CS225598B1 - Tri-substituted 3-/4-tolyl/-1,2,3,4-tetrahydroisoquinolines and their salts - Google Patents

Description

The invention relates to the trisubstituted 3- (4-tolyl) -1,2,3,4-tetrahydroisoquinolines of the formula I,

wherein R is hydrogen or methyl and R ¹ is hydrogen, methyl or 3,4-dimethoxybenzyl, and salts thereof with pharmaceutically acceptable inorganic acids.

The compounds of formula I and their salts show pharmacodynamic and antimicrobial activity in biological assays, so that they can find use as medicaments. Some of them act centrally to inhibit and potentiate the cataleptic effect of neuroleptics, so their usefulness in neurology and psychiatry can be expected. Others lower blood pressure, so they can find use in the therapy of hypertonic disease. They are also effective locally anesthetically (used for local anesthesia in surgery) and antispasmodic (used in the treatment of epilepsy). Finally, they show antimicrobial effects in in vitro assays suggesting their usefulness in chemotherapy for invasive diseases. Now on the properties of the individual substances according to the invention.

6.7-Dimethoxy-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline was tested as the hydrochloride. When administered intravenously to mice, it exhibits an acute toxicity characterized by an LD ₅₀ value of 37.5 mg / kg. At a concentration of 0.5 to 1% it acts locally anesthetically in the rabbit eye anesthesia test. At intravenous doses higher than 7 mg / kg, it shows the indicated central stimulatory efficacy in mice (increases spontaneous motility). At concentrations of 100 µg / ml, they inhibit growth of Saccharomyces pasterianus, Trichophyton mentagrophytes and Aspergillus niger (specific focus on yeast and lower fungi).

6.7-Dimethoxy-1-methyl-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline was also tested as the hydrochloride. Its acute toxicity in my225598 when administered orally is very low, LD ₅₀ = 1 g / kg. At concentrations of 100 µg / ml, the substance inhibits the growth of the same microorganisms as the former.

6.7- dimethoxy-l- (3,4-dimethoxybenzyl) -3- (4-tolyl-l, 2,3,4-tetrahydrolsochinolin also tested as the hydrochloride. The substance is almost netoxlcká. When administered orally LD ₅₀ is higher than 2500 mg / kg At an oral dose of 300 mg / kg, it inhibits the convulsive effect of pentetrazole The central depressant effect in mice occurs only at doses higher than 300 mg / kg orally (motility suppression) At concentrations of 100 / zg / ml it inhibits growth Saccharomyces pasterianus, Candida albicans and Aspergillus niger, growth of Trichophyton mentagrophytes is already inhibited by a concentration of 50 µg / ml.

6.7-Dihydroxy-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline was tested as hydrobromide. Acute toxicity in mice, LD ₅₀ = 75 mg / kg iv An intravenous dose of 7.5 mg / kg causes significant reductions in blood pressure in normotensive rats. Intravenous doses of 10-15 mg / kg significantly potentiate the duration of thiopental sleep in mice, suggesting a tranquilizing effect. This proves likely inhibitory motility of mice at doses higher than 15 mg / / kg iv Compound inhlbuje growth following organisms at the concentrations indicated in _t ug / / ml Staphylococcus pyogenes aureus 50 Pseudomonas aeruginosa 50, Proteus vulgaris 100 Mypqbacterium tuherculosis 100 Saccharomyces pasterianus 100, Trichophyton mentagrophytes

6.7-Dihydroxy-1-methyl-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline has been tested as hydrobromide, Acute toxicity in mice is greater than 500 mg / kg p.o. non-toxic (i.e., no dying or part of the mice). At an oral dose of 25 mg / kg, the compound potentiates catalapsia in rats. perfenazine-induced; it has a procathaleptogenic effect. At the following concentrations (in µg / ml), they inhibit the following microorganisms: Streptococcus (3-haemolyticus 100, Streptococcus faecalis 100, Saccharomyces pasterianus 100, Trichophyton mentagrophytes 50, Candida albicans 100, Aspergillus niger 100.

The compounds of formula I of the present invention are accessible from the N-acyl derivatives of 2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethylamine of formula II,

wherein R ¹ has the same meaning as in formula I, which in a first step, cyclized in the Bischler-Napieralski reaction to 3,4-dihydroisoquinoline derivatives of general formula III

R ¹ (III) wherein R ¹ is again the same as in Formula I. This cyclization is achieved by heating II with phosphorus oxychloride or a mixture thereof with phosphorus pentoxide in toluene. The starting amides of formula (II) are all novel and the methods for their preparation are described in the examples.

In the second step, the compounds of formula III are reducted with sodium hydride, preferably in ethanol, to give tetrahydroisoquinolines which already correspond to the general formula I, but with a limitation of the meaning of R to the methyl group. The intermediates of formula III are partially unstable and are therefore preferably not isolated in the pure state but in the crude state directly subjected to reduction with sodium borohydride as described in the examples.

If it is desired to prepare compounds of formula I wherein R = H, it is necessary to use yet another reaction step consisting in the demethylation of compounds of formula I where R = methyl. Either heating with hydrobromic acid or a very selective and gentle method consisting of this can be used for this demethylacetate. in reaction with boron tribromide in chloroform or di ₇ chloromethane at room temperature. This last reaction usually results in the bromoboronate ester of the desired compound, which must be decomposed into the free phenolic derivative, which usually requires heating with ethanol. Crystallization from this solvent then directly produces the hydrobromide of the desired phenolic amine. _T Further details of embodiments for preparing compounds of Formula I resulting from the examples below.

The compounds according to the invention and the intermediates of formulas II and III are novel substances whose identity has been established both analytically and by spectral methods. i,

He did

6,7-Dimethoxy-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline. A mixture of 29.9 g of N- [2- (3,4-dimethoxyphenyl) -1- (4-tolylethyl) formamide, 150 ml of toluene and 100 ml of phosphorus oxychloride is stirred and refluxed for 4.5 hours. poured into 1.5 L of 2M-HCl The precipitated 6,7-dimethoxy-3- (4'-tolyl) -3,4-dihydrolsoquinoline hydrochloride was collected by filtration, washed with ethanol and ether and dried, 21 g [66%] mp 187.5-188 ° C. The material was purified by crystallization from a mixture of ethanol and ether. The acidic aqueous filtrate was basified with 10% sodium hydroxide solution and extracted with chloroform. The extract yielded by drying and evaporation of 4.0 g of 6,7-dimethoxy-3- (4-tolyl) -3,4-dihydroisoquinoline base, thereby increasing the overall yield to 80%. Crystallization from a mixture of cyclohexane and a small amount of ethanol gave the base in analytically pure and melting at 92-94 ° C.

A solution of 146 g of the preceding hydrochloride in 3 l of ethanol is neutralized with 5M-NaOH to pH 6.5 and 59 g of sodium borohydride are added in small portions with stirring over 1 h. The mixture was then refluxed for 6 hours, most of the ethanol was evaporated under reduced pressure and the residue was quenched by the addition of 500 ml of water. Add 500 mL of 1M-NaOH and extract with toluene. The extract was dried over potassium carbonate, evaporated under reduced pressure, the residual oil was dissolved in 1 L of ethanol and a slight excess of a solution of hydrogen chloride in ether was added. On standing, 147 g (100%) of the desired 6,7-dimethoxy-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride crystallized from ethanol and melted at 255-257 ° C in pure form.

The starting N- [2- (3,4-dimethoxyphenyl) -1- (4-tolylethyl) formamide used is a novel compound which is prepared, for example, as follows:

To a stirred suspension of 450 g of anhydrous aluminum chloride in 700 ml of toluene, a solution of 430 g of homoveratroyl chloride (Haworth RD et al., J. Chem. Soc. 125, 1686, 1924) in 800 ml of toluene was added dropwise over 3 h at 15 ° C; the mixture is stirred for 6.5 h at 15 ° C, left at room temperature overnight and then quenched by pouring into a mixture of 5 L of 5M-HCl and 5 kg of ice. The mixture was stirred for 45 min. and extracted with chloroform after thawing the ice. The extract was washed with water, 5% sodium hydroxide solution and water, dried over magnesium sulphate and evaporated under reduced pressure. 387 g '(72%) of crude crystalline 2- (3,4-dimethoxyphenyl) -4'-methylacetophenone melting at 98-102 ° C (south of 94 ° C) is obtained. This substance ¹ is sufficiently pure for further processing. For characterization, a completely pure material melting at 104-105.5 ° C can be obtained by crystallizing the sample from methanol. Also for characterization, a sample of the oxime can be prepared by reacting this ketone with hydroxylamine hydrochloride in boiling ethanol in the presence of sodium bicarbonate, which crystallizes from aqueous ethanol and melts at 113-115.5 ° C.

A mixture of 270 g of the previous ketone, 680 g of formamide and 140 g of 98% formic acid was slowly heated until a temperature of 170-180 ° C was reached, maintaining the mixture for 12 h. After cooling, the mixture was diluted with 3 L of water at 60 ° C, stirred for 1 h, cooled to 30 ° C and the precipitated solid N- [2- (3,4-dimethoxyphenyl) -1- (4-tolylethyl) formamide was filtered off with suction, washed with water and dried. m.p. 128 DEG-131 DEG C. The sample is purified by crystallization from aqueous methanol for characterization and then melted at 134 DEG-135 DEG C. For characterization.

Example 2

6,7-Dimethoxy-1-methyl-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline 31 g of N- / 2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethyl acetate, 150 ml of toluene and 150 g of phosphorus oxychloride are refluxed for 3.5 h, poured into 1 L of 1M HCl under cooling after cooling, and the separated aqueous layer is made alkaline at 10 ° C with 5M-NaOH and precipitated. The base of 6,7-dimethoxy-1-methyl-3- (4-tolyl) -3,4-dihydroisochlnoline is isolated by extraction with chloroform: 14 g (48%), mp 126.5 - 128 ° C [cyclohexane]. in a mixture of 96% ethanol and ether provides the hydrochloride monohydrate, which crystallizes from 96% ethanol and melts at 178-183 ° C.

To a stirred solution of 5.0 g of the previous base in 150 ml of ethanol was slowly added 2.0 g of sodium borohydride. The mixture is boiled for 30 min. The mixture was cooled, acidified with dilute hydrochloric acid and the solution was evaporated under reduced pressure. The residue was quenched with 200 mL 2.5M-NaOH and extracted with benzene. The extract was dried over potassium carbonate and evaporated. The residue was dissolved in 50 ml of ethanol and a slight excess of a solution of hydrogen chloride in ether was added. 5.0 g (88%) of the desired 6,7-dimethoxy-1-methyl-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride crystallized, melting at 245-246 ° C. Three crystallizations from ethanol yielded 3.0 g of the product with a constant melting point of 252 DEG-253 DEG C. with decomposition, which is to be regarded as one homogeneous racemate of the desired compound.

The starting N- [2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethyl] acetamide used is a novel compound which can be obtained, for example, by the following procedure:

A mixture of 297 g of N- [2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethyl] formamide (see Example 1j), 350 ml of ethanol and 310 g of 85% potassium hydroxide is stirred and refluxed for 3 h in a bath. 120 DEG C. The mixture was diluted with 1.5 L of water and the base extracted with ether, dried over potassium carbonate and evaporated to give 252 g (93%) of oily 2- (3,4-dimethoxyphenyl) -1- (4-). Ethyl amine is dissolved in 500 ml of ethanol, a slight excess of a solution of hydrogen chloride in ether and a further 1 liter of ether is added and 240 g (78%) of crystalline hydrochloride precipitate upon cooling and melting at 228-229.5 ° C. and is practically clean and suitable for further processing.

To a mixture of 154 g of the preceding hydrochloride and 600 ml of pyridine, 260 g of acetic anhydride at 25-30 ° C are added dropwise with stirring. The mixture was stirred at room temperature for 3 h and allowed to stand overnight. Then part of the pyridine is evaporated in vacuo and the residue is poured into

1.5 1 water. After standing for several hours, the precipitated N- [2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethyl] acetamide was filtered, washed with water and dried to give 155 g (93%) of the title compound after crystallization from benzene. melts when

Mp 167.5-168.5 ° C.

Example 3

6.7-Dimethoxy-1-methyl-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline. A mixture of 125 g of N- [2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethyl] acetamide (see Example 2), 600 ml of toluene, 400 ml of phosphorus oxychloride and 40 g of phosphorus pentoxide is stirred and boiled. It was then evaporated under vacuum and the evaporation was repeated after the addition of 500 ml of benzene, the residue was dissolved in 1 L of ethanol, neutralized with 500 ml of 2.5M-NaOH (pH 6.5 and stirred while stirring). 50 g of sodium borohydride are slowly added over 30 minutes, the mixture is refluxed for 3 hours, evaporated in vacuo, 200 ml of 5M-NaOH is added to the residue, and extracted with benzene, shaken with a slight excess of 1M-HCl and 80 g (60%), m.p. 250 DEG-258 DEG C. Recrystallization from ethanol gives a product melting at 252 DEG-253 DEG C., identical to the product obtained in Example 2.

Example 4

6.7-Dimethoxy-1- (3,4-dimethoxyphenyl) -3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline 90 g N- / 2- (3,4-dimethoxyphenyl) -1 - (4-tolyl) ethyl / -3,4-dimethoxyphenylacetamide, 400 ml of toluene, 300 ml of phosphorus oxychloride and 30 g of phosphorus pentoxide are refluxed for 4 h and evaporated in vacuo, and the residue is dissolved in 1.5 l of ethanol, The solution is neutralized with 350 ml of 5M-NaOH and 30 g of sodium borohydride are slowly added over 30 minutes with stirring, the mixture is refluxed for 3 hours, evaporated in vacuo, basified with 5M-NaOH and the base extracted with benzene. The resulting hydrochloride is filtered off with suction after several hours, washed with ethanol / ether and dried to give 61 g (65%) of the hydrochloride which melts with decomposition at 217-218.5 ° C. Three crystallizations from 80% ethanol give a substance with a constant melting point of 220-221 ° C with decomposition. a homogeneous racemate.

The starting N72- (3,4-dimethoxyphenyl) -1- [4-tolyl) ethyl] -3,4-dimethoxyphenylacetamide used is a novel material which can be prepared, for example, by the following procedure:

To a mixture of 62 g of 2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethylamine hydrochloride (Example 2) and 300 ml of pyridine was added dropwise with stirring over 7.5 h at 60 to 70 ° C. g of homoveratroyl chloride in 100 ml of toluene. After cooling, the mixture is freed from most pyridine by evaporation in vacuo, the residue is taken up in 500 ml of water and the desired amide formed is filtered off with suction, washed with water, dried and recrystallized from 1 l of toluene. It is obtained in a yield of 73 g (82%), 1.1.152-155 ° C and after solidification again 163-164 ° C.

Example 5

6.7-Dihydroxy-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline. A mixture of 18 g of 6,7-dimethoxy-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride (Example 1) and 200 ml of 46% hydrobromic acid is stirred at reflux for 6.5 h. temperature 100 ° C. It is then cooled to 0 ° C for 12 h. 18 g (95%) of the hydrobromide of the title compound crystallized, crystallizing from 95% ethanol and melting at 262-264 ° C. Example 6

6,7-Dimethoxy-1-methyl-3- (4-tolyl) -1,2,3-dihydroxy-1-methyl-3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline 4-Tetrahydroisoquinoline (Example 2) (34 g) was quenched with 200 ml of 20% aqueous ammonia and the liberated base was extracted with chloroform to give 31 g of an oil, dissolved in 300 ml of chloroform and stirred at 0 ° C for stirring A solution of 100 g of boron tribromide in 150 ml of chloroform was added dropwise over 1 hour, stirred at room temperature for 6 hours, 300 ml of ethanol was added dropwise over 30 minutes, and the mixture was evaporated under reduced pressure. sp induces crystallization by addition of 250 ml of ether to give 21 g (78%) of the hydrobromide of the desired substance, melting at 254 < 257 &gt; to 257 DEG C. This product appears to be one homogeneous racemate. melting only rises to 257-259 ° C with decomposition and no longer changes.

Claims (1)

SUBJECT VYNALEZU The trisubstituted 3- (4-tolyl) -1,2,3,4-tetrahydroisoquinolines of formula I, (I) wherein R is hydrogen or methyl and R ¹ is hydrogen, methyl or 3,4-dimethoxybenzyl, and salts thereof with pharmaceutically acceptable inorganic acids.