Patent GB-1268607-A (GB)
Title: NEW PYRAZOLO[3,4-e][1,4]DIAZEPIN-7(1H)-ONE COMPOUNDS AND METHODS FOR THEIR PRODUCTION
IPC: C07D231/20
Filed: 1970-05-13
Abstract: 1,268,607. Pyrazolodiazepines. PARKE DAVIS & CO. 13 May, 1970 [14 May, 1969], No. 23086/70. Heading C2C. Novel compounds of Formula I (in which R 1  is CH 3  or C 2 H 5 , R 2  is Cl or C 1-3  alkyl, R 3  is H or CH 3  and Ar is phenyl, ofluorophenyl or o-chlorophenyl) and pharmaceutically acceptable salts thereof, are prepared by (a) reacting a compound of Formula II with hydrazine, or (b) reacting a compound of Formula III (in which Z is Br, Cl, I or alkyl- or aryl-sulphonyloxy) or a salt thereof, with ammonia, or (c) cyclizing a compound (which may be prepared in situ) of Formula IV or (d) (for Compounds I in which R 3  is H and R 2  is C 1-3  alkyl) reacting a compound of Formula V (in which R 4  is C 1-3  alkyl) with a compound of formula X-CH 2 -CO-X 1  (in which X is Cl, Br or I and X 1  is Br or Cl) optionally followed in each case by methylation of Compounds I in which R 3  is H, and/or by salt formation. Compounds of Formula II are prepared by reacting a compound of Formula VI with phthalimidoacetyl chloride in an unreactive solvent. Compounds of Formula III are prepared by reacting a compound of Formula VI with a compound of formula X-CH 2 -CO-X 1  or with a 2-(alkyl- or aryl-sulphonyloxy)acetyl chloride. Compounds of Formula IV are prepared by reducing a compound of Formula VII which are themselves prepared by reacting a compound of Formula III (in which Z is Cl, Br or I) with sodium azide in an unreactive solvent medium, and optionally methylating the product. Compounds of Formula V are prepared by reacting a compound of, Formula VIII with a compound of Formula Ar-M (in which M is Li or MgBr) and hydrolyzing the reaction product under mild neutral conditions. Compounds of Formula III.-Those compounds in which R 2  is C 1-3  alkyl are prepared by reacting a compound of formula R 1 -NHNH 2  with a compound of formula to produce a 1-R 1 -3-R 4 -5-pyrazolone, reacting this with POCl 3  to produce a 1-R 1 -3-R 4 -5- chloropyrazole, reacting this with an aroyl chloride Ar-COCl to produce a 1-R 1 -3-R 4 -4- aroylpyrazole and reacting this with an amine R 3 NH 2 . Those compounds in which R 2  is Cl are prepared by reacting a 1-R 1 -3-hydroxy-5- aminopyrazole with an acid Ar-COOH in polyphosphoric acid to produce a 1-R 1 -3- hydroxy-4-aroyl-5-arylamidopyrazole, reacting this with POCl 3  to produce a 1-R 1 -3-chloro-4- aroyl-5-arylamido pyrazole, and hydrolysing this, optionally after methylation, with HBr in acetic acid. 5 - Amino - 4 - benzoyl - 1,3 - dimethylpyrazole and 5-amino-4-benzoyl-1-methyl-3-ethylpyrazole are also prepared by reacting 5-amino- 4-cyano-1,3-dimethylpyrazole or 5-amino-4-cyano-3-ethyl-1-methylpyrazole with phenyl lithium and hydrolysing the product. 5-(Methylamino) - 4 - (o - fluorobenzoyl) - 1,3 - dimethylpyrazole is also prepared by reacting 5-amino- 1,3-dimethylpyrazole with o-fluorobenzoyl chloride to produce 5-(o-fluorobenzamido)-4-(o-fluorobenzoyl)-1,3-dimethylpyrazole, reacting this with methyl iodide to produce 4-(o-fluorobenzoyl)-1,3- dimethyl-5-(N-methyl-o-fluorobenzamido)pyrazole and hydrolysing this with hydrobromic acid. 5- Amino - 3 - ethyl - 4 - (o - fluorobenzoyl) - 1- methylpyrazole is prepared similarly but without the methylation step. Pharmaceutical compositions having central nervous system depressant activity, for oral or parenteral administration, comprise a compound of Formula I together with a pharmaceutical carrier.