HU186519B - Process for producing 8-bracket-carbamoyl-amino-bracket-closed-4-aryl-2-methyl-tetrahydro-isoquinoline derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of a compound of formula (I) wherein R is a C1-C6 alkyl group and R1 is a hydrogen atom, a halogen atom or a C1-C4 alkyl group and an acid addition salt thereof; the compound is reacted with an isocyanate of formula (111); or b) ring closure of a compound of formula IV; and, if desired, converting a resulting compound of formula (I) into an acid addition salt thereof. The novel compounds of formula (I) can be used in medicine for their valuable central nervous system effects, in particular as antidepressant and / or antifungal agents. R1 3 HN-CO-NH-R (I) R 'nh 2 (II) R-NCO (III.) -1-

Description

SUMMARY OF THE INVENTION The present invention relates to the preparation of pharmaceutically active novel 8- (carbamoylamino) -4-aryl-2-methyl letrahydroisoquinoline derivatives.

Of the amino group, saturated or unsaturated aliphatic carboxylic acids having up to 6 carbon atoms, aromatic ^! acyl substituted 8-amino-4-aryl-2-alkyl-tetrahydroisoquinoline derivatives derived from a carboxylic acid or a C 7 -C 10 arylaliphatic carboxylic acid; United Kingdom Patent No. 4,197,198. These compounds possess centers ¹ and ti nervous system stimulant thymoleptic activity. Similar derivatives are disclosed in U.S. Patent No. 1,670,848. Published German Patent Application No. 1,795,829; Federal Republic of Germany, published U.S. patents have been presented with what is ^one application.

The present invention relates to a process for the preparation of 8- (carbamoylamino) -4-aryl-2-methyl-tetrahydroisoquinoline derivatives of formula (I) wherein R is C 1-6 alkyl and ² R ¹ is hydrogen, halogen or

C 1 -C 4 alkyl) and their pharmaceutically acceptable acid addition salts by

a) (II) of formula 8-amino-4- ² aryl-2-methyl-tetrahydro-isoquinoline derivative (wherein ^R1 is as hereinbefore defined above) of a compound (III) with an isocyanate of formula (Meiya wherein R is above); or i

b) ring closure of a compound of formula IV wherein R and R ¹ are as defined above; and optionally converting a compound of formula (I) prepared according to process (a) or (b) to a pharmaceutically acceptable acid addition salt thereof.

The term "lower alkyl" denotes a straight or branched C 1-6 - preferably 1-4 - carbon atoms ^z valid (e.g. methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl. group, etc.). The term "halogen" includes fluorine, bromine and chlorine.

The acid addition salts of the compounds of formula (I) are pharmaceutically acceptable salts of inorganic or organic acids (e.g., mineral acids such as hydrogen halides, preferably hydrochloric or hydrobromic acid, or sulfuric or phosphoric or formic, propionic, salts of lactic acid, maleic acid, tartaric acid, benzoic acid, salicylic acid, etc.).

Particularly preferred compounds of the formula I are the following:

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

8- (n-butylcarbamoylamino) -2-methyl-4- (p -ololyl) -1,2,3,4-tetrahydroisoquinoline and their pharmaceutically acceptable acid addition salts, in particular their maleates. ι

In the process (a) of the present invention, the reaction of the amino compound (II) with the isocyanate (III) is carried out in a solvent medium. Aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) may be used as the reaction medium.

The reaction may be carried out under heating, preferably at the boiling point of the reaction mixture.

The reaction mixture may be worked up in a manner known per se. For example, such that the residue obtained after distilling off the solvent is purified by column chromatography.

The starting materials of formula (II) may be prepared by ring closure of compounds of formula (V) wherein R ¹ is as defined above. The reaction may be carried out analogously to process b).

In process b) of the present invention, the ring closure 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 chloride, etc.) may be used. Sulfuric acid has proved to be a very advantageous acid catalyst. The reaction may be carried out in an organic solvent medium. The reaction medium is preferably a halogenated hydrocarbon (e.g., methylene chloride, chloroform, etc.). The reaction temperature depends on the activity of the catalyst. When sulfuric acid is used as the catalyst, the reaction proceeds rapidly at 0-6 ° C.

The reaction mixture may be worked up by methods known per se. If a sulfuric acid catalyst is used, the sulfuric acid mixture is poured onto ice and the product is isolated by extraction after basification. Chlorinated hydrocarbons (e.g. chloroform) are preferably used for the extraction.

The starting materials of formula (IV) may be prepared by reacting a compound of formula (V) with the corresponding isocyanate of formula (III). The reaction may be carried out analogously to process a).

Compounds of formula (V) are known (British Patent No. 1,164,192).

The compounds of formula (I) may, if desired, be converted into their pharmaceutically acceptable acid addition salts. The salt formation is carried out in a manner known per se, by reacting a compound of formula (I) and preferably a stoichiometric amount of the appropriate acid in an inert organic solvent.

The compounds of formula (I) obtainable by the process of the present invention have a number of valuable central nervous system effects and are useful in medicine in particular as antidepressant and / or antiparkinsone agents.

The compounds of formula (I) may be used in medicine in the form of pharmaceutical compositions containing the active ingredient and inert non-toxic solid or liquid carriers. The formulations may be formulated for oral (e.g., tablet, capsule, dragee, solution, emulsion or suspension) or parenteral (e.g., injection solutions). As a carrier, e.g. talc, starch, magnesium stearate, magnesium carbonate, calcium carbonate, water, alcohols, polyalkylene glycols, etc.)

186,519 can be glazed. The pharmaceutical compositions may also contain conventional pharmaceutical excipients (e.g. wetting agents, disintegrating and flavoring additives, coloring agents, etc.).

The pharmaceutical compositions may be prepared by methods well known in the art of pharmaceutical manufacture.

The activity of the compounds of formula I is confirmed by the following tests:

1. Acute toxicity, DL ₅₀ measured after 96 hours of sc treatment.

2. Catalysis induced by haloperidol at 13 µmol / kg was inhibited in half of mice by s.c. dose.

3. Minimum i.p. that increases or decreases spontaneous motility of mice. dose.

4. Catalysis of 110 pmol / kg tetrabenazine was inhibited in half of the mice by s.c. dose.

5. S.c., which inhibits ocular closure induced by 79 μηιοΐ / kg tetrabenazine in half of the mice. quantity.

6. Minimum s.c. for inhibition of rectal temperature reduction after a dose of 1.6 μmol / kg rescrpin. dose in the mouse.

Ί. The smallest i.v. effect of dopamine on blood pressure and mucous membranes was observed. portion of my cat

8. The smallest stereotype-inducing s.c. dose per rat.

9. After electrolytic lesion of the substantia nigra, 10 in rats at the dose causing characteristic rotational behavior.

10. Significant reduction in proactin levels after 4 days treatment with 0.073 pmol / kg oestradiol in rats 3 weeks prior.

The following test compound compounds are used:

Compound A = Example 4 Compound B = Example 5

Table I

Test FD compound 1 2 ED YOU 3 ED + / -TI 4 ED TI ED 5 YOU 6 ED YOU ed _4th THE > 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. spreadsheet

Test- compound Test 7 8 9 10 THE 6.1 275 143 B > 11 178 107

Further details of the process are set forth in the following examples, without limiting the invention to these examples.

/. example

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

8-amino-4-phenyl-2-methyl-1,2,3,4-50 tetrahydroisoquinoline (3.6 g, 0.015 mol), ethyl isocyanate (1.17 g, 0.0165 mol) and anhydrous (40 ml) the benzene mixture was refluxed for 2 hours. The reaction mixture is concentrated in vacuo, the residue is dissolved in 40 ml of chloroform, the solution is applied from 80 g of silica gel to 40 ml of carbon tetrachloride in a preparative column and eluted successively with 250 ml of 10% chloroform containing 250 ml of 20% ethanol. The combined eluents were evaporated and the residue treated with petroleum ether. A solid product (3.8 g) is obtained which is reacted with θθ (3.5 g, 0.029 mol) in 60 ml of ethanol. The reaction mixture was diluted with ether (200 mL), and upon cooling, the precipitated material was filtered (5.0 g) and recrystallized from a mixture of ethanol (50 mL) and ether (50 mL). 4.5 g of the title compound are obtained, m.p. gg

137-139 C (dec.). The product was recrystallized from 20 ml of ethanol to give 3.7 g (77%) of the title compound as pale yellow crystals. 140 'C (dec.).

Analysis: C ₂₃ H ₂₇ N ₃ O _S Calcd (425.49). Calculated: C, 64.93; H, 6.40; N, 9.88. Found: C, 65.13; H, 5.49; N, 9.92.

Example 2

Preparation of 4-Phenyl-2-methyl-8- (n-propylcarbamoylamino) 1,2,3,4-tetrahydroisoquinoline maleinate

The procedure described in Example 1 was performed except that n-propyl isocyanate was used instead of ethyl isocyanate. Yield: 3.5 g (53.0%) of yellowish white crystals, m.p. 149-150 ° C.

Calcd for C ₂ 4H _{2 <N 3} O ₅ (439.515) calcd: Analysis% C, 65.59; H, 6.65; N, 9.56. Found: C, 65.80; H, 7.08; N, 9.48.

Example 3

Preparation of 8- (n-Bullylcarbamoylamino) -4-phenyl-2-methyl-1,2,3,4-letrahydroisoquinoline maleinate The procedure described in Example 1 was carried out by substituting n-ethyl isocyanate as starting material. butyl isocyanate. 1.9 g of the title compound are obtained in the form of a white powder, m.p. 145 DEG C. (dec.), Yield 42%.

186,519

Analysis: Calculated for C ₂₅ H ₃ N ₃ O ₅ (453.54): C, 66.20; H, 6.89; N, 9.26; Found: C, 66.32; H, 6.37; N, 9.44.

Example 4

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

The procedure described in Example 1 was carried out with the exception that starting material was 8-amino-4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline and n-butyl isocyanate. Yield: 7.8 g (32%), m.p. 134 ° C (dec.).

Analysis calculated for C ₂₅ H ₃₀ CIN ₃ O ₅ (487.99): C, 61.53; H, 6.20; N, 8.61;

Cl, 7.27;

Found: C, 60.97; H, 6.30; N, 8.64.

Cl, 7.51.

Example 5

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

The procedure of Example 1 was carried out with the exception that 8-amino-2-methyl-4- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline and n-butyl isocyanate were used as starting materials.

Yield: 8.4 g (41.5%). The yellowish-white powder melts at 169 ° C with decomposition.

Analysis calculated for C ₂₅ H ₃₀ ClN ₃ O ₅ (487.99): C, 66.79; H, 7.11; N, 8.99; Found: C, 66.30; H, 7.30; N, 8.89.

Example 6

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

A mixture of 5.2 g (0.02 mol) of N- (2-aminobenzyl) -1-phenyl-2-methylamino-1-ethanol and 2.2 g (0.022 mol) of n-butyl isocyanate in 100 ml of anhydrous benzene was added for 2 hours. and the reaction mixture is concentrated in vacuo. 7.2 g of a stationary, gray solid oil are obtained which is N- [2- (butylcarbamoylamino) benzyl] -1-phenyl-2-methylamino-1-ethanol.

7.2 g of the crude product obtained in the preceding paragraph are dissolved in 100 ml of dichloromethane, the solution is added dropwise to 4.4 ml of concentrated sulfuric acid under stirring and cooling at 2-6 ° C over 45 minutes, and the reaction mixture is heated at 6 ° C. After stirring for 1 minute, it is poured onto 100 g of ice, made basic with 30% sodium hydroxide solution and extracted with chloroform (4 x 100 ml). The combined chloroform extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. 5.4 g of a yellowish-white solid are obtained, which is dissolved in 30 ml of ethanol and 2.75 g (0.0235 mol) of maleic acid are added. To the reaction mixture was added portionwise 300 ml of ether, cooled, and the precipitate was filtered off. The yellowish white product was recrystallized from a mixture of ethanol and ether. 6.0 g (61.6%) of the title compound are obtained as a white powder, m.p. 145 ° C. The product a

Identical to the compound prepared in Example 3.

Claims (10)

A process for preparing 8- (carbamoylamino) -4-aryl-2-methyl-tetrahydroisoquinoline derivatives of formula (I): R 1 is C 1 -C 6 alkyl and R ¹ is hydrogen, halogen or C 1-4 alkyl) and their pharmaceutically acceptable acid addition salts, characterized in that a) reacting an 8-amino-4-aryl-2-methyl-tetrahydroisoquinoline derivative of the Formula II (wherein R ¹ is as defined above) with an isocyanate of the Formula III (wherein R is as defined above); ; obsession b) ring closure of a compound of formula IV wherein R and R ¹ are as defined above; and optionally converting a compound of formula (I) prepared according to process (a) or (b) into a pharmaceutically acceptable acid addition salt thereof. Process for carrying out process a) according to claim 1, characterized in that the reaction is carried out in an aromatic hydrocarbon. 3. The process according to claim 2, wherein the reaction medium is benzene. Method a) according to claim 1 and steps 2-3. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out under heating, preferably at the boiling point of the reaction mixture. A process for carrying out process b) according to claim 1, characterized in that the ring closure is carried out in the presence of an acid catalyst. The sixth embodiment of the method according to claim 5, characterized in that a mineral acid or Lewis acid is used as acidic catalyst ₌ application. 7. A process according to claim 6, wherein the acid catalyst is sulfuric acid. 8. A process according to claim 7, wherein the reaction is carried out at 0-6 ° C. 9. a) or b) A method embodiment according to claim 1, wherein R is n-butyl and R compounds and maleates having ¹ is para-methyl or chloro; formula (I) thereof, characterized in that a) reacting a compound of formula (II) having the chlorine or methyl group at the p-position with n-butyl isocyanate; obsession b) R 1 is n-butyl and R ¹ is p-chloro or methyl; 186,519 compounds of formula IV are ring-closed; and, if desired, converting the compound thus obtained to maleinate. 10. A process for the preparation of a pharmaceutical composition, characterized in that a compound of the formula (I) - in which R and R ¹ are as defined in claim ¹ Or a pharmaceutically acceptable acid addition salt thereof, as defined in claim 1, as an active ingredient in an inert, non-toxic solid or liquid pharmaceutical formulation. It is mixed with excipients and formulated in a pharmaceutical composition.