CS247177B2 - Method of 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline new derivatives production - Google Patents

Abstract

Process for preparing novel 8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of formula (I) and pharmaceutically acceptable addition thereof salts with acids, characterized in that they are a compound of formula II and pharmaceutically acceptable addition thereof salts with acids, characterized in that they are a compound of formula II

Description

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

-tetrahydroisoquinoline 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.

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

8-carbamoylamino-4-aryl-2-methyl-1,2,3,4-tetrahydrofuran;

r! represents a hydrogen atom, a halogen atom or a (C1-C4) alkyl group,

R represents a C 1 -C 6 alkyl group, and pharmaceutically acceptable acid addition salts thereof having valuable pharmacological properties.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel compounds of formula I and their pharmaceutically usable acid addition salts by reacting a compound of formula II

N-CH ₃ (II) wherein r 1 is 1; is as defined above, with an isocyanate of formula III

R-NCO (III) of which

R is as defined above, then optionally converting the compound of formula I so obtained into a pharmaceutically acceptable acid addition salt.

The term alkyl group as used herein describes a straight or branched chain hydrocarbon group having a carbon, i.e., 1 to 6 or 1 to 4 carbon atoms, e.g. number of atoms group, ethyl group, isobutyl group etc.

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.). ).

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

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 invention, the 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 and so on) are preferably used as the reaction medium.

This reaction is carried out with heating, preferably at the boiling point of the reaction mixture.

The reaction mixture may 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 formula II can be prepared by cyclization of compounds of formula V

in which

R ^- is as defined above.

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

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

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

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

The compounds of formula (V) are known (cf. British Patent Specification No. 1,614,192).

The compounds of formula (I) may be converted into their acid addition salts formed with pharmaceutically acceptable salts. 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) may be released from its non-pharmaceutically acceptable salt using a strong base, and the resulting free base of formula (I) may then be reacted with the corresponding pharmaceutically acceptable acid.

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 acceptable 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 stearate, magnesium carbonate, calcium carbonate, water, alcohols, polyalkylene glycol, etc.). These preparations may also contain conventional 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 _5Q 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 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 temperature decrease in the rectum induced in mice by a dose of 1.6 µmol / kg reserpine.

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 0.073 µmol / kg estradiol dose in rats that had been ovariectomized three weeks previously.

The following compounds were tested:

Compound A = Example 4 Compound B = Example 5

Nomifensine = Comparative 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 Tables I and II below.

Table I Tests

tested 1 2 3 4 5 6 ed ₂ compound ED TI ED +/- TI 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 2049 246 8 31- 66 90 23 31 66 205 2.7 (B) 2566 214 12 43- 60 128 20 May 32 80 86 30 1.7

II

Table

Test compound

Nomifensin * 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 2-6 were also performed on mice. Doses are expressed in micromol / kg. The therapeutic index (TI) is the ratio of LD / ED.

In test 3, + increased motility means decreased motility.

The designation indicates that the compound is inactive at the dose administered.

TBZ = tetrabenazine.

Tests 7-10 are performed in 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 antiparkin sonic 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.

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 high for Nomifensin (1.6) and Compound A (2.7) and B (1.7). That is, these compounds are a relatively potent antidepressant agent than an antiparkinsonian agent.

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- (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 (0.016 mol) of ethyl isocyanate and 40 ml of absolute benzene is heated for 2 hours to reflux. 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, eluting with 250 ml of chloroform containing 10% ethanol and 250 ml of chloroform containing 20% ethanol. The combined eluates were evaporated and the residue (3.8 g) was treated with petroleum ether. The solid product was treated with a solution of 3.5 g (0.029 mol) of maleic acid in 60 ml of ethanol.

The reaction mixture was diluted with ether (200 mL) and cooled. The precipitated product was filtered off (5.0 g) and recrystallized from a mixture of ethanol and ether. Thus, 4.5 g of the title compound are obtained. M.p. 137-139 ° C (dec.). 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 was as described in Example 1 except that n-propyl isocyanate was used instead of ethyl isocyanate. Thus, 3.5 g of the title compound is obtained as yellowish white crystals. Yield 53.0%. Mp 149-150 ° C.

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

H, 6.65; H, 7.08

N, 9.56. N, 9.48.

Example 3

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

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

Analysis: for C 25 H 31 N 3 O 5 (MW 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 was as in Example 1 except that 8-amino-4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline and n-butyl isocyanate were used as starting materials. Thus

is obtained melting 134 7.8 g of the title compound in ° C (dec.). form on: Analysis: ^C 25 ^H 30 ^C 3 ^N 3 ^O 5 (molecular mass calculated %: 61.53% 6.20% H N, 8.61 found: 60.97% C 6.30% H N, 8.64

487.99)

7.27% Cl, 7.51% Cl.

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

(MW 487.99) calculated: found:

66.79% C 66.30% C

H, 7.11; H, 7.30

N, 8.99; N, 8.89.

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.