Pyrazolo benzodiazepines

Some tricyclic systems have been prepared by intramolecular cyclization from A-aryl-pyrazoles carrying substituents both in the pyrazole ring at C-5 and in the phenyl ring at the o-position. Thus pyrazolo[l,5-n]quinazolines (563) (69JHC947) and pyrazolo[l,5-n]-[l,4]benzodiazepines (564) (77JHC1163, 77JHC1171) can be prepared from suitable precursors. 

The term benzodiazepine refers to a specific chemical structure. Numerous benzodiazepine-receptor ligands exist which have different structures. These include the jS-carbolines (e.g. methyl-6,7-dimethoxy-4-ethyl-jS-carboline 3-carboxylate DMCM), triazolopyridazines (e.g. CL 218872), imidazopyridines (e.g. zolpidem), and pyrazolo-quinolinones (e.g. CGS 8216). In experimental animals these compounds produce... 

Structurally related sets of triazinoquinoline, triazinoisoquinoline and pyridotriazine derivatives have been synthesized and their binding to benzodiazepine receptors studied <06EJM445>. Pyridazino[3 ,4 3,4]pyrazolo[5,l-c]-l,2,4-triazines have been prepared and their antimicrobial activity evaluated <06PS809> <06PS2505>. 

Some new spirothiadiazolepyrazolo[l, 4-e/][1,5] benzodiazepines have been reported by Rakilo et al. They are prepared by a regioselective 1,3-dipolar cycloaddition of a nitrile imine with pyrazolo[l,5,4-e/][ 1,5]benzodiazepine-thione <00H(53)571>. 

Pyrazolo[l,5-a]pyrimidine, the central scaffold in zaleplon, is present in 5, 6 and 7. Compound 5 inhibits the binding of tritiated benzodiazepine in synaptosomal fractions from rat cortex [20] and 6 and 7 inhibit the al GABAa subunit with K, — 53 nM and 17nM, respectively, and showed sedative-hypnotic action following i.p. administration to mice (<90% inhibition of motor activity)... 

The 1,7-electrocyclization of nitrile imines 47 has been proposed as a key step in the conversion of the stable phosphorus ylides 45 to pyrazolo[4,3-d] [2,3]benzodiazepines 48, upon refluxing in xylene (Scheme 16). Ringopening of the triazoles 45 and recyclization is postulated to give the pyra-zoles 46. Migration of the triphenylphosphine group, followed by the elimination of triphenylphosphine oxide, would then give the nitrile imine 47 (95TL5637). 

Unexpected results lead to the discovery of pyrazolo[4,3-r/][2,3]benzodiazepine 87 preparation from l -(/V,Ar-diaroyl)-amino-4-phenyl-[l,2,3]triazol-5-yl-methyltriphenylphosphonium ylide 85. Ylide formation was followed by a Dimroth-type rearrangement to 86 and to product 87 <1995TL5637> (Scheme 17). 

Chemical Name 4,9-Dihydro-l,3-dimethyl-4-[(4-methyl-l-piperazinyl) acetyl]pyrazolo[4,3-b][l,5]benzodiazepin-10-(lH)-one... 

The antianxiety effects of chlordiazepoxide (165) were described in 1960 and this compound was followed by diazepam (135). These two drugs have captured 75% of the market for sedatives in the USA. Other benzodiazepines used as antianxiety agents include oxazepam (166 R = H), a metabolite of diazepam that is better tolerated, lorazepam (166 R = Cl) and potassium clorazepate (167). Prazepam is the iV-cyclopropylmethyl analogue of diazepam. The benzodiazepines have other therapeutic applications, many being used for inducing sleep, diazepam and nitrazepam are anticonvulsants and flurazepam (168) is both an antianxiety agent and a potent hypnotic. Thieno- and pyrazolo-1,4-diazepinones isosteric with diazepam have similar pharmacological properties (B-81 Ml 10604). 

Diastereoselective intramolecular 1,3-dipolar cycloaddition reactions were deftly exploited in the synthesis of a number of enantiopure pyrazolo-pyrrolo- and triazolo-pyrrolo-fused 1,4-benzodiazepine systems <05S2246>. 

Naphthyridines 18 (R2=H) without substituents at nitrogen have served as the starting compounds to pyrazolo[3,4-c]naphthyridines, which act as modulators of benzodiazepine receptors and possess sedative and antispasmodic activities (1984EUP115469, 1986EUP168350, 1986USP4560691). 

When the 1 -aroyamino-4-phenyl-l, 2,3-triazol-5-yl-aroylmethylphospho-rus ylide was boiled under reflux in xylene or chlorobenzene, it rearranged to the pyrazolo[4.3-rf][2,3]benzodiazepines (95TL5637) (Scheme 93a). The mechanism involved a ring opening of the triazole and a recyclization to a pyrazole (Scheme 93A). 

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