CS247178B2 - Process for preparing novel 8-alkoxycarbonylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives - Google Patents

Abstract

A process for the production of new 8-alkoxycarbonylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of the compound of general formula I (I), in which X represents a hydrogen or halogen atom and R represents an alkyl group with 1 to 6 carbon atoms, a haloalkyl group with 1 to 6 carbon atoms or a phenylalkyl group with 1 to 6 carbon atoms in the alkyl moiety, and their pharmaceutically usable acid addition salts are obtained by cyclization of the compound of general formula II X hoch N CH3 I HN-COOR and optionally by converting the obtained compound of general formula I into a pharmaceutically usable acid addition salt.

Description

The invention relates to a process for the preparation of novel 8-alkoxycarbonylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives having valuable pharmacological properties.

British Patent Specification No. 1,164,192 discloses 8-amino-4-aryl-2-alkyl-tetrahydroisoquinoline derivatives which are substituted on the amino group with an acyl group derived from a saturated or unsaturated aliphatic carboxylic acid containing up to 6 carbon atoms, aromatic carboxylic acids or arylaliphatic carboxylic acids containing 7 to 10 carbon atoms. These compounds have the ability to stimulate the central nervous system and further have a thymoleptic effect. Compounds having a similar structure are already described in DOS Nos. 1,670,848 and 1,795,829.

We have now found novel 8-alkoxycarbonylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of the formula I

n-ch ₃

HN-COOR wherein hydrogen or halogen represents an alkyl group having 1 to 6 carbon atoms, a halogen substituted alkyl group having 1 to 6 carbon atoms or a phenylalkyl group having 1 to 6 carbon atoms in the alkyl moiety, and pharmaceutically acceptable addition salts thereof with acids having valuable pharmacological properties.

The present invention provides a process for the preparation of novel 8-alkoxycarbonylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of formula I and their pharmaceutically usable acid addition salts by cyclizing the compound of the general formula (II): wherein

BOY

HN-COOR

(II) are as hereinbefore defined, then optionally converting the compound of formula (I) so obtained into a pharmaceutically acceptable acid addition salt.

A preferred representative of the compounds of formula I is 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline and pharmaceutically acceptable acid addition salts thereof, especially the hydrochloride. This compound has particularly favorable therapeutic properties.

The term lower alkyl as used herein denotes a straight or branched chain aliphatic hydrocarbon group having 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.).

t

The term halogen includes fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be formed from suitable inorganic or organic acids. Such salts may be formed using mineral acids (e.g. hydrohalides such as hydrochlorides, hydrobromides, sulfates, phosphates, etc.) or using organic acids (such as formates, acetates, propionates, lactates, maleates, tartrates, benzoates, salicylates etc.). ).

The cyclization according to the invention can be carried out in the presence of an acid catalyst, for example mineral acids (such as hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.) or Lewis acids (for example aluminum chloride, boron trifluoride, zinc chloride, tin tetrachloride etc.). It is particularly preferably carried out in the presence of sulfuric acid as a catalyst.

The reaction is carried out in an inert organic solvent. As the reaction medium preferably halogenated hydrocarbons (e.g. methylene chloride, chloroform, etc.) can be used. The reaction temperature depends on the activity of the catalyst. The reaction is generally carried out at temperatures from 0 to 80 ° C.

The compounds of the formula I obtained can be isolated from the reaction mixture by methods known per se. For example, the acidic solution is poured onto ice, basified and the compound of formula (I) is obtained by extraction with an organic solvent (e.g. chloroform).

The starting compounds of formula II can be prepared by reacting a compound of formula V

X

i nh ₂ in which

X is as defined above, with the haloformate of formula IV

Hlg-COOR (IV) in which

R is as defined above and

H 1g is halogen, preferably chlorine or bromine.

In this reaction, preference is given to starting compounds of formula IV in which Hg is chlorine. The reaction is carried out in an inert organic solvent. As reaction medium, aromatic hydrocarbons such as benzene, toluene, xylene, etc. are preferred.

The reaction is preferably carried out with heating, preferably at the boiling point of the reaction mixture. This reaction can also be carried out in the absence of a solvent. Preferably, the reaction is carried out in the presence of an acid binding agent, such as tertiary amines, for example triethylamine or pyridine.

The compounds of formula (I) may be converted into their acid addition salts which are pharmaceutically acceptable. The salt formation can be carried out according to generally known and used methods

The base of formula I is reacted with the corresponding acid in a suitable inert organic solvent. The acid is preferably used in a stoichiometric amount. Alternatively, the compound of formula I can be liberated from its non-pharmaceutically acceptable salt using a strong base, and the resulting free base of formula I is then reacted with the corresponding pharmaceutically acceptable acid of formula I .

The compounds of formula (v) are known (cf. British Patent No. 1,164,192).

The novel compounds of the formula I and their pharmaceutically usable acid addition salts have valuable pharmacological properties and show particularly valuable central nervous system effects. In particular, the compounds of the formula I can be used as active ingredients of antidepressant and / or antiparkinsonian agents.

The present invention also relates to pharmaceutical compositions comprising as active ingredient one or more compounds of formula (I) or a pharmaceutically acceptable acid addition salt thereof and an inert, non-toxic, solid or liquid pharmaceutically usable carrier.

The pharmaceutical preparations may be presented in forms suitable for oral administration (e.g. in the form of tablets, capsules, dragees, solutions, emulsions, suspensions, etc.) or for parenteral administration (e.g. in the form of injections). The pharmaceutical preparations may contain conventional inert solid or liquid carriers (such as talc, starch, magnesium stearic acid, magnesium carbonate, calcium carbonate, water, alcohols, polyalkylene glycol, etc.). These preparations may also contain usually pharmaceutical auxiliaries (such as wetting agents, disintegrants, flavor enhancers, etc.).

The pharmacological activity of the compounds produced by the process of the present invention is determined by the following tests:

1) Acute toxicity, subcutaneous administration, LD ^ q values measured after 96 hours of observation.

2) Subcutaneous dose that inhibits catalepsy induced by 13 µmol / kg haloperidol by 50% in mice.

3) The lowest intraperitoneal dose that increases or decreases mouse motility.

4) Subcutaneous dose that inhibits catalepsy induced by a dose of 110 yumol / kg tetrabenazine in 50% of mice.

5) Subcutaneous dose that prevents ptosis induced by a dose of 79 µmol / kg tetrabenazine in 50% of mice.

6) The lowest subcutaneous dose that avoids the decrease in rectal temperature induced in mice by a 1.6 µmol / kg reserpine dose.

7) The lowest intravenous dose that increases blood pressure in cats and increases the effect of dopamine on nictitans.

8) The lowest subcutaneous dose that still induces stereotipia in the rat.

9) Dose that elicits characteristic circular movements after electrolytic damage of substantia nigra.

10) Dose that causes a significant decrease in prolactin levels after 4 days of treatment with a dose of 0.073 µmol / kg estradiol in rats that had been ovariectomized three weeks previously.

The following compounds were tested:

Compound A = compound of the invention, ie 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

Nomifensine = reference compound, ie 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (a compound known from British Patent Specification No. 1,164,192).

The test results are summarized in Tables I and II below.

Table I Test results

tested compound 1 ED 2 TI 3 ED +/- TI 4 5 6 ^ED 2 ED TI ED TI ED TI ed ₄ Nomifensin 1128 56 20 May 28+ 40 37 30 4.2 268 28 40 1.6 AND 2176 55 40 7.9 -275 13 167 1.6 1360 26 84 4.2

Table II

Test compound

Nomifensin

AND

1.4

1.3

Test

9 10

42 28

39 26

Acute toxicity Doses are expressed

In Test 3, means were determined in mice. Tests 2-6 were also performed on mice. in micromol / kg. The therapeutic index (TI) is the ratio of LD / ED.

increase motility decrease motility.

TBZ = tetrabenazine.

Tests 7-10 are performed on cats and rats and doses are expressed in micromoles / kg.

Tests 2, 8, 9 and 10 are suitable for evaluating the stimulation of the dopaminergic effect of test compounds (a potential antiparkinsonian agent).

Tests 4, 5, 6 and 7 provide information on the catecholamine uptake inhibitory effect (potential antidepressant effect).

Nomifensin is used as a reference in the table. This known drug has sonic antiparkin and antidepressant effects.

The spectrum of action of the compounds of the invention differs from that of Nomifensin. Compounds of formula I do not increase spontaneous motility in mice. In contrast, Nomifensin has the ability to increase spontaneous motility. The absence of said psychomotor stimulating effect, which is similar to that of amphetamine, is a beneficial factor in therapeutic terms.

Compound A has excellent therapeutic properties. This compound has a significantly lower toxicity and a higher effect than Nomifensin. According to various tests, the therapeutic index of Compound A is 2 to 6.8 times higher than the Nomifensinv therapeutic index.

Based on a comparison of the results of the anti-haloperidol test (dopaminergic type) and the anti-tetrabenazine efficacy, which are characteristic of the antidepressant effect, the following can be stated:

The quotient of ED values from columns 2 and 4 is highest for compound A (55:13 = 4.2).

That is, this compound is a relatively potent antidepressant agent than an antiparkinsonian agent. This value is also high for Nomifensin (1.6).

Further details are apparent from the following examples, which are not intended to limit the scope of the invention in any way.

Example 1

Preparation of 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

a) Preparation of the starting base, ie 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

Ί

A solution of 13.1 g (0.047 mol) of 8-amino-4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline and 300 ml of absolute benzene is mixed with a solution of 6.8 g (0.062 5). mol, 6 ml) of ethyl chloroformate and 60 ml of absolute benzene. The reaction mixture was refluxed for 2.5 hours and the benzene was distilled off in vacuo. The residue was dissolved in 10 ml of water, basified with 10 ml of concentrated ammonium hydroxide solution and extracted three times with 100 ml of chloroform each. The chloroform extracts were combined, dried over anhydrous sodium sulfate, evaporated, and the residue was recrystallized from ethanol. There was thus obtained 7.3 g of the title compound as white crystals. Yield: 45.6%. Mp 155 ° C.

(molecular weight

344,845) calculated: found:

66.19% C 66.79% C

6.14% H 5.89% H

N, 8.12. N, 8.42

10.28% Cl, 10.56% Cl.

b) 7.3 g (0.021 2 mol) of the base prepared according to a) are suspended in 50 ml of ethanol, and 10 ml of ethanol saturated with hydrogen chloride are added thereto under cooling.

Ether was then added to the reaction mixture, and precipitation of the product was complete by scratching the stick with the wall of the reaction flask. The precipitated product is filtered off and washed with ether. Thus, 8.1 g of the title compound is obtained in the form of a white powder. The yield is almost 100%. 145 DEG-150 DEG C. (decomposition).

Analysis: ^C 19 ^H 22 ^C '''2 ^O 2 ^N 2 (molecular weight 381.30) calculated: C 59.85% found: 59.74% C,

5.82% H 7.35% N 18.60% Cl 9.30% Cl

6.06% H 7.17% N 18.54% Cl. 9.21% Cl

Example

Preparation of 8- (ethoxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline

2.6 g (0.01 mol) of N- (2-aminobenzyl) -1-phenyl-2-methylamino-1-ethanol are dissolved in 30 ml of ether. 0.79 g (0.01 mol) of absolute pyridine was added to the obtained solution, and 1.3 g (0.012 mol) of ethyl chloroformate were added under vigorous stirring and cooling, and the reaction was carried out at 15 ° C. The reaction mixture was stirred at room temperature for 30 minutes, then poured into 30 ml of ice-cold water. The aqueous phase is extracted three times with 100 ml of ether each time, the combined extracts are dried over anhydrous sodium sulphate and evaporated under reduced pressure. 2.8 g of N- [2- (ethoxycarbonylamino) benzyl] -1-phenyl-2-methylamino-1-ethanol are thus obtained in the form of a yellowish white oil which is used as is for the next reaction without purification.

2.8 g of the oily residue obtained in the preceding paragraph are dissolved in 40 ml of dichloromethane and this solution is poured into 15.4 ml of concentrated sulfuric acid at a temperature of 5 to 6 [deg.] C. in half an hour. cooling and stirring. The reaction mixture was stirred at this temperature for an additional 20 minutes and then poured onto 60 g of ice. The mixture was made alkaline with cooling with stirring with a 30% aqueous sodium hydroxide solution and extracted three times with 80 ml of chloroform each. The organic phases were combined, dried over anhydrous sodium sulphate and evaporated in vacuo. 2.3 g of a yellowish-white solid are obtained. Recrystallization from ethanol gave 2.0 g of the title compound as white crystals. Melting point 174 ° C. Yield 64.5%.

The following compounds were further prepared in an analogous manner to that described in Example 2:

8- (butoxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline

Melting point: 106 ° C (white powder),

4-Phenyl-8- (O-chloroethoxycarbonylamino) -2-methyl-1,2,3,4-tetrahydroisoquinoline

154 ° C,

8- (benzyloxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 147-148 ° C,

8- (benzyloxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline maleate Melting point 166-167 ° C,

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of novel 8-alkoxycarbonylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of the general formula I X HN-COOR (i) in which X R is hydrogen or halogen and represents a (C1-C6) alkyl, (C1-C6) haloalkyl or (C1-C6) phenylalkyl group in the alkyl moiety, and pharmaceutically acceptable acid addition salts thereof, The process of claim 1 wherein the compound of formula II is cyclized wherein, n-ch ₃ HN-COOR (II) X and R; are as defined above, whereupon the compound of formula (I) thus obtained is converted into a pharmaceutically acceptable acid addition salt. 2. Process according to claim 1, characterized in that the cyclization is carried out in the presence of an acid catalyst, such as a mineral acid or a Lewis acid, preferably in the presence of sulfuric acid. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out in a halogenated hydrocarbon. Process according to one of Claims 1 to 3, characterized in that the reaction is carried out at a temperature of from 0 to 80 ° C. A process according to any one of claims 1 to 4 for the preparation of 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline and its hydrochloride, characterized in that starting from compounds of the formula II in which X represents a chlorine atom in the p-position and R represents an ethyl group, followed by the optionally obtained 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1, 2,3,4-tetrahydroisoquinoline is converted to its hydrochloride.