5//-1,3,5-Triazepine-2,4-dione

The reaction of 208 with methylhydrazine gave the iV -methyhl. SJtriazepine diones 26, 209, and 210. The A2-methyl[l,2,5]triazepine-2,6-diones 211 and 212 were synthesized from the reaction of chloroacetyl (2A)-proline with A2-/i rt-butoxycarbonyl-T1-methylhydrazine. The 1,2,5-triazepine dione 213 was also synthesized similarly. 

The triazepine dione derivatives 94 (R, R, R, R = H, alkyl groups) have neurotrophic activity and are potentially useful in the treatment and prevention of neuronal disorders including, for example, Parkinson s disease, Alzheimer s disease and multiple sclerosis <03WOP028734>. 

Treatment of the acylproline esters 72 with methylhydrazine results in the cyclisation with inversion to form the l,3,5-triazepin-3,5-diones 73 <96CC85>. 4,5-Dihydro-1//-1,3,4-benzotriazepines have been prepared by the cyclisation of amidrazones with carbonyl compounds <95AP505, 96H(43)2549> and a route to 3,4-dihydro-l//-l,3,4-benzotriazepine-2,5-diones is reported <96JHC1131>. 

A light-induced ring expansion of the tetrazolo-uracil 147 afforded ready access to the ring expanded 57f-l,3,5-triazepine-2,4-dione nucleoside derivative 148 in 80% yield <06JOC1742>. 

N(2) of benzamidrazinium, the only product in the reaction with pentane-2,4-dione was 1,2,4-triazolinium iodide 79C. This isomer is formed by intramolecular NH-group addition to the C=N bond. The formation of a seven-membered 1,2,4-triazepine isomer has not been detected. 

The triazepines 88-90 react with acetic anhydride affording A -acetyl-l S-triazepine-Sjh-diones 91 (Scheme 18)... 

Fused l,2,5-triazepine-3,6-diones 88-90 were synthesized from (2 S )-proline methyl ester 205 by treating the latter with bromoacetic acid 206 in the presence of tiro-butyl chloroformate 207 (Scheme 46). The resultant bromoacetamide 208 on further treatment with hydrazine hydrate in EtOH gave 88-90 via cyclization through displacement of bromine <1996CC85>. 

The dione 214 upon treatment with hydrazine afforded 215, which was converted into 2,2 -bis(bromomethyl)-3,3 -biquinazoline-4,4 -dione 217 (Scheme 47) via 216. The racemic 1,2,5-triazepine ( )-53 was obtained from 217 by reaction with aqueous ammonia in THF. The enantiomerically pure (—)-53 was formed by refluxing ( )-53 with (+)-CSA (camphorsulfonic acid) <1999CC1991>. It is interesting that this work is the first nonracemic example of a C2-symmetric bis-heterocycle, which is atropisomeric by virtue of retarded rotation around an N-N bond. 

In the synthesis of l,2,5-triazepine-l,5-diones, which are expected to mimic the structural features of or-peptidyl prolin-amides, the preparation of N2,N3-disubstituted derivatives 213a from the reaction of (Z)-alanine with the N2-substituted triazepines 213 resulted in lower yields. It has been reported that these fused triazepinediones could be elaborated to give constrained rir-peptidyl proline peptide mimetics of defined stereochemistry and sequence <1997J(P1)2297>. 

Reaction of various aromatic or heteroaromatic diamines with iV-acyl isothiocyanates gave the corresponding benzo- or heterocycle-fused l,3,5-triazepine-2-thiones, for example, 16 (Figure 3) from 5,6-diamino-1,3-dimethyl-uracil and D-gluconyl isothiocyanate <1981CPB1832>. Cycloaddition of iVjiV -disubstituted ethylenediamines with bis(isocyanato)dimethylsilane or bis(isothiocyanato)dimethylsilane followed by treatment with 1,1 -carbonyldi-imidazole or 1,1 -thiocarbonyldiimidazole afforded a series of 1,5-disubstituted l,3,5-triazepine-2,4-diones, -2,4-dithiones, and 4-oxo-l,3,5-triazepine-2-thiones <1980AGE327>. 

Further applications of the use of the versatile starting material, diaminomaleonitrile 166, in the synthesis of heterocyclic derivatives have been reported. For example, reaction of 166 with chlorocarbonylisocyanate 167 in the presence of triethylamine gave the isocyanate 168 which, on heating in the presence of sodium hydroxide, cyclised to the l,3,5-triazepine-2,5-dione 169. This heterocycle then served as a precursor for the synthesis of a range of other ring fused triazepinediones <04MI71>. 

Syntheses of various 4-aryl-5-imino-3-phenyl-lH-naphtho[2,3 -l,2,4-triazepine-6,ll-diones 84a-f were reported by Aly et al. (08ZNF(B)223). Their successful synthesis depends on the reaction of amidrazones 83a-f with 2 (Scheme 25). 

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