CS266192B1 - Basic derivatives of tetrahydronaphthalene, chromene and thiochroman and a process for their preparation - Google Patents

Abstract

The subject of the solution are basic derivatives of tetrahydronaphthalene, chroman and thiochroman of the general formula I in which X = CH2< O or S and R = H or methyl, their addition salts and a method for their preparation. These substances show significant calcium antagonistic activity in animal tests and have the prerequisites for use in the treatment of cardiovascular diseases. The method for preparing substances of the general formula I consists in the reductive alkylation of N-methylhomoveratrylamine with aldehydes of the general formula in which X and R denote the same as in the formula I, which are prepared by acidic hydrolysis of their acetals. The obtained bases of the general formula I are converted by neutralization with inorganic or organic acids into addition salts.

Description

The invention relates to basic derivatives of tetrahydronaphthalene, chromate and thiochroman of the general formula I.

_OCH3 wherein X = CH ^, O or S and R = H or CH ^, their addition salts with pharmaceutically acceptable inorganic and organic acids and a process for their preparation.

The compounds of the formula I have calcium antagonistic activity in animal pharmacological tests and are therefore suitable for use in the treatment of ischemic heart disease, hypertension and certain types of cardiac arrhythmias. They are relatively low in toxicity. The LD50 values found in acute toxicity tests in mice range from 35 to 70 mg / kg when administered intravenously and between 450 and 750 mg / kg when administered orally. Calcium antagonist activity was demonstrated in vitro by determining binding to receptor sites in rat cerebral cortex using tritium-labeled desmethoxyverapamil as a reference substance. It was demonstrated in vivo in a test in anesthetized rats in which a rapid intravenous calcium chloride solution induces ventricular fibrillation with subsequent death. The compounds of formula I significantly reduce mortality in this test.

The preparation of the compounds of the formula I is based on the generally known carbinols of the formula II

CQ-

R ¹ (II).

in which = OH and X and R are the same as in formula I. By treating an excess of thionyl chloride in an aprotic solvent, for example anhydrous ether, at room temperature to the boiling point of the reaction mixture they are converted into chlorine derivatives of formula II in which R 1 = Cl and X and R is the same as in formula I, which are obtained in the crude state by distilling off the solvent and other volatile substances under reduced pressure. By reacting the crude chloro derivatives with trimethylsilyl cyanide in a suitable organic solvent, for example dichloromethane in the presence of a catalytic amount of stannous chloride, the obtained nitriles of formula II in which R ₃ = CN and X and R are the same as in formula I are isolated by quenching the reaction mixture with water, shaking separate aqueous layers with the organic solvent used, combining the separated solutions and, after drying, for example with anhydrous sodium sulfate, distilling off the solvent. The crude nitriles thus obtained are purified by distillation under reduced pressure.

In the next step, the nitriles are converted by alkylation with 3,3-diethoxypropyl chloride or 2- (2-bromoethyl) dioxolane to acetals of formula III

NC CH ₂ CH ₂ R ₂ (ni), in which r ₂ denotes diethoxymethyl or 2-dioxolanyl and X and R denote the same as in formula I. This alkylation can be carried out by treating the nitrile of formula II in which R ₁ = CN and X and R denote the same as in formula I, metalated in the alpha-position, for example with lithium diisopropylamide, prepared by treating n-butyllithium with diisopropylamine in hexamethylCS 266 192 B1 phosphorotriamide as a solvent in a nitrogen atmosphere at a temperature of about 10 ° C. The alkylation is carried out in hexamethylphosphoric triamide at 0 DEG to 20 DEG C. for 1 to 2 hours. The acetal of formula III is isolated by mixing the reaction mixture with water and shaking into an organic solvent such as ether and washing the separated solution with water and drying over sodium sulfate by distilling off the solvent. The crude acetal can be purified, for example, by column chromatography on silica gel. The pure acetals thus obtained are in the next step converted by acid-catalyzed hydrolysis to aldehydes of general formula TV

NC CH ₂ CH ₂ CHO (IV) in which X and R denote the same as in formula 1. The hydrolysis can be carried out, for example, in a mixture of water and acetone or in a wet ether in the presence of an inorganic acid, for example sulfuric or hydrochloric acid, or an organic acid , for example p-toluenesulphonic acid, oxalic acid or trifluoroacetic acid at a temperature of 20 to 50 ° C for 2 to 10 hours. In the case of hydrolysis of acetals of formula III in which R ₂ is diethoxymethyl, the hydrolysis is preferably carried out by heating oxalic acid in anhydrous or aqueous acetone to 30 to 40 ° C for 3 to 6 hours. The aldehyde of formula IV is isolated by neutralizing oxalic acid with aqueous potassium carbonate solution, aspirating the precipitated potassium oxalate, distilling off the acetone, stirring the residue with water and suitable water. an insoluble solvent, such as ether, and distilling off the solvent from the separated solution. The hydrolysis of acetals of formula III in which R ₂ is 2-dioxolanyl is preferably carried out by heating with about 90% trifluoroacetic acid with stirring at 15 DEG C. for 3 to 6 hours. After neutralizing the trifluoroacetic acid with, for example, sodium bicarbonate solution, the product is isolated shaking, for example, into ether and distilling off the ether. The aldehydes of formula IV thus prepared can be used in the next step without purification.

The crude aldehydes of formula IV are used in the final step of the synthesis to reductively alkylate N-methylhomoveratrylamine. The reductive alkylation can be carried out either under catalytic hydrogenation conditions or preferably using formic acid as reducing agent in for example benzene or toluene, lower aliphatic alcohol having 1 to 4 carbon atoms, chloroform, ethyl acetate or aqueous dimethylformamide at 20 ° C to boiling point reaction mixture. Preferably, the reductive alkylation is carried out by heating a mixture of the aldehyde of formula IV, N-methylhomoveratrylamine and formic acid in toluene to boiling until the evolution of carbon dioxide has ceased. The basic product of formula I is isolated from the cooled reaction mixture by shaking in dilute sulfuric acid or hydrochloric acid, basifying the separated aqueous solution with, for example, sodium hydroxide solution, shaking the precipitated base in a water-immiscible organic solvent, e.g. toluene, ether, dichloromethane or chloroform, and distilling off the solvent. . The bases of the formula I thus prepared can be converted into addition salts by neutralization with inorganic or organic acids.

Details of the process for the preparation of the compounds of formula I are given in the following examples, which do not limit the scope of the invention in any way.

Example 1

4-cyanochroman

To a solution of 31.5 g (0.21 mol) of 4-chloromannol in 200 ml of anhydrous ether was added 70.0 g (0.58 mol) of thionyl chloride, and the mixture was stirred at room temperature for 4 hours. reduced pressure from a maximum bath temperature of 40 ^U C to give 35.3 g of crude 4-chlorochromate is dissolved in 200 ml of dichloromethane and to the solution were added under stirring 25.0 g (0.25 mol) of trimethylsilyl cyanide and a few drops of stannic chloride . After a short exotherm, the reaction mixture was stirred for 1 h. The dark reaction mixture was poured into 300 mL of water. The dichloromethane layer was separated and the aqueous layer was shaken with dichloromethane.

CS 266 192 Bl

The combined dichloromethane solutions were washed with saturated brine and dried over anhydrous sodium sulfate. The dark oily residue obtained by distilling off dichloromethane is distilled off under reduced pressure to give 25.7 g (77% of theory) of product, m.p. 116 DEG-118 DEG C. at 105 Pa. The identity of the product was confirmed by elemental analysis and NMR and 10 spectra.

In an analogous manner no ptlpi sv:

4-cyanothiochroman in a yield of 69.1%, m.p. 168-170 ° C at 400 Pa,

3-methyl-4-cyanothiochexan in a yield of 82.3%, m.p. 128-130 ° C at 85 Pa, m.p. 26-32 ° C,

1-cyano-1,2,3,4-tetrahydronaphthalene in a yield of 30%, b.p. 91-96 ° C at 55 Pa, and 1-cyano-2-methyl-1,2,3,4-tetrahydronaphthalene in yield 29.5 l, m.p. 100-106 ° C at 55 Pa, m.p. 41-52 ° C.

Example 2

4- [2- (2-dioxolanyl) ethyl] -4-cyanothiochroman

To a stirred solution of 5.77 g (0.057 mol) of diisopropylamine in 30 ml of hexamethylphosphoric triamide cooled to 10 DEG C. under nitrogen was added 24.3 ml of a 15% solution of n-butyllithium in n-hexane (0.057 mol) and the mixture was stirred under nitrogen. A solution of 5.0 g (0.028 mol) of 4-cyanothiochroman in 30 ml of hexamethylphosphoric triamide was added to the dark red reaction mixture at 10 DEG C. with stirring, and after stirring for 1 hour, a solution of 6.5 g (0.036 mol) was added. 2- (2-bromoethyl) dioxolane in 30 ml hexamethylphosphoric triamide. After stirring for 1 hour, the reaction mixture is poured into 400 rolls of water with stirring. The product is shaken three times with 150 ml of ether and the combined ether solutions are washed with water and dried over anhydrous sodium sulfate. The colored oily product obtained by distilling off the ether under reduced pressure was purified by silica gel column chromatography. Delusion of a mixture of benzene, diisopropyl ether and chloroform (4: 1: 1.5) gave 7.3 g (92.9% of theory) of pure product, the identity of which was confirmed by elemental analysis and NMR and IC spectra.

In an analogous manner prepare:

4- [2- (2-dioxolanyl) ethyl] chromate (using 3,3-diethoxypropyl chloride instead of 2- (2-bromoethyl) dioxolane) in a yield of 77%,

4- (3,3-diethoxypropyl) -4-cyano-3-methylthiochroman in a yield of 77.5%,

1- (3,3-diethoxypropyl) -1-cyano-1,2,3,4-tetrahydronaphthalene in a yield of 89.2%,

1- (3,3-diethoxypropyl) -1-cyano-2-methyl-1,2,3,4-tetrahydronaphthalene in a yield of 76.9%.

Example 3

4-cyano-4- (3-oxopropyl) chroman

A solution of 15 g of 4- [2- (2-dioxolanyl) ethyl] -4-cyanochroman in 55 ml of 90% trifluoroacetic acid is stirred at room temperature for 6 hours. It is neutralized with stirring with 400 ml of saturated sodium bicarbonate solution and the product is extracted three times with 150 ml. ml of ether. The combined ether solutions were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. Drying over anhydrous sodium sulfate and distilling off the ether under reduced pressure gave 13.1 g (85% of theory according to NMR spectrum) of the product in the form of a colored viscous oil, which was used without purification for reductive alkylation.

CS 266 192 Bl

It is prepared in an analogous manner

4-Cyano-3- (3-oxopropyl) thiochroman in 90% yield.

Example 4

4-cyano-3-methyl-4- (3-oxopropyl) thiochroman

To a solution of 13.2 g (0.041 mol) of 4- (3,3-diethoxypropyl) -4-cyano-3-methylthiochroman in a mixture of 100 ml of acetone and 30 ml of water was added 6.12 g of oxalic acid dihydrate, and the mixture was stirred. 6 h at 40 ° C. After cooling to about 20 ° C, the pH is adjusted to 6.5 to 7.0 with 50% potassium carbonate solution. The precipitated potassium oxalate is filtered off with suction and the filtrate is evaporated under reduced pressure. The residue is stirred with 400 ml of water and the product is extracted three times with 200 ml of ether. The combined ether solutions were washed with saturated brine, dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure. 10.4 g (91% of theory according to NMR spectrum) of product are obtained in the form of a pale yellow viscous oil.

In an analogous manner prepare:

1-cyano-2-methyl-1- (3-oxopropyl) -1,2,3,4-tetrahydronaphthalene in a yield of 99.5% and

1-Cyano-1- (3-oxopropyl) -1,2,3,4-tetrahydronaphthalene in 94.7% yield.

Example 5

4-cyano-4- [3- (N-methylhomoveratrylamino) propyl] thiochroman

A mixture of 4.4 g (0.017 mol, NMR content 90%) of 4-cyano-4- (3-oxopropyl) thiochroman, 3.4 g of N-methylhomoveratrylamine, 1.0 g of 99% formic acid and 30 ml of anhydrous toluene stir and heat to reflux for 90 minutes. After cooling, the mixture is poured into 50 ml of water and the pH is adjusted to 4 with concentrated hydrochloric acid. The toluene layer is separated and shaken five times with 50 ml of 2% hydrochloric acid. The combined solutions were washed with ether. The base which precipitates with 50% sodium hydroxide solution is taken up in ether. The ether solution was washed with saturated brine and dried over anhydrous sodium sulfate. Distillation of the ether under reduced pressure gave 6.8 g (96.8%) of the product base, which was converted into hydrogen oxalate by neutralization with oxalic acid, m.p. 203-204 ° C (1,2-dichloroethane). The base liberated from the hydrogen oxalate in the usual manner, the structure of which was confirmed by NMR and IC spectra, was converted into hydrogen fumarate, m.p. 154-156.5 ° C (2-propanol).

In an analogous manner prepare:

1-cyano-1- [3- (N-methylhomoveratrylamino) propyl] -1,2,3,4-tetrahydronaphthalene, m.p. 173-173.5 ° C (methanol) and m.p. 161 C,

4-cyano-4- [3- (N-methylhomoveratrylamino) propyl] chromate, m.p. hydrogen oxalate 197.5-200 ° C (methanol) or 147-150 ° C (2-propanol),

4-cyano-3-methyl-4- [3- (N-methylhomoveratrylamino) propyl] thiochroman, m.p. 143-155 ° C (methanol) and 1-cyano-3-methyl-1- [3- (N -methylhomoveratrylamino) propyl] -1,2,3,4-tetrahydronaphthalene, m.p. hydrogen oxalate 188-191 ° C (ethanol).

Claims (5)

OBJECT OF THE INVENTION Basic derivatives of tetrahydronaphthalene, chromate and thiochroman of general formula I och ₃ in which X = CH 2, O or S and R = H or CH 2, and their addition salts with pharmaceutically acceptable inorganic and organic acids. 2. A process for the preparation of basic derivatives of tetrahydronaphthalene, chromate and thiochroman according to item 1 of general formula I, characterized in that the acetal of general formula III NC CH ₂ CH ₂ R ₂ in which X and R denote the same as in formula I and R 1 denotes a diethoxymethyl group or 2 -diodolanyl, acid hydrolyzes to the aldehyde of formula IV NC CH ₂ CH ₂ CH = O (IV), in which X and R are the same as in formula I, the crude aldehyde obtained is reductively alkylated with N-methylhomoveratrylamine and the isolated basic product of formula I is converted by neutralization with an inorganic or organic acid to addition salt. 3. A process according to claim 2, wherein the hydrolysis of acetals of formula III, in which R1 is diethoxymethyl and X and R are the same as in formula I, is carried out by stirring their solutions in aqueous acetone with oxalic acid dihydrate at a temperature of 20 to 40 °. C for 3 to 6 h. 4. The process of claim 2, wherein the hydrolysis of the acetals of formula III, wherein R ₂ is 2-dioxolanyl and X and R are the same as in formula I, is carried out by stirring with 90% trifluoroacetic acid at a temperature of 15 to 30 ° C. 3 to 6 h. 5. The process of claim 2, wherein the reductive alkylation of N-methylhomoveratrylamine with aldehydes of formula IV is performed using formic acid as a reducing agent in toluene at the boiling point of the reaction mixture for 1 to 2 hours.