PL90027B1 - - Google Patents

Description

The subject of the invention is a process for the preparation of new racemic or optically active 1-phenoxy-2-hydroxy-3-cycloalkylaminopropanes and their acid addition salts. The new compounds correspond to formula 1, in which R is an alkyl group containing up to 5 carbon atoms, Ri is nitrile (-C1N), or halogen, R2 is hydrogen, halogen, nitrile or an alkyl, alkoxy or alkenyl group of up to 5 carbon atoms, R3 is hydrogen, halogen, alkyl or alkoxy of up to 5 atoms carbon and n is an integer of 2-7. The new compounds are prepared according to the invention by diazotizing a compound of formula 2, wherein R, R2 and R3 and n are as defined above, and heating with cuprous cyanide or with a cuprous halide. 2 already contain the ready skeleton of 1-phenoxy-2-hydroxy-3-cycloalkylaminopropane and can be prepared starting from the corresponding phenol, which is reacted with epichlorohydrin and formed 1-phenoxy-2,3 -epoxypropane is reacted with cycloalkylamine. The compounds according to the invention have an asymmetric carbon atom in the CHOH group and therefore occur as racemates and in the form of optical antipodes. The latter can be obtained by resolving the racemate with the usual auxiliary acids, such as dibenzoyl-D 4 -tartaric acid or D-3-bromocamphor-8-sulfonic acid, as well as by using optically active starting compounds. The phenoxy-3-cycloaminopropanols of the formula I can be converted into physiologically acceptable acid addition salts in a known manner. Suitable acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid or 8-chlorothophyllin. Compounds of formula I or their physiologically acceptable acid addition salts show in tests in guinea pigs, as experimental animals, valuable therapeutic properties, in particular o-blocking activity, and can therefore be used for the treatment and prevention of coronary artery diseases and cardiac arrhythmias, especially tachycardia, in medicine. The blood pressure lowering effect2 90027 is also therapeutically interesting, especially the compounds of formula I in which R is methyl, R3 and R3 are especially hydrogen, and the alkyl group and Rt are primarily the nitrile group (in especially in the 2-position of the propanol chain) and n 4, 5 or 6. Also, when R is methyl, Ri is halogen and R2 is hydrogen or methyl and R3 is hydrogen, and n ¦ 4,5 or 6 the compounds show strong 0-adrenaline action. Therapeutically valuable are: 1- (2-nitrilophenoxy) -2-hydroxy-3- (1-methylcyclopentyl) -aminopropane and 1- (2-nitrilephenoxy) -2-hydroxy-3- (1-methylcyclohexyl) -aminopropane, 1- (2-chloro-5-methylphenoxy) -2-hydroxy-3- (1-methylcyclopenty * yl) -aminopropane and 1- (2-bromophenoxy) -2-hydroxy-3- (1-methylcycloheptyl) ) -aminopropane or their physiologically acceptable flower additive, 1- (2-nltrilophanokiy) -2-hydroxyy-3- (1-methylcyclopentyl) -imyl-1-propane is especially interesting due to its considerable mtagglottic action against isoprotective compounds. nole, with almost complete absence of its own bradycardia effect. Particularly active are compounds which in the phenyl group are substituted with a nitrile group in position 2 and, at the same time, with a lower alkyl group, especially methyl in position 5, e.g. 1- (2-nitrile-5-methylphenoxy-2-hydroxy-3- (1- methylcyclopentylamino) propane, 1- (2-nitril-5-methylphenoxy) 2-hydroxy-3- (1-methylcyclohexylamino) propane and 1- (2-nt * tryl-5-methylphenoxy) -2-hydroxy- 3- (1-methylcycloheptylamino) -propane, relatively physiologically acceptable acid addition salts of these compounds with acids. The unit dose of the compounds according to the invention is 1-300 mg, especially 100 mg (orally) or 1-20 mg (parenterally). The galenic treatment of the compounds according to the invention into the usual use forms, such as solutions, emulsions, tablets, dragees or long-acting preparations, is carried out in a known manner, usually using galenic auxiliaries, carriers, disintegrants, binders. or lubricants, flavors, sweeteners, sro Prolonging and dissolving agents. The compounds obtained according to the invention can be combined with other substances having a pharmacodynamic effect, such as e.g. coronary vasodilators, sympathomimetic agents, cardiac glycosides or sedatives. Example 1- 2. -cyanophenoxy) -2-hydroxy-3- (1-methylcyclohexylamino) -prcpan. To a hot solution of 5 g of copper sulphate, 5.8 g of copper cyanide and 30 ml of water is slowly added dropwise the solution of the diazonium salt prepared from 3.52 g (0.01 mol) 1- (2-aminophenoxy) -2-hydroxy-3- (1-methylcyclohexylamino) propane hydrochloride, 4 ml concentrated HCl, 20 ml water and an aqueous solution of 1.4 g (0.01 mol) NaN02. After 30 minutes of stirring at 90 ° C, it is cooled and made alkaline with NaOH. When chloroform is added, the insoluble matter is separated. The organic phase is separated, washed with water and dried over MgSO 4. After CHCl 3 has been distilled off, the residue is dissolved in ethanol and ethereal HCl is added. The crystallizing crystals are recrystallized once more in ethanol while adding ether. Yield: 950 mg. Melting point: 161-164 ° C. Example II. 1- (2-N-ethylphenoxy) -2-hydroxy-3- (1-methylcyclohexylamino) -proparW hydrochloride, * 3.52 g (0.01 mol) 1- (2-aminophenoxy) -2-hydroxy-3- ( 1-methylcyclohexylamino) propane is dissolved in 20 ml of H 2 O and 4 ml of concentrated HCl. 1.4 g (0.02 mol) of NaNO 2 are dissolved in 5 ml of water and slowly added dropwise to the amine solution. The temperature is kept at 0 ° to + 5 ° C by cooling with ice. After the addition is complete, the solution is kept for an additional 15 minutes at a temperature of approximately 0 ° C. 5 g of CuSO 4 x 5H 2 O (0.02 mol), 5.8 g of KCN (0.04 mol) and 30 ml of H 2 O are combined and heated to 90 ° C with stirring. The diazonium solution is mixed with the hot Cu / I / CN solution and The whole thing is kept for 30 minutes at a temperature of 90 ° C. After cooling and treating with 10% NaOH solution, extraction was carried out with chloroform. The CHCl3 solution is washed with water, dried over MgSO4 and concentrated. The residue is dissolved in ethanol and acidified with an alcoholic HCl solution. Upon addition of ether, the product crystallizes out. After a further recrystallization from the alcohol / ether system, 950 mg of product are obtained, mp: 161-163 ° C. Example III. 1- (2-Nitrile-5-methylphenoxy) -2-hydroxy-3- (1-methylcyclohexylamino) propane hydrochloride. 2.92 g (0.01 mol) of 1- (2-amino-5-methylphenoxy) -2-hydroxy-3- (1-methylcyclohexylamino) propane were dissolved in 20 ml of water and 6 ml of concentrated HCl. 1.4 g (0.02 mol) of NaNO 2 are dissolved in 5 ml of water and slowly added dropwise with stirring to the amine solution. The temperature is kept at 0 ° to + 5 ° C by cooling with ice. After the addition is complete, the solution is kept at a temperature of about 0 ° C for 15 minutes. g of CuSO 4 X 5 H 2 O (0.02 mol), 5.8 g of KCN (0.09 mol) and 30 ml of H 2 O are combined and, with stirring, heated to 90 ° C. The diazonium solution is added dropwise to the hot Cu / I / CN solution with stirring and left to react for 30 minutes at 90 ° C. After cooling and quenching with 10% NaOH, extraction was carried out with chloroform. The chloroform extract is washed with water, dried over MgSO 4 and dried. The remainder is dissolved in acetonitrile and acidified with an alcoholic HCl solution. The hydrochloride that crystallizes out is recrystallized once more from acetonitrile. Melting point: 170-173 ° C, yield: 500 mg By analogy to the examples above, the following compounds of formula 1 are prepared: Melting point Melting point Rt R, Rf R n ° C (hydrochloride) 2-Br 2-a 2 -Br 2-Br 2-a 2-a 2?: N ^ CN 2-a 2-CN 2-CN 2-CN 2-CN 2-CN H "CsH, H II -CHj -CH, HH -CH, H 4-a -CH, -ch, HHHHHHHHHHHHHHH CH, CH, CH, CH, CH, C2H5 C, H5 iC, H7 CH, CH, CH, CH, CH, CH, 4 4 6 6 6 6 4 4 156- 157 170-172 157-158 167-168 174-177 179-180 157-158 200-201 191-194 160-161 194-196 192-194 143-146 132-134 ^ 2 II R WZ0R 1 ^ 73 ^ 0CH2 -CH0H-CH2-NH-CjCH2) n WZ0R2 Printing UP PRL Edition 120 + 18 Price PLN 10 PL PL PL PL PL PL

Claims (2)

1. Claim 1. A method for the preparation of the new 1-phenoxy-2-hydroxy-3-cycloalkylaminopropanes of formula 1, in which R is an alkyl group of up to 5 carbon atoms, R is a nitrile or halogen group, R2 is hydrogen, halogen , nitrile or alkyl, alkoxy or alkenyl group of up to 5 carbon atoms, R3 is hydrogen, halogen, alkyl or alkoxy of up to 5 carbon atoms and n is an integer 2.-7, in the form of the racemate or optically active isomers and their physiologically acceptable acid addition salts, characterized in that the compound of formula II, wherein R, R2 and R3 and n are as defined above, are diazotized and reacted with cyanide cuprous or cuprous halide and the resulting compound of formula I, if present in the form of a racemate, is optionally converted into diastereomeric salts with suitable auxiliary acids, and the latter are separated by fractional crystallization and the compounds of formula I are optionally converted into their physiologically acceptable salts acid addition. 90 027 OCK-CHOH-CH-NH-n & H,) ,, and 2 Nw * PL PL PL PL PL PL