Patent GB-1474561-A (GB)
Title: Derivatives of 3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acids methods for their preparation and compositions containing them
IPC: C07C235/34
Filed: 1974-08-09
Abstract: 1474561 Derivatives of 3,7-dimethyl-nona- 2,4,6,8-tetraen-1-oic acids F HOFFMANN LA ROCHE & CO AG 9 Aug 1974 [10 Aug 1973] 35178/74 Headings C2C and C2P Novel compounds I in which one of the pairs R 1  and R 5 , R 5  and R 4 , R 4  and R 3 , or R 3  and R 2  represents -(CH 2 ) 3 -, -(CH 2 ) 4 , -CH = CH-CH = CH-, or -O-CH 2 -CH = CH- (these groups being optionally substituted by one or more C 1-6  alkyl groups) and the other symbols R 1  to R 5  are hydrogen, halogen C 1-6  alkyl, C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenoxy, NO 2 , NH 2 , mono- or di-C 1-6  alkylamino or a N-attached heterocyclic group (at least one of the symbols being other than hydrogen) and R 6  is formyl, hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carboxyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, carbamoyl, mono- or di-C 1-6  alkyl carbamoyl or N-bound-heterocyclyl-carbonyl and the salts of amines and acids are prepared by condensing a compound II with a compound III in which one of the symbols A and B is -CHO and the other -CH 3 -PY 3 #Z# (where Y is aryl and Z is an anion of an acid) and R 7  is alkoxy methyl, alkanoyloxymethyl, carboxyl, alkoxycarbonyl, alkenoxycarbonyl or alkynoxycarbonyl when B is -CHO or R 7  is formyl, carboxyl, alkoxycarbonyl, alkenoxycarbonyl or alkynoxycarbonyl when B is -CH 2 -PY 3 #Z# and m = 1 and n = 0 or m = 0 and n=1; thereafter, if desired, a carboxylic acid obtained is esterified or amidated, a carboxylic acid ester obtained is hydrolysed or amidated, a carboxylic acid or ester thereof obtained is reduced to the corresponding alcohol which may be further etherified or esterified, or an alcohol or alcohol ester obtained is oxidized to the corresponding carboxylic acid or an alcohol ester obtained is saponified to give the corresponding alcohol. Compounds I disclosed are 9-(4,6-dimethylindan - 5 - yl) - 3,7 - dimethyl - nona - 2,4,6,8- tetraen - 1 - oic acid; 9 - (8 - methoxy - 6,7 - dimethyl - tetralin - 5 - yl) - 3,7 - dimethyl - nona- 2,4,6,8 - tetraen - 1 - oic acid; 9 - (4 - methoxy- 2,3 - dimethyl - naphthalen - 5 - yl) - 3,7 - dimethyl - nona - 2,4,6,8 - tetraen - 1 - oic acid; 9- (2,2,5,7,8 - pentamethyl - chroman - 6 - yl) - 3,7- dimethyl - nona - 2,4,6,8 - tetraen - 1 - oic acid; 9 - (5,7,8 - trimethyl - 2H - chroman - 6 - yl) - 3,7- dimethyl - nona - 2,4,6,8 - tetraen - 1 - oic acid and their ethyl and n-butyl esters. Ethyl or butyl 7-formyl-3-methyl-octa-2,4,6- trien-1-oate is prepared by reacting methylglyoxal dimethylacetal with acetylene in strong base to form 4,4-dimethoxy-3-methyl-but-1-yn-3- ol which is reduced to the corresponding olefine which on reaction with phosgene yields 2- formyl - 4 - chloro - but - 2 - ene which is reacted with triphenylphosphine to give (2-formyl-but- 2 - en - 4 - yl) - triphenylphosphonium chloride which is reacted with ethyl or butyl 3-formylcrotonate. Compounds I are active against neoplasia and premalignant lesions and form with a carrier a pharmaceutical composition which may be administered orally, parenterally or rectally. The composition may contain an antioxidant (tocopherol, N-methyl-γ-tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene).