3,461,164 United States Patent Office Patented Aug. 12, 1969 2 3,461,64 propyl-(1), 1-phenoxypropyl-(2), o-, m- or p-hydroxy HYDROXY-2AMNO-1-PHENYLALKANES benzyl, o-, m- or p-methoxybenzyl, o-, m- or p-ethoxy AND THE SALTS THEREOF benzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyi, 3,4,5- Karl Schulte and Wolfgang Fruhstorfer, Darmstadt, Hein trihydroxybenzyl, 3,4,5-trimethoxybenzyl or 3.4-methyl rich Muller, Pfungstadt, Hans Friebel, Darmstadt-Eber endioxybenzyl. stadt, Hans Joachim Enenkel, Darmstadt, and Josef Particularly preferred compounds are: Gilissen, Escholbrucken, Germany, assignors to E. Merck Aktiengesellschaft, Darmstadt, Germany N-1-(3'-tert, butyl-4'-hydroxy-5'-methyl-phenyl)- No Drawing. Filed Apr. 27, 1964, Ser. No. 364,355 1-hydroxy-butyl-2-N-isopropylamine Claims priority, application Germany, Apr. 25, 1963, N-(1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- M 56,597; May 25, 1963, M 56,960 O 1-hydroxy-propyl-2)-N-methylamine Int, C. CO7 91/18 N-1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- U.S. C. 260-570.6 22 Claims 1-hydroxy-propyl-2-N-ethylamine N-(1-(3'-tert.butyl-4-hydroxy-5'-methyl-phenyl)- This invention relates to substituted 1-hydroxy-2-amino 1-hydroxy-propyl-2-N-isopropylamine 1-phenyl-alkanes. 5 N-1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- It is a principal object of this invention to provide novel 1-hydroxy-propyl-2-N-(4-phenyl-butyl-2)-amine and unobvious chemical compounds. N-E1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- Another object is to provide processes for the produc 1-hydroxy-propyl-2-N-(1-phenoxy-propyl-2)-amine tion of these compounds. N-2-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- A further object is to provide novel pharmaceutical 2-hydroxy-ethyl-N-methylamine compositions, and still another object is to provide novel N-(2-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- processes for effecting therapeutic activities in mammals. 2-hydroxy-ethyl-N-isopropylamine Upon further study of the specification and claims other N-(2-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- objects and advantages of the present invention will be 2-hydroxy-ethyl-N-(4-phenyl-butyl-2)-amine come apparent. 25 N-2-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- To attain the objects of this invention, there are pro 2-hydroxy-ethyl)-N-(1-phenoxy-propyl-2)-amine vided the following compounds and acid-addition salts N-(1-(4'-tert, butyl-3'-hydroxy-phenyl)-1-hydroxy thereof, said compounds having the formula I propyl-2-N-methylamine OH N-1-(4'-tert.butyl-3'-hydroxy-phenyl)-1-hydroxy Rs 30 propyl-2-N-isopropylamine -CHOH-CHR-NHR N-(2-(4'-tert.butyl-3'-hydroxy-2,6'-dimethyl R. mile phenyl)-2-hydroxy-ethyl-N-methylamine R N-1-(4'-tert.butyl-3'-hydroxy-2,6'-dimethyl phenyl)-1-hydroxy-propyl-2)-N-methylamine wherein N-(2-(4'-tert.butyl-3'-hydroxy-2,6'-dimethyl R represents hydrogen or alkyl of 1-4 carbon atoms, phenyl)-2-hydroxy-ethyl)-N-isopropylamine R2 represents any of hydrogen, alkyl of 1-6 carbon atoms, N-(1-(4'-tert.butyl-3'-hydroxy-2,6'-dimethyl hydroxyalkyl of 2-3 carbon atoms, phenoxyalkyl of phenyl)-1-hydroxy-propyl-2)-N-isopropylamine 40 2-(3'-tert, butyl-4'-hydroxy-5'-methyl-phenyl)- 7-1 carbon atoms, or a radical of the formula 2-hydroxy-ethylamine Rg 1-(3'-tert, butyl-4'-hydroxy-5'-methyl-phenyl)- XY-R- 1-hydroxy-2-aminopropane. With respect to the tertiary alkyl group Rs it should be noted that generally the tertiary carbon atom is the t / R11 carbon atom which is joined to the benzene nucleus. According to this invention the compounds of Formula wherein I can be produced by any one of the following processes: Ra represents alkyl of 1 to 5 carbon atoms, (a) A reducing agent is reacted with a compound of Rg, R10 and R1 are each any of hydrogen, hydroxy, Formula II methoxy, ethoxy, or two of R9, R10 and R11 forming methylene dioxy, R5 represents a tertiary alkyl of 4-6 carbon atoms; and OH --|-- R6 and R are each any of hydrogen, methyl or ethyl. 5 5 The compounds of Formula I which are especially therapeutically efficacious are those in which the phenyl R6X -- --Y group is substituted by a hydroxyl group and at least 2 R alkyl groups of which one is tertiary. Preferably, for that purpose are ethanolamine derivations which have one of 60 wherein the following groups-3'-tert.butyl-4'-hydroxy-5'-methyl phenyl,4'-tert.butyl-3-hydroxy-phenyl and 4'-tert.butyl-3'- R5, R6, and R have the previously indicated meanings, hydroxy-2,6'-dimethyl-phenyl. and wherein The group R1 is preferably hydrogen, methyl, ethyl, X is =O or H, OH and n-propyl, isopropyl, n-butyl, sec. butyl, isobutyl or tert. Y is -CHR1-NHR2 or a group that can be converted butyl. The group R2 in the end-product, besides hydrogen, into the latter by reaction, and where is preferably any of methyl, ethyl, n-propyl, isopropyl, R1 and R2 have the meanings already stated and also n-butyl, sec.butyl, isobutyl, tert.butyl, n-amyl, isoamyl, where instead of the hydrogen atoms there can be hy neopentyl, n-hexyl, isohexyl, benzyl, 1-phenylethyl, 2 drogenolytically removable groups; but where when X phenylethyl, 3-phenylpropyl-(1), 4-phenylbutyl-(1), 4 70 is H, OH, Y can be -CHRNHR- simultaneously phenylbutyl-(2), 2-hydroxyethyl, 3-hydroxypropyl, phen only when at least one hydrogenolytically removable oxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 1-phenoxy group is present. 3,461, 164 3 . 4 Groups which can be converted by reduction into the o-benzylamino-3-benzyloxy-4-tert-butyl-2,6- group CHR-NHR2 are for example the following: dimethyl-acetophenone, -CR=NOH (which may be esterified, preferably with o-(N-benzyl-N-methylamino)-3-tert, butyl-4- an alkane-carboxylic acid with up to 4 carbon atoms, e.g. hydroxy-5-methyl-acetophenone, acetic acid), -CHR1-N3, CN, -CHR1-NO2, -propiophenone, -CHR1-NH-NH2 -butyrophenone, (where one or both of the H-atoms of the terminal N -isobutyrophenone, atom can be optionally substituted by lower alkyl or aryl -Valerophenone and -isovalerophenone, groups, preferably by methyl, ethyl or phenyl), ox-(N-benzyl-N-ethylamino)-3-tert, butyl-4-hydroxy-5- -CRFN-NH2 methyl-acetophenone, (also optionally substituted by a lower alkyl or aryl group, O propiophenone, Preferably by a methyl, ethyl or phenyl group), -butyrophenone, -CO-NH2, -CR-N-R, -CHR1-NH-R'-OH, -isobutyrophenone, -CHR-NH-acyl. -valerophenone and -isovalerophenone, In the above groups R and R2 have the meanings pre 5 o-(N-benzyl-N-methylamino)-4-tert.butyl-3-hydroxy viously given and R is an alkylidene, aralkylidene, hy acetophenone, droxy-alkylidene or phenoxy-alkylidene group. -propiophenone and -butyrophenone, R" can thus e.g. be methylene, ethylidene, propylidene, o-(N-benzyl-N-isopropylamino)-4-tert.butyl-3-hydroxy isopropylidene, butylidene-1, butylidene-2, 2-phenylethyli acetophenone, dene, 4-phenyl-butylidene-2, 1-phenoxypropylidene-2. 20 -propiophenone and -butyrophenone, Suitable hydrogenolytically removable groups are e.g. ce-(N-benzyl-N-methylamino)-4-tert.butyl-3-benzyloxy N-benzal-, O- or N-benzyl-, substituted O- or N-benzyl and acetophenone, carbobenzoxy-groups, also nitroso-, amino- or arylsulfonyl -propiophenone and -butyrophenone, groups attached to amino groups, and/or halogen atoms 0-methylamino-3-tert.butyl-4-hydroxy-5-methyl preferably aromatic nuclei. 25 acetophenone, Suitable starting substances for process (a) are pref -propiophenone, erably the following- - -butyrophenone, -isobutyrophenone, o-benzylamino-3-tert.butyl-4-hydroxy-5-methyl -valerophenone and -isovalerophenone, acetophenone, 30 a-ethylamino-3-tert-butyl-4-hydroxy-5-methyl-aceto -propiophenone, phenone, -butyrophenone, -propiophenone, -isobutyrophenone, -butyrophenone, -valerophenone and -isovalerophenone, -isobutyrophenone, ox-benzylamino-4-tert, butyl-3-hydroxy 35 -Valerophenone and -isovalerophenone, acetophenone, o-isopropylamino-3-tert-butyl-4-hydroxy-5-methyl-aceto c-benzylamino-4-tert, butyl-3-benzyloxy-acetophenone, phenone, a-azido-3-tert.butyl-4-hydroxy-5-methyl-acetophenone, -propiophenone, -propiophenone, -butyrophenone, -butyrophenone, 40 -isobutyrophenone, -isobutyrophenone, -Valerophenone and -isovalerophenone, -valerophenone and -isovalerophenone, o-propylamino-3-tert-butyl-4-hydroxy-5-methyl-aceto ox-azido-4-tert, butyl-3-hydroxy-acetophenone and phenone, -propiophenone, -propiophenone, cy-azido-4-tert.butyl-3-benzyloxy-acetophenone and -butyrophenone, -propiophenone, -isobutyrophenone, c-isonitroso-3-tert.butyl-4-hydroxy-5-methyl -valerophenone and -isovalerophenone, acetopenone, O-isobutylamino-3-tert, butyl-4-hydroxy-5-methyl-aceto -propiophenone and butyrophenone, phenone, 2-benzylamino-1-(3'-tert.butyl-4'-hydroxy-5'-methyl propiophenone, phenyl)-butanol-(1), -butyrophenone, 4-tert, butyl-3-hydroxy-benzaldehyde cyanhydrin, -isobutyrophenone, % ox-benzylamino-4-tert.butyl-3-hydroxy-2,6-dimethyl -valerophenone and isovalerophenone, acetophenone and C-Sec. butylamino-3-tert-butyl-4-hydroxy-5-methyl-aceto -propiophenone, 55 phenone, cx-benzylamino-4-tertamyl-3-hydroxy-2,6- -propiophenone, dimethyl-acetophenone and -butyrophenone, propiophenone, -isobutyrophenone, ox-benzylamino-4-(3'-methylpentyl-3)-3-hydroxy -Valerophenone and -isovalerophenone, 2,6-dimethylacetophenone and 60 C-tert-butylamino-3-tert.butyl-4-hydroxy-5-methyl-aceto -propiophenone, phenone, cy-benzylamino-4-tert.butyl-3-hydroxy-2,6- -propiophenone, dimethylbutyrophenone, -butyrophenone, D-amino-4-tert.butyl-3-hydroxy-2,6-dimethyl -isobutyrophenone, propiophenone, 65 -Valerophenone and -isovalerophenone, o-amino-4-tert.amyl-3-hydroxy-2,6- 0-butylamino-3-tert.butyl-4-hydroxy-5-methyl-aceto dimethylpropiophenone, phenone, 2-benzylamino-1-(4'-tert.butyl-3'-hydroxy-2,6- -propiophenone, dimethyl-phenyl)-butanol-(1). -butyrophenone, o-azido-4-tert.butyl-3-hydroxy-2,6- 70 -isobutyrophenone, dimethylacetophenone, -Valerophenone and -isovalerophenone, -propiophenone and -butyrophenone, O-(4-phenylbutyl-2-amino)-3-tert, butyl-4-hydroxy-5- c-azido-4-tertamyl-3-hydroxy-2,6-dimethyl methyl-acetophenone, propiophenone, 75 -propiophenone, 3,461,164 5 6 -butyrophenone, product to split off the hydrogenolytically removable -isobutyrophenone, grOllp.