CS247188B2 - Method of 8-alkoxycarbonylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline new derivatives production - Google Patents

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 up to 10 carbon atoms.

These compounds have the ability to stimulate the central nervous system and further have thymleplastic activity. Compounds of similar structure are disclosed in DOS Nos. 1,670,848 and 1,795,829.

New derivatives of 8-alkoxycarbonylamino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline of formula I have now been found

at

t.

HN COOR

247188 in which

X represents a hydrogen atom or a halogen atom, and

R 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, as well as their pharmaceutically usable acid addition salts 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 acceptable acid addition salts, which comprises: of formula IXI

in which

X is as defined above, with a formic acid ester of formula IV

Hlg - COOR (IV) in which

R is as defined above and

H 1g is halogen, preferably chlorine or bromine, whereupon the compound of formula (I) thus obtained is converted 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 salt. 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.).

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 and hydrobromides, sulfates, phosphates, etc.) or organic acids (such as formates, acetates, propionates, lactates, maleates, tartrates, benzoates, salicylates, etc.). ).

In the process of the invention, a compound of formula III is treated with a haloformate of formula IV. It is preferred to use compounds of formula IV in which H1g is chlorine as starting materials. This reaction is carried out in an inert organic solvent. Aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) are preferred as the reaction medium.

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. The reaction is preferably carried out in the presence of an acid binding agent, such as tertiary amines, for example triethylamine or pyridine.

The reaction mixture is worked up by methods known per se. Work-up can be accomplished by concentrating the reaction mixture, basifying the residue (e.g. ammonium hydroxide) and extracting the desired compound of formula X with a suitable solvent (e.g. chloroform).

The compounds of formula III which are used as starting materials can be prepared by cyclization of compounds of formula V

X is as defined above.

This reaction is carried out in the presence of an acid catalyst such as mineral acids (such as hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.) or Lewis acids (such as aluminum chloride, boron trifluoride, zinc chloride, tin tetrachloride, etc.). It is particularly preferred to work in the presence of sulfuric acid as a catalyst.

*

This reaction is carried out in an inert organic solvent. Preferably, halogenated hydrocarbons (e.g. methylene chloride, chloroform, etc.) can be used as the reaction medium. 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 formula III obtained can be isolated from the reaction mixture by methods known per se. For example, the acidic solution may be poured onto ice, the mixture basified and the compound of formula III obtained by extraction with an organic solvent such as chloroform.

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 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.

Compounds of formulas III and V are known (cf. British Patent Specification 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 acceptable carrier.

The pharmaceutical preparations may be presented in a form suitable for oral administration (e.g. in the form of tablets, capsules, dragees, solutions, emulsions, suspensions, etc.) or in a form suitable 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 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 ₅₀ 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 ptose elicited at 79 _of umol / kg tetrabenazine in 50% of mice.

6) The lowest subcutaneous dose, which prevents mice from decreasing the temperature measured in the rectum induced by administration of a dose of 1.6 _from 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) A dose which produces a significant lowering of prolactin levels after 4 days of exposure dose of _from 0.073 mol / kg of estradiol in the rat, which was removed three weeks before the ovary.

The following compounds were tested: compound A = compound of Example 1

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

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

Tabulkal

Test results:

Tested compound 1 2 3 ED +/- TI 4 5 6 ED ^ ed ₄ ED TI ED TI ED TI ED TI Nomifensin 1 128 56 20 May 28+ 40 37 30 4.2 268 28 40 1.6 AND 2 176 55 40 7.9 -275 13 167 1.6 1 360 26 84 4.2

Table 2

Test compound test

9 10

Nomifensin

1.4

42 28

1.3

39 26

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, increasing motility means decreasing 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 antiparkinsonian 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. In the presence of said psychomotor stimulating effect, which is similar to that of amphetamine, it 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 therapeutic index of Nomifensin.

Based on a comparison of the results of the anti-haloperidol test (dopaminergic type) and the anti-tetrabenazine activity, 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

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, 0625 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. The yield was 45.6%. Mp 155 ° C.

Analysis:

(Molecular Weight 344,845) calculated 66.19% C, 6.14% H, 8.12% N, 10.28% Cl; found: C, 66.79; H, 5.89; N, 8.42; Cl, 10.56.

Example 2

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

7.3 g (0.0212 mol) of the base prepared according to Example 1 were suspended in 50 ml of ethanol, and 10 ml of ethanol saturated with hydrogen chloride were added thereto under cooling.

Ether was then added to the reaction mixture, and precipitation of the product was complete by scratching the bar with the wall of the reaction flask.

The precipitated product was filtered off and washed with ether. Thus, 8.1 g of the title compound is obtained in the form of a white powder. Yield nearly 100%. 145 DEG-150 DEG C. (decomposition).

Analysis:

(MW 381.30) calculated C 59.85, H 5.82, N 7.35, Cl 18.60, found C 59.74, H 6.06, N 7.17% Cl 18.54, calculated Cl 9.30;

found, 9.21% Cl.

Example 3

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

To a solution of 5.5 g (0.023 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline and 50 ml of absolute benzene is added a solution of 3.4 g (0.031 mol) of ethyl chloroformate and 30 g of benzene. ml of absolute benzene. The reaction mixture is refluxed for 3 hours, the benzene is distilled off in vacuo and the residue is dissolved in 5 ml of water.

The solution was made basic by the addition of 30% aqueous sodium hydroxide solution and extracted three times with 50 ml of chloroform each. The chloroform extracts were combined, dried over sodium sulfate and evaporated. The residue was washed with somewhat cooled ethanol and recrystallized from ethanol. This gave 3.0 g of the title compound as white crystals. Yield 37.5%. Melting point 178 ° C.

Analysis:

(Molecular Weight 346.86) calculated C 73.84%, H 7.15%, N 9.02%; Found: C, 73.96; H, 7.51; N, 8.95.

Example 4

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

A solution of 2.4 g (0.1 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline in 100 ml of absolute benzene is mixed with a solution of 1.4 g (0.012 mol) butyl chloroformate and 10 ml of absolute benzene and the reaction mixture is heated at reflux for 2 hours.

After cooling, the mixture is diluted with 50 ml of ice-cold water, the pH is adjusted to 9 with concentrated ammonium hydroxide solution, the benzene phase is separated and the aqueous phase is extracted twice with 20 ml of benzene each.

The combined benzene solutions were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual orange-colored oil was crystallized twice from ethanol. 1.8 g of the title compound are obtained. Yield 52.9%. Melting point 106 ° C (white powder).

Analysis:

(molecular weight

338.454) found

75.43% C, 75.19% C,

H, 6.63; N, 8.37. H, 6.44; N, 8.57.

Example 5

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

3.5 g (0.015 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline are dissolved in 100 ml of absolute benzene, 1.28 g (0.016 mol) of anhydrous pyridine are added and a solution of 2.14 g (0.015 mol) of (.beta.-chloroethyl) chloroformate in 10 ml of absolute benzene is added dropwise with stirring at room temperature. The reaction mixture is stirred at room temperature for one hour, poured into 50 ml of ice-cold water, the organic phase is separated, and the aqueous layer is extracted three times with 30 ml of benzene each.

The combined organic solutions were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. 4.5 g of a yellowish-white product are obtained. This product was recrystallized twice from ethanol. Obtain 2.7 g of the title compound. Yield 52%. The white crystals melt at 154 ° C.

Analysis:

(Molecular Weight 344,845) calculated C 66.18, H 6.14, N 8.12, Cl 10.28; Found: C, 66.29; H, 6.24; N, 8.10; Cl, 10.38.

Example 6

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

4.6 g (0.02 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline are dissolved in 100 ml of absolute benzene. 6.2 g of 90% benzyloxycarbonyl chloride (5.2 ml, 0.03 mol) was added dropwise at 18 ° C.

The reaction mixture was stirred for 2 hours, then quenched with 150 µl of ice-cooled water and made alkaline by adding 10 ml of 30% aqueous sodium hydroxide while cooling with ice. The benzene phase is separated, the aqueous layer is extracted twice with 150 ml of benzene each time, the solution is dried over anhydrous sodium sulphate and concentrated.

The residue is stirred with 150 ml of ether, cooled, the precipitated product is filtered off and washed with cooled ether. 4.7 g of a yellowish-white powder are thus obtained. M.p. 142-146 ° C. Recrystallization from ethanol gave 3.6 g of the title compound. Yield 49%. The white crystals melt at 147-148 ° C.

Analysis:

(MW 372.474) calculated C 77.39, H 6.49, N 7.50; Found: C, 77.50; H, 6.78; N, 7.70.

2.4 g (0.0064 mol) of the above base were suspended in 70 ml of ether and a solution of 0.75 g (0.0064 mol) of maleic acid and 5 ml of ethanol was added with stirring. The reaction mixture was stirred for 10 minutes and cooled to 0 ° C. The precipitated product is filtered off, washed with ethanol / ether (1: 9) and then with ether and recrystallized from ethanol.

2.4 g of 8- (benzyloxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline maleate are thus obtained. Yield 79%. The white powder melts at 166-167 ° C.

Analysis:

^C 28 ^H 28 ^N 2 ^O 6 (MW 488.544) calculated C 68.84%, H 5.98%, N 5.73%; Found: C, 68.76; H, 5.95; N, 5.82.

Claims (7)

SUBJECT OF THE INVENTION A process for the preparation of novel 8-alkoxycarbonylainino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of the general formula I N-CHo HN-COOR (I) wherein X is hydrogen or halogen; and R represents an alkyl group having 1 to 6 carbon atoms, halogenoalkyl having 1 to 6 carbon atoms or phenylalkyl having 1 to 6 carbon atoms in the alkyl moiety, _T, and their pharmaceutically usable acid addition salts, characterized in that the compound of formula III (III), n-ch ₃ NHo in which X is as defined above, with a formic acid ester of formula IV Hlg - COOR ί 1 V) in which R is as defined above and H1g represents a halogen atom, preferably a chlorine or bromine atom, and optionally the compound of formula I thus obtained is converted into a pharmaceutically acceptable acid addition salt. 2. The process of claim 1, wherein the starting material is a compound of formula IV wherein Hg is chlorine and R is as defined in point 1. 3. The process of claim 2 wherein the reaction is carried out in the presence of an acid binding agent. 4. The method of claim 3 wherein the acid binding agent is triethylamine or quinoline. 5. Process according to claim 1 or one of claims 2 to 4, characterized in that the reaction is carried out in an aromatic solvent, preferably benzene. Process according to one of Claims 1 to 5, characterized in that the reaction is carried out at the boiling point of the reaction mixture. A process according to any one of claims 1 to 6 for the preparation of 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline and its hydrochloride, characterized in that it is the starting materials use compounds of formulas III and IV in which X represents a chlorine atom in the p-position, R represents an ethyl group and Hg represents a halogen, preferably chlorine, followed by the optionally obtained 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) ) -2-methyl-1,2,3,4-tetrahydroisoquinoline is converted to its hydrochloride salt.