjustment to a pH of 4 to 5 with 2 η H ₂ SO ₄ crystallize on cooling 43g 1-ethyl-2- (2-guanidinoethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline sulphate from, mp. 162-

Example 3

21 g of 2- (2-aminoethyl) -1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 20 ml of ethanol, 20 ml of water and 9.8 g of S-methylisothiourea suifate are heated to boiling for 2 hours. After adjusting the solution to pH 4 to 5 with sulfuric acid, 32.7 g of 1-benzyl-2- (2-guanidinoethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline crystallize. from sulfate. For recrystallization, the salt is dissolved hot in 40 ml of water and 250 ml of i-propanol. The pure salt crystallizes in very fine white crystals. Yield: 24.5 g, mp 153-156 ⁰ C.

Example 4

32 g of 2- (2-aminoethyl) -1-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 19.2 g of S-methylisothiourea sulfate are dissolved in 120 ml of ethanol-water (1: 1) for 2 hours heated to boiling. After cooling, the pH is adjusted to 4 to 5 with sulfuric acid and the mixture of water-ethanol is completely distilled off. The residue is washed with 100 ml of i-propanol. There remain 36.7g white crystals of 2- <2-gu3nidinoethyl) -1-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline sulfate, mp. 230-247 ⁰ C.

Example 5

31.5 g of 2- (2-aminoethyl) -6,7-dimethoxy-1-n-propyl-1,2,3,4-tetrahydroisoquinoline are dissolved in 120 ml of a mixture of equal volumes of ethanol and water with 19 g of S-methylisothiourea sulfate Boiled for 2 hours at reflux condenser to boiling.

The pH of the solution is adjusted to 4 to 5 with 2 η H ₂ SO ₄ and the solvent mixture is completely filtered off with suction in vacuo. The residue is dissolved with a mixture of 25 ml of water and 230 ml of i-Propanoi hot; it crystallize after cooling 39g 2- (2-guanidino) -6,7-dimethoxy-1-n-propyl-1,2,3,4-tetrahydrofsochinolin-sulfate from, mp. 200-203 ⁰ C.

Example 6

10 g anion exchangers (eg Wofatit SBK or Dowex 1 χ 8) are converted in a suitable glass tube with drain cock with 100 ml of 3N HCl in the СП form, then washed free of acid with distilled water. 1 g of 2- (2-guanidinoethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline sulfate are dissolved in 20 ml of water and added at a rate of 1 drop / s over the anion exchanger. The effluent solution contains 2- (2-guanidinoethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as the hydrochloride. The solution and the necessary water for washing (to С negative) are completely evaporated to dryness in vacuo, the residue is crystallized from ethanol, whereby white crystals are obtained.

Seismic Example 7

10 g of anion exchangers (eg Wofatit SBK or Dowex 1 χ 8) are converted into the OH "form in a suitable glass tube with a drain cock with 100 ml of 3N NaOH, then washed with distilled water until free of alkali: 1 g of 2- {2-guanidinoethyl) - 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-suifate are dissolved in 20 ml of water and passed through the anion exchanger at a rate of 1 drop / sec. The effluent and the water required for the alkali-free washing of the exchanger are dissolved in The residue is taken up in isopropanol and i-propanol / HCl to give 2- (2-guanidinoethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as the hydrochloride in white crystals Instead of the i-propanol / HCl, other acids can be used to obtain the corresponding salts.

Claims (1)

-1 - 261 894 1 Invention claim: A process for the preparation of novel 2- (2-Guamdinoethyl) _-6-r 7 din8thoxy-1,2,3,4-tetrahydroisoquinolines of the general formula I CH ₃ O
CH ₃ O NH