FI69837C - PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL PROPERTIES OF 4-MINO-PHENYLOXAZOLIDES AND DESS SYRAADDITIONSSALTER - Google Patents

Description

69837

Process for the preparation of pharmacologically valuable 4-amino-phenyl-oxazolidine and its acid addition salts -Förfarande för framställning av pharmacologiskt värdeful 4-aminophenloxazolidin och dess syrraadditionssalter.

Separated from patent application 3770/73 Avdelad ur patentansökningen 3770/73

The present invention relates to a process for the preparation of pharmacologically valuable 4-amino-phenyloxazolidines of the formula O-CH-Rc

1 I

R, _ CH N - R3 xrw h2n J r2 where

R 1 is a chlorine or bromine atom, R 2 is a fluorine atom or a trifluoromethyl group, R 3 is a tertiary butyl group and R 5 is a hydrogen atom or a C 1-3 alkyl group, and for the preparation of their physiologically acceptable acid addition salts i.

69837

The compounds of the above general formula I have valuable pharmacological properties, in addition to analgesic, uterine spasmolytic and anti-spastic musculoskeletal activity, in particular β-kinetic and / or β-blocking activity, whichever is preferred depending on the substitution of the compounds, d ( In particular, the +) compounds have a selective effect on? 2 receptors and the 1 (-) compounds act primarily on the O 2 receptors.

The process according to the invention is characterized in that 4-amino-phenylethanolamine of the formula OH R.

I / 3 (II) "CH2" N \

M V

R2 where

R1 and R3 are as defined above, are reacted with an aldehyde of the formula R5 to CHO (Hi) wherein R5 is a hydrogen atom or a straight or branched alkyl group, and the resulting compound of formula (i) is optionally converted into a physiologically acceptable acid addition salt with an inorganic or organic acid.

3,69837

The reaction with the aldehyde of formula III is conveniently carried out in a solvent such as ethanol, benzene, toluene or dioxane and under water-decomposing conditions, for example in the presence of anhydrous copper (II) sulphate, at temperatures up to 20 ° to the boiling point of the solvent used, e.g. C.

However, it can also be performed without a solvent. However, the reaction is particularly preferably carried out using a water separator and in the presence of a solvent such as benzene or toluene.

The compounds of the general formula I obtained can, if desired, be converted with their inorganic or organic acids into their physiologically acceptable acid addition salts using 1, 2 or 3 equivalents of the acid in question. Suitable acids have, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid and fumaric acid.

The compounds used as starting materials are obtained by methods known from the literature, e.g. Belgian patent publication 808 743.

As already mentioned above, the novel compounds of the general formula I have valuable pharmacological properties, in particular a 2-kinetic and / or β-blocking effect, with either effect being preferred, depending on their substitution. In particular, the d (+) compounds have a selective effect on the R 1 receptors and the 1 (-) compounds act primarily on the R 2 receptors.

For example, the effect of a compound on β-receptors was studied: A-5- (4-amino-3-bromo-5-fluorophenyl) -3-tert-butyl oxazolidine dihydrochloride.

69837 The β-kinetic effect was investigated in the Konzett-Rössler experimental design i.v. after application as an adverse effect on cough bursts in narcotic guinea pigs triggered by administration of i.v. 20 y / ka acetylcline. The percentage reduction in cough spikes obtained at Fri doses was determined graphically by extrapolation of the ED50 value (see Table I).

The acute toxicity of the substance was determined in groups of 10 mice. According to the method of Litchfield and Wilcoxon, the LD50 value was calculated at which dose 50% of the animals died within 14 days after intravenous administration of the compound (see Table II).

Table I

Substance β2 ~ kinetic effect duration ——-- minutes nl n2 ED50 // kg i.v.

A 5 4 6.7> 110 n ^ = Number of animals / dose; n2 = number of doses taken into account when calculating the ED5Q value.

Table II

Substance LD5Q m9 / kg i.v.

A 27.2 nl = Number of animals / dose n2 = Number of doses 5 69837

The following examples illustrate the invention.

Example 1 5- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -3-tert-butyl-1,3-oxazolidine-1.35 g of 1- (4-amino-3-chloro- 5-Trifluoromethyl-phenyl) -2-tert-butylamino-ethanol is dissolved in 30 ml of benzene and 1.2 ml of a 40% aqueous formaldehyde solution are added. Evaporate to half volume under normal pressure, add about 35 ml of benzene and boil at reflux for 5 hours.

An additional 1.5 ml of formaldehyde solution is then added and the procedure described is repeated three more times. Evaporate to dryness in vacuo, dissolve in ether and filter off the insoluble flakes. The filtrate is weakly acidified with ethereal hydrochloric acid and the precipitated product is crystallized by trituration. Separate by suction and recrystallize from acetone / ether. The hydrochloride obtained from the above compound melts at 163-165 ° C (decomposes).

Example 2 5- (4-Amino-3-bromo-5-fluoro-phenyl) -3-tert-butyl-oxazolidine_

Melting point of the dihydrochloride: 64-178 ° C (decomposes).

Prepared according to Example 1 from 1- (4-amino-3-bromo-5-fluorophenyl-2-tert-butylaminoethanol and 40% formaldehyde solution.

6

Example 3 6 9 8 3 7 2-Ethyl-5- (4-amino-3-bromo-5-fluoro-phenyl) -3-tert-butyl-oxazolidine 5 g of 1- (4-amino-3-bromo- 5-Fluoro-phenyl) -2-tert-butylamino-ethanol is dissolved in 100 ml of benzene. To this is added 5 g of propionaldehyde and heated for 6 hours at reflux temperature and using a water separator. 5 g of propionaldehyde are then added again and the mixture is further heated for 3 hours. After cooling, it is evaporated to dryness in vacuo and the residue is chromatographed on a chromatography column packed with 50 g of silica gel. In this case, benzene is used as eluent. The eluates containing the substance are combined and evaporated to dryness in vacuo, whereupon said compound precipitates as a foam.

The structure is shown by NMR spectrum (CDCl 3): 0.7 to 1.8 ppm multiplet [14 protons, -C (CH 3) 3 and -CH 2 -CH 3]; 2.5 to 2.95 and 3.1 to 3.7 μm 2 multiplets [2 protons Ar-CH-CH 2 ~ NC]; 4.0 to 4.3 ppm singlet [2 protons NH2]; 4.4 to 5.2 ppm multiplet [2 protons, Ar-CH-CH p-NC and -Q-CH-CH (CH 2) p]; Λ 6.8 to 7.35 ppm multiplet [2 aromatic protons], n

Example 4 69837 7 5- (4-Amino-3-bromo-5-fluoro-phenyl) -3-tert-hutyl-2-isopropyl-oxazolidine

Prepared according to Example 3 from 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol and isobutyraldehyde. Amorphous substance; structure is shown by NMR spectrum (CDCl 3) 0.85 to 1.2 ppm multiplet £ 15 proton, -C (<21 * 3) 3 and CH-CH (CH 3) δ 17 1.5 to 1.85 μm multiplet £ 1 protons, ~ CH-CH (CH3)? 2.5 to 2.9 and 3.2 to 3.7 ppm multiplet of £ 2 protons, Ar-CH-CH2-NJ; 3.9 to 4.2 ppm singlet £ 2 proton, NH2It 4.4 to 4.9 ppm multiplet £ 2 proton, Ar-CH-CH2-N and -O-CH-CH (CHrQ? J;

OF

l \ 6.8 - 7.3 ppm multiplex £ 2 aromatic protons !.

Example 5 5- (4-Amino-3-bromo-5-fluoro-phenyl) -3-tert-butyl-oxydolidine

Melting point of the dihydrochloride: 164-178 ° C (decomposes).

Prepared according to Example 3 from 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol and formaldehyde.

R

Example 6 69837 5- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -3-tert-butyl-2-methyl-oxazolidine

Melting point of hydrochloride: 199-202 ° C (decomposes). Prepared according to Example 3 from 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol and acetaldehyde.

Claims (3)

69837 Claim A process for the preparation of pharmacologically valuable 4-amino-phenyl-oxazolidines of the formula 0. CH - R5 1 IR, CH 3 - R 3 R 2 wherein R 1 is a chlorine or bromine atom, R 2 is a fluorine atom or a trifluoromethyl group, R 3 is a tertiary butyl group and R 5 is a hydrogen atom or a C 1-3 alkyl group, and for the preparation of their physiologically acceptable acid addition salts, characterized in that 4-amino phenylethanolamine of the formula OH R3 1 / R CH - CHo - N 'rr H2N (II) R2 wherein R1 and R3 are as defined above is reacted with an aldehyde of the formula R5 - CHO (III) wherein R5 is as defined above, and optionally converting the obtained compound of formula (I) into a physiologically acceptable acid addition salt with an inorganic or organic acid.