US3657244A

US3657244A - 1-(2' 3' 4'-trisubstituted phenyl)-2-amino-alkanols-(1) and salts thereof

Info

Publication number: US3657244A
Application number: US713265A
Authority: US
Inventors: Anton Mentrup; Karl Zeile; Otto Thoma; Kurt Schromm
Original assignee: CH Boehringer Sohn AG and Co KG
Current assignee: CH Boehringer Sohn AG and Co KG; Boehringer Ingelheim GmbH
Priority date: 1966-10-18
Filing date: 1967-10-16
Publication date: 1972-04-18
Anticipated expiration: 1989-04-18
Also published as: ES360963A1; ES360964A1; AT288357B; DE1543374C3; DE1543374A1; NL6714161A; BE705312A; CH490323A; ES360965A1; AT285582B; DK130070C; DE1543374B2; SE368196B; NL158480B; ES360961A1; SE380792B; GB1204195A; ES360962A1; CH523219A; CH507200A

Abstract

THE COMPOUNDS ARE 1-(2'',3'',4''-TRISUBSTITUTED-PHENYL)-2AMINO-ALKANOLS-(1) AND ACID ADDITION SALTS THEREOF, USEFUL AS SYMPATHOMIMETICS IN WARM-BLOODED ANIMALS.

Description

ABSTRACT OF THE DISCLOSURE The compounds are 1-(2',3,4-trisubstituted-phenyl)-2- amino-alkanols-(l) and acid addition salts thereof, useful as sympathomimetics in warm-blooded animals.

This invention relates to novel 1-(2',3',4'-trisubstitutedphenyl)-2-secondary amino-alkanols-(l) and acid addition salts thereof, as well as to various methods of preparing these compounds.

More particularly, the present invention relates to racemic mixtures of a novel class of compounds of the formula R10 R2 R3 mama-mun,

wherein R is hydrogen or acyl,

R is straight or branched alkyl of 1 to carbon atoms, stright or branched alkoxy of 1 to 5 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms,

R is hydrogen or lower alkyl, and

R is straight or branched alkyl of l to 8 carbon atoms;

cycloalkyl of 3 to 7 carbon atoms, benzodioxanyl-Z- alkyl whose alkyl moiety contains from 1 to 3 carbon atoms, or

where Z is straight or branched alkylene of 2 to 6 carbon atoms,

n is 0 to 1, and

R and R which may be identical to or difierent from each other, are each hydrogen, hydroxyl, lower alkyl or lower alkoxy or, together with each other, methylenedioxy,

with the proviso that R, is other than isopropyl when R is hydrogen, R is methyl or methoxy and R is hydrogen, methyl or ethyl; their stereoisomeric components; their diastereomeric antipodes; and non-toxic, pharmacologically acceptable acid addition salts of said racemic mixtures, stereoisomers or diastereomeric antipodes.

The compounds according to the present invention may be prepared by a number of different methods involving well known chemical principles, among which the following have proved to be particularly convenient and efficient:

United States Patent 0 Method A By reducing a ketone of the formula mo 2 o I! R'O c on mum,

wherein R R and R have the same meanings as in Formula I; each R either has the same meanings as R; in Formula I or is a protective group which may subsequently be split off, preferably by hydrolysis or hydrogenation, such as acyl or benzyl; or both R, together with each other and the oxygen atoms to which they are attached, form an acetal group whose hydrocarbon moiety preferably contains the diphenylmethylene or cyclohexylidene group; and R is hydrogen or a protective group, such as benzyl.

The reduction may be carried out with the aid of hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum or palladium; or also with the aid of complex hydrides, especially sodium borohydride or lithium aluminum hydride; or also by means of the Meerwein-Ponndorf-Verley Reduction.

The various protective groups may be split off all at once or in stepwise fashion, during or after the reduction, by conventional methods.

A starting compound of the Formula II may be obtained by customary methods, such as by reacting a com pound of the formula 9 I am c crmgx m wherein R and K, have the same meanings as in Formula I, R has the same meanings as in Formula II, and X is chlorine, bromine or iodine, with an amine of the formula wherein R, has the same meanings as in Formula I and R" has the same meanings as in Formula II.

Method B By reducing a compound of the formula I R Q R2 9 mo n c R (V) wherein R and K, have the same meanings as in Formula I, R has the same meanings as in Formula II and R is C(') or CH(OH), in the presence of an amine of the formula H2NR4 (VI) The reduction may be effected with hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel or palladium, or with a complex hydride, such as lithium aluminum hydride or sodium borohydride. If the reduction is carried out with the aid of a complex hydride, it is preferred if each R in the starting compound of the Formula V is a protective group, especially benzyl, and these protective groups may be removed in customary fashion subsequent to the reduction reaction. If desired, in those cases where R, is CH(OH)-, the Schiffs base formed by the condensation reaction between compound V and amine VI may also be used as the starting compound.

A dicarbonyl compound of the Formula V may be obtained by customary methods, such as by oxidation of an analogously substituted aceto-, propio-, butyroor valerophenone with selenium oxide.

Method C By reacting a compound of the formula (Ill-R3 (VIIa) or am a n'o- -cn-ca-n l on (VIIb) (VIII) wherein R R R and X have the meanings defined above, with sodium borohydride.

Method D By reacting an amine of the formula wherein R R and R have the same meanings as in Formula VIIa, under reducing conditions, with a compound of the formula $3 en cu ma wherein R is hydrogen or s traight-chain lower alkyl; R is straight or branched lower alkyl, the sum of the carbon atoms in R and R being no greater than 7; and R may further be 1,4 benzodioxan 2 yl, 1,4 benzodioxan 2-ylmethyl, 1,4-benzodioxan-2-ylethyl or wherein Z is lower alkylene, the sum of the carbon atoms in Z and R being no more than 5, and R R and n have the same meanings as in Formula Ia; and R and R together with each other, may also be alkylene of no more than 6 carbon atoms.

The reducing agent may be hydrogen in the presence of a hydrogenation catalyst, such as platinum. If R in Formula X is a protective group which may be split off by hydrogenation, these protective groups may simultaneously be split off. If R is acyl, these may be removed subsequent to the reduction in customary fashion, if desired.

A complex hydride, such as sodium borohydride or lithium aluminum hydride, may also be used as the reducing agent. Under those conditions, it is preferred to use as the starting material a compound of the Formula IX wherein R is a protective group, especially benzyl or diphenylmethyl, and any protective groups present in the reaction product may subsequently be split off in customary fashion.

An amine of the Formula IX may be obtained by well known methods from an analogously substituted isonitrosoketone, cyanhydrin, benzoylcyanide, hydrazine, hydrazide, azidophenone or diazophenone. However, it is not necessary to prepare and isolate the amine IX separately; instead, an analogously substituted starting compound mentioned in the preceding sentence may be subjected, as such, to the reductive substitution reaction, whereby the amine IX is formed in situ and undergoes reaction with compound X.

Method E For the preparation of a compound of the Formula I wherein R is hydrogen, by reducnig a compound of the formula R'Q R2 a'b a co mm,

(XI) wherein R and K, have the same meanings as in Formula I, R has the same meanings as in Formula II, and R; has the same meanings as in Formula V, preferably with a complex hydride, such as lithium aluminum hydride. Especially suitable as a starting material is a carboxylic acid amide of the Formula XI wherein the hydroxyl groups in the 3- and 4-positions on the phenyl ring are protected in the form of acetal or benzylether groupings. These protective groups may be split off again subsequent to the reduction.

Method F By reacting a compound of the formula CH CH NHR" OH (XII) wherein R and R have the same meanings as in Formula I and R and R have the same meanings as in Formula II, with a compound of the formula R Y (XIII) wherein R, has the same meanings as in Formula I and Y is chlorine, bromine, iodine, arylsulfonyl or alkylsulfonyl. The reaction is advantageously carried out in the presence of an acid-binding condensation agent, such as sodium carbonate or potassium carbonate; however, the amine XII may itself also serve as the acid-binding agent, provided it is present in suflicient excess over and above the stoiehiometrically required amount. The protective groups may subsequently be removed in customary fashion.

In those cases where methods A through F yield an end product of the Formula I wherein R is hydrogen, these hydroxyl groups may subsequently be acylated with a conventional acylating agent to convert them into acyloxy groups.

The compounds of the Formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, cyclohexylsulfarnic acid, 8-chlorotheophylline or the like.

In those instances where methods A through F yield initially an acid addition salt of a compound of the Formula I, this salt may be converted into the free base or into another acid addition salt of conventional methods, if desired.

If a starting compound for any of the methods described above exists in stereoisomeric forms, a pure stereoisomer thereof may be used as the starting compound.

If an end product of the Formula I contains only one asymmetric carbon atom, a racemic mixture thereof may, if desired, be separated into its optical antipode components by conventional methods. If more than one center of asymmetry are present, the racemates of the diastereomeric pairs of antipodes may be separated from each other, and each pair may in turn be separated into the individual antipodes. For the separation of the mirrorimage-isomers it is preferred to use fractional crystallization of their addition salts formed with optically active acids, such as dibenzoylor ditoluyl-a-tartaric acid.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the instant invention is not limited solely to the particular examples given below.

EXAMPLE 1 Preparation of 1-(2'-ethoxy-3',4'-dihydroxy-phenyl)-1- hydroxy-Z-isopropylamino-ethane by Method A 2 hydroxy-3,4-diphenylmethylenedioxy-acetophenone was converted into its sodium salt with sodium hydroxide in acetone, and the sodium salt was reacted with ethyl iodide in ethanol to form 2-ethoxy-3,4-diphenylmethylenedioxyacetophenone, M.P. 82 C., 72 gm. of which were reacted in benzene first with cc. of bromine and then with 60 gm. of benzylisopropylamine at 60 C. to form raw 1-(2-ethoxy 3',4 diphenylmethylenedioxy-phenyl)-loxo-2-(benzyl-isopropylamino)-ethane. 81 gm. of this raw base were dissolved in a mixture of 540 cc. of methanol and 270 cc. of water, the solution was purified by filtering it through animal charcoal, and the filtrate was hydrogenated in the presence of palladized charcoal. The 1-(2'- ethoxy-3',4'-dihydroxypheny1) 1 oXo-2-isopropylaminoethane formed thereby was isolated as its hydrochloride, M.P. 3-205 C. (recrystallized from 95% isopropanol), with the aid of acetone.

20 gm. of the aminoketone hydrochloride thus obtained were dissolved in 200 cc. of methanol, and the solution was hydrogenated in the presence of platinum (from 1 gm. of PtO yielding 18 gm. of 1(2-ethoxy-3',4'-dihydroxy-phenyl)-1-hydroxy-2-isopropylamino-ethane hydrochloride, M.P. 182 C.; recrystallized from ethanol, the product of the formula Ho mam TH; HO-(JHCHa-NH(IJH OH CH;

has a melting point of 184 C.

EXAMPLE 2 Preparation of 1-(2'-n-propyl-3',4-dihydroxy-phenyl)- 1-hydroxy-2-isopropylamino-ethane by Method A 3-hydroxy-4-methoxy-acetophenone was reacted with allylbromide to form 3-allyloxy-4-methoxy-acetophenone, B.P. 180-182 C. at 4 mm. Hg, and the latter was subjected to a thermal rearrangement reaction to form 2- al1yl-3-hydroxy-4-methoxy-acetophenone, M.P. 8789 C., which in turn was hydrogenated in the presence of palladium to saturate the olefinic side chain and form 2-npropyl-3-hydroxy-4-methoxy-acetophenone. The saturated product was acetylated and brominated to form 2-n-propyl-3-acetoxy-4-methoxy-bromoacetophenone, which in turn was reacted with N-n-propyl-benzylamine to form 1-(2'-n-propyl-3'-acetoxy 4' methoxy-phenyl)-1oxo-2- (N-benzyl-isopropylamino)-ethane, which was hydrolized with methanolic hydrochloric acid, yielding 1-(2-mi-propyl-3'-hydroxy 4 methoxy-phenyD-l-oxo-Z- (N-benzylisopropylarnino)-ethane which was isolated as its hydrochloride, M.P. 100 C.

113 gm. of the hydrochloride thus obtained were dissolved in aqueous methanol and de-benzylated by hydrogenation in the presence of palladium, yielding 1-(2'- n-propyl-3'-hydroxy-4-methoxy-phenyl) 1 oxo-2-iso propylamino-ethane hydrochloride, M.P. 93-95 C., which was de-methylated by boiling with 50% hydrogen bromide, yielding l-(2-n-propyl-3,4'-dihydroxy-phenyl)- l-oxo-2-isopropylamino-ethane hydrochloride, M.P. 181- 182 C., which was converted into the free base. 27.5 gm. of the base were hydrogenated at 60 C. in methanol with Raney nickel as a catalyst, and after almost the theoretical amount of hydrogen had been absorbed the 1-(2'-n-propyl-3,4'-dihydroxy-phenyl) 1 hydroxy-2- isopropylamino-ethane formed thereby was isolated as its hydrochloride, M.P. 158-l59 C. (recrystallized from ethanol), of the formula Preparation of 1-(2-methyl-3,4'-dihydroxyphenyl)-2-('yphenyl-n-propyl-amino)-ethanol-(1) by Method A 97 gm. of 2-methyl-3,4-dimethoxy-acetophenone were dissolved in benzene, 25 cc. of bromine were gradually added at 75 C., the benzene was distilled off in vacuo, and the residue was diluted with isopropanol, whereby a-bromo-2-rnethyl-3,4-dimethoxy-acetophenone, M.P. 88 C., crystallized out, which was reacted with 2 mol equivalents of N-benzyl-(v-phenyl-n-propyl)-amine in acetonitrile at room temperature. The N-benZyl-(y-phenyl-npropyl)-amine hydrobromide formed thereby and the solvent were distilled off, the residue was taken up in ether, and the solution was acidified with oxalic acid, yielding a- (N-benzyl-'y-phenyl-n-propylamino -2-methyl- 3,4-dimethoxy-acetophenone hydrogenoxalate, M.P. 118- 121 C. The hydrogenoxalate was dissolved in a mixture of methanol and water (2:1 by volume), and the solution was hydrogenated at 60 C. and 5 atmospheres in the presence of palladized charcoal, yielding a solution of OL- (v-phenyl-n-propyl-amino) 2methyl3,4-dimethoxyacetophenone hydrogenoxalate, which was made alkaline with aqueous ammonia. The free base liberated thereby was dissolved in acetonitrile, and the solution was acidified with ethereal hydrochloric acid, yielding the hydrochloride of u-('y-phenyl-n-propylamino)-2-methyl-3,4-dimethoxy-acetophenone, M.P. 2l0 -2l7 C.

50 gm. of the hydrochloride thus obtained were admixed with 920 cc. of 40% hydrobromic acid, and the mixture was refluxed for minutes and was thereafter allowed to cool, whereby w('y-phenyl-n-propylamino)-2- methyl-3,4-dihydroxy-acetophenone hydrobromide, M.P. 179 C., precipitated out. The hydrobromide was converted into the free base, M.P. 130-138 C., which in turn was converted in ethanol with ethereal hydrochloric acid into its hydrochloride.

30 gm. of the hydrochloride of a,('y-phenyl-n-propylamino)-2-methyl 3,-4 dihydroxy-acetophenone thus obtained were dissolved in 300 cc. of methanol, and the solution was hydrogenated at atmospheric pressure in the presence of platinum (from 5 gm. of 'PtO as a catalyst, the solution being briefly heated to 65 C. at the beginning of the hydrogenation. Thereafter, the catalyst was filtered off, the methanol was distilled off in a stream of hydrogen under a vacuum, and the residue was reprecipitated from dilute hydrochloric acid and then recrystallized from ethanol and dilute hydrochloric acid, yielding 1-(2'-methyl-3',4-dihydroxy-phenyl)-2-('yphenyl-n-propylamino)-ethan0l-(1) hydrochloride, M.P. 176 C., of the formula 7 EXAMPLE 4 Preparation of 1-(2'-methyl-3',4'-dihydroxy-phenyl)-2-[2- (p-hydroxy-phenyl)-isopropyl-amino]-ethanol (1) by Method A ot-[2-(p-methoxy-phenyl)-isopropylamino] 2 methyl- 3,4-dimethoxy-acetophenone hydrochloride, MJP. 205 C., was prepared by reacting ot bromo-2-methyl-3,4-dimethoxy-acetophenone with 2 mol equivalents of N- benzyl-(p-methoxyphenyl-isopropyl)-amine in ethyl acetate, followed by hydrogenation of the reaction product in methanol at 60 C. at 5 atmospheres in the presence of palladized charcoal as a catalyst, and acidification of the free base hydrogenation product with hydrochloric acid. The hydrochloride thus obtained was boiled for 90 minutes with 48% hydrobromic acid, yielding Ot-[Z-(P- hydroxy-phenyl)-isopropylamino]-2-methyl 3,4 dihydroxy-acetophenone hydrobromide, M.P. l l25 C., which was converted into the hydrochloride, MP. 120 135 C., by dissolving it in water and acidifying the solution with concentrated hydrochloric acid.

gm. of u-[Z-(p-hydroxy-phenyl)-isopropylamino]-2- methyl-3,4-dihydroxy-acetophenone hydrochloride were dissolved in 200 cc. of methanol, and the solution was hydrogenated at 20 C. and atmospheric pressure in the presence of platinum (from 2 gm. of PtO as a catalyst until the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was filtered off, 3 gm. of benzoic acid were added to the filtrate, and the methanol was distilled off in vacuo. The residue was diluted with 200 cc. of ethanol and was then shaken for 45 minutes with 8.4 gm. of sodium benzoate, the sodium chloride precipitated thereby was filtered off, the filtrate was evaporated in vacuo, and the residue was stirred with a small amount of ether. The oil obtained thereby crystallized after some time of standing with acetonitrile, the crystals were extracted with hot methyl ethyl ketone, and the extract solution was allowed to cool, whereby a crystalline substance having a melting point of 110 C. separated out, which was identified to be 1-(2'-methyl-3',4- dihydroxy-phenyl) 2 [2- (p-hydroxy-phenyl)-isopropylamino]-ethanol-(1) benzoate of the formula Preparation of 1-(2'-methoxy-3',4'-dihydroxy-phenyl)-'2- cyclopentylamino-ethanol-( l) by Method A 270 gm. of 2,3,4-trihydroxy-acetophenone [prepared according to Badhwar, Org. Synthesis 14, 14 (1934)] were admixed with 772 cc. of acetone, 131 cc. of pyridine and 388 gm. of diphenyl-dichloro-methane, and the mixture was allowed to stand overnight. Thereafter, a solution of 200 gm. of sodium hydroxide in 500 cc. of water was added thereto in small portions, whereby the temperature of the reaction mixture rose to between 50 and 60 C. After about two hours of standing the reaction mixture was acidified with concentrated hydrochloric acid, the resulting stilf crystalline slurry was diluted with water, the crystals were separated by vacuum filtration and washed with water, the filter cake was suspended in methanol, the slurry was vacuum filtered, and the filter cake was washed with methanol, yielding 2- hydroxy-3,4-diphenylmethylenedioxyacetophenone, M.P.

249 gm. of Z-hydroxy 3,4 diphenylmethylenedioxyacetophenone were admixed with .1250 cc. of methanol and 288 cc. of dimethylsulfate, the mixture was heated to 40 C., and then a solution of 204 gm. of potassium hydroxide in 813 cc. of methanol was slowly added while stirring, whereby the temperature of the reaction mixture rose to 53 C. The mixture was stirred for 45 minutes more, was then cooled to room temperature, the precipitate formed thereby was separated by vacuum filtration, and the filter cake was taken up in ether by stirring. The insoluble potassium bisulfate was separated by vacuum filtration, the filtrate was filtered through charcoal, and the ether was distilled off. The residue was poured on a plate, whereby 2-methoxy 3,4 diphenylmethylenedioxyacetophenone crystallized out. 39 gm. of this compound were dissolved in 346 cc. of benzene, 10 cc. of bromine were added to the solution dropwise, and the bromination was allowed to proceed at C. After the bromination had gone to completion the benzene was distilled off, the residue was crystallized from isopropanol, the crystalline product was collected by vacuum filtration, and the filter cake was washed with petroleum ether, yielding a bromo-2-methoxy-3,4-diphenylmethylenedioxy acetophenone, M.P. 137 C.

63.8 gm. of this bromoketone were admixed with 52.5 gm. of N-benzyl-cyclopentylamine and 250 cc. of benzene, the mixture was refluxed for two hours, ether was then added to the reaction solution, and the precipitated N- benzyl-cyclopentylamine hydrobromide was separated by vacuum filtration. The filtrate was evaporated in vacuo, the residue was dissolved in methanol, the solution was neutralized with dilute hydrochloric acid, and an equal amount of water was added. The aqueous solution was then hydrogenated at 60 C. and 5 atmospheres until the theoretical amount of hydrogen had been absorbed, the catalyst was separated by vacuum filtration, and the filtrate was evaporated. The residue was dissolved in a mixture of equal parts of methanol and concentrated hydrochloric acid, and the solution was refluxed for two hours. Thereafter, the methanol was distilled otf, the residue was allowed to cool, and the precipitate formed thereby was recrystallized from ethanol, yielding a-cyclopentylamino-2- methoxy-3,4-dihydroxy-acetophenone hydrochloride, M.P. 202203 C.

6 gm. of the aminoketone thus obtained were dissolved in methanol, and the solution was hydrogenated at room temperature and atmospheric pressure in the presence of platinum as a catalyst until the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was filtered off, the filtrate was evaporated, and the residue was heated with acetonitrile, whereby the initially oily product became crystalline. 1-(2'-methoxy-3,4-dihydroxyphenyl)-2-cyclopentylamino ethanol (l) hydrochloride, M.P. 161162 C., of the formula HO 0cm CH2CH1 HO CHCHr-NHCH -HCl H CH2} Hz was obtained.

EXAMPLE 6 Preparation of 1-(2'-methoxy-3',4-dihydroxy-phenyl)-2- (fi-phenoxyethyl-amino)-ethanol-(1) by Method A 106.3 gm. of a-bromo-2-methoxy-3,4-diphenylmethylenedioxy-acetophenone were admixed with 800 cc. of benzene and 114.5 gm. of N-benzyl-(fl-phenoxyethyl)-arnine, and the mixture was refluxed for three hours. Thereafter, the reaction solution was cooled to room temperature and was then diluted with ether, whereby N-benzyl-fl-phenoxyethyl-amine hydrobromide precipitated out, which was separated by vacuum filtration. The benzene was distilled out of the filtrate in vacuo, the residue was dissolved in ethyl acetate, and the solution was acidified with ethereal hydrochloric acid, whereby a-(N-benzyl-B-phenoxyethylamine)-2-methoxy 3,4 diphenylmethylenedioxy-acetophenone hydrochloride crystallized out, which was recrystallized from a mixture of methylenechloride and ethyl acetate, whereupon it had a melting point of 159-161 C.

89 gm. of the compound thus obtained were dissolved in a mixture of 1000 cc. of methanol and 300 cc. of water, and the solution was hydrogenated at 60 C. and 5 at mospheres pressure in the presence of palladized charcoal until the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was separated by vacuum filtration, the filtrate was evaporated in vacuo, and the residue was washed with ethyl acetate, yielding a-(B- phenoxyethylamino) 2 methoxy 3,4 diphenylmethylenedioXy-acetophenone hydrochloride, M.P. 190-192 C.

60 gm. of this product were admixed with a mixture of 250 cc. of concentrated hydrochloric acid and 350 cc. of methanol, the mixture was refluxed for two hours, the reaction solution was then filtered through activated charcoal while still hot, and the filtrate was allowed to cool. During that time ot-(fl-phenoxyethyl-amino)-2-methoxy- 3,4-dihydroxy-acetophenone hydrochloride precipitated out, which was stirred with a small amount of methyl ethyl ketone and then recrystallized from ethanol, whereupon it had a melting point of 174175 C.

The hydrochloride thus obtained was converted into the free base a-(fi-phenoxyethyl-amino)-2-methoxy-3,4- dihydroxy-acetophenone with concentrated aqueous ammonia, the free base was dissolved in methanol, and the solution was hydrogenated at standard temperature and pressure in the presence of Raney nickel as a catalyst until substantially the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was filtered off, the filtrate was evaporated in vacuo in a stream of nitrogen, the residue was dissolved in acetone, and the solution was acidified with ethereal hydrochloric acid. The precipitate formed thereby was recrystallized from a mixture of ethanol and acetone, yielding 1-(2-methoxy-3,4'-dihydroxy phenyl) 2 (fl-phenoxyethylamino)-ethanol- (l) hydrochloride with /2 mol of acetone of crystalli zation, M.P. 8788 C., of the formula EXAMPLE 7 Preparation of l-(2'-methoxy-3',4'-dihydroxy-phenyl)-2- (B-p-tolyloxyethyl-amino) -ethanol-(1) by Method A a ([3 p tolyloxyethyl amino) -2-methoxy-3,4-dihydroxy-acetophenone hydrochloride, M.P. 181-182 C., was synthesized in a manner analogous to that described for the synthesis of a-(B-phenoxyethyl-anfino) -2-methoxy- 3,4-dihydroxy-acetophenone hydrochloride in Example 4.

The amino-acetophenone salt thus obtained was dissolved in methanol, and the solution was hydrogenated at standard temperature and pressure with platinum as a catalyst until substantially the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was filtered off, the methanol was distilled out of the filtrate in vacuo, and the oily residue was allowed to stand with a mixture of isopropanol and ethyl acetate, whereby it became crystalline. The crystalline substance was recrystallized from acetonitrile, yielding 1-(2'-methoxy-3,4'-dihydroxy-phenyl) 2 (B-p-tolyloxyethyl-amino)-ethanol- (l) hydrochloride, M.P. 109-111 C., of the formula EXAMPLE 8 Preparation of 1- (2-methoxy-3,4'-dihydroxy-phenyl -2- (tert.butyl-an1ino)-ethanol-(1) by Method A A mixture consisting of 85 gm. of a-bromo-2-methoxy- 3,4-diphenylmethylenedioxy-acetophenone, 500 cc. of benzene and 32 gm. of tert.butylamine was refluxed for two hours. Thereafter, the benzene was distilled off in vacuo, the residue was taken up in ether, the insoluble tert.butylamine hydrobromide was separated by vacuum filtration, and the filtrate was evaporated in vacuo after having been w washed with water. The residue was dissolved in ethyl acetate, and the solution was acidified with ethereal hydrochloric acid, yielding ot-tert.butylamino-2-methoxy-3,4- diphenylmethylenedioxy acetophenone hydrochloride, M.P. 182183 C.

23 gm. of this amino-acetophenone compound were admixed with cc. of concentrated hydrochloric acid and cc. of methanol, and the mixture was boiled for two hours. Thereafter, the methanol was distilled off in vacuo, benzene was added to the residue, and the mixture of benzene and water was distilled off. The residue was stirred with hot methyl ethyl ketone and ethyl acetate, whereby it crystallized. The crystalline product was recrystallized from a mixture of ethanol and ether, yielding a-tert.butylamino 2 methoxy 3,4 dihydroxy-acetophenone hydrochloride, M.P. 189-190" C.

15 gm. of the amino-acetophenone salt thus obtained were dissolved in cc. of methanol, and the solution was hydrogenated at standard temperature and pressure in the presence of platinum as a catalyst until substantially the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was removed by vacuum filtration, the filtrate was evaporated, and the residue was recrystallized from acetone, yielding 1-(2-methoxy-3,4' dihydroxy-phenyl) 2 tert.butylamino-ethanol-(1) hydrochloride with /2 mol of water of crystallization, M.P. 9799 C.

EXAMPLE 9 Preparation of 1-(2-methoxy-3',4-dihydroxy-phenyl)-2- (B-o-tolyloxyethyl-amino)-ethanol-(1) by Method A a-(fl-o-tolyloxyethyl-arnino) 2 methoxy-3,4-dihydroxy-acetophenone hydrochloride, M.P. 197199 C., was synthesized in a manner analogous to that described for the synthesis of a-(,8-phenoxyethyl-amino) 2 methoxy 3,4 dihydroxy-acetophenone hydrochloride in Example 6. The amino-acetophenone salt thus obtained was dissolved in methanol and hydrogenated under standard temperature and pressure conditions in the presence of platinum as a catalyst, yielding 1-(2'-methoxy-3',4-dihydroxy-phenyl) 2 (fi-o-tolyloxyethyl-amino)-ethanol- (1) hydrochloride, M.P. l34135 C. (recrystallized from acetonitrile) EXAMPLE 10 Using a procedure analogous to that described in Example 9, 1-(2'-methoxy-3,4-dihydroxy-phenyl) 2 (fim-tolyloxyethyl-amino) ethanol (1) hydrochloride, M.P. 126-127 C. (recrystallized from acetonitrile), was prepared from z-(m-tolyloxyamino) 2 methoxy-3,4-dihydroxy acetophenone hydrochloride (M.P. 172 C.).

EXAMPLE 11 Using a procedure analogous to that described in Example 9, 1-(2'-methoxy-3,4'-dihydroxy-phenyl) 2 (,8- o-methoxyphenoxyethyl amino) ethanol (1) hydrochloride with 1 mol of acetonitrile of crystallization, M.P. 7880 C., of the formula was prepared from a-(B-o-methoxyphenoxyethyl-amino)- Z-methoxy 3,4 dihydroxy acetophenone hydrochloride (M.P. 152153 C.).

EXAMPLE 12 Using a procedure analogous to that described in Example 8, 1-(2-methoxy-3',4'-dihydroxy-phenyl) 2 [(OL, a-dimethyl-v-phenyl-n-propyl) amino] ethanol (1) hydrochloride, M.P. 176 C. (recrystallized from ethanol/ ether), of the formula was prepared from a-[a',ct'-dimethyl 'y' phenyl-n-propyl)-amino] 2 methoxy-3,4-diphenylmethylenedioxyacetophenone hydrochloride (M.P. 174-176 C.) through a-[(a',a-dimethyl 'y phenyl n propyl)-amino]-2- methoxy 3,4' dihydroxy acetophenone hydrochloride (M.P. 173-175 C.) as an intermediate.

EXAMPLE 13 Using a procedure analogous to that described in Example 8, 1-(2'-methoxy-3',4'-dihydroxy-phenyl) 2 [(oc,- a-dimethyl-y-p-tolyl-n-propyl) amino] ethanol (l) hydrochloride, M.P. 168-170 C. (recrystallized from ethanol/ether), was prepared from a-[(u',a'-dimethyl-'y'- p-tolyl-n-propyl)-amino] 2 methoxy-3,4-dihydroxyacetophenone hydrochloride (M.P. 166-167 C.).

EXAMPLE 14 Preparation of 1-(2-methyl-3',4'-dihydroxy-phenyl)-2- tert. butylamino-ethanol-(l) by method A A mixture consisting of 31 gm. of a-bromo-2-methyl- 3,4-di-benzyloxy-acetophenone (M.P. 123 C.), 155 cc. of benzene and 27 gm. of tert, butylarnine was stirred for two hours at 40-50 C. Thereafter, the reaction mixture was extracted with water, the aqueous extract solution was discarded, the benzene solution was evaporated, the residue was dissolved in acetonitrile, and the solution was acidified with etheral hydrochloric acid, yielding atert. butylamino-2-methyl-3,4-di-benzyloxy-acetophenone hydrochloride, M.P. 199-204 C.

The hydrochloride thus obtained was converted into the free base by treating it with aqueous ammonia, extracting the alkaline aqueous mixture with ether, and evaporating the ethereal solution. 16 gm. of the free base were dissolved in 100 cc. of ethanol, 0.73 gm. of sodium borohydride was added thereto, and the mixture was allowed to stand at room temperature for 12 hours. Thereafter, the reaction mixture was evaporated, the residue was decomposed with water, the aqueous mixture was extracted with ether, the ethereal extract solution was evaporated, and the residue was recrystallized from petroleum ether, yielding crystalline l (2 methyl 3',4'-di-benbyloxyphenyl) 2 tert. butylamino-ethanol-(l), M.P. 111- 112 C.

14 gm. of the base thus obtained were dissolved in 250 cc. of methanol, and the solution was hydrogenated in 250 cc. of methanol, and the solution was hydrogenated in the presence of palladized charcoal as a catalyst at standard temperature and pressure until substantially the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was removed by filtration, the methanol was distilled out of the filtrate, and the residue was recrystallized from acetonitrile, yielding the free base 1 (2' methyl 3,4-dihydroxy-phenyl)-2-tert. butylamino-ethanol-(l). The free base was dissolved in ethylacetate, the solution was acidified with the calculated amount of etheral benzoic acid, and the precipitate was recrystallized from isopropanol, yielding 1(2'-methyl3', 4'-dihydroxy-phenyl -2-tert. butylamino-ethanol-( 1 benzoate, M.P. 179-l81 C., of the formula HO 0 CH3 Preparation of 1-(2-methoxy-3',4'-dihydroxy-phenyl)-2- isopropylamino-butanol-(l) by method A 2 methoxy 3,4 diphenylmethylenedioxy-butyrophenone (M.P. 9394 C.) was synthesized in a manner analogous to that described for the synthesis of the corresponding acetophenone in Example 5. The butyrophenone was then brominated at 40 C. with bromine in benzene solution to form a-bromo-2-methoxy-3,4-diphenylmethylenedioxy-butyrophenone, which in turn was reacted in ethanolic solution at 5060 C. with 5 mol-equivalents of isopropylamine to form a-isopropylamino-Z-methoxy- 3,4-diphenylmethylenedioxy-butyrophenone, whose hydrochloride had a melting point of 93-94 C. after recrystallization from ethanol. The free amino-butyrophenone base thus obtained was refluxed with methanolic 15% hydrochloric acid, yielding a-isopropylamino-2-methoxy- 3,4-dihydroxybutyrophenone, which was converted into its hydrochloride, M.P. 188189 C. (decomposition).

6 gm. of the hydrochloride thus obtained were dissolved in cc. of methanol, and the solution was hydrogenated in the presence of platinum as a catalyst at standard temperature and pressure until substantially the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was removed by filtration, the methanol was distilled out of the filtrate, and the residue was recrystallized from a mixture of methanol and acetonitrile, yielding 1-(2'-methoxy-3,4'-dihydroxy-phenyl)-2- isopropylamino-butanol-(1) hydrochloride, M.P. 220- 222 C., of the formula HO OCH:

I I CzHs CHCHNHCH(OH 1101 EXAMPLE 16 Preparation of 1-(2'-methyl-3,4'-diacetoxy-phenyl)-2-isopropylamino-ethanol-(l) hydrochloride by method A H3O 00o (3H3 H3O o0o-Q-on-om-rm-omonm HCl EXAMPLE 17 Preparation of 1-(2'-methoxy-3',4'-diacetoxy-phenyl)-2- isopropylamino-ethanol-(1) hydrochloride by method A 12 gm. of a-isopropylamino-Z-methoxy-3,4-diacetoxyacetophenone hydrochloride, M.P. 166167 C., were dissolved in 100 cc. of methanol, and the solution was hydrogenated in the presence of platinum as a catalyst at 25 C. and atmospheric pressure until substantially the theoretical amount of hydrogen had been absorbed, which required about 30 minutes. Thereafter, the catalyst was removed from the reaction solution by filtration, the filtrate was evaporated, the oily residue was dissolved in hot isopropanol and the solution was allowed to cool. 1 (2' methoxy 3,4' diacetoxy phenyl)-Z-isopropylamino-ethanol-(l) hydrochloride crystallized out.

The compounds according to the present invention, that is, racemic mixtures of those embraced by Formula I, their pure stereoisomers, diasteromeric antipode pairs thereof, and non-toxic, pharmacologically acceptable acid addition salts of any of these, have useful pharmacodynamic properties. More particularly, they exhibit sympathomimetic activities in warm-blooded animals, such as mice and rats; especially, they exhibit bronchospasmolytic and antipuritic activities and dilate the peripheral 13 blood vessels in warm-blooded animals, such as those above referred to.

Particularly active in this respect are those compounds of the Formula I wherein R is methoxy, ethoxy, methyl, ethyl or propyl, R is hydrogen, methyl or ethyl, and R is alkyl of up to 8 carbon atoms, cycloalkyl of 5 to 6 carbon atoms or a substituent of the Formula Ia where Z is alkylene of 2 to 5 carbon atoms, and R and R are each hydrogen, hydroxyl, methyl or methoxy.

For pharmaceutical purposes the compounds of the present invention are administered to warm-blooded animals topically, perorally or parenterally as active ingredients in customary dosage unit compositions, that is compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as sprays, tablets, coated pills, granulates, suppositories, ointments, solutions or suspensions. One eifective dosage unit of a compound according to the present invention is from 0.1 to 10.0 mgm./ kg. body weight.

EXAMPLE 18 Tablets The tablets are compounded from the following in- Compounding procedure The t1-(2-ethoxy-3',4'-dihydroxy-phenyl)-1-hydroxy-2- isopropylamino-ethane hydrochloride is thoroughly admixed with the lactose, 25.0 parts of the corn starch and 4.0 parts of the SiO and the resulting mixture is uniformly moistened with a 5% ethanolic solution of the polyvinyl pyrrolidone. The moist mass is then passed through a 1 mm. mesh screen. The resulting granulate is dried for about 24 hours at 60 C. in a drying chamber with fresh air circulation. The dry granulate is again passed through a 1 mm. mesh screen. 70.0 parts of this granulate are admixed in a suitable mixer with a mixture consisting of the remainder of the SiO the remainder of the corn starch and all of the magnesium stearate, this mixture having previously been passed through a 1 mm. mesh screen. The resulting mixture is then pressed into tablets Weighing 80 mgm. each and containing 5.0 mgm. of the active ingredient. These tablets break up in the stomach within fifty seconds.

EXAMPLE 19 2% inhalation solution This solution is packaged in m1. bottles, the contents of each bottle being composed of the following ingredients:

1-(2'-ethoxy-3',4'-dihydroxy phenyl)-1-hydroxy-2- isopropylamino-ethane hydrochloride mgm 200.0 Sodium pyrosulfite mgm 1.0 Disodium salt of ethylene diamine tetraacetic acid mgm 5.0 1/10 N HCl q.s. ad. pH 3. Minerals-free water, q.s. ad. ml 110.0

These ingredients form a clear, colorless solution with a pH of 3, which may be dispensed with the aid of an aerosol inhalation vaporizer, having an aerosol output capacity of 12.5 liters per minute for bronchopasmolytic therapy.

1 1 EXAMPLE 20 Ampules with hypodermic solution Each ampule contains the following ingredients:

1-(2' methyl 3',4' dihydroxy phenyl)-2-('yphenyl n propyl-amino)-ethanol-(l) hydro- The suppositories are compounded from the following ingredients:

Parts 1-(2'-methoxy 3',4' dihydroxy-phenyl)-2- (B-phenoxyethyl-amino)-ethano1 (1) bydrochloride 5.0 Lactose, powdered 45.0 Suppository base (cocoa butter) 1650.0

Total 1700.0

Compounding procedure The 1-(2-methoxy-3,4'-dihydroxy phenyl) 2 (flphenoxyethyl-amino)-ethanol-(l) hydrochloride is thoroughly blended with the powdered lactose and the resulting mixture is homogeneously distributed in the molten cocoa butter. The composition is then poured into suppository molds holding 1.7 gm. of the composition. Each suppository contains 5 mgm. of the active ingredient.

EXAMPLE 22 Starch capsules for peroral administration The contents of the capsules are compounded from the following ingredients:

Parts 1-(2'-methyl-3',4'-dihydroxy-phenyl) 2 [2 (phydroxyphenyl)-isopropylamino]-ethanol (1) benzoate 5.0

Lactose 495.0 Corn starch 500.0

Total 1000.0

Compounding procedure The l-(2'-methyl-3',4-dihydroxy-phenyl) 2 [2-p-hydroxyphenyl)-isopropylamino]-ethanol (1) benzoate is gradually admixed with the lactose. When all of the lactose has been incorporated, the mixture is blended with the corn starch. The resulting mixture is filled into capsules holding 1 gm. of the mixture. Each capsule contains 5.0 mgm. of the active ingredient.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that our invention is not limited to those particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim: 1. A racemic mixture of a compound of the formula l a R4 OH R5 wherein R is hydrogen or acetyl, R is alkoxy of 1 to 5 carbon atoms, R is hydrogen or lower alkyl,

15 Z is alkylene of 2 to 6 carbon atoms, and R and R are each hydrogen or lower alkyl;

a pure stereoisomer thereof; a diastereomeric antipode pair thereof; or a non-toxic, pharmacologically acceptable acid addition salt of said racemic mixture, stereoisomer or diastereomeric antipode pair.

2. A racemic mixture of a compound of the formula R is hydrogen or alkyl of 1 to 3 carbon atoms, Z is alkylene of 2 to 6 carbon atoms, and R and R are each hydrogen or lower alkyl;

a pure stereoisomer thereof; a diastereomeric antipode pair thereof; or a non-toxic, pharmacologically acceptable acid addition salt of said racemic mixture, stereoisomer or diastereorneric antipode pair.

3. A compound according to claim 1, which is a racemic mixture of 1-(2-methoxy 3',4 dihydroxy-phenyl)-2- 16 [(a,a-dimethyl-' -p-stereoisomer thereof, or a non-toxic, pharmacologically acceptable acid addition salt of said racemic mixture or stereoisorner.

4. A compound according to claim 2, which is a racemic mixture of 1-(2'-methoxy 3',4 dihydroxy-phenyl)-2- a,u-dimethyl-'y-phenyl-n-propyl)-amino] -ethanol-( 1 a pure stereoisomer thereof, or a non-toxic, pharmacologically acceptable acid addition salt of said racemic mixture or stereoisomer.

References Cited UNITED STATES PATENTS 3,056,836 10/1962 Moed 260570.7

FOREIGN PATENTS 118,298 8/1918 Great Britain 260-479 789,033 1/1958 Great Britain 260479 JAMES A. PATTEN, Primary Examiner US. Cl. X.R.

260340.3, 340.5, 343.7, 348 A, 348 R, 348.6, 501.18, 570.5 C, 570.5 CA, 570.6, 590, 592; 424282, 311, 330

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 4 Dated April 18, 1972 Inventor(s) ANTON I IENTRUP, KURT SCHBOMM, KARL ZEILE and OTTO THOMA It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 1,- line 12, "(Fled" should read --(Fi1ed--,' 1

line "36, "stright" should read --straight--.

Col. 8, correct the formula to read:

Col. 11, correct the first formula to read:

HO OCH3 9 3 HO- QH-CHg-NH-O-CHg-CHg-C6H5 91 OH CH line 6, insert parenthesis after "["5 line &6, correct the spelling of "benzylox'y";

line 50, 51, erase "250 cc. of methanol, and the solution was hydrogenated in";

line 61, correct the spelling of "ethereal".

Cols. 15 16, Claim 3, in line i of Col. 16, insert before stereoisomer" the following: --tolyl-npropyl)-amino]-ethano1-(1), a pure--.

Signed and sealed this 6th day of February 1973.,

(SEAL) Attest:

EDWARD M.PLETCHER,JR. ROBERT OOTTSCHALK Attesting Officer Commissioner of Patents