HU186518B - Process for producing 8-bracket-amino-acyl-amino-bracket closed-4-aryl-2-methyl-1,2,3,4-tetrahydro-isoquinoline derivatives - Google Patents

Abstract

The present invention relates to 8- (amino-acylamino) -4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of formula (I) wherein R1 is C1-6alkyl. and R 2 is hydrogen or R 'and R 2 together with the adjacent nitrogen to which they are attached form a 5- or 6-membered saturated ring optionally having an oxygen atom as an additional heteroatom, R is hydrogen, halogen or C 1-4 alkyl and n is 1, 2, 3 or 4) and pharmaceutically acceptable acid addition salts thereof, by the preparation of a compound of formula (II) wherein H is halogen and R and n are as defined above or a salt thereof with an amine of formula III wherein R 1 is as defined above. and R2 is as defined above) or is reacted with a salt thereof. sen anlidepresszív and / or useful antiparkinson agents. N-CH3 (1) HN-CO- (CH2) n NR1 R2 NHR.1R2 (III) -1-

Description

SUMMARY OF THE INVENTION The present invention relates to the preparation of novel pharmaceutically effective 8- (aminoacylamino) -4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives.

The 8-amino-4-aryl-2-alkyltetrahydroisoquinoline derivatives of amino acids, saturated or unsaturated, with an acyl group derived from an aliphatic carboxylic acid having up to 6 carbon atoms, an aromatic ⁵ carboxylic acid or a C 7-10 arylaliphatic carboxylic acid are disclosed in U.S. Patent No. 1,164.192. United Kingdom Patent No. 4,197,198. These compounds have central nervous system stimulating and thymoleptic effects. Similar derivatives are disclosed in U.S. Patent No. 1,670,848. Published German Patent Application No. 1,795,829; They have also been disclosed in 15 patent applications published in the Federal Republic of Germany.

The present invention relates to a process for preparing 8- (aminoacylamino) -4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of formula (I):

R ¹ is C 1 -C 6 alkyl and R ² is hydrogen or R ¹ and R ² together with the adjacent nitrogen to which they are attached form a 5 or 6 membered saturated ring optionally containing an additional heteroatom,

R is hydrogen, halogen or (C 1 -C 4) alkyl, and n is 1, 2, 3 or 4) and pharmaceutically acceptable acid addition salts thereof, by reacting a compound of formula (II) wherein halogen and R and n are as defined above) or its salt with an amine (III) of the formula (wherein R 35 ^l and R ² are as defined above), or its salt.

As used herein, the term "lower alkyl" refers to straight or branched C 1-6 alkyl (methyl, 40 ethyl, η-propyl, isopropyl, η-butyl, isobutyl, etc.). The term "halogen" includes fluorine, chlorine and bromine. When R 'and R ² together with the adjacent R nitrogen to which they are attached form a 5- or 6-membered saturated heterocyclic ring 45, it may be preferably pyrrolidino, piperidino or morpholino, preferably "n" is 1 or 2. R is preferably a p-substituent.

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

Particularly preferred compounds of formula (I) are the following:

8- (ethylaminoacetylamino) -4- (p-chlorenenyl) -2- 60 methyl-1,2,3,4-tetrahydroisoquinoline; 8- (n-BuLi-amino-acetylamino) -4- (p-chlorophenyl) -2metii-1,2,3,4-tetrahydroisoquinoline;

8- (ethylaminoacetylamino) -2-methyl-4- (p- (tolyl) 1,2,3,4-tetrahydroisoquinoline;

8- (n-butylamino-acetylamino) -2-methyl-4- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline; and their pharmaceutically acceptable acid addition salts, in particular maleinates.

The reaction of the compounds of formula (II) with the amines of formula (III) is preferably carried out in an inert organic solvent medium. The reaction medium is preferably aliphatic alcohols, especially methanol or ethanol, and the reaction is carried out under heating, preferably at the reflux temperature of the reaction mixture.

The starting materials of formula (III) and the amines of formula (III) may also be used in the form of their acid addition salts (e.g., their hydrochlorides).

The reaction mixture may be worked up in a manner known per se. Alternatively, the solvent may be distilled off and the product isolated by organic solvent extraction.

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

The starting materials of formula (II) can be prepared from the compounds of formula (VI) in two ways (wherein R is as defined above).

In one preparation process, a compound of formula VI is ring-reacted and the compound of formula IV thus obtained (wherein R is as defined above) is reacted with an acid halide of formula VII wherein X is halogen, preferably chlorine).

The ring closure of the compounds of formula (VI) may be carried out in an inert organic solvent medium. The reaction medium may be halogenated hydrocarbons (e.g., methylene chloride, chloroform, etc.). The reaction may be carried out in the presence of an acidic catalyst. For this purpose, mineral acids (e.g. sulfuric acid, polyphosphoric acid or polyphosphate esters) may be used. The reaction can be carried out at low temperature (0-5 'C).

The reaction of the resultant compound of formula IV with the ω-haloacid halide of formula VII can be carried out in an inert organic solvent medium. The reaction medium is preferably aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.). The reaction is preferably carried out under heating, preferably at the boiling point of the reaction mixture. The reaction may be carried out in the presence of an acid scavenger, and tertiary organic bases (e.g. triethylamine or quinoline, etc.) are preferably used.

The compounds of formula (II) are readily isolated from the reaction mixture by known methods (e.g., cooling, crystallization). The compounds of formula (II) can be used crude without further purification for the preparation of compounds of formula (I).

The compounds of formula (II) may also be prepared in a manner such that one of the compounds of formula (VI)

186,518 nos are reacted with an ω-haloacid halide of formula VII and the resulting compound of formula V (wherein R, Dil and n are as defined above) is cyclized.

The reaction of the compounds of formula (VI) and (VII) may be carried out analogously to the reaction of the compounds of formula (IV) and (VII) and the ring closure of the compounds of formula (V) may be carried out in an analogous manner.

Many of the compounds of formulas IV and VI are known (United Kingdom Patent No. 1,164,192).

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 antiparkinson 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.). 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 (1) is confirmed by the following assays.

1. Acute toxicity, DL _S0 measured after 96 hours of treatment with sc.

2. Haloperidol 13 gmol / kg induced catalepsy in half of the mice inhibited 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 tetrabenazine-induced ocular closure at 79 pmol / kg in half of mice. quantity.

6. Minimum s.c. inhibiting rectal temperature reduction after a dose of 1.6 pmol / kg reserpine. dose in the mouse.

7. The lowest i.v. dose of dopamine to increase blood pressure and bladder effect. dose in cats.

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

9. After electrolytically damaging the substantia nigra, the dose causing a specific rotational behavior in the rat.

10. A significant decrease in prolactin levels after 4 days treatment with 0.073 gmol / kg oestradiol in rats 3 weeks earlier.

The following test compounds are used:

Compound A - Example 4 Compound B = Example 8 Compound C = Example 10 Compound D = Example 11 Compound E = Example 13 Compound F = 12. Prepared according to example.

Table I

Test ED compound I 2 ED YOU 3 ED + / -YOU 4 ED YOU 5 5: ED YOU 6 ED YOU EE\ THE 653 86 8 206- 3 62 11 43 15 86 8 1.4 B 1925 428 5 342- 6 321 6 1267 7 428 5 1.3 C 686 53 13 42- 16 51 13 i ^14th 49 11 62 1.0 D 637 48 13 > 40 <16 27 24 7.8 82 10 64 1.8 E 664 29 23 10 66 71 9 ⁵ 133 21 32 0.4 F 706 33 21 22 32 99 7 ¹² 59 44 16 0.3

II. Table 55

Test compound Test 7 8 9 10 THE 5.2 89 144 B 4.3 > 178 96 C 1.1 68 D 1.0 64 36 E 2.1 108 F 2.2 183

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

7 p / da

Preparation of 8- (ethylaminoacetylamino) -4-phenyl-2-methyl-1,2,3,4-telrahydroisoquinoline maleinate

5.3 g (0.015 mol) of 4-phenyl-8- (chloroacetylamino) -2-methyl-2,3,4-tetrahydroisoquinoline hydrochloride

-3-86 518 and 15 ml (10.4 g, 0.23 mol) of edl amine in 50 ml of ethanol were reacted in a bomb tube at 60 ° C for 5 hours. The reaction mixture was evaporated and the residual yellow oil (7.1 g) was triturated with 50 ml of water, made basic with stirring and cooling with 30 ml of 30% sodium hydroxide solution and extracted with 10 x 100 ml of ether. The ethereal solution was dried over anhydrous sodium sulfate and evaporated. The residual oil was triturated with petroleum ether. The crude title base (4.3 g, 0.0133 mol) was dissolved in ethanol (30 ml) and treated with a solution of maleic acid (1.6 g, 0.0138 mol) in alcohol (15 ml). The precipitated material is filtered off.

5.2 g of the title compound are obtained (m.p. 169 ° C), which is recrystallized from 50 ml of ethanol. Yield: 4.7 g (71.2% of theory), m.p. 170 'C.

Analysis: Calculated for C ₂₄ H ₂₉ N ₃ O ₄ (439.515): C, 65.60; H, 6.65; N, 9.56; Found: C, 65.38; H, 6.74; N, 9.62.

8- (ethylaminoacetylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline melts at 111 ° C (crystallized from benzene / petroleum ether).

Analysis: Calculated for C ₂₀ H ₂₅ N ₃ O (323.439): C, 74.27; H, 7.79; N, 12.99; Found: C, 74.41; H, 7.97; N, 13.13.

Example 2

4-Phenyl-2-methyl-8- (isopropyl-amino-acetylamino) -1,2,3,4-tetrahydroisoquinoline maleate

4.27 g (0.0122 mole) of 4-phenyl-8- (chloroacetylamino) 2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride in 50 ml of ethanol were added in 15 ml (10.4 g). (0.176 mol) isopropylamine is refluxed for 5 hours. The reaction mixture was then evaporated to give 6.5 g of a sticky substance which was dissolved in 100 ml of water and made basic with 10 ml of 30% sodium hydroxide solution with cooling. The aqueous phase was extracted with ether (5 x 200 mL), and the combined ether solution was dried over anhydrous sodium sulfate and concentrated in vacuo. To a solution of 4.4 g of a yellow oil in 50 ml of ethanol was added 3.5 g (0.03 mol) of maleic acid in 10 ml of ethanol! of the prepared solution is poured with stirring. After cooling, the precipitate was filtered, washed with 2 x 10 mL ethanol (6 g) and recrystallized from 45 mL ethanol:

5.3 g, mp 170 ° C (dimaleinate salt).

To a solution of the dimaleinate salt in water (30 ml) was added ether (100 ml), basified with stirring and cooling with sodium hydroxide (30 ml, 30%), the ether layer was separated and the aqueous layer was further extracted with ether (2 x 100 ml). extracted. The combined ethereal solution was dried over anhydrous sodium sulfate, and the ether was evaporated in vacuo to give 3.15 g (9.35 mmol) of crude base (m.p. 89 'C). This was treated with a solution of maleic acid (1.1 g, 9.45 mmol) in ether (47 mL) to give a white powder (4.1 g) which was recrystallized from ethanol (40 mL) to give the title compound (3.45 g, 62.6%). , op. 134 ° C.

Analysis: C ₂₅ H ₃₁ N ₃ O ₅ (M = 453.543).

Calculated: C, 66.22; H, 6.89; N, 9.29; Found: C, 66.23; H, 7.03; N, 9.33.

Base: yellowish white crystals

91 ° C (benzene petroleum ether)

Analysis for C ₂₁ H ₂ -N ₃ O

Found: C, 74.74; H, 8.07; N, 12.45. Found: C, 74.68; H, 8.21; N, 12.49.

Example 3

8-n- (Butylaminoacetylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (DZO-136)

3.5 g (0.01 mol) of 4-phenyl-8- (chloroacetylamino) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride in 50 ml of ethanol were added in 10 ml (7.39 g: 0, 1 mole of n-butylamine is refluxed for 5 hours. The reaction mixture was concentrated in vacuo and the residue was washed with anhydrous ether (10 x 50 mL). The ethereal solution is evaporated to dryness in vacuo, the residue is mixed with 3 x 10 mL of benzene and the benzene is evaporated in vacuo. The yellow oil (3.3 g) thus obtained was dissolved in ethanol (30 ml) and a solution of maleic acid (1.2 g, 0.01 mol) in ethanol (10 ml) was added with stirring. The precipitate (2.9 g, m.p. 172 ° C) was recrystallized from 60 ml of ethanol to give 2.3 g of pure title compound, yield 49.2%, m.p. 174 'C.

Analysis: C ₂₆ H ₃₃ N ₃ O ₅ (M = 467.57).

Calculated: C, 66.79; H, 7.11; N, 8.99 Found: C, 66.80; H, 7.10; N, 9.24.

Example 4

4-Phenyl-2-methyl-8- (pyrrolidinoacetylamino) 1,2,3,4-tetrahydroisoquinoline dimaleinate (DZO143)

7.0 g (0.02 mol) of 4-phenyl-8-chloroacetylamino-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride in 70 ml of ethanol were treated with 20 ml (17.0 g: 0, 24 moles of pyrrolidine were refluxed for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in a mixture of water (100 mL) and ether (100 mL), basified with 30 mL of 30% sodium hydroxide with cooling and stirring, and the aqueous layer was extracted with ether (5 x 100 mL); The organic layer was dried over anhydrous sodium sulfate, triturated with charcoal and evaporated. The residue was dissolved in ethanol (100 mL) and reacted with a solution of maleic acid (6.6 g, 0.057 mol) in ethanol (40 mL) and diluted with ether (1000 mL). After filtering off the ether, the slightly sticky solid (dimaleinate salt) was dissolved in 100 ml of water. With cooling and stirring, it is made basic with 60 µl of 30% sodium hydroxide solution, the aqueous phase is extracted with 200 ml + 4 x 100 ml of ether, the ethereal solution is dried over anhydrous sodium sulfate and decolorized with activated carbon. After evaporation of the ether, the product was washed with 40 mL of 1: 1 = ether: petroleum ether to give 5.4 g (0.0154 mole) of white crystalline title base. Mp 130 ° C. It is suspended in 100 ml of ethanol and reacted with a solution of maleic acid (3.6 g, 0.0315 mol) in ethanol (36 ml). After the basic solution was diluted with 150 ml of ether, the precipitate was filtered off (9 g) after cooling and recrystallized from 80 ml of ethanol / 30 ml of ether. 7.3 g

186,518 (62.9% yield), m.p. 120 'C.

Analysis: C ₃₀ H _{3 S} N ₃ O ₉ (M = 581.62).

Found: C, 61.95; H, 6.07; N, 7.22. Found: C, 61.64; H, 6.40; N, 6.93. Base: white crystals, m.p. 130 ° C.

Analysis: C ₂₂ H ₂₇ N ₃ O

Calculated: C, 75.61; H, 7.81; N, 12.02 Found: C, 75.77; H, 8.02; N, 12.16.

Example 5

4-Phenyl-2-methyl-8- (piperidinoacetylamino) 1,2,3,4-tetrahydroisoquinoline dimaleinate (DZO139)

4-Phenyl-8- (chloroacetylamino) 2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.3 g, 0.0122 mole) in ethanol (70 ml) was treated with 15 ml (12.9 ml). g (0.15 mol) of piperidine was refluxed for 5 hours. The reaction mixture was evaporated and the resulting residue was dissolved in water (100 ml) and basified with 15 ml of 30% sodium hydroxide solution with cooling and stirring. The aqueous solution was extracted with benzene (200 mL, 4 x 100 mL), dried over anhydrous sodium sulfate, and evaporated. A solution of the oily residue (5.6 g) in ethanol (50 ml) was reacted with a solution of maleic acid (3.5 g, 0.08 mol) in ethanol (10 ml). After cooling, the precipitate was filtered off (5.9 g) and recrystallized from 30 ml of ethanol to give 5.0 g of the dimaleinate salt.

The dimaleinate salt was dissolved in water (30 mL) and ether (100 mL) was added and basified with 10 mL of 30% sodium hydroxide solution under cooling and stirring. After separation, the aqueous phase was further extracted with ether (2 x 100 mL and 2 x 50 mL), and the combined ether solutions were dried over anhydrous sodium sulfate and evaporated. 3.2 g (0.0085 mol) of base are obtained in the form of an off-white solid.

This was dissolved in ethanol (38 mL), treated with maleic acid (2.03 g, 0.0175 mol) and diluted with ether (20 mL). After cooling, the precipitate was filtered off (5.1 g of a white powder) and recrystallized from 25 ml of ethanol to give 4.55 g of the title compound as a white powder. Yield 61%. The melting point is protracted, not typical.

Analysis: C _3! H ₃₇ N ₃ O ₉ (M = 609.66)

Calculated: C, 62.51; H, 6.26; N, 7.05; Found: C, 62.28; H, 6.29; N, 7.20.

Base: oil

Analysis: C ₂₃ H ₂₉ N ₃ O

Calculated: C, 75.99; H, 8.04; N, 11.56 Found: C, 75.60; H, 8.02; N, 11.67.

Example 6

4-Phenyl-2-methyl-8- (morpholinoacetylamino) -1,2,3,4-tetrahydroisoquinoline dimethylene (DZO-142) g (0.02 mol) 4-phenyl-8- (chloro) -acetylamino) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride in ethanol (70 ml) was heated with morpholine (20 ml, 20.0 g, 0.23 mol) for 5 hours. The reaction mixture was concentrated in vacuo, the residue was dissolved in a mixture of water (200 ml) and ether (30 ml), 30% sodium hydroxide solution (30 ml) was added, and the aqueous layer was further extracted with ether (4 x 200 ml). The combined ethereal phases were dried over anhydrous sodium sulfate and evaporated. The oily residue (6.7 g) was dissolved in ethanol (100 ml) and treated with a solution of maleic acid (6.6 g, 0.057 mol) in ethanol (30 ml). After cooling, the precipitate was filtered off to give 10.7 g of a beige powder. It is dissolved in 100 ml of water, basified with 60 ml of 35% sodium hydroxide solution under cooling and stirring and extracted with 200 ml + 4 x 100 ml of ether. The ether solution was dried over anhydrous sodium sulfate, decolorized with activated carbon, the ether evaporated and the residue crystallized from a mixture of 80 mL of ether and 120 mL of petroleum ether. 5.1 g (0.014 mol) of white crystalline pure base are obtained. Op. 120'C.

This was dissolved in ethanol (70 mL) and reacted with a solution of maleic acid (3.3 g, 0.0284 mol) in ethanol (30 mL). The solution was diluted with ether (15 mL). After cooling, the precipitated crystals were filtered off to give 8.0 g of a white powder, which was recrystallized from 120 ml of ethanol to give 6.9 g of the title compound as a white crystal. Yield 58%. 176 'C (b).

Analysis: C ₃₀ H ₃₅ N ₃ O ₁₀ (M = 597.62).

Calculated: C, 60.29; H, 5.90; N, 7.03; Found: C, 60.11; H, 5.83; N, 7.02.

Base: mp 120 ° C (ether-petroleum ether) white crystal Analysis: C ₂₂ H ₂₇ N ₃ O ₂

Calculated: C, 72.30; H, 7.45; N, 11.50. Found: C, 72.45; H, 7.49; N, 11.58.

Example 7

8 - [<3'-Ethylamino) -propionyl] -amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline maleinate (DZO-549)

4.8 g (0.013 mol) of 4-phenyl-8- (3'-chloropropionyl) amo-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride in 50 ml of ethanol were added in 15 ml (10.4 ml). g, 0.23 mol) of ethylamine was reacted in a bomb tube at 60 ° C for 5 hours. The reaction mixture was concentrated and the residual yellow oil was triturated with water (50 mL). with stirring and cooling, made basic with 20 ml of 30% sodium hydroxide and extracted with 5 x 100 ml of ether and 3 x 200 ml of benzene. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to give 3.5 g of an off-white powder. (0.0104 mol crude base). This was dissolved in ethanol (35 mL), treated with a solution of maleic acid (1.2 g, 0.010 mol) in ethanol (5 mL) and diluted with ether (100 mL). The cooled precipitate was filtered to give 4.0 g of a white powder, which was recrystallized from 45 ml of ethanol to give 2.8 g of the title compound as white crystals, yield 47.4%, m.p.

Analysis: C ₂₅ H ₃₁ N ₃ O ₅ (M = 453.54).

Calculated: C, 66.22; H, 6.89; N, 9.29. Found: C, 66.13; H, 7.07; N, 9.47.

186,518

Example 8

4-Phenyl-8 - [(3'-isopropylamino) -propionyl] amino-2-methyl-1,2,3,4-tetrahydroisoquinoline maleinate (DZO-151)

4.8 g (0.013 mol) of 4-phenyl-8- (3'-chloropropionyl) amino-2-methyl-1,2,3,4-tetrahydroisoquinoline hydro chloride in 50 ml of ethanol were added in 15 ml (10.4 g). After refluxing for 5 hours with 0.176 mol of isopropylamine, the reaction mixture was concentrated in vacuo, basified with 50 ml of water under cooling and stirring with 20 ml of 30% sodium hydroxide solution and extracted with 6 x 150 ml of benzene. The benzene solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting 5.3 g of a white oil is treated with 1.5 g (0.013 mol) of maleic acid in 50 ml of ethanol, diluted with 50 ml of ether and, after cooling, the precipitate is filtered off to give 5.6 g of a white powder. Recrystallization from 50 ml of ethanol gave 5.0 g (77.2%) of the title compound as white crystals. 158 'C.

Analysis: C ₂₆ H ₃₃ N ₃ O ₅ (M = 467.57).

Calculated: C, 66.79; H, 7.11; N, 8.99; Found; C, 66.77; H, 7.32; N, 8.93.

Example 9

8 - [(3'-n-Butylamino) -propionyl] amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline maleinate (DZO-150)

4.8 g (0.013 mol) of 4-phenyl-8- (3'-chloropropionyl) amino-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride in 50 ml of ethanol were treated with 15 ml (11.0 g of O). (15 moles) of n-butylamine was refluxed for 5 hours. The reaction mixture was evaporated in vacuo and the residue taken up in 50 ml of water with stirring and cooling with 20 ml of 30% sodium hydroxide solution. basified and extracted with ether (6 x 150 mL). The ethereal solution was dried over anhydrous sodium sulfate and concentrated in vacuo. 5.3 g of a colorless oil are obtained. This was treated with maleic acid (1.3 g, 0.0112 mol) in ethanol (60 mL), diluted with ether (100 mL), filtered to give 5.6 g of a white powder. This was recrystallized from 60 ml of ethanol to give 4.5 g of the title compound as white crystals. Yield 71.8%, m.p. 147 ° C.

Analysis: C ₂₇ H ₃₅ N ₃ O _S (M = 481.60).

Calculated: C, 67.34; H, 7.33; N, 8.72. Found: C, 67.49; H, 7.60; N, 8.67.

Example 10

8- (Ethylaminoacetyl) amino-4- (p -chlorophenyl) -2-methyl-1,2,3,4-letrahydroisoquinoline maleinate (DZO-167)

7.6 g (0.02 mol) of 8- (chloroacetyl) amino-4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride in 100 ml of ethanol were treated with 40 ml of ethyl acetate. 27.8 g (0.61 mol) of ethylamine! reaction at 60 'C for 5 hours. The reaction mixture was concentrated and the yellow oil of the residue taken up in 50 ml of water with stirring and cooling, made basic with 30 ml of 35% sodium hydroxide solution and extracted with 6 x 150 ml of ether. The ethereal solution was dried over anhydrous sodium sulfate and evaporated to give 8.1 g of a yellow oil. This was dissolved in ethanol (30 mL) and treated with a solution of maleic acid (2.3 g, 0.02 mol) in ethanol (5 mL) and diluted with ether (40 mL). The precipitate was filtered off, dried (10 g), recrystallized from 450 ml of ethanol to give 6.2 g of the title compound as white microcrystals.

Yield 65.2%. 189 'C (b).

Analysis: C ₂₄ H ₂₈ ClN ₃ O ₅ (M = 473.96).

Calculated: C, 60.82; H, 5.95; Cl, 7.48. Found: C, 60.98; H, 6.04; Cl, 7.56.

Example 77

8- (n-Butylaminoacetyl) amino-4- (p-chlorophenyl) 2-methyl-1,2,3,4-tetrahydroisoquinoline maleate (DZO-168)

6.2 g (0.016 mole) of 8- (chloroacetyl) amino-4- (p-chlorophenyl) -2-methyl-2,3,4-tetrahydroisoquinoline hydrochloride in 120 ml of ethanol were treated with 20 ml 78 g; 0.2 mol) of n-butylamine was refluxed for 5 hours. The reaction mixture was concentrated in vacuo and the residue taken up in 50 ml of water with stirring and cooling with 25 ml of 30% sodium hydroxide solution and 6 x Extract with 150 ml of benzene. The benzene solution was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, the remaining 7.3 g of a yellow solid was treated with a solution of maleic acid (1.9 g, 0.0164 moles) in ethanol (200 mL) in ethanol (5 mL) and diluted with ether (400 mL). The precipitated 7 g of white powder (m.p. 152 'C) was 100 m! recrystallized from ethanol to give 4.6 g of the title compound as white microcrystals. Yield 57.5%. 154 'C.

Analysis: C ₂₆ H ₃₂ ClN ₃ O ₅ (M = 502.018) Calculated; C, 62.21; N, 6.43; N, 8.37

Cl% = 7.06

Found: C, 62.36; N, 6.70; N, 8.38

Cl, 7.04

Example 12

8- (Ethylaminoacetyl) amino-2-methyl-4- (p-tolyl) 1,2,3,4-tetrahydroisoquinoline maleinate (DZO-176)

5.2 g (0.0145 mole) of 8- (chloroacetyl) amino-2-methyl-4- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride in 100 ml. ethanol was reacted with ethylamine (30 mL, 20.8 g, 0.45 mol) in a bomb tube at 70 ° C for 5 hours. The reaction mixture was evaporated and the residual orange oil was dissolved in ethanol (50 mL) and treated with maleic acid (1.8 g, 0.0155 mol), diluted with ether (150 mL), filtered and washed with 1: 5 acetone / ether. . The product was obtained as a white powder (5.7 g, m.p. 157 ° C (b)). Recrystallization from ethanol (80 mL) and ether (20 mL) gave the title compound (4.3 g) as a white powder. Yield: 66%. 176'C (b).

186,518

Analysis: C ₂₅ H 31 N ₃ O ₃ CM = 453.546)

Calculated: C, 66.20; H, 6.89; N, 9.26 Found: C, 66.10; H, 7.39; N, 9.25.

Example 13

8- (n-Butyl-1-aminoacetyl) -amino-2-methyl-4- (ptol'l) · 1,2,3,4-tetrahydro-isoquinoline maleate (DZO175)

4.9 g (0.0135 mol) of 8- (chloroacetylamino) -2-methyl-4- (p-phenyl) -1,2,3,4-tetrahydroisoquinine hydrochloride in 300 ml of ethanol were treated with 20 ml of 78 g (0.2 mol) of n-butylamine was refluxed for 5 hours. The reaction mixture was evaporated in vacuo, the residue taken up in 50 ml of water with stirring and cooling, made basic with 25 ml of 30% sodium hydroxide solution and extracted with ether (6 x 150 ml) and dried. The solvent was evaporated in vacuo and the residual yellowish white oil taken up in EtOH (50 mL) was treated with maleic acid (1.6 g, 0.143 mol), diluted with ether (50 mL), filtered and washed with acetone / 1: 4. 6 g of the title compound are obtained in the form of a white powder. Yield: 92.0%. Mp 172 ° C (b).

Analysis: C ₇ H ₃₅ N ₃ O ₅ (M = 481.6).

Calculated: C, <67.34; II, 7.33; N, 8.73 Found: C, 67.60; H, 7.50; N, 8.47.

Example 14

4-Phenyl-8- (chloroacetylamino) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (DZO-152)

31.9 g (0.09 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline nialeinate are dissolved in 200 ml of water and 500 ml of ether are added, followed by vigorous stirring and ice-cooling. while basifying with 150 ml of 30% sodium hydroxide solution. The ether layer was separated and the aqueous layer was extracted with additional ether (3 x 300 mL). The combined ethereal solution was dried over anhydrous sodium sulfate and concentrated in vacuo (25 ° / 20 torr). That's how it got

Dissolve 22.5 g of a yellow oil in 600 ml of anhydrous benzene and add a solution of 7.6 ml (11.4 g, 0.101 mol) of chloroacetyl chloride in 40 ml of anhydrous benzene and reflux for 2 hours. After cooling, the precipitated material is filtered off with 3 x 60 ml of anhydrous benzene and 3 x 70 ml of anhydrous ether. washed. 32 g of a white powder are obtained. Mp 217 ° C (b). Recrystallization from 230 ml of ethanol gave 25.5 g of the title compound as a white powder. Yield: 81%. Mp 222 ° C (b).

Analysis: C ₁₈ H ₂₀ N ₇ Cl ₂ O (M = 351.278) Calculated: C 61.54% H% = 5.74 N% = 7.97

% C, 20.19% C, 10.09 Found: C, 61.23; H, 5.66; N, 8.00.

Cl% = 20.41 Cl% = 10.17

Example 15

4-Phenyl-8- (3'-chloropropionyl) amino-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (DZO153) g (0.11 mol) of 8-amine; 4-Phenyl-2-methyl-1,2,3,4-teinhydro-isoquinoline maleate was dissolved in 200 ml of water and 500 ml of ether was added thereto with 150 ml of 30% sodium hydroxide solution under vigorous stirring and ice-cooling. made alkaline. The ether layer was separated and the aqueous layer was extracted with additional 3 x 300 mL ether. The combined ethereal solution was dried over anhydrous sodium sulfate and concentrated in vacuo (25 ° / 20 torr). That's how it got

A solution of 24.3 g of yellow oil in 600 ml of anhydrous benzene is added dropwise with stirring to a solution of 14.2 g (0.112 mol) of 3-chloropropionic acid chloride in 50 ml of benzene over 20 minutes and the reaction mixture is refluxed for 2 hours. After cooling, the precipitate was filtered off, washed with ether (5 x 100 mL), air dried to give 32.0 g of a white powder. It was recrystallized from 180 ml of ethanol and diluted warm with 50 ml of ether.

22.5 g of the title compound are obtained in the form of white crystals. Yield: 60.4%. 220 ° C (b). Analysis: C ₉ H ₂₂ N ₂ OCl ₂ (M -365.305).

Found: C, 62.47; H, 6.07; N, 7.67

Cl% = 19.63 Cl% = 9.81 ~

Found: C, 62.72; H, 6.17; N, 7.68

Cl% = 19.33 Cl ⁼ % '= 9.60 "..... ......

Example 16

8-Chloroacetylamino-4- (p-chloro-phenyl) -2-methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride

A solution of crude 8-amino-4- (p-chlorophenyl) 2-methyl-1,2,3,4-tetrahydroisoquinoline (10.9 g, 0.04 mol) in dry benzene (220 ml) was added dropwise with stirring. 5.4 g (0.047 mol; 3.6 ml) of chloroacetate chloride in 30 ml of anhydrous benzene. After the addition, the reaction mixture was refluxed for 2.5 hours. The precipitate was then filtered cold. Wash with 20-20 mL benzene, acetone and ether then dry. 14 g of the title compound are obtained in the form of a white powder. Yield: 90.9%. 220 ° C (b).

Analysis: C ₁₈ H ₁₉ Cl ₃ N ₂ O (M = 384.7)

Calculated: C, 56.05; H, 4.96; N, 7.26

Cl% = 27.25% = 9.08 Found ·%: C = 56.21% H = 5.12% N = 7.42

Cl% = 27.32 ΟΓ% = 9.12 '

Example 17

8- (chloro-acetyl) - amino-2-methyl-4- (p-tolyl) -l, 2,3,4tetiahidro isoquinoline hiriioklorid

A solution of 7.6 g (0.03 mol) of 8-amino-2-diethyl-4- (p-tolyl) -1,2.3.4-tetralyldiO-isoquinoline in 100 ml of anhydrous benzene was added dropwise with stirring to 4.05 g (0.035 mol; 2). (7 mL) of chloroacetyl chloride dissolved in 30 mL of anhydrous benzene. The reaction mixture was refluxed for 5 hours. After cooling, the precipitate was filtered off and washed with ether (5 x 50 mL). The title compound is obtained in the form of a white powder. Yield: 92.6%. Mp 228 ° C (b).

Analysis: C ₁₉ EI ₂₂ Cl ₂ N ₂ O (M = 365.3).

Calculated: C, 62.47; H, 6.07; N, 7.67

Cl, 19.41 Cl, 9.70 Found: C, 62.69; H, 6.45; N, 7.58.

Cl% = 19.64 ° C -% = 9.73

186,518

Example 18

4-Phenyl-8- (chloroacetyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

3.12 g (0.012 mol) of N- (2-aminobenzyl) -1-phenyl-2- ^! Methylamino-1-ethanol was dissolved in 70 ml of anhydrous ether and 0.95 g (0.012 mol) of anhydrous pyridine were added, followed by 1.62 g (0.0144 mol) of vigorous stirring and cooling with ice at 3-6 ° C. reaction with chloroacetyl chloride. The yellowish-white precipitate ^one reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-water (100 ml) and extracted with ether (3 x 100 ml). The ether solution was dried over anhydrous sodium sulfate for 30 minutes, then concentrated in vacuo without heating and gave 4.2 g of an orange oil ^1. The N-chloroacetyl derivative thus obtained is cyclized crude and immediately.

The oil was dissolved in dichloromethane (30 mL) and filtered, dropwise added to concentrated sulfuric acid (20 mL) with cooling and stirring at 0-3 ° C for 15 minutes and then stirred at the temperature for ² minutes. The reaction mixture was then poured onto 100 g of ice and extracted with chloroform (4 x 200 ml).

The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to give 3.0 g of an orange powder. It's washed 3 x 30 ml of ether,

2.3 g of beige powder are obtained, which are recrystallized from ethanol to give 1.6 g of base as a white powder. Yield: 42.4%. Mp: 240 'C (b).

Analysis: C ₁₈ H ₁₉ ClN ₂ O (M = 314.817) <

Calculated: C, 68.67; H, 6.08; N, 8.90

Cl, 11.26

Found: C, 68.42; H, 5.95; N, 8.96

Cl% = 11.12

The base (1.5 g, 0.00475 mol) was suspended in ethanol (5 ml), mixed with ether (5 ml) saturated with hydrochloric acid under cooling and clouded with ether (50 ml). After cooling, the precipitate was filtered off to give 1.5 g of the title compound as a white powder. Total yield: 38.2%. M.p. 222 'C (b).

Claims (6)

Patent claims A process for the preparation of 8- (aminoacylamino) -4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline derivatives of formula (I): R ¹ is C 1-6 alkyl and R ² is hydrogen or R ¹ and R ² together with the adjacent nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing an additional heteroatom; R is hydrogen, halogen or (C 1 -C 4) alkyl, and n is 1,2,3 or 4) and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula II (wherein H 2 is halogen and R and n is as defined above) or a salt thereof is reacted with an amine of formula III (wherein R 1 and R ² are as defined above) or a salt thereof. Process according to claim 1, characterized in that it is carried out during the reaction heating, preferably at the boiling point of the reaction mixture. 3. A process according to claim 1 or 2, wherein the reaction is carried out in an organic solvent medium. 4. A process according to claim 3, wherein the organic solvent is an aliphatic alcohol, preferably ethanol. 5. A process for the preparation of a process according to claim 1 wherein the compounds of formula (I) wherein R ² is p-chloro or methyl, R ² is hydrogen and R ¹ is ethyl or n-butyl (where n is 1) and pharmaceutically acceptable acid addition salts thereof, particularly maleinates, wherein the starting materials are the compounds of formula (III) and (III) wherein R, R ¹ , R ² and n are as defined in the claims and H . 6. A process for the preparation of a pharmaceutical composition comprising the compound of formula I (wherein R, R ¹ , R ² and n are as defined in claim 1) or a pharmaceutically acceptable acid addition salt thereof obtained by the process of claim 1. as an active ingredient in admixture with inert, non-toxic solid or liquid pharmaceutical carriers and making them pharmaceutical compositions.