CS247182B2 - Process for preparing novel 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives - Google Patents

Abstract

A process for the preparation 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 IV is cyclized, after which the compound of the general formula I thus obtained is optionally converted into a pharmaceutically usable acid addition salt. The compounds of the general formula I and their salts are useful as antidepressants and as antiparkinsonian agents.

Description

(54) Process for the production of new derivatives of 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline

Process for the production of new derivatives of 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline of general formula I

,n-ch ₃

HN-CO-NH-R (i), and their pharmaceutically acceptable acid addition salts, characterized in that the compound of general formula IV is cyclized

(IV) ,

-N-CH2 HN-CO-NH-R, whereupon the compound of general formula I thus obtained is optionally converted into a pharmaceutically usable acid addition salt.

The compounds of general formula I and their salts are useful as antidepressants and as antiparkinsonian agents.

The invention relates to a process for the production of new 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives 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 No. 1,670,848 and 1,795,829.

New derivatives of 8-carbamoylamino-4-aryl-2methyl-1,2,3, 4-tetrahydroisoquinoline of the general formula I have now been found.

wherein R1 represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms and

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 preparation of novel compounds of general formula I and their pharmaceutically usable acid addition salts, which consists in cyclizing a compound of general formula IV

R ¹ (IV),

BOY

HN-CO-NH-R in which

R and R1 have the meanings given above, whereupon the compound of the general formula I thus obtained is optionally converted into a pharmaceutically usable acid addition salt.

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

In the process of the invention, the compound of general formula IV is cyclized. 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, boron trichloride, zinc chloride, and 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.).

The reaction temperature depends on the activity of the catalyst. If sulfuric acid is used as the catalyst, the reaction proceeds rapidly even at low temperatures, for example at temperatures 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.

The starting compounds of general formula IV can be prepared by reacting a compound of general formula V _1

R

BOY

nh ₂ in which r! has the above meaning, with an isocyanate of the general formula III

R - NCO (III), in which

R has the meaning given above.

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. The reaction is carried out under heating, preferably at the boiling point 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.

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

The compounds of formula I can be converted into their pharmaceutically acceptable acid addition salts. The formation of salts can be carried out by generally known and used methods. The base of formula I is reacted with the corresponding acid in a suitable inert solvent.

The acid is preferably used in a stoichiometric amount. Alternatively, the compound of formula I is liberated from its pharmaceutically unacceptable salt with a strong base and the free base of formula I obtained is then reacted with the corresponding pharmaceutically acceptable acid.

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 preparations 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, disintegrants, 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^q 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 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 a dose of 0.073 µmol/kg of 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

Tested Tests

compound 1 2 3 4 5 6 ^ED 2 ED YOU ED + /- TI ED YOU ED THIS ED YOU ^ED 4 Nomifensine 1 128 56 20 28 + 40 37 30 4.2 268 28 40 1.6 A >2 049 246 >8 31- > 66 90 >23 31 >66>205 2.7 B >2 566 >214 >12 43- >60 128 >20 32 >80 86 >30 >1.7

Table II

Tested Test

compound 7 8 9 10 Nomifensine 1.4 23 42 28 A 6.1 275 143 B >11 178 107

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, +” means increased motility and 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 effects of the compounds according to the invention differs from the spectrum of effects 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 the anti-tetrabenazine effect, 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 Compound A (2.7) and Compound 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-(n-butylcarbamoylamino)-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoniline maleate

A mixture of 5.2 g (0.02 mol) of N-(2-aminobenzyl)-1-phenyl-2-methylamino-1-ethanol, 2.2 g (0. (0.022 mol) of n-butyl isocyanate and 10 ml of absolute benzene is heated to reflux for 2 hours, after which the reaction mixture is evaporated in vacuo. 7.2 g of the oil obtained solidifies on standing.

The product is N-(2-butylcarbamoylamino)benzyl-1-phenyl-2-methylamino-1-ethanol.

7.2 g of the crude product, which was prepared according to the previous paragraph, is dissolved in 100 ml of methylene chloride, the resulting solution is added dropwise to 4.4 ml of concentrated sulfuric acid at a temperature of 2 to 6 °C for 30 minutes, after which it is poured onto 100 g of ice, the mixture is made alkaline with 30% aqueous sodium hydroxide solution and extracted four times with 100 ml of chloroform each time.

The combined chloroform extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to give 5.4 g of a yellowish white solid. This product was dissolved in 30 ml of ethanol and 2.75 g (0.0235 mol) of maleic acid were added.

The reaction mixture is diluted with 300 ml of ether (portionally), cooled and the precipitated product is filtered off and recrystallized from a mixture of ethanol and ether. 6.0 g of the title compound are obtained. Yield 61.6%. Melting point 145 °C.

By an analogous procedure to that described in Example 1, the compounds shown in the following Examples 2 to 5 are prepared.

Example 2

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

Melting point: 140 °C (decomposition).

Analysis for:

^23^27 ^N 3^5 ÍH^molecular weight 425.49)

Ί calculated 64.93% C, 6.40% H, 9.88% N; found 65.13% C, 6.49% H, 9.92% N.

Example 3

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

Melting point: 149 to 150 °C

Analysis for:

^C 24 ^H 29 ^N 3°5 ( ^{molecular weight} 439.515) calculated 65.59% C, 6.65% H, 9.56% N ^; found 65.80% C, ^7.08 % H, 9.48% N.

Example 4

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

Melting point: 134 °C (decomposition).

Analysis for:

^< “25 ^H 30 ^C ^' ^řJ 3°5 ( ^m °l ^e spherical mass 487.99) calculated 61.53% C, 6.20% H, 8.61% N, 7.27% Cl; found 60.97% C, 6.30% H, 8.64% N, 7.51% Cl.

Example 5

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

Melting point: 169 °C (decomposition)

Analysis for:

^25 ^H 30 ^C ^ ^N 3°5 ( ^{raC) molecular weight} 487.99).

Calcd. 66.79% C, 7.11% H, 8.99% N; found 66.30% C, 7.30% H, 8.89% N.

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of novel 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of the general formula: HN — CO — NH — R wherein R ¹ represents a hydrogen atom, a halogen atom or a C 1 -C 4 alkyl group; R represents a C 1 -C 6 alkyl group, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula IV HO-CH (IV) is cyclized, HN-CO-NH-R wherein R @ ¹ and R @ ¹ are as defined above, whereupon the compound of formula (I) thus obtained is converted into a pharmaceutically acceptable acid addition salt. 2. The process according to claim 1, wherein the cyclization is carried out in the presence of an acid catalyst. 3. The process of claim 2 wherein the catalyst is a mineral acid or a Lewis acid. 4. A process according to claim 3 wherein the catalyst is sulfuric acid. The method according to clause 4, characterized in that the reaction is carried out at a temperature of 0 to 6 ° C. 6. 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 of the formula IV are used as starting materials. R and R ¹ have at this point as described above.