Pyrrolo benzodiazepine-5,11-diones

Reduction of all three of the double bonds in the pyrrolo-benzodiazepine-5,11-dione 105 with excess potassium provides the corresponding trans fused hexahydrobenzene derivative 106 in high yield with complete stereochemical control. The preparation of (+)-perhydro-219A 108 from 106 has been reported 3 and a general method of preparation of derivatives of /ra i-2-aminocyclohexanecarboxylic acid e.g. 107) has recently appeared. 

ASYMMETRIC SYNTHESIS OF TRANS-2-AMINOCYCLOHEXANECARBOXYLIC ACID DERIVATIVES FROM PYRROLO BENZODIAZEPINE-5,11 -DIONES... 

Pyrrolo-benzodiazepine dione 244 can be obtained from the ketoester 243 in refluxing AcOH in high yield (Scheme 52 (1991ZOR1951, 1992CE649, 1996PHA548, 2005H2451)). 

Alkylation of pyrrolo-benzodiazepine dione 244 with methyl iodide occurs on both positions N9 and ClOa, while reaction with 2-bromo diethylaminoethane leads to the low yield of the 4-substituted 248. Acylations with benzoyl and 2-chloroacetyl chlorides are directed exclusively to position 4 to afford 247 (Scheme 52, Section 3.1.1.4 (1992CE649, 2005H2451)). Alkylation of 5H-benzo[/]-pyrrolo[l,2-d][l,4]diazepin-6(7H)-one with a substituted phenethyl bromide has been reported (Scheme 36, Section 3.1.1.1 (1992BMCL1639)). 

A suspension of 29.8 mmol of sodium hydride (55 percent oil dispersion) in 40 ml of dry dimethylformamide is treated at 20-30°C with 27.1 mmol of (S)-6-bromo-1,2,3, lla-tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepine-5,11 (10H)-dione, the mixture is stirred in the above temperature range for 45 min and then at -35°C 27.1 mmol of diethylchlorophosphate are added dropwise thereto. 

S)-(+)-2,3-Dihydro-1 H-pyrrolo[2,1 -c][1,4]benzodiazepine-5,11 (1 OH, 11 aH)-dione was purchased from the Aldrich Chemical Company, Inc. Other reagents, solvents, and drying agents were obtained from either Aldrich Chemical Company, Inc. or Fisher Scientific Company. 

Reaction of 5-substituted isatoic anhydride with allylamines gave 2-amino-5-substituted-jV-alkyl-A -(2-propenyl)benzamides which were subjected to diazotization followed by subsequent nucleophilic substitution and cyclization to give 2-methyl-l,4-benzodiazepin-5-ones. A non-covalent DNA-binding agent like pyrrolo[2,l-c][l,4]benzodiazepine-5,ll-dione has been synthesized. 

A number of metabolites which appear to be derived from Tyrosine, Dopa, or Topa residues and to have similar biogenetic origins to the tunichromes have been reported. Rigidin (48), isolated from the Okinawan marine tunicate Eudistoma c.f. rigida exhibited calmodulin antagonistic activity with an IC50 of 5 x lO M against calmodulin-activated brain phosphodiesterase [42]. Some other pyrrolo[2,3d]pyrimidine-2,4-diones which have been synthesised have shown weak affinity for the benzodiazepine receptor. 

Rearrangement of pyrrolo[2,l-c][l,4]benzodiazepine-5,ll-diones 332 (n— 1) and pyrido[2,l-c][l,4]benzodiazepine-6,12-diones 333 ( = 2) into 5-chloro-l,2,3,4-tetrahy-dro-benzo[/i][l, 6]naphthyridine 334 and 6-chloro-2,3,4,5-tetrahydro-l/7-azepino... 

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