NO148108B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE ISOQINOLINE ACETAMIDE DERIVATIVES - Google Patents

Description

The present invention relates to an analogous method for the production of new, therapeutically active 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline derivatives with the general formula:

where

R"*" is hydrogen or benzyloxycarbonyl, and

R 2 is pyridyl, thiazolyl, quinoxalyl or phenyl, where the phenyl group is optionally substituted with C₁₄₄ alkoxy, C₂₄₄-alkanoyl, C₁₄₄-alkyl and/or with 1 or 2 halogen atoms.

The new compounds of formula I can be prepared by reacting 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid with the formula:

with benzyloxycarbonyl halide and react the thus formed 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid with the formula: or a reactive acid derivative with the general formula:

hence, where

R 3 is C₁₄₄₄ alkoxy or phenoxy optionally substituted with nitro,

with an amine of the general formula:

where R 2 is as indicated above, and optionally remove the benzyloxy-carbonyl group, and optionally transfer the obtained compound of the general formula I to a pharmaceutically acceptable salt thereof or to liberate it from its salt.

The 1-(2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolyl)- and 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamides with the general formula I are new compounds. The N-alkyl and N-aralkylacetamide derivatives which are structurally most similar to the compounds of the invention were prepared by Lombardino, J.G. et al. [J. With. Chem. 3, 505 (1961), USP

No. 3,021,331 C. A. 57, 786 d (1962)], and the compounds were used as starting materials in the preparation of condensed cyclic compounds.

The above-mentioned compounds were used as starting materials also according to US P No. 3,654,281 C. A. 11_, 19688a (1972). The biological activity of the compounds of the general formula I produced according to the invention could not be predicted on the basis of the above-mentioned publications.

In the present method, 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid of the general formula IX is reacted with benzyloxycarbonyl chloride. The reaction is carried out in a solvent or in the absence of a solvent at a reaction temperature of from -10° to +100°C. During the reaction, hydrochloric acid is released which binds with an organic or inorganic base. Tertiary amines, such as triethylamine, dimethylamine or pyridine, can preferably be used as organic bases, but an excess of the isoquinoline derivatives can also be used as an acid-binding agent. As inorganic bases, an alkali hydroxide, alkali carbonate, alkaline earth metal hydroxide or

-carbonate is used. The reaction can be carried out in a solvent. Water, lower alkyl alcohols, ketones and ethers can be used as solvents. The reaction can be carried out by adding 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid

to the solution of the equimolar base, and benzyloxycarbonyl chloride is added dropwise with stirring and cooling. The reaction is complete after stirring for 1 - 8 hours. The product is isolated after acidification by filtration or possibly by evaporation. The solid thus obtained is optionally purified by crystallization or by other physical methods.

The 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid obtained is reacted with an amine of the general formula:

where R 2 is as indicated above,

in the presence of a tertiary amine such as triethylamine and alkoxycarbonyl chloride such as isobutyloxycarbonyl chloride. The reaction is optionally carried out in a solvent. Ketones, ethers such as acetone, methylethyl ketone and tetrahydrofuran can preferably be used as solvents. The reaction can be carried out at a temperature in the range from -15°C to +30°C. The temperature is preferably kept below +5°C during the reaction and ends at 20 to 25°C. The product is preferably isolated from the reaction mixture by filtering off the formed tertiary amine salt and evaporating the filtrate. The residue contains the desired product, which may be purified by a physical method such as crystallization.

According to a further embodiment of the present method, an alkyl or aryl ester of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acid is reacted with the general formula XI (prepared from an acid or an acid chloride of the general formula X, in a manner known per se) with an amine of the general formula V. The reaction can be carried out in a solvent or in the absence of a solvent by heating the reactants. Aromatic or aliphatic hydrocarbons, alcohols or ethers can be used as solvents. The alcohol formed during the reaction is preferably distilled off. The reaction can be carried out by using so-called active esters, such as p-nitrophenyl ester. The reaction temperature and reaction time depend on the substituent R 3, i.e.

the type of ester used in the reaction. In the case of alkyl esters, a higher temperature (50 - 150°C) and a longer reaction time (2 - 10 hours) are required than when aryl esters, particularly active esters, are used. After the reaction has ended, c the solid is removed by filtration or evaporation. The solid substance is optionally purified by physical methods such as crystallization.

In a further alternative of the method according to the invention, 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acid is reacted with amines with the gene

or formula V in the presence of carbodiimides, such as dicyclohexylcarbodiimide. The reaction is preferably carried out in a solvent. Aromatic or aliphatic hydrocarbons such as benzene and homologues thereof, petrol, etc., ketones such as acetone, acetophenone, ethers such as ethyl ether, dioxane and tetrahydrofuran are preferably used as solvents. The reaction takes place easily, and it is therefore preferably carried out at a low temperature such as from -20° to +30°C. During the reaction, a urea derivative is formed from the carbodiimide which collects as an insoluble solid. After the reaction is complete, the insoluble urea derivative is filtered off and the filtrate is evaporated to recover the product, which is optionally purified by crystallization or by another physical method.

In a further alternative of the method according to the invention, 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acid of the general formula X is preferably reacted under heating with amines of the general formula V. The reaction can carried out in the presence or absence of a solvent. A solvent that is not miscible with water is preferably used as a solvent, and the water formed during the reaction is removed by azeotropic distillation. The equilibrium is thus shifted in the direction of formation of the acid amides with formula I. When working without a solvent, the acids with the general formula X are heated together with the amines with the general formula V at 100 - 200°C. Removal of the formed water is also desirable in this case. This can be done by carrying out the reaction in an open vessel, or nitrogen or another inert gas is passed over the reaction mixture. The reaction can be carried out in a vacuum. When a solvent is used, the solvent is removed by distillation after the reaction is complete, and the product thus obtained is optionally purified by crystallization.

The benzyloxy-carbonyl group is then optionally removed from the obtained 2-benzyloxycarbonyl-6,7-dimethoxy-152 , 3>4-t rahydro-1-isoquinoline-acet amdd derivatives by dissolving the benzyloxycarbonyl derivative in concentrated acetic acid containing hydrogen bromide, and after standing, a 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamide derivative crystallizes

from the solution and can be isolated by filtration.

The benzyloxycarbonyl group can likewise be removed by catalytic hydrogenation. The benzyloxycarbonyl derivative is dissolved in a solvent and hydrogenated in the presence of a hydrogen transfer catalyst such as palladium/charcoal. The catalyst is filtered off, and the product can be recovered by filtration or evaporation.

The process compounds are effective anti-inflammatory agents. This anti-inflammatory activity is higher than the anti-inflammatory activity of the known phenylbutazone, and the toxicity of the compounds is also lower than that of the phenylbutazone. Thus N-(2-quinoxalyl)-6, 7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamide causes an inhibitory

ing of 44% in a carrageenin foot edema test in mice at a 25 mg/kg i.p. dose, an inhibition of 30% at a dose of 2.5 mg/kg in rats and an inhibition of 47% at a dose of 10 mg/kg in rats. In case of administration i.p. of a dose of 80 mg/kg no death of mice occurred.

N-(p-methoxyphenyl)-6,7-dimethoxy-1,2,3,4~tetrahydro-1-isoquinoline-acetamide produces a 25% inhibition in a carrageenin photoedema test in rats administered i.p. in a dose of 10 mg/kg, and an inhibition of 57% in a dose of 25 mg/kg. The toxicity administered to mice i.p. is 280 mg/kg.

1-(p-chlorobenzoyl)-2-methyl-5-methoxy-2-indolyl-acetic acid,. the known indomethacin, causes an inhibition of 50% in the carrageenin foot edema test in rats administered i.p. in a dose of 10 mg/kg, and the toxicity is 33 mg/kg administered per us.

The phenylbutazone, (4-n-butyl-1,2-diphenyl-1-pyrazolidine-3,5-dione), produces a 22% inhibition in a carrageenin foot edema test in rats at a dose of 30 mg/kg, and the toxicity administered p.o. for mice is 660 mg/kg.

The pharmaceutical preparations of the process compounds can be prepared in the form of oral, parenteral or local routes of administration. Unit dosage forms of tablets, capsules or dragees, solutions for injection, ointments, talcum and sprays, etc., can be prepared. The pharmaceutical preparations may contain inorganic or organic solid or liquid carriers, such as water, polyethylene glycol, talc, starch, calcium carbonate, magnesium stearate, cocoa butter, vaseline, etc.

The usual remedies can also be added as stabilizers, disintegrants, etc. The preparations are prepared in a manner known per se.

Further details of the present invention are illustrated by the following examples.

Production of starting material

28.7 g (0.1 mol) of 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid are dissolved in 50 ml of an aqueous solution of sodium hydroxide. The solution is cooled to from -10° to -15 C,

and 17 g (0.1 mol) of benzyloxycarbonyl chloride are added dropwise to the solution while cooling over the course of 30 minutes. The cooled reaction mixture is stirred for a further 3 hours, after which it is acidified with 40 ml of 20% hydrochloric acid. The precipitated crystals are filtered off, washed with water, dried and recrystallized. 32,592-benzyloxy-carbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid is obtained. Mp.: 153 - 154°C.

Analysis for the formula c2i<H>26<N>06

Example 1

0.02 mol of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetra-hydro-1-isoquinoline-acetic acid is dissolved in 80 ml of anhydrous tetrahydrofuran, the solution is cooled to from -10 to -15°C, and at the same time 0.02 mol of triethylamine and 0.02 mol of isobutyloxycarbonyl chloride in 5 ml of tetrahydrofuran are added dropwise over the course of 5 minutes to the solution while stirring. After stirring for a further 5 minutes, 0.02 mol of the corresponding amine is added dropwise to the reaction mixture in 20 ml of tetrahydrofuran, the mixture is stirred for 5 hours and allowed to stand overnight. The precipitated triethylammonium chloride is filtered off and washed with tetrahydrofuran. The tetrahydrofuran solutions are evaporated. The residue is dissolved in 70 ml of ethyl acetate and washed with 2.6 ml of water and 1% sodium hydroxide solution, and again with water to neutrality. The ethyl acetate is dried over sodium sulphate and evaporated in vacuo. The residue is crystallized. Data for the compounds obtained are given in Table I.

Example 2

7.7 g (0.02 mol) of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid are dissolved in 30 ml of chloroform, and the solution is heated with 2.839 (0.024 mol) thionyl chloride under reflux for 1 hour. The reaction mixture is then evaporated in vacuo, and the remaining acid chloride is dissolved in 10 ml of benzene.

2.9 g (0.02 mol) of 2-amino-quinoxaline is dissolved in 10 ml of benzene

and is added dropwise to the mixture at 0°C simultaneously with the solution of 2-benzyloxycarbonyl-6,7-dimethoxy-1-isoquinolyl-acetyl chloride prepared as described above together with 15 ml of 2 N sodium hydroxide. After the addition is complete, the mixture is allowed to warm and stir at room temperature for 3 hours. After separation, the benzene layer is washed with 2 N sodium hydroxide and water. The benzene solution is dried and evaporated. 9.4 g of 2-(2-benzyloxycarbonyl)-6,7-dimethoxy-1,2,3,4~t rahydro-1-isoquinolyl-acetamido)-quinoxaline are obtained. Mp.: 166- - 167°C (from ethanol and ether).

Example 3

10.12 g (0.02 mol) p-nitrophenyl-(2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline)-acetate and 2.149

(0.02 mol) p-toluidine is heated in 50 ml of toluene under reflux i

3 hours. The reaction mixture is cooled and washed with 1 N sodium hydroxide and with water. The toluene solution is dried over anhydrous sodium sulfate and evaporated. 9.2 g of N-tolyl-(2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl)-acetamide are obtained. Temp. 167 - 169°C (ethanol).

Example 4

7.7 g (0.02 mol) of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid and 1.86 g (0.02 mol) of aniline are dissolved in 80 ml of tetrahydrofuran, and at 0°C 4.52 g (0.022 mol) of dicyclohexylcarbodiimide dissolved in 20 ml of tetrahydrofuran are added dropwise while stirring. This mixture is stirred at 0°C for 1 hour and at room temperature for 2 hours. The precipitated dicyclohexylurea is filtered off, washed with tetrahydrofuran, and the filtrate is evaporated.

9.2 g of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl-acetanilide are obtained. Mp.: 104 - lo6°C (benzene:et here) .

Example 5

7.7 g (0.02 mol) of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid and 2.9 g (0.02 mol) of 2-amino- quinoxaline is mixed together, and the mixture is heated at 170 - 180°C

for 3 hours under a gentle stream of nitrogen. Upon cooling, 8.2 g of 2-(2-benzyloxycarbonyl-6,7-dimethox<y->1,2,3,4-tetrahydro-1-isoquinolyl-acetamido)-quinoxaline are obtained with m.p. 165 - 166°C (ethanol:ether

Example 6

0.02 mol of one of the substituted 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamides listed in Table I is dissolved in a solution of 4 - 5 equivalents of 30% ig hydrogen bromide solution in glacial acetic acid. After 30 to 50 minutes, crystals separate from the solution, and the solution becomes solid. After adding ether, the precipitation of crystals will be complete, and the solid substance is filtered off and washed with ether. After drying, recrystallization follows. Data for the products obtained are collected in Table II.

Claims (3)

1. Analogy method for the preparation of therapeutically active compounds with the general formula: and salts thereof, where R*" is hydrogen or benzyloxycarbonyl, and R 2 is pyridyl, thiazolyl, quinoxalyl or phenyl, where the phenyl group is optionally substituted with C^_4~ alkoxy, C^_4~ alkanoyl, C^_4~ alkyl and/or with 1 or 2 halogen atoms, characterized in that 6, 7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-acetic acid with the formula: is reacted with benzyloxycarbonyl halide, and the obtained 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid with the general formula: or a reactive derivative thereof with the general formula: where R 3 is -a C 3 -C 6 -alkoxy- or an optionally NO 2 -substituted phenoxy group, is reacted with an amine of the general formula: 2 where R is as stated above, and if desired the benzyloxycarbonyl group is removed, and the resulting compound is optionally transferred of the general formula I to a pharmaceutically acceptable salt thereof, or it is liberated from its salt. 2. Process according to claim 1 in the preparation of N-[2-quinoxalyl]-6,7-methoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamide, characterized in that a compound of formula (X) or ( XI) is reacted with an amine of formula (V) where R 2 is 2-quinoxalyl, and the benzyloxycarbonyl group is removed. 3. Process according to claim 1 in the preparation of N-[p-methoxyphenyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamide, characterized in that a compound of formula (X) or ( XI) is reacted with an amine of formula (V) where R 2 is p-methoxyphenyl, and the benzyloxycarbonyl group is removed.