Patent GB-1047860-A (GB)
Title: 4-(piperazinoalkyl)-pyrazoles and their preparation
IPC: A23K1/16
Filed: 1965-10-18
Abstract: Novel 4 - (piperazinoalkyl) - pyrazoles of general formula <FORM:1047860/C2/1> wherein R1 is hydrogen, alkyl with 1-4 carbon atoms, an aralkyl group with 7-10 carbon atoms, or Ar, R2 and R3 are hydrogen or alkyl of 1-4 carbon atoms, R4 is an alkyl group of 1-6 carbon atoms, a cycloalkyl or cycloalkenyl group of 5-7 carbon atoms, an aralkyl group with 7-10 carbon atoms, Ar or a 5 or 6-membered heterocyclic radical with 3-10 carbon atoms which may or may not be condensed with a benzene ring and/or may or may not be substituted with from 1-3 lower alkyl or alkoxy groups, Ar being an aryl group with a total of 6-12 carbon atoms optionally substituted with from 1-3 lower alkyl groups, lower alkoxy groups, phenyl groups, hydroxy, lower alkyl mercapto, trifluoromethyl, halogen or a methylene dioxy group (the lower alkyl and lower alkoxy groups contain 1 to 4 carbon atoms), and Y is a straight chain or branched hydrocarbon radical of 1-10 carbon atoms, and acid addition salts thereof, are prepared by condensing a compound of formula <FORM:1047860/C2/2> where X is Cl, Br, I, OH, acyloxy, alkysulphonyloxy, or alkoxy each with 1-6 carbon atoms, or arylsulphonyloxy with 6-10 carbon atoms with a compound of formula <FORM:1047860/C2/3> (this process may be modified by reacting the latter reactant with an aldehyde of the formula <FORM:1047860/C2/4> wherein m is 0 to 9 under catalytic hydrogenation conditions or with a suitable pyrazolyl-4-carboxylic acid and reducing the resulting cyclic amide) or by condensing together compounds of formulae <FORM:1047860/C2/5> wherein X has the above meaning or the two X groups together denote an oxygen atom, or by condensing a compound of formula <FORM:1047860/C2/6> with a compound of formula H2N-R4 or condensing a compound of formula <FORM:1047860/C2/7> with a compound of formula X-CH2-CH2-X X being as defined above, or by condensing a compound of formula <FORM:1047860/C2/8> with a compound of formula H2N-NHR1, or by treating a compound of the first general formula above, which additionally contains one or more groups which are hydrogen-substitutable, such as halogen, keto, hydroxy, or benzyl groups and/or C-C multiple bonds, with a chemical reducing agent or catalytically activated hydrogen.  R1, R2, R3 and R4 in the above formulae Ar, and Y are as hereinbefore defined.  Acid addition salts of the novel compounds are referred to.  3,5 - Dimethyl - 4 - (3 - chloropropyl) pyrazole is prepared by reaction of the sodium compound of acetyl acetone with b -chloropropionic acid-ethyl ester followed by reaction with hydrazine lithium aluminium hydride and thionly chloride.  1 - Benzyl - 4 - (4 - chlorobutyl) pyrazole is prepared by reaction of 1-benzyl-4-(3-chloropropyl) pyrazole with potassium cyanide to give 1 - benzyl - 4 - (3 - cyanopropyl) pyrazole reaction with ethanol/sulphuric acid to give 4 - (1 - benzyl pyrazole - 4) butyric acid ethyl ester, reduction with L1AlH4 to 1-benzyl-4-(4-hydroxybutyl) pyrazole and reaction with thionyl chloride.  4 - (5 - chloropentyl) - pyrazole, 1 - benzyl - 4-(7 - chloroheptyl) pyrazole and 1 - benzyl - 4 - (9- chlorononyl) pyrazole are prepared from the required 4-(chloroalkyl) pyrazole having two fewer carbon atoms, by reaction with malonic acid diethyl ester, followed by saponification, decarboxylation and re-esterification, reduction of the resulting ethyl esters of 5-(1-benzyl-pyrazolyl-4)-pentanoic acid, 7-(1-benzyl-pyrazolyl-4)-heptanoic acid and 9-(1-benzyl-pyrazolyl-4)-nonanoic acid to the corresponding 5-hydroxy-pentyl. 7-hydroxy-heptyl and 9-hydroxy-nonyl alcohols with L1AlH4 (if desired, the benzyl group is split off by reaction with sodium in liquid ammonia), and treatment with thionyl chloride to form the desired chloro substituted compounds.  3 - [3 - (N1 - phenylpiperacino) propyl] pentane dione-(2,4) is prepared by reaction of 1-phenyl-4-(3-chloropropyl) piperacine with the sodium compound of acetyl acetone.  (1 - benzyl - pyrazolyl - 4) - [3 - (N1 - phenyl-piperacino) propyl] carbinol is prepared by reaction of the Grignard compound of N - phenyl - N1 - (3 - chloropropyl) piperazine with 1-benzyl-4-formyl-pyrazole.  1 - benzyl - 4 - (2 - anilino - ethyl - imino-methyl) pyrazole and 1-benzyl-4-(2-anilino-ethyl-amino-methyl) pyrazole are prepared by reaction of 1 - benzyl - 4 - formyl pyrazole with N-phenylethylene diamine and subsequent hydrogenation in the presence of platinum oxide.  1 - Methyl - 4 - (3 - aminopropyl) pyrazole is prepared by reaction of 1-methyl-4-(3-chloropropyl) pyrazole with potassium phthalimide and subsequent hydrolysis.  Pharmaceutical compositions having hypotensive, analgesic, anti-phlogistic and/or local anaesthetic activity and which may be administered parenterally or enterally in the form of solutions, suspensions, emulsions, or implants, as tablets, or dragees and contain a compound of the first general formula above as the active ingredient.