US3804899A

US3804899A - 3-alkylamino-2-(3,4-dihydroxyphenyl)propanols and the salts thereof

Info

Publication number: US3804899A
Application number: US00183633A
Authority: US
Inventors: A Ebnother; K Hasspacher
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1970-09-30
Filing date: 1971-09-24
Publication date: 1974-04-16
Anticipated expiration: 1991-04-16
Also published as: BE773204A; FR2108100B1; AU3403671A; GB1359871A; DE2148551A1; HU162651B; DD99159A5; NL7112938A; ES395494A1; FR2108100A1

Abstract

THE PRESENT INVENTION PROVIDES NEW AMINOPROPANOL DERIVATIVES OF THE FORMULA:

(3,4-DI(HO-)PHENYL)-CH(-CH2-OH)-CH2-NH-R1

WHEREIN R1 IS HYDROGEN, CYCLOALKYL OF 3 TO 7 CARBON ATOMS, ALKYL OF 1 TO 8 CARBON ATOMS, CYCLOALKYLALKYL, IN WHICH THE CYCLOALKYL RING IS OF 3 TO 7 CARBON ATOMS AND THE ALKYL RESIDUE IS OF 1 TO 6 CARBON ATOMS, OR PHENYLALKYL OR DIPHENYLALKYL, IN WHICH THE PHENYL RADICALS MAY BE SUBSTITUTED IN THE 3, 4 OR 5 POSITION BY 1 TO 3 HYDROXY OR METHOXY GROUPS, OR IN THE 3,4 POSITION BY A METHYLENEDIOXY GROUP, AND IN WHICH THE ALKYL RESIDUE IS OF 1 TO 6 CARBON ATOMS, AND ACID ADDITION SALTS THEREOF. PROCESSESS FOR THE PRODUCTION THEREOF AND INTERMEDIATES THEREFOR ARE ALSO DESCRIBED. THE COMPOUNDS EXHIBIT BRONCHOLYTIC PROPERTIES.

Description

United States Patent US. Cl. 260-5706 13 Claims ABSTRACT OF THE DISCLOSURE The present invention provides new aminopropanol denvatives of the formula:

(I) H: O H H0- CH-CHr-NH-Rt wherein and acid addition salts thereof.

Processes for the production thereof and intermediates therefor are also described.

The compounds exhibit broncholytic properties.

The present invention relates to aminopropanol derivatives.

In accordance with the invention there are provided new compounds of Formula I,

l CHzOH HO CH-CHr-NH-Rt wherein R is hydrogen, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to '8 carbon atoms, cycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue is of 1 to 6 carbon atoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals may be substituted in the 3, 4 or 5 position by 1 to 3 hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxy group, and in which the alkyl residue is of 1 to 6 carbon atoms, a

and acid addition salts thereof.

Further, in accordance with the invention a compound of Formula I may be obtained by a process comprising (2.) Converting the ether groups into hydroxy groups in a compound of Formula II,

(iJHaOH R20 CH-C Hg-NH-Rl wherein R is as defined above, and

R, is methyl, ethyl or benzyl,

3,804,899 Patented Apr. 16, 1974 to produce a compound of Formula Ia,

([lHzOH H0- -cH-cm-NHRi (Ia) wherein (b) Hydrogenolytically debenzylating a compound of Formula III,

(EHIOH Bro CH-CHPliI-Rl R3 (III) wherein R is hydrogen, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 8 carbon atoms, cycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue is of 1 to 6 carbon atoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals may be substituted in the 3, 4 or 5 postion by 1 to 3 hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxy group, and are separated from the nitrogen atom by at least two carbon atoms, and in which the alkyl residue is of 2 to 6 carbon atoms,

R is hydrogen or benzyl, and

R is benzyl or, when R, is benzyl, is hydrogen or benzyl,

to produce a compound of Formula Ib,

wherein R is as defined above, or

wherein R is as defined above,

with a compound of Formula V,

R, is hydrogen, alkyl of 1 to 7- carbon atoms, or eycloalkyl or cycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue is of l to 5 carbon atoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals may be substituted in the 3, 4 or 5 position by 1 to 3 hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxy group, and are separated from the oxygen atom by at least two carbon atoms, and in which the alkyl residue is of 1 to 5 carbon atoms, and

R is hydrogen or alkyl of 1 to 7 carbon atoms, or

R and R together with the carbon atom to which the oxygen atom is joined form a cycloalkyl group of 4 to 7 carbon atoms, provided that when R is alkyl, when R, is alkyl the total number of carbon atoms in R and R is not greater than 7, and when R, is cycloalkylalkyl, phenylalkyl or diphenylalkyl the total number of carbon atoms in R and in the alkyl residue of R is not greater than 5,

under reductive alkylation conditions, to produce a compound of Formula Ic,

wherein R is cycloalkyl of 4 to 7 carbon atoms, primary or secondary alkyl of l to 8 carbon atoms, cycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue is of 1 to 6 carbon atoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals may be substituted in the 3, 4 or 5 position by 1 to 3 hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxy group, and are separated from the nitrogen atom by at least 2 carbon atoms, and in which the alkyl residue is of 2 to 6 carbon atoms, or

(d) Treating a compound of Formula VId,

R is as defined above, and each of R and R is alkyl of 1 to 4 carbon atoms,

with a metal hydride which will reduce an ester to an alcohol, and hydrolyzing the resulting reaction product, to produce a compound of Formula I; and, if desired, separating any resulting racemates of the compounds of Formula I into their optical antipodes and/or converting the resulting compounds of Formula I into their acid addition salts.

The alkyl groups represented by the symbols R may be straight-chained or branched and preferably contain 1 to 4 carbon atoms; the cycloalkyl groups preferably contain ring members. The alkyl residue of the aralkyl group may be straight-chained or branched and is preferably of 2 to 5 carbon atoms.

Process variants (a) may be effected in accordance with conventional methods for ether splitting. Thus, for example, a compound of Formula II may be allowed to react with a Lewis acid, e.g. boron tribromide or aluminium chloride, in an inert organic solvent, e.g. a halogenated hydrocarbon such as methylenechloride or carbon tetrachloride, or an aromatic hydrocarbon such as toluene or benzene, at --80 to -+70 C., or a compound of Formula II may be treated for a short period with a strong mineral acid, e.g. hydrobromic or hydriodic acid, optionally at an elevated temperature, e.g. at approximately 20 to 100 C., or a hydrochloride, hydrobromide or hydriodide of an organic base such as aniline or pyridine is allowed to act on a compound of Formula II at an elevated temperature, e.g. about 20 to 100 C. In this process any methoxy or methylenedioxy groups which are present in the substituent R are also converted, so that a compound of Formula Ia is obtained.

The debenzylation in accordance with process variant (b) may, for example, be effected by catalytic hydrogenation in an inert solvent, e.g. ethyl acetate, or a lower alkanol such as methanol or ethanol. Hydrogenation is preferably effected at a temperature from 20 to 100 C., at a hydrogen pressure of 1 to 100 atmospheres. A palladium catalyst may, for example, be used as hydrogenation catalyst.

Process variant (c) may, for example, be efiected by catalytic reduction with a platinum, palladium or nickel catalyst, at l to 100 atmospheres hydrogen pressure and at 20 to 80 C., in an inert solvent such as ethanol.

In process variant (d) the metal hydrides suitable for the reaction are, for example, optionally complex aluminium metal hydrides, such as lithium aluminium hydried, aluminium hydride, diisobutyl aluminium hydride, trialkoxy lithium aluminium hydrides, sodium dihydro-bis- (2 methoxyethoxy)aluminate, or dibroane or lithium borohydride, and the reaction is preferably effected at room temperature. Reaction times under preferred conditions are from approximately /2 to several hours.

The compounds of Formula I may be isolated from the reaction mixture in conventional manner.

When optically active starting materials are used, the processes of the invention yield optically active compounds of Formula I. When racemic compounds are used as starting materials, the processes of the invention yield racemates of the compounds of Formula I, which, if desired, may be separated into the optical antipodes in conventional manner, e.g. by converting the racemates with optically active acids into a mixture of their diastereoisomeric salts, and isolating the optical antipodes of the compounds of Formula I therefrom.

The compounds of Formula II may be obtained by a process comprising (on) Reducing the ester group in a compound of Formula VIa,

C 0 CR5 mo-Q-hn-cm-Nn-m wherein R R and R are as defined above, or 3) Reducing a compound of Formula VII,

wherein R and R are as defined above,

to produce a compound of Formula IIa,

wherein R is as defined above, or

('y) Reductively reacting a compound of Formula IIc,

wherein R is methyl or ethyl,

(IIa) wherein R and R are as defined above.

Process variants (oz) and 8) may, for example, be effected in an inert solvent, e.g. an ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, with lithium aluminium hydride or aluminium hydride.

Process variants (a) and (7) yield optically active compounds of Formula II when optically active compounds are used as starting materials. When racemic compounds are used as starting materials in both processes, as well as in process variants (p), racemates of compounds of Formula II are obtained, which may be separated into their optical antipodes in conventional manner, e.g. by converting racemates with optically active acids into a mixture of their diastereoisomeric salts, and isolating the optical antipodes of the compounds of Formula II therefrom.

wherein R is as defined above,

may, for example, be obtained by converting the ether groups into hydroxy groups in a compound of Formula 0 H: O H mocyms m wherein R and R are as defined above,

e.g. as described in process variant (a).

Compounds of Formula 111b,

onion omo A m-cuppa.

RI (IIIb) wherein R and R are as defined above,

may, for example, be obtained by reducing a compound ofFormula VIb,

C O 0 RI @0310 oH-om-I I-Rl" wherein R R, and R, are as defined above,

as described in process variant (3) Compounds of Formula VIII may, for example, be obtained by reducing a compound of Formula VIc,

wherein R R and R are as defined above,

as described in process variant The compound of Formula IVa wherein R and R are as defined above,

are a special case of the compounds of Formula IH.

Compounds of Formula VI,

COORs m0oH-orrr-N-R1 1i; wherein R R R and R are as defined above,

may, for example, be obtained by addition of a compound of Formula X,

NH-R

wherein R and R areas defined above,

to a compound of Formula IX,

wherein R and R are as defined above.

The reaction may, for example, be effected at 20 to C., using equimolar amounts of both compounds, and optionally in an inert solvent, e.g. a lower alcohol.

Compounds of Formula VId may, for example, be obtained by reacting a compound of Formula IXa,

C O 0 Rs magma wherein R and R are as defined above, with a compound of Formula Xa,

NHg-R wherein R is as defined above,

in accordance with the process described for the production of compounds of Formula VI.

Insofar as the production of the starting materials is not particularly described, these are known or may be produced in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.

The compounds of Formula I are useful because they possess pharmacological activity in animals. In particular, the compounds are useful in the treatment of bronchospasms, such as in bronchial asthma, as indicated by their exhibition of generalized sympathomimetic, especially broncholytic, properties, as illustrated by their effect in vagally induced bronchospasms, and bronchospasms produced by histamine and acetylcholine in cats and guinea pigs.

For the above-mentioned use, the dosage administered will, of course, vary depending on the compound employed, mode of administration and treatment desired. However, in general satisfactory results are obtained when administered at a daily dosage of from about 0.005 to 5 mg./kg. animal body weight, conveniently given in divided doses 2 to 3 times a day, or in sustained release form. For the larger mammals the total daily dosage is in the range of from about 10 to 20 mg., and dosage forms suitable for oral administration comprise from about 3 to 10 mg. of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.

3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol has particularly interesting properties.

The compounds of Formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts possess the same order of activity as the free bases and are readily prepared in conventional manner. Suitable such salt forms include organic acid salts such as the fumarate, maleate, tartrate, methane-, ethaneand benzenesulphonate, citrate and malate, and mineral acid 7 salts such as the hydrochloride, hydrobromide and sulphate.

The compounds of Formula I or their pharmaceutically acceptable acid addition salts may be used as medicaments on their own or in the form of appropriate medicinal preparations, e.g. tablets, drages, capsules, granules, suppositories or injectable solutions or suspensions, for enteral or parenteral administration. Aside from the usual inorganic or organic pharmaceutically acceptable adjuvants, e.g. lactose, starch, talc, stearic acid, water, alcohols, natural or hardened oils and waxes, these preparations may also contain suitable preserving stabilizing or wetting agents, solubilizers, sweetening or coloring substances and flavorings.

The invention accordingly also provides a pharmaceutical composition comprising as active agent a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or diluent.

In the following non-limitative examples all temperatures are indicated in degrees centigrade and are uncorrected.

EXAMPLE 1 2-(3,4-dihydroxyphenyl(-3-(isopropylamino)propanol [process variant (a)] 20 g. of 2-(3,4-dimethoxyphenyl)-3-isopropylaminopropanol are dissolved in 250 cc. of methylene chloride and cooled to 75". 45 g. of boron tribromide in the form of a 1 molar solution in methylene chloride are slowly added dropwise while stirring at such a rate that the temperature does not exceed 70. After 5 hours the solvent is distilled off in a vacuum, the residue is heated under reflux for 1 hour with 100 cc. of ethanol, the reaction solution is concentrated by evaporation and the residue is recrystallized from ethanol/ether. The bydrobromide of the title compound has a M.P. of 87-91".

The 2 (3,4-dimethoxyphenyD-3-(isopropylamino)propanol, required as starting material, may be produced as follows:

(a) A solution of 472 g. of 3,4-dimethoxyatropic acid ethyl ester in 200 cc. of ethanol is added dropwise to a solution of 140 g. of isopropylamine in 200 cc. of ethanol at room temperature while stirring. The reaction solution is subsequently heated to 50 for 3 hours, is filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is taken up in chloroform and extracted with 2 N hydrochloric acid. The hydrochloric acid solution is rendered alkaline with concentrated ammonia while cooling, whereby crude 2-(3,4-dimethoxyphenyl)-3-(isopropylamino)propionic acid ethyl ester separates as a yellow oil, and this is taken up in chloroform. The solution is dried over sodium sulphate and concentrated by evaporation; the residue is converted into the hydrochloride with hydrochloric acid in ethanol. M.P. 159-162".

(b) 96 g. of 2-(3-di'methoxyphenyl)-3-(isopropylamino)propionic acid ethyl ethyl ester are reduced in 1000 cc. of ether with 11.4 g. of lithium aluminium hydride by heating under reflux for two hours. After decomposing with a small amount of water, filtration is effected, the ether solution is dried and concentrated by evaporation, and 2-(3,4-dimethoxyphenyl) 3 (isopropylamino)propanol is crystallized. M.P. 59-61; the hydrochloride has a M.P. of 150-152.

EXAMPLE 2 3-tert.-butylamino-2-(3,4-dihydroxyphenyl) propanol 3-tert.-butylamino-2-(3,4 di-methoxyphenyl)-propanol (obtained in a manner analogous to Example 1, M.P. 71- 73) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 113-115".

8 EXAMPLE 3 3-sec.butylamino-2-( 3,4-dihydroxyphenyl) propanol 3-sec.butyla'mino-2-(3,4-dimethoxyphenyl)propanol obtained in a manner analogous to Example 1, oil) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of -89".

EXAMPLE 4 3-butylamino-2- 3,4-dihydroxyphenyl)propanol 3-butylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, M.P. 70- 72) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 93-9'5.

EXAMPLE 5 '3-cyclohexylarnino-2-(3,4-dihydroxyphenyl)propanol 3-cyclohexylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, oil) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 95-97".

EXAMPLE 6 3-cyclopentylamino-2- 3,4-dihydroxyphenyl propanol 3-cyclopentylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, M.P. of the bis-naphthalene 1,5-disulphonate 231-235) is reacted in accordance with the process described in Example l. The hydrobromide of the title compound has a M.P. of 92-95 EXAMPLE 7 3-cyclopropylamino-2- (3,4-dihydroxyphenyl) propanol 3-cyclopropylamino-2-(3,4 dimethoxyphenyDpropanol (obtained in a manner analogous to Example 1, M.P. of the hydrochloride 132-134") is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 56-60".

EXAMPLE 8 2-(3,4-dihydroxyphenyl) -3-(3-phenylpropylamino propanol 2-(3,4-dimethoxyphenyl) 3 (3-phenylpropylamino) propanol (obtained in a manner analogous to Example 1, M.P. of the hydrochloride Ill-114) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 108-110".

EXAMPLE 9 2-( 3,4-dihydroxyphenyl -3- l-phenyl- 2-propylamino propanol 2-(3,4-dimethoxyphenyl)-3-(l-phenyl 2 propylamino) propanol (obtained in a manner analogous to Example 1, M.P. of the bis-naphthalene-1,5-disulphonate 76-80, decomp.) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 109-1l0.

EXAMPLE 10 9 EXAMPLE 11 20 g. of 3-amino 2 (3,4 dimethoxyphenyl)propanol are dissolved in 250 cc. of methylene chloride and 52.5 g. of boron tribromide in the form of a 1 molar solution in methylene chloride are slowly added at --75 while stirring. After hours the solvent is distilled off in a vacuum, the residue is heated under reflux with 100 cc. of ethanol for 1 hour, the reaction solution is concentrated by evaporation and the residue is recrystallized from ethanol/ ether. The hydrobromide of the title compound has a M.P. of 87-91".

The 3-amino 2 (3,4-dimethoxyphenyl)propanol, required as starting material, may be obtained as follows:

13 g. of concentrated sulphuric acid are added dropwise to a suspension of 10.7 g. of lithium aluminium hydride in 500 cc. of tetrahydrofuran while stirring and cooling with ice. The mixture is stirred for a further 15 minutes and a solution of 25 -g. of 3,4-dimethoxy-phenylcyanoacetic acid ethyl ester in 50 cc. of tetrahydrofuran is added dropwise at 20. The reaction mixture is subsequently stirred at 50 for a further 3 hours, the residual lithium aluminum hydride is then destroyed with a caustic soda solution, filtration is effected, the tetrahydrofuran solution is dried over potassium carbonate and the solvent is distilled ofi. The resulting oil is converted into the hydrochloride and recrystallized from ethanol/ether. The hydrochloride has a M.P. of 204-206.

EXAMPLE 12 2-(3,4-dihydroxyphenyl)-3-(n-propylamino)propanol 2-(3,4 dimethoxyphenyl) 3 (n-propylamino)propanol (obtained in a manner analogous to Example 1, M.P. 72-74") is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 84-85 EXAMPLE 13 2-(3,4-dihydroxyphenyl)-3-(4-methyl-2- pentylamino propanol 2-(3,4 dimethoxyphenyl) 3 (4-methyl-2-pentylamino) propanol (obtained in a manner analogous to Example l, M.P. of the hydrochloride 125127) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 145-147.

EXAMPLE 14 2-(3,4-dihydroxyphenyl)-3- (phenethylamino)propanol 2-(3,4 dimethoxyphenyl) 3 (phenethylamino)propanol (obtained in a manner analogous to Example 1, M.P. of the hydrochloride 149-151) is reacted in accordance with the process described in Example 1. The bydrobromide of the title compound has a M.P. of 65-70.

EXAMPLE 15 2- 3,4-dihydroxyphenyl) -3- (n-pentylamino) propanol 2-(3,4 dimethoxyphenyl) 3 n-pentylamino)propanol (obtained in a manner analogous to Example 1, M.P. of the hydrochloride 133-136) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 139141.

EXAMPLE 16 3- (n-hexylamino) -2- (3,4-dihydroxyphenyl propanol 3-(n-hexylamino) 2 (3,4-dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, M.P. of the hydrochloride 94-97") is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 92-95.

10 EXAMPLE 11 3-(n-heptylamino)-2-(3,4-dihydroxyphenyl)propanol S-(n-heptylamino) 2 (3,4-dimethoxyphenyl)propa- 1101 (obtained in a manner analogous to Example 1, oil) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 128-13l.

EXAMPLE l8 2-(3,4-dihydroxyphenyl)-3-(4-phenylbutylamino)propanol 2-(3,4-dimethoxyphenyl) 3 (4 phenylbutylamino) propanol (obtained in a manner analogous to Example 1, M.P. of the hydrochloride 116-118) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 117 EXAMPLE 19 3-(p-hydroxyphenethylamino)-2-(3,4-dihydroxyphenyl)propanol 3-(p-methoxyphenethylamino) 2 (3,4 dimethoxyphenyl)propanol (obtained in a manner analogous to Example l, M.P. of the hydrochloride 144-146) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 6570.

EXAMPLE 20 2-(3,4-dihydroxypheny1)-3-[3-(p-hydroxyphenyl) propylarnino]propanol 2-(3,4-dimethoxyphenyl)-3 [3 (p methoxyphenyl) propylamino]propanol (obtained in a manner analogous to Example 1, M.P. 6467, M.P. of the hydrochloride 104-106") is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of -168".

EXAMPLE 21 2-(3,4-dihydroxyphenyl) -3- 1-phenyl-3-butylamino) propanol 2-(3,4-dimethoxyphenyl)-3-( l-phenyl 3 butylamino) propanol (obtained in a manner analogous to Example 1, M.P. of the hydrochloride 118120) is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 90-94".

EXAMPLE 22 3-ethylamino-2-(3,4-dihydroxyphenyl)propanol 3'ethylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, M.P. 67- 69") is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 93-95 EXAMPLE 23 3-(4-hydroxybenzylamino)-2-(3,4-dihydroxyphenyl) propanol 3-(3,4-dihydroxyphenethylamino)-2-(3,4-dihydroxyphenyl)propanol 3-(3,4-dimethoxyphenethylamino)-2-(3,4 dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, M.P. of the hydrogen fumarate (SS-67) is reacted in accordance with the process described in Example 11 1. The hydrobromide of the title compound has a M.P. of 77-80".

EXAMPLE 25 2-(3,4-dihydroxyphenyl)-3-(2,2-diphenylethylamino) propanol (+)-3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol hydrobromide (+)-3-tert.butylamino 2 (3,4 dimethoxyphenyl) propanol is reacted in accordance with the process described in Example 1. The title compound has a M.P. of

102-104, [a] =+31.5 in ethanol.

EXAMPLE 27 -3 -tert.butylamino-2- (3 ,4-dihydroxyphenyl propanol hydrobromide ()-3-tert.butylamino 2 (3,4 dimethoxyphenyl) propanol is reacted in accordance with the process described in Example 1. The title compound has a M.P. of 107-109, [a] =32.1 in ethanol.

The starting materials for Examples 26 and 27, i.e.

(+)- or ()-3-tert.butyl-amino 2 (3,4 dimethoxyphenyl)propanol, are obtained as follows:

(a) A solution of 472 g. of 3,4-dimethoxyatropic acid ethyl ester in 200 cc. of ethanol is added dropwise to a solution of 175 g. of tert.butylamine in 200 cc. of ethanol at room temperature while stirring. The reaction mixture is subsequently heated to 50 for 3 hours, filtration is etfected and the filtrate is concentrated by evaporation in a vacuum. The residue is taken up in chloroform and extracted with 2 N hydrochloric acid. The hydrochloric acid solution is rendered alkaline with concentrated ammonia while cooling, whereby a yellow oil separates, which is taken up in chloroform. The solution is dried over sodium sulphate and concentrated by evaporation. The residue, i.e. 3-tert.butylamino-2-(3,4 dimethoxyphenyl)propionic acid ethyl ester, is converted into the hydrochloride with hydrochloric acid in ethanol.

(b) 105 g. of 3-tert.butylamino-2 (3,4 dimethoxyphenyl)propionic acid ethyl ester are reduced in 1000 cc. of ether with 11.4 g. of lithium aluminium hydride by heating under reflux for two hours. After decomposing with a small amount of water, filtration is effected, the ether solution is dried and concentrated by evaporation, and the residue, the racemate form of 3-tert.butylarnino-2- (3,4 dimethoxyphenyl)propanol, is crystallized. The racemate has a M.P. of 71-73 -(c) 40 g. of racemic 3-tert.butylamino-2-(3,4-dimethoxyphenyl)propanol are dissolved in 4 liters of ethanol and a solution of 60 g. of ()di-O (p toluoyl) L- tartaric acid in 4 liters of ethanol is added. (+)-3-tert. butylamino-Z-(3,4-dimethoxyphenyl) propanol hydrogen- (-)di-O-(p-toluoyl)-L-tartrate crystallizes. M.P. after recrystallization from methanol l91-192.

The salt of the optically active base is decomposed with 2 N caustic soda solution/ chloroform; the base resulting from the chloroform phase is recrystallized from cyclohexane. (+)-3-tert. butylamino-2-(3,4-dimethoxyphenyl) propanol is obtained. M.P. 707l, [a] =I-31.90 in ethanol.

((1) The ethanolic mother liquor obtained in (c) above is concentrated by evaporation, the resulting salt mixture is decomposed with 2 N caustic soda solution, the liberated base is taken up in chloroform, the solution is dried over sodium sulphate, the chloroform is distilled 011 and the resulting base is dissolved in 2.5 liters of ethanol. A solution of 40 g. of (+)-di-O-(p-toluoyl)-D-tartaric acid in 2.5 liters of ethanol is added to this solution. ()-3-tert. butylamino-2-(3,4 dimethoxyphenyl)propanol hydrogen- (+)-di-O-(p-toluoyl)-D-tartrate crystallizes. M.P. after recrystallization from methanol 191-192".

The salt of the optically active base is decomposed with 2 N caustic soda solution/ chloroform. The base resulting from the chloroform phase is recrystallized from cyclohexane. )-3-tert.butylamino-2-( 3,4 dimethoxyphenyl)propanol is obtained. M.P. 77-79 [a] =32.5 in ethanol.

EXAMPLE 28 3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol 10.0 g. of racemic 3-tert.butylamino 2-(3,4-dimethoxyphenyl)propanol (prepared as described in Example 27) are heated under refiux in 100 cc. of 48% hydrobromic acid for 15 minutes. The reaction solution is subsequently evaporated to dryness and the residue is recrystallized from ethanol/ether.

The hydrobromide of the title compound has a M.P. of 113-1 15.

EXAMPLE 29 2(3,4-dihydroxyphenyl)-3-(p-methoxyphenethylamino) propanol [process variant (b)] 11.0 g. of 2-(3,4-dibenzyloxyphenyl) 3 (p-methoxyphenethylamino)propanol are dissolved in 200 cc. of ethanol, 1.0 g. of palladium on charcoal (10%) is added and hydrogenation is efiected at room temperature for 30 minutes. The catalyst is then filtered 01f, the solution is concentrated by evaporation and the residue is converted into the hydrochloride of the title compound. M.P. 198-200.

The starting material is obtained as follows:

(a) 7.6 g. of sodium are dissolved in 200 cc. of ethanol, the solution is evaporated to dryness in the absence of moisture and the residue is suspended in 200 cc. of absolute toluene. 80 g. of oxalic acid diethyl ester are added dropwise and subsequently 123 g. of 3,4-dibenzyloxyphenylacetic acid ethyl ester are added dropwise at 35- 40 while stirring. The mixture is heated under reflux while stirring for 2 hours, is then cooled to 45 and cc. of 4 N sulphuric acid are added. 40 g. of 36% formalin and cc. of a saturated potassium carbonate solution are added over a period of 3 hours. The reaction mixture is stirred at room temperature over night, is then diluted with 250 cc. of water and the toluene phase is separated. After drying over sodium sulphate the solvent is distilled off, and the resulting a-(3,4-dibenzyloxyphenyl)acrylic acid ethyl ester is used for the next reaction without previous purification.

(b) 38.8 g. of u-(3,4-dibenzyloxyphenyl)acrylic acid ethyl ester and 14 g. of p-methoxyphenethylamine are heated under reflux in cc. of ethanol for 10 hours. After distilling off the ethanol, the residue is dissolved in 300 cc. of ether and the solution is shaken with 25 cc. of 4 N hydrochloric acid, whereby the hydrochloride of 2-(3,4-dibenzyloxyphenyl) 3 p methoxy-phenethylaminopropionic acid ethyl ester crystallizes. M.P. 85-88 after recrystallization from ethanol/ether.

(c) 16.7 g. of 2-(3,4-dibenzyloxyphenyl)-3-p-methoxyphenethylaminopropionic acid ethyl ester are reduced in 200 cc. of tetrahydrofuran with 2.0 g. of lithium aluminium hydride. The reaction is complete after heating under reflux for 2 hours. After decomposing the excess reducing agent with a small amount of water, filtration is effected and the tetrahydrofuran solution is dried over sodium sulphate and the solvent is distillated ofi. The resulting 2-(3,4-dibenzyloxyphenyl)-3-(p methoxyphenethylamino)propanol is recrystallized from ethyl acetate/ petroleum ether. M.P. 81-82".

13 EXAMPLE 3o 2- 3,4-dihydroxyphenyl) -3- (isopropylamino propanol [process variant 3-n-butylamino-2- (3 ,4-dihydroxyphenyl) propanol 5.0 of 3 amino-2-(3,4 dihydroxyphenyl)propanol hydrobromide are reacted with butyraldehyde in analogous manner to Example 30. The hydrobromide of the title compound has a M.P. of 93-95 EXAMPLE 32 3 -sec.butylamino-2- (3 ,4-dihydroxyphenyl) propanol 3-amino-2-(3,4 dihydroxyphenyl)propanol is reacted with methyl ethyl ketone in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 85-89".

EXAMPLE 33 3-cyclohexylamino-2-(3,4-dihydroxyphenyl)propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with cyclohexanone in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 95-97".

EXAMPLE 34 3-cyclopentylamino-2-(3,4-dihydroxyphenyl)propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with cyclopentanone in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 92-95.

EXAMPLE 35 2-(3,4-dihydroxyphenyl)-3-(3-phenylpropylamino) propanol 3-amino-2-(3,4dihydroxypheny1)propanol is reacted with 3-phenylpropionaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 108-110".

EXAMPLE 36 2- (3 ,4-dihydroxyphenyl) -3 1-phenyl-2-propylamino) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with benzyl methyl ketone in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 109-110".

EXAMPLE 37 2-(3,4-dihydroxyphenyl)-3-(3,3-diphenylpropylamino) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with 3,3-diphenylpropionaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 98402".

EXAMPLE 38 2- (3,4-dihydroxyphenyl)-3-(n-propylamino) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with propionaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 84-85.

14 EXAMPLE 39 2-(3,4-dihydroxyphenyl)-3-(4methyl-2-pentylamino) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with 4-methyl-2-pentanone in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of l45-147.

EXAMPLE 4O 2- 3,4-dihydroxyphenyl) -3- (phenethylamino propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with phenylacetaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 65-70.

EXAMPLE 41 2-(3,4-dihydroxyphenyl)-3-(n-pentylamino)propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with valeraldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 139-141.

EXAMPLE 42 3- n-hexylamino -2- 3 ,4-dihydroxyphenyl propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with hexanal in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 92-95 EXAMPLE 43 3-(n-heptylamino -2- (3,4-dihydroxyphenyl) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with n-heptanal in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 128-13l.

EXAMPLE 44 2- (3,4-dihydroxyphenyl) -3 (4-phenylbutylamino) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with 4-phenylbutyraldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 115-117".

EXAMPLE 45 3- (p-hydroxyphenethylamino -2- 3 ,4-dihydroxypheny1) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with p-hydroxy-phenylacetaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 65-70".

EXAMPLE 46 2.- 3,4-dihydroxyphen'yl) -3- 3- (p-hydroxyphenyl) propylamino1propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with 3-(p-hydroxyphenyl)propionaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of l65-16=8.

EXAMPLE 47 2-(3,4-dihydroxyphenyD-3-(l-phenyl-3-butylamino) propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with 4-phenyl-2-butanone in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of -9'4.

1 EXAMPLE 48 3-ethylamino-2-(3,4-dihydroxyphenyl)propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with acetaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 93-95".

EXAMPLE 49 3-(3,4-dihydroxyphenethylamino)-2-(3,4-dihydroxyphenyl propanol S-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with 3,4-dihydroxy-phenylacetaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 77-80.

EXAMPLE 50 2-(3,4-dihydroxyphenyl)-3-(2,2-diphenylethylamino) propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with diphenylacetaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of (HS-117.

EXAMPLE 51 2-(3,4 dihydroxyphenyl)-3-(p-methoxyphenethylamino) propanol 3-amino 2 (BIA-dihydroxyphenyl)propanol is reacted with p-methoxy-phenylacetaldehyde in accordance with the process described in Example 30. The hydrochloride of the title compound has a M.P. of 198-200.

EXAMPLE 5 2 3-[ (cyclopentylmethyl) amino] -2-( 3,4-dihydrox'yphenyl) propanol [process variant (a)] 20.0 g. of 3-[(cyclopentylmethyl)amino]-2-(3,4-dimethoxyphenyDpropanol are dissolved in 250 cc. of methylene chloride and 39 g. of boron tribromide, dissolved in 250 cc. of methylene chloride, are added dropwise thereto while maintaining the reaction temperature at -75. The cooler is then removed, the reaction mixture is stirred at room temperature for 1 hour and the solvent is then distilled 01f. The residue is boiled under reflux with 100 cc. of ethanol for 1 hour. The solution is concentrated and ether is added until the reaction product crystallizes as hydrobromide. M.P. 87-91 (decomp.).

The starting material is obtained as follows:

(a) 52.0 g. of 3,4-dimethoxyatropic acid ethyl ester and 19.8 g. of cyclopentylmethylamine are heated to 60 with 20 cc. of ethanol for 3 hours. The reaction mixture is concentrated by evaporation in a vacuum, the oily residue is dissolved in chloroform and extraction is effected with 2 N hydrochloric acid. The hydrochloric acid solution is rendered alkaline with concentrated ammonia while cooling and is then extracted with chloroform. The chloroform extract is dried over sodium sulphate and concentrated by evaporation and the residue, i.e. 3-[(cyclopentylmethyl amino] -2- (3,4 dimethoxyphenyl) propionic acid ethyl ester, is converted into the hydrochloride with hydrochloric acid in ethanol. M.P. 127-129.

(b) 50 g. of 3-[(cyclopentylmethyl)amino]-2-(3,4-dimethoxyphenyl)propionic acid ethyl ester are reduced in 400 cc. of tetrahydrofuran with 6.5 g. of lithium aluminium hydride by heating for 2 hours. After decomposing the residual reducing agent with a small amount of water, filtration, drying and concentrating by evaporation are effected and 3-[(cyclopentylmethyl)amino]-2-(3,4-dimethoxyphenyl)propanol is crystallized from ethyl acetate/petroleum ether. M.P. 67-70.

16 EXAMPLE s3 3,(3-cyclopentylpropylamino)-2-(3,4-dihydroxyphenyl) propanol EXAMPLE 54 3-[ (cyclohexylmethyl) amino] -2- 3,4-dihydroxyphenyl) propanol 3-[ (cyclohexylmethyl) amino]-2-(3,4 dimethoxyphenyl)propanol is reacted in accordance with the process described in Example 1. The hydrobromide of the title compound has a M.P. of 112-115".

The starting materials are produced in a manner analogous to that described in Example 52:

(a) Reaction of 3,4-dimethoxyatropic acid ethyl ester with cyclohexylmethylamine yields 3 [(cyclohexylmethyl)amino] 2 (3,4 dimethoxyphenyl)propionic acid ethyl ester, M.P. of the hydrochloride -133, and

(b) Reduction of the latter yields I i-[(cyclohexylmethy1)amino] 2 (3,4 dimethoxyphenyl)propanol, M.P. 130-132.

EXAMPLE 55 3- (cyclopentylmethyl)amino] -2-(3,4- dihydroxyphenyl propanol 3 amino 2-(3,4-dihydroxyphenyl)propanol is reacted with cyclopentylformaldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 87-91 (decomp.).

EXAMPLE 5 6 3- 3-cyclopentylpropylamino) -2- 3,4-dihydroxyphenyl) propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with 3 cyclopentylpropanone in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 164-167.

EXAMPLE 5 7 3- (cyclohexylmethyl) amino] -2-( 3,4-dihydroxyphenyl propanol 3 amino 2 (3,4-dihydroxyphenyl)propanol is reacted with cyclohexylfor-maldehyde in accordance with the process described in Example 30. The hydrobromide of the title compound has a M.P. of 112-115 What is claimed is:

1. A compound of the formula:

R is alkyl of l to 8 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1, which is 2-(3,4-dihydroxyphenyl) 3 (isopropylamino)propanol.

3. The compound of claim 1, which is 3-tert. butylamino-2-(3,4-dihydroxyphenyl)propanol.

1 7 4. The compound of claim 1, which is 3-sec. butylamino-2-( 3,4-dihydroxyphenyl prop anol.

5. The compound of claim 1, which is 3-butylamino- 2-(3,4-dihydroxyphenyl)propanol.

6. The compound of claim 1, which is 2-(3,4-dihy- 5 droxyphenyl) -3- n-propylamino propanol.

7. The compound of claim 1, which is 2-(3,4-dihydroxyphenyl)-3-(4-methyl-2-pentylamino)propanol.

8. The compound of claim 1, which is 2-(3,4-dihydroxyphenyl)-3-(n-pentylamino)propanol.

9. The compound of claim 1, which is 3-(n-hexylamino) -2- 3,4-dihydroxyphenyl) propanol.

10. The compound of claim 1, which is S-(n-hcptylamino)-2-(3,4-dihydroxypheny1)propanol.

18 12. The compound of claim 1, which is 3-tert.- butylamino 2-(3,4-dihydroxyphenyl)proanol hydrobromide.

13. The compound of claim 1, which is 3 tertbutylamino 2 (3,4-dihydroxyphenyl)propanol hydrobromide.

References Cited Meschino et al.: Journal of Organic Chemistry, vol. 28, No. 11, pp. 3129-3134 (1963).

ROBERT V. HINES, Primary Examiner US. Cl. X.R.

11. The compound of claim 1, which is 3-ethy1amino- 5 260-4405, 465 DF, 471 A, 473 S, 501.17, 501.18, 501.19,

2-(3,4-dihydroxyphenyl)propanol.