Patent GB-1193687-A (GB)
Title: Derivatives of Bis (p-Hydroxyaryl) Alkanoic Acids
Inventor: FRIED JOSEF
IPC: C07C37/11
Filed: 1967-04-25
Abstract: 1,193,687. Bis(aminoalkoxyphenyl)- compounds. E. R. SQUIBB & SONS Inc. 25 April, 1967, No. 648/70. Divided out of 1,193,686. Heading C2C. Novel compounds of Formula I wherein P represent one of the radicals of the formulµ wherein R represents hydrogen, hydroxy, nitro, lower alkyl, lower alkoxy, lower alkanoyl, halo or dialkylamino-lower alkylene, R<SP>2</SP> represents hydrogen or hydroxy, R<SP>3</SP> represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (R) m -phenyl, (R) m -naphthyl, (R) m -phenyllower alkyl, (R) m -naphthyl-lower alkyl, C 3 -C 7  cycloalkyl, (C 3-7  cycloalkyl)-lower alkyl, thienyl, pyridyl, thienyl-lower alkyl or pyridyllower alkyl or R<SP>2</SP> and R<SP>3</SP> together represent oxo, R<SP>4</SP> represents lower alkyl, lower alkenyl, lower alkynyl, (R) m -phenyl, (R) m -naphthyl, (R) m -phenyl - lower alkyl, (R) m -naphthyllower alkyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)- lower alkyl, thienyl, pyridyl, thienyl-lower alkyl, or pyridyl-lower alkyl, R<SP>5</SP> represents hydrogen, lower alkyl, hydroxy-lower alkyl, phenyl-lower alkyl or lower-alkyl-phenyl-lower alkyl or the two symbols R<SP>5</SP> represent together tetra-, penta- or hexa-methylene, oxatetra- or oxapenta-methylene, azatetra-, azapenta- or azahexa-methylene or thiatetra- or thiapentamethylene which may also be substituted by one or two groups represented by R, hydroxy-lower alkyl or lower alkanoyloxy-lower alkyl, m is 0 to 3 and n is 1 to 5 (lower means 1 to 8 carbon atoms) and acid addition salts thereof; (a) the preparation of a compound of the above general formula where n, R and R<SP>2</SP> have the above significance, R<SP>3</SP> and R<SP>4</SP> are the same and represent lower alkyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, aralkyl, cycloalkyllower alkyl, thienyl, pyridyl, thienyl-lower alkyl or pyridyl-lower alkyl and R<SP>5</SP> represents hydrogen, lower alkyl, hydroxy-lower alkyl, phenyllower alkyl, lower alkyl-phenyl-lower alkyl or the two R<SP>6</SP> radicals together with the nitrogen atom form a 5 to 7 membered monocyclic ring optionally containing an oxygen, sulphur or additional nitrogen atom with a limit of two hetero atoms in the ring and optionally substituted by one or two R groups or hydroxy-lower alkyl or lower alkanoyloxy-lower alkyl, by (a) reacting a compound of the R<SP>2</SP>, formula wherein R<SP>7</SP> is hydrogen or -lower alkylene- N(R<SP>5</SP>) 2 , R 5  having the significance immediately above, with an excess of a Grignard reagent and then with water to form a compound of the formula and, if desired, reacting this compound with a fatty acid anhydride to eliminate one mole of water, hydrolysing the resulting compound with a base to form a compound of the formula and, if desired, when R<SP>7</SP> is hydrogen, reacting the compound of the last formula with an alkali metal alkoxide and a halide of the formula Hal-lower alkylene-N(R<SP>5</SP>) 2  and, if desired, hydrogenating to form a compound of the formula wherein R<SP>1</SP> is -lower alkylene-N(R<SP>5</SP>) 2 ; and (b) the preparation of a compound I above wherein n, R and R<SP>2</SP> have the above significance, R<SP>3</SP> represents hydrogen or R<SP>2</SP> and R<SP>3</SP> together represent oxo, R<SP>4</SP> and R<SP>5</SP> have the significance indicated for process (a) by reacting a compound of formula wherein R<SP>6</SP> represent a dialkylaminoalkylene radical or a protecting group, with an R<SP>4</SP>- cadmium reagent to form a compound of formula if desired, removing the said protecting group or reducing the compound of the previous general formula to form the corresponding compound in which the oxo group is replaced by H(OH) and, if desired, reacting the latter compound with a fatty acid anhydride to eliminate one mole of water and, if R<SP>7</SP> is hydrogen in the said latter compound, hydrolysing with a base to form a compound of the formula and when R<SP>7</SP> in the latter compound is hydrogen, reacting this compound with an alkali metal alkoxide with Hal-lower alkylene-N(R<SP>5</SP>) 2 , and if desired, hydrogenating as in process (a). Pharmaceutical compositions for oral or parenteral administration contain a compound of formula I above as active ingredient. The active compounds are hypocholesteremic agents. Methyl 4,4 - bis[3,5 - bis(dimethylaminomethyl) - 4 - hydroxyphenyl]valerate is prepared by the reaction of methylamine, formaldehyde and methyl 4,4 - bis - (4 - hydroxyphenyl)pentanoate.