NO122314B - - Google Patents

Description

Analogous process for the preparation of a therapeutically effective 1-(3^,4^-dihydroxyphenyl)-2-alkylamino-butanol (1) compound.

The present invention relates to a method for producing a compound with the formula:

as well as therapeutically acceptable acid addition salts of this compound.

A number of α-alkylaminoalkyl-3,4-dihydroxybenzyl alcohols are known. Among these compounds are isoprenaline (II) and isoetarine (III).

However, isoprenaline has two main disadvantages that reduce its therapeutic application; a) it has a very strong stimulating effect on the heart muscles (positive inotropic and chronotropic effect). Many asthmatics cannot tolerate the cardiac stimulation produced by this compound. b) oral administration results in very poor absorption from the intestinal tract.

Isoetarin (III) has been described and has a less stimulating effect on the heart muscle.

According to the present invention, it has been relatively surprisingly found that a compound with the formula

as well as therapeutically acceptable salts thereof, combine very low cardiac stimulation, good bronchospasmolytic activity and good absorption from the intestinal tract after oral administration.

The compound of formula I is prepared by reducing a compound of the formula where R is hydrogen or an araliphatic protecting group such as benzyl, thereby producing a compound of the formula

where R has the same meaning as stated above, after which R, if it is a protecting group, is cleaved off, and/or a compound obtained is optionally transferred into an acid addition salt, and/or optionally separated into its optical isomers.

The reduction of compound IV can be carried out by catalytic hydrogenation. When R is an araliphatic protecting group such as e.g. benzyl, then it can be split off by catalytic hydrogenation at the same time as the ketone group is reduced. >an thereby obtains the erythroform in analogy with syntheses in this field.

Starting compounds with formula IV where R is hydrogen can be prepared by the following reaction scheme:

where Z<1> is an aliphatic protecting group such as methyl and ethyl. Z<1> is preferably a methyl group.

Starting compounds of formula IV where R is an araliphatic protecting group can be prepared by the following reaction scheme:

where Z 2 is an araliphatic protecting group. Z 2 is preferably a benzyl group.

The compound of formula I exists in the form of optically active isomers, and these can be isolated in any principle known way for splitting an amine, and it is understood that such a method forms part of the present invention.

The racemate obtained by the above reaction can be resolved into the enantiomers by converting the free base into a salt or amide of an optically active acid and regenerating the amine after a normal separation of the diastereomeric mixture obtained.

D'en bronchospasmolytic activity for the compound

is highest in the optical isomer with steric formula in Fischer's projection (ir, the 2S form according to the nomenclature in Cahn-Ingold-Prelog)

(Fischer's projection)

However, it is understood that the compound of formula I can either be used as a purified isomer that is biologically active or in the form of a mixed isomeric product obtained as a natural consequence of the above described reaction sequence, or possibly other reaction sequences that have been used for the preparation of this compound, and which results in a mixed isomeric product containing the biologically active isomer or isomers.

The compound of formula I, i.e. 1-(3<1>><1>t'<1>"-dihydroxy-phenyl)-2-.tert.butylamino-butanol (1), and then especially its optical isomers with the steric formula shown above is a very good bronchodilator, has very low positive chronotropic and inotropic effects on the heart and is also very well absorbed from the intestinal tract after oral administration.The ratio of the lethal dose (LDj-q) for intravenous and oral administration , which is a measure of absorbability from the intestinal tract, shows that 1-(3<1>,4"'"-dihydroxyphenyl)-2-tert.butylamino-butanol(l) is better than both isoprenaline and isoetarin with respect to oral absorption from the intestinal tract.

The relationship between the heart stimulating effect and the bronchospasmolytic effect has been investigated in vitro on bronchial muscles and heart muscles from guinea pigs, and where the muscles were placed in the same bath in Krebs solution. The above compound I was found to be ca. 2.5 times less cardiac stimulating in this sample than isoetarin. This result was confirmed in vivo with anesthetized dogs.

The new compound can be added in the form of salts

with physiologically acceptable acids. Suitable acids as in this respect

can be used is e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, citric acid, tartaric acid, maleic acid or succinic acid.

The following examples illustrate the invention. Example 1.

Production of 2-t. butylamino-(31,4'1"-dihydroxy)-butyrophenone" used as starting material. ■ *

a) 2-bromo-(3<1>,<i>*"<1>"-dimethoxy)-butyrophenone:

130 g of 3,4-dimethoxybutyrophenone was dissolved in 375 ml of ether,

after which 100 g of bromine was added in small portions at reflux temperature. After the addition of bromine, the brominated ketone separated rapidly. It was filtered off and washed with petroleum ether. It was sufficiently clean for the next manufacturing step. Temp. 91°C.

b) 2-h . butylamino-O^^-dimethoxyJ-butyrophenone:

28.7 g of 2-bromo-(3<1>J4<1->dimethoxy)-butyrophenone was dissolved in 287 ml of dioxane after which 30 g of tert-butylamine was added. After 15 hours at 100°C, the mixture was filtered from the precipitated tert-butylamino hydrobromide, and the filtrate was evaporated to dryness in vacuo. The residue was partitioned between ether and 2N sodium hydroxide. The ether layer was extracted with 5N-HCl, and the acid base was made alkaline with 5N-NaOH. The ketobase was extracted with ether and after drying with KgCOj the hydrochloride of the product was precipitated with hydrochloric acid. Recrystallization was carried out from methanol-ether. Temp. 230°C.

c) 2-tert-butylamino-(3<1>,^-dihydroxy)-butyrophenone:

13.9 g of the hydrochloride from example 1b) was refluxed with 100 ml of concentrated hydrobromic acid for 2.5 hours and then evaporated to dryness in vacuo. The residue was dissolved in 100 ml of water, decolorized with charcoal and made alkaline with concentrated ammonia. The crystalline base was recrystallized from propanol. Temp. 138°C.

Example 2.

Preparation of 1-(3<1>,4<1->dihydroxyphenyl)-2-tert.butylamino-butanol (l).

25.1 g of 2-t.butylamino-(3<1>,4<1->dihydroxy)-butyrophenone was converted to the hydrochloride (methanol + hydrochloric acid) and catalytically hydrogenated in ethanol in the presence of 2 g of palladium on charcoal (10$ ). After absorption of the calculated amount of H2 (2400 ml), the solution was filtered, evaporated in vacuo after which the residue was recrystallized from methanol-ether. Temp. 220°C.

Example 3-

Preparation of 1-(3<1>,4<1->dibenzyloxyphenyl)-2-t.butyl-amino-butanol (1) used as starting material.

a) 3,4-dibenzyloxybutyrophenone.

53.2 g (0.296 mol) of 3,4-dihydroxybutyrophenone was dissolved in 300 ml of absolute alcohol. 107 g of K 2 CO 2 were added followed by 85 ml of benzyl chloride. The mixture was refluxed for approx. 4 hours, filtered and washed with hot alcohol. The product was crystallized from the mother liquor and filtered off. The mother liquor was then evaporated. The remaining product was recrystallized from methanol. 93.8 g of 3,4-dibenzyloxy-butyrophenone with a m.p. at 85°C.

b) 2-bromo-(3<1>,4^-dibenzyloxy)-butyrophenone.

93.5 g (0.219 mol) of 3,4-dibenzyloxybutyrophenone was

dissolved in 400 ml of ether. Some benzoyl peroxide was added, after which 13.3 ml (41.5 g) of Brg was added dropwise to the solution. The bromoketone was crystallized, filtered off and washed with petroleum ether (40-60°C). The product was recrystallized from methanol. 98.0 g of 2-bromo-(3<1>,4<1->dibenzyloxy)-butyrophenone with a m.p. at 105°C.

c) 2-tert.butylamino-(31,41-dibenzyloxy)-butyrophene.

49 g (0.11 mol) of 2-bromo-(3<1>34<1->dibenzyloxy)-butyrophenone, 320 ml of dioxane and 80.2 g (1.1 mol) of t-butylamine were mixed and refluxed overnight . The separated t-butylamino hydrobromide was filtered off, after which the filtrate was evaporated. The residue was treated with 2 M NaOH, filtered and recrystallized from isopropyl ether. The base was dissolved in ether and precipitated as the hydrochloride by adding HCl gas dissolved in ether to a pH of 4. The precipitate was filtered off and washed with ether. The hydrochloride was dissolved in water, after which the solution was made strongly alkaline by adding a NaOH solution. This solution was then extracted with ether, dried and evaporated. 23.6 g of 2-t.butylamino-(3<1>,4<1->dibenzyloxy)-butyrophenone were obtained in the form of the free base with a m.p. at 68°C.

d) 1-(31,4"'"-dibenzyloxyphenyl)-2-t.butylamino-butanol (1).

0.2 g of 2-t.butylamino-(3"'",41-dibenzyloxy)-butyrophenone

was dissolved in 10 ml of methanol and cooled in an ice bath to 5°C • During the cooling, 0.2 g of sodium brohydride was then added. The mixture was set aside for approx. 45 min. at room temperature and then diluted with 1^0 and then extracted with ether. The ether phase was dried and evaporated to dryness. The base was precipitated in ether as the hydrochloride. This precipitate was filtered off, washed with ether and recrystallized from

acetone-ether. 0.1 g of the hydrochloride of 1-(3"1',41-dibenzyloxyphenyl)-2-t-butylamino-butanol (1) was obtained with a melting point of 163°C. Example 4.

Preparation of l-(31,41-dihydroxyphenyl)-2-t.butylamino-butanol (l). 1 g of the hydrochloride of 1-(3<1>J4<1->dibenzyloxyphenyl)-2-t.butylamino-butanol (1) was dissolved in 20 ml of ethanol and catalytically hydrogenated in the presence of 100 mg of Pd/C. When 2 moles of hydrogen had been absorbed, the solution was filtered, the filtrate evaporated in vacuo to dryness, after which the residue was recrystallized from methanol-ethyl acetate. As a yield, 0.55 g of the hydrochloride of 1-^<1>,<*>*<1->dihydroxyphenyl)-2-t.butylamino-butanol (1) was obtained with a m.p. at 220°C.

Example 5 -

Preparation of 1-(31,41-dihydroxyphenyl)-2-t.butylamino-butanol (1) by catalytic hydrogenation of 2-t,butylamino-(3,41-dibenzyloxy)-butyrphenone. 1 g of the hydrochloride of 2-t-butylamino-(3<1>,4<1->dibenyl-oxy)-butyrophenone was dissolved in 20 ml of ethanol and catalytically hydrogenated in the presence of 100 mg of Pd/C. When 3 moles of hydrogen had been absorbed, the solution was filtered, the filtrate evaporated in vacuo, after which the residue was recrystallized from methanol-ethyl acetate. As a yield, 0.53 g of the hydrochloride of 1-(31,4"L-dihydroxy-phenyl)-2-t-butylamino-butanol (1) with a melting point of 220°C was obtained.

Example 6.

Pharmacological tests.

a) Toxicity tests.

The intravenous and oral toxicity was determined by

LDt-0 in mice. 45 male animals, breed NMRI, with a body weight varying from 18-20 g were used. The results obtained are shown in table 1.

b) Oral absorption.

The ratio of lethal dose (LD^Q) for intravenous and

oral administration can be used as a measure of the absorbability from the intestinal

the channel. It appears from table 1 that 1-C3<1>,4<1->dihydroxyphenyl)-2-tert.butylamino-butanol(1) is better than both isoprenaline and isoetarin with regard to oral absorption from the intestinal tract. This was confirmed by tests on guinea pigs, where 2 mg/kg p.o. for 1-(J>dihydroxyphenyl)-2-tert.butylamino-butanol(1) protected the animals for 1 hour against the bronchoconstrictive effects of a histamine aerosol, while 2.0 mg/kg of isoprenaline or isoetarine were ineffective .

c) Effect on the heart.

The relationship between the cardiac stimulating effect and the

bronchospasmolytic effect was studied in vitro on auricle-trachea preparations from guinea pigs. To compare the effect on the heart and the effect on the bronchial muscles under identical conditions, both the spontaneously beating auricle and the spirally cut trachea were placed in the same bath in a Krebs solution. Both preparations were taken from the same animal. The compound to be tested was slowly added to the solution. In this way, the threshold dose could very easily be observed for the various preparations. The addition was made within 10 min., and isoprenaline was used as a reference. After washing and recovery, the sample solution was added in the same way, and the effect of this agent on the two preparations could then be compared in relation to the effect of isoprenaline. The relationship between the bronchospasmolytic activity and the positive intropic effect on the heart muscle for the tested substances is indicated in table 2, (isoprenaline = 1).

The relationship between the cardiac stimulating effect and the bronchospasmolytic effect was also tested in vivo. Five dogs (body weight varying from 10-12 kg) were anesthetized with mebumal.

After thoracotomy and artificial respiration, isoprenaline, isoetarine, and compound I were infused intravenously in increasing doses over 1 minute. Antagonism against histamine-induced bronchospasm was then studied according to the method of Konzett-Rossler (Arch.

Exp. Path. Pharm. 195 (1940), 71), together with the effect on heart rate and force of contraction. The results obtained are . indicated in Table 2 (isoprenaline = 1).

It appears from table 2 that 1-(3<1>,4<1->dihydroxyphenyl)-2-tert.butylamino-butanol (1) is approx. 2.5 times less cardiac stimulating than isoetarin in vitro samples, and approx. 2.7 times less cardiac stimulating than isoetarin in vivo tests in equivalent bronchospasmolytic doses.

Example 7»

Preparation of (IR, 2S)-erythro-1-(31,4-dihydroxyphenyl)-2-t. - butylamino-butanol (l).

a) 15.6 g of the racemic 3,4-dihydroxy-α-tert.butylamino-butyrophenone (IV, R=H) and 9 g of L-(-)-tartaric acid are dissolved in

250 ml of 99.5$ alcohol and hydrate in the presence of 1 g of Pd/C. After absorption of 1500 ml of hydrogen, the reaction was stopped, the mixture was filtered and placed in a cool room. After a couple of hours, the deposited crystals were collected. By adding ether to the mother liquor, the yield of (IR, 2S)-erythro-1-(3<1>,4<1->dihydroxyphenyl)-2-t-butylamino-butanoCl)-L-bitartrate could be increased. The salt was recrystallized from ethanol-ether and shows a m.p. of l8l-82°C and (a)^g^=-38.3°

(C=0.04 M, in 0.1 molar HCl in ethanol).

By a similar process by adding D-(+)-tartaric acid (to form the bitartrate) the physiologically inactive antipode can be obtained with (a)^g^ = +38.3°.

The hydrochloride of (IR, 2S)-erythro-1-(31,41-dihydroxy-phenyl)-2-tert.butylamino-butanol-(1) is characterized by a specific rotation of (a)^g^=+228.

b) By the same procedure, 3,4-dibenzyloxy-a-t.butylamino-butyrophenone IV (R = CHgCgH^) or 3,4-dibenzyloxy-(l-t-butylaminobutyl)-benzyl alcohol V (R=CH2CgH^) can be hydrated in the presence of an equimolar amount of L-(-)-tartaric acid to the L-bitartrate of

(IR, 2S)-erythro-1-(31, i^-dihydroxyphenyl)-2-t-butylamino-butanol(1)

(c^g5 -38.3°). The substance IV absorbs 3 moles of hydrogen; the substance V

2 moles

Claims (1)

Analogous method for the preparation of a therapeutically effective 1-(3"'',41-dihydroxyphenyl-2-alkylamino-butanol(1) compound of the formula: as well as therapeutically acceptable acid addition salts thereof, characterized by reducing one compound with the formula: where R is hydrogen or an araliphatic protecting group, whereby a compound with the formula is produced: where R has the same meaning as stated above, after which any remaining protective groups are cleaved off, and/or a compound obtained is, if desired, transferred in an acid addition salt, and/or if desired split into its optical isomers.