CS247177B2 - Process for the preparation of new 8-carbamoylamino-4-aryl-2-methyl 1,2,3,4-tetrahydroisoquinoline derivatives - Google Patents

Abstract

A process for the production of novel 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of the general formula I and their pharmaceutically usable acid addition salts, characterized in that the compound of the general formula II and their pharmaceutically usable acid addition salts, characterized in that the compound of the general formula II

Description

The invention relates to a process for the production of new derivatives of 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4

-tetrahydroisoquinoline, which have valuable pharmacological properties.

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

New isoquinoline derivatives of the general formula I have now been found

8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydro-

r1 represents a hydrogen atom, a halogen atom or an alkyl group with 1 to 4 carbon atoms,

R represents an alkyl group with 1 to 6 carbon atoms, and their pharmaceutically usable acid addition salts which have valuable pharmacological properties.

The subject of the invention is a process for the production of new compounds of general formula I and their pharmaceutically usable acid addition salts, which consists in reacting a compound of general formula II

N-CH ₃ < II) in which r! has the above meaning, with an isocyanate of the general formula III

R-NCO (III)z in which

R has the above-mentioned meaning, whereupon the compound of general formula I thus obtained is optionally converted into a pharmaceutically usable acid addition salt.

The term "alkyl group" used in the description of this invention means a straight or branched chain hydrocarbon group containing the indicated number of carbon atoms, i.e. 1 to 6 or 1 to 4 carbon atoms, for example, methyl, n-propyl, isopropyl, n-butyl, ethyl, isobutyl, etc.

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

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

Preferred representatives of compounds of general formula I are the following compounds:

8-(n-butylcarbamoylamino)-4-(p-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline,

8-(n-butylcarbamoylamino)-4-(p-tolyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline and their pharmaceutically usable acid addition salts.

According to the present invention, a compound of formula II is treated with an isocyanate of formula III. This reaction is carried out in an inert organic solvent. Aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) are preferably used as the reaction medium.

This reaction is carried out under heating, preferably at the boiling temperature of the reaction mixture.

The reaction mixture can be worked up by methods known per se. For example, the solvent is distilled off and the residue is purified by chromatographic methods.

The starting compounds of general formula II can be prepared by cyclization of compounds of general formula V

in which

R^ ^- has the meaning given above.

The cyclization is carried out in the presence of an acid catalyst. For this purpose, mineral acids (e.g. sulfuric acid, polyphosphoric acid, etc.) or Lewis acids (e.g. boron trifluoride, aluminum chloride, zinc chloride, tin tetrachloride, etc.) can be used.

* A particularly preferred acid catalyst is sulfuric acid. The reaction is carried out in an inert organic solvent, preferably in halogenated hydrocarbons (for example, in methylene chloride, chloroform, etc.).

Reaction temperatures depend on the activity of the catalyst. If sulfuric acid is used as a catalyst, the reaction proceeds rapidly even at low temperatures, for example at a temperature of 0 to 6 °C.

The reaction mixture can be worked up by methods known per se. If sulfuric acid is used as a catalyst, the reaction mixture is poured onto ice, the mixture is made alkaline and the product is isolated by extraction with an organic solvent. Halogenated hydrocarbons (e.g. chloroform) are preferably used as the extraction agent.

Compounds of the general formula V are known (cf. British Patent Specification No. 1,614,192).

The compounds of the general formula I can be converted into their addition salts formed with pharmaceutically acceptable acids. The formation of salts can be carried out by generally known and used methods. «The base of the general formula I is reacted with the corresponding acid in a suitable inert organic solvent. The acid is preferably used in a stoichiometric amount. It is also possible to proceed in such a way that the compound of the general formula I is liberated from its salt, which is not pharmaceutically acceptable, using a strong base, and the free base of the general formula I obtained is then reacted with the corresponding acid, which is pharmaceutically acceptable.

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

The present invention also relates to pharmaceutical compositions which contain as active ingredient one or more compounds of the general formula I or a pharmaceutically acceptable acid addition salt thereof and inert non-toxic, solid or liquid pharmaceutically acceptable carriers.

Pharmaceutical preparations may be in forms suitable for oral administration (for example, in the form of tablets, capsules, dragees, solutions, emulsions, suspensions, etc.) or for parenteral administration (for example, in the form of injections). Pharmaceutical preparations may contain conventional inert solid or liquid carriers (such as talc, starch, magnesium stearate, magnesium carbonate, calcium carbonate, water, alcohols, polyalkylene glycol, etc.). These preparations may also contain conventional pharmaceutical auxiliaries (such as wetting agents, disintegrating agents, flavoring agents, 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 application, LD ₅₀ values measured after 96 hours of observation.

2) A 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 µmol/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 prevents the decrease in rectal temperature in mice induced by administration of a dose of 1.6 µmol/kg of reserpine.

7) Lowest intravenous dose that increases blood pressure and enhances the effect of dopamine on the nictitating membrane in cats.

8) Lowest subcutaneous dose that still induces stereotypy in rats.

9) The dose that induces characteristic circular movements after electrolytic damage to the substantia nigra.

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

The following compounds were tested:

compound A = compound from example 4 compound B = compound from example 5

Nomifensine = reference compound, i.e. 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline, which is described in British Patent Specification No. 1,164,192.

The test results are summarized in the following Tables I and II.

Table I Tests

tested 1 2 3 4 5 6 edition ₂ compound ED YOU ED+/-TI ED YOU ED YOU ED YOU edition ₄ Nomifensine 1128 56 20 28+ 40 37 30 4.2 268 28 40 1.6 A 2049 246 8 31- 66 90 23 31 66 205 2.7 B 2566 214 12 43- 60 128 20 32 80 86 30 1.7

II

Table

Test compound

Nomifensine * 1.4

A 6.1

B >11

Test

8 9 10 23 42 28 275 143 178 107

Acute toxicity was determined in mice. Tests 2 to 6 were also performed in mice. Doses are expressed in micromol/kg. The therapeutic index (TI) is the ratio of LD/ED.

In test 3, + indicates increased motility, decreased motility.

The designation means that the compound is ineffective at the dose applied.

TBZ = tetrabenazine.

Tests 7 to 10 are performed in cats and rats and doses are expressed in micromol/kg.

Tests 2, 8, 9 and 10 are suitable for evaluating the stimulation of the dopaminergic effect of the test compounds (potential antiparkinsonian agent). Tests 4, 5, 6 and 7 provide information on the inhibitory effect on catecholamine uptake (potential antidepressant effect).

The table uses Nomifensine as a comparator. This well-known drug has antiparkinson and antidepressant effects.

The spectrum of action of the compounds according to the invention differs from the spectrum of action of Nomifensine. The compounds of formula I do not increase spontaneous motility in mice. In contrast, Nomifensine has the ability to increase spontaneous motility. The absence of the aforementioned psychomotor stimulating effect, which is similar to the effect of amphetamine, is a favorable factor from a therapeutic point of view.

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

The quotient of the ED values from columns 2 and 4 is high for Nomifensine (1.6) and compounds A (2.7) and B (1.7). This means that these compounds are relatively more potent antidepressant agents than antiparkinsonian agents.

Further details are apparent from the examples given below, which, however, do not limit the scope of the invention in any way.

Example 1

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

A mixture of 3.6 g (0.015 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline, 1.17 g (0.0165 mol) of ethyl isocyanate and 40 ml of absolute benzene is heated to reflux for 2 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in 40 ml of chloroform and the solution is chromatographed on a silica gel column and eluted with 250 ml of chloroform containing 10% ethanol and 250 ml of chloroform containing 20% ethanol. The combined eluates are evaporated and the residue (3.8 g) is treated with petroleum ether. The solid product is reacted with a solution of 3.5 g (0.029 mol) of maleic acid in 60 ml of ethanol.

The reaction mixture was diluted with 200 ml of ether and cooled. The precipitated product was filtered off (5.0 g) and recrystallized from a mixture of ethanol and ether. This gave 4.5 g of the title compound. Melting point 137-139 °C (decomposition). Recrystallization from ethanol gave 3.7 g of the pure title compound. Yield 77%. Melting point 140 °C (decomposition).

(molecular weight 425.49) calculated: 64.93% C 6.40% H 9.88% N, found: 65.13% C 6.49% H 9.92% N.

Example

Preparation of 4-phenyl-2-methyl-8-(n-propylcarbamoylamino)-1,2,3,4-tetrahydroisoquinoline maleate

The procedure is as described in Example 1, except that n-propyl isocyanate is used instead of ethyl isocyanate. 3.5 g of the title compound are thus obtained in the form of yellowish-white crystals. Yield 53.0%. Melting point 149-150°C.

Analysis: ^C 24 ^H 29 ^N 3°5 (molecular weight 439.515) calculated: 65.59% C found: 65.80% C

6.65% H 7.08% H

9.56% N, 9.48% N.

Example 3

Preparation of 8-(n-butylcarbamoylamino)-4-phenyl~2-methyl-1,2,3,4-tetrahydroisoquinoline maleate

The procedure is as in Example 1 except that n-butyl isocyanate is used instead of ethyl isocyanate. 1.9 g of the title compound is thus obtained in the form of a white powder. Yield 42%. Melting point 145 °C (decomposition).

Analysis: ^25^31^3^5 (molecular weight 453.54) calculated: 66.20% C 6.89% H 9.26% N, found: 66.32% C 6.37% H 9.44% N.

Example 4

Preparation of 8-(n-butylcarbamoylamino)-4-(p-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline maleate

The procedure is as in Example 1 with the difference that 8-amino-4-(p-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline and n-butyl isocyanate are used as starting materials. Thus

is obtained melting 134 7.8 g of the title compound at °C (decomposition). form to: Analysis: ^C 25 ^H 30 ^C ''' ^N 3 ^O 5 (molecular weight calculated : 61.53% C 6.20% H 8.61% N found: 60.97% C 6.30% H 8.64% N

487.99)

7.27% Cl, 7.51% Cl.

lute of white powder. Yield 32%. Temperature

Example 5

Preparation of 2-methyl-8-(n-butylcarbamoylamino)-4-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline maleate

The procedure is as described in Example 1, except that 8-amino-2-methyl-4-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline and n-butyl isocyanate are used as starting materials. 8.4 g of the title compound are thus obtained in the form of a yellowish-white powder. Melting point 169 °C (decomposition). Yield 41.5%.

(molecular weight 487.99) calculated: found:

66.79% C 66.30% C

7.11% H 7.30% H

8.99% N, 8.89% N.

Claims (5)

1. A process for the preparation of the isoquinoline of the general novel 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydrofuran derivatives _. HN — CO-NH — R wherein r! represents a hydrogen atom, a halogen atom or a (C 1 -C 4) alkyl group; and R represents an alkyl group having 1 to 6 carbon atoms, and the pharmaceutically usable acid addition salts thereof, characterized in that the compound of formula II is as defined above, is treated with an isocyanate of formula III R-NCO (III) wherein R is as defined above, whereupon the compound of formula (I) thus obtained is converted into a pharmaceutically acceptable acid addition salt. 2. A process according to claim 1 wherein the reaction is carried out in the aromatic hydrocarbon as a solvent. 3. A process according to claim 2 wherein the solvent is benzene. 4. Process according to claim 1, 2 or 3, characterized in that the reaction is carried out at the boiling point of the reaction mixture. 5. A process according to claim 1 for the preparation of compounds of the formula I in which the methyl or chlorine atom is in the p-position and R is the n-butyl group, characterized in that the compounds II and III are used as starting materials, in which R and R ¹ have at this point as described above.