BENZODIAZEPINE DERIVATIVES AND MANUFACTURE THEREOF

摘要

1306451 Benzodiazepines F HOFFMANNLA ROCHE & CO AG 11 Feb 1970 [14 Feb 1969] 6450/70 Heading C2C Compounds of the general Formula (I) (R 1 =halogen, NO 2 ; R 2 = Ph, Py, halophenyl; R 3 = H, alkyl, hydroxyalkyl, acyloxyalkyl, haloalkyl, carbalkoxy, alkylaminoalkyl, dialkylaminoalkyl; R 4 = alkoxy, haloalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl; R 5 = H, OH; R 6 = H, carbalkoxy), their 4-oxides (R 5,6 = H) and salts are prepared by (a) reacting a compound of the Formula (II) or 4-oxide thereof with R 7 R 8 CHX (R 7 =H, alkyl, haloalkyl, carbalkoxy, acyloxyalkyl ; R8 = alkoxy, haloalkoxy, alkylthio, alkoxyalkoxy; X=halogen, leaving group), (b) reacting (II), R 6 =H, with an alkyl vinyl ether, (c) reacting a compound of the Formula (VI) (R 10 = H, alkyl, hydroxyalkyl, haloalkyl, alkylaminoalkyl, dialkylaminoalkyl, acyloxyalkyl; R 11 =R 4 , but at least one of R 10,11 =monohaloalkyl or monohaloalkoxy) or 4-oxide thereof with an alkylamine or dialkylamine, (d) alkylating a compound of the Formula (VII) (R 12 = alkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio, aminoalkoxy; R 13 =H, alkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, but at least one of R 12,13 = aminoalkoxy, alkylaminoalkoxy, aminoalkyl or alkylaminoalkyl) or 4-oxide thereof, (e) removing the protecting group from a compound of the Formula (VIII) (R 14 = alkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio, protected alkylaminoalkoxy; R 15 = H, alkyl, alkylaminoalkyl, dialkylaminoalkyl, acyloxyalkyl, protected alkylaminoalkyl, but at least one of R 14,15 = protected group) or 4-oxide thereof, (f) replacing the aliphatically bound halogen atom(s) by OH in a compound of the Formula (IX) (R 16 = alkoxy, haloalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkylthio; R 17 =H, alky], hydroxyalkyl, haloalkyl, carbalkoxy, alkylaminoalkyl, dialkylaminoalkyl, acyloxyalkyl, but at least one of R 16,17 = monehaloalkyl or monohaloalkoxy) or 4-oxide thereof, (g) oxidizing a compound of the Formula (X) (R 18 = alkylthio; R 19 = H, alkyl, hydroxyalkyl, haloalkyl, carbalkoxy, acyloxyalkyl) or 4- oxide thereof, (h) cyclizing a compound of the Formula (XI) (i) hydrolysing a compound of the Formula (XII) (R 20 = acyl), (j) deoxygenating a compound of the Formula (XIII) (R 21 = alkoxy, haloalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkylthio), (k) dehydrating a compound of the Formula (XIV) (R 22 = alkoxy, alkoxyalkoxy, dialkylaminoalkoxy; R 23 =H, alkyl, carbalkoxy, dialkylaminoalkyl, acyloxyalkyl, (1) oxidizing or dehydrogenating a compound of the Formula (XV) (B 24 =alkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy; R 25 =H, alkyl, hydroxyalkyl, carbalkoxy, alkylaminoalkyl, dialkylaminoalkyl, acyloxyalkyl), (m) saponifying and decarboxylating a compound of the Formula (XVI) (R 26 = alkyl; R 27 = H, alkyl, hydroxyalkyl, haloalkyl, alkylaminoalkyl, dialkylaminoalkyl, acyloxyalkyl), (n) oxidizing a compound of the Formula (XVII) to the 3-hydroxy compound, (o) converting a compound of the Formula (XVIII) (R 28 = acyl; R 29 = alkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy) with a base into the corresponding 4,5- dehydro compound, (p) converting a compound of the Formula (XIX) (R 30 =mesyl, tosyl; R 31 =H, alkyl, hydroxyalkyl, carbalkoxy, dialkylaminoalkyl, acyloxyalkyl ; R 32 = alkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl) with a strong base into the corresponding 4,5-dehydro compound, (q) rearranging the corresponding 3,4-dehydro compound, (r) acylating a compound of the Formula (XXI) (R 40 = hydroxyalkyl ; R 41 = alkoxy, haloalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl) or 4-oxide thereof, or (s) replacing the aliphatically bound halogen atom by an acyloxy group in a compound of the Formula (XXII) (R 42 haloalkyl; R 43 = alkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl) or 4-oxide thereof, optionally followed in each case by salt formation. The above compounds are anticonvulsants, muscle relaxants, sedatives and anxiolytics, and may be administered in the form of pharmaceutical preparations containing them in association with a carrier.