1358609 Substituted bisphenoxy or phenylthio- -carboxylic acids MERCK PATENT GmbH 16 Nov 1972 [18 Dec 1971] 53005/72 Heading C2C Novel compounds of Formula I in which ZSP1/SP and ZSP2/SP are each O or S, RSP1/SP is H or alkyl with 1-10 C atoms, RSP2/SP is H or COORSP7/SP, RSP3/SP and RSP4/SP are RSP8/SP, RSP8/SP-CH 2 -, p-RSP8/SP-C 6 H 4 -, 3-hydroxypyrrolidino, 3-hydroxy-piperidino, morpholino, isoindolino, 1,2,3,4-tetra-hydroquinolino, 1-RSP9/SP-1,2,3,4-tetrahydro-4-quinolyl, 1-RSP10/SP-4-piperidyl or 1-pyrryl, RSP5/SP and RSP6/SP are each H, alkyl with 1-4 C atoms or Hal, RSP7/SP, RSP9/SP and RSP10/SP are each H or alkyl with 1-10 C atoms, RSP8/SP is pyrrolidino, piperidino or homopiperidino, and Hal is F, Cl, Br or I, and their physiologically acceptable salts with acids and bases (e.g. cylohexylamine) are prepared by one of the following methods: (a) a compound of Formula II or a metal salt thereof is reacted with a compound of Formula III wherein X is OH, esterified OH, or Cl, Br or I; (b) cyclizing a compound of Formula IV wherein Y is tetramethylene, pentamethylene, hexamethylene, 2-hydroxy-tetramethylene, 2- hydroxy-pentamethylene, 3-oxapentamethylene or o-xylylene, XSP1/SP is Cl, Br, I, NH 2 or a hydroxy group which may optionally be esterified or etherified and XSP2/SP is a bond, methylene or pphenylene; (c) treating a compound of Formula V wherein W is an optionally functionally modified carboxylic group with solvolysing, thermolysing, or ester forming agent to convert W into -COORSP1/SP; (d) reacting a compound of Formula VI wherein XSP3/SP is H, Cl, Br, I, NH 2 or SO 3 M where M is one equivalent of a metal atom, with the compound RSP3/SP-XSP4/SP in which XSP4/SP is H, M or X provided that XSP3/SP and XSP4/SP are different and one of them is H or, for XSP4/SP M. In all cases a salt may be then formed and if required any radical RSP2/SP may be converted to another value of RSP2/SP and racemates may be resolved. 4-Piperidino-thiophenol is prepared by the reduction of 4-piperidinobenzene sulphochloride with Sn/HCl. Various phenols of Formula II above, Z 1 = OH, are prepared in the examples by splitting off the methyl group from the corresponding anisoles prepared in situ (a) by reaction of the corresponding amine with -#-dihaloalkane or an -#-dialkylether, both optionally hydroxy substituted or an o-xylylene dibromide or a 2,5- dialkoxytetrahydrofuran, or (b) by reaction of a methoxy-benzyl chloride with pyrrolidine, piperidine or homopiperidine, or (c) dehydrohalogenation of a haloanisole. Other methods for preparation of the phenols of Formula II are as follows: (a) 3-chloro-4-(3-hydroxy-piperidino)- phenol (obtainable by reaction of 3-nitro-4- bromo-anisole with 3-hydroxy-piperidine to give 3-nitro-4-(3-hydroxy-piperidino)-anisole, hydrogenation on 5% Pd/C to give 3-amino-4-(3- hydroxy-piperidino)-anisole, diazotization and Sandmeyer reaction to give 3-chloro-4-(3- hydroxy-piperidino)-anisole; or (b) 4-(1,2,3,4- tetrahydro-quinolino)-phenol obtainable by reaction of N-p-methoxyphenylanthranilic acid with acetic anhydride and subsequent saponification to give 1-p-methoxyphenyl-4-hydroxy-2- quinolone, reaction with POCl 3 to give 1-pmethoxyphenyl-4-chloro-2-quinolone, hydrogenation to give 1-p-methoxyphenyl-3,4-dihydro- 2-quinolone, reduction with LiAlH 4 to give 1-pmethoxy - phenyl - 1,2,3,4 - tetrahydroquinoline; (c) 4-(1,2,3,4-tetrahydro-4-quinolyl)-phenol and hydrochloride obtainable by cyclization of pmethoxy-cinnamic acid anilide with polyphosphoric acid to give 4-(p-methoxyphenyl)-1,2,3,4- tetrahydro-2-quinolone, reduction with LiAlH 4 to give 4-(p-methoxyphenyl)-1,2,3,4-tetrahydroquinoline and splitting of the ether with HBr; (d) 4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)- phenol obtainable by methylation of 4-(pmethoxyphenyl) - 1,2,3,4 - tetrahydro - quinoline with formaldehyde/H 2 , 5% Pd/C, to give 1- methyl-4-p-methoxyphenyl-1,2,3,4-tetrahydroquinoline and splitting of the ether with HBr; and (e) 4-(1-methyl-4-piperidyl)-phenol (obtainable by treatment of 1-methyl-4-piperidinol with phenol/AlCl 3 in benzene or of 1-methyl-4- piperidone with p-anisylmagnesium bromide with subsequent dehydration, hydrogenation and splitting the ether with HBr. Pharmaceutical compositions in conventional forms for oral, rectal, topical or parenteral administration having activity in lowering of cholesterol and triglyceride levels comprise an above novel compound or salt and a carrier or excipient.
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