Hexahydro analogues

Regioselectivity was observed when the reaction was extended to the use of substituted hydrazines, where the reaction of 3,4-pyridinedicarboximide derivatives 305 or 306 with methylhydrazine in boiling ethanol gave the corresponding 3-methyl-l,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-r pyridazine 307 and 2-methyl-l,4,5-trioxo-1,2,3,4,5,6-hexahydro analogue 308, respectively, via opening of the imide ring and evolution of ammonia gas... 

The reaction is proposed to proceed from the anion (9) of A/-aminocatbonylaspattic acid [923-37-5] to dehydrooranate (11) via the tetrahedral activated complex (10), which is a highly charged, unstable sp carbon species. In order to design a stable transition-state analogue, the carboxylic acid in dihydrooronate (hexahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) [6202-10-4] was substituted with boronic acid the result is a competitive inhibitor of dibydroorotase witb a iC value of 5 ]lM. Its inhibitory function is supposedly due to tbe formation of tbe charged, but stable, tetrabedral transition-state intermediate (8) at tbe active site of tbe enzyme. 

Mutschler, E. Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes. 

Among the hydrogenated derivatives, we distinguish dihydro from the tetrahydro/hexahydro class, as the former bear an intimate relationship to their aromatic analogues. 

Reaction of l-(3,4-dimethoxybenzyl)-9-hydroxy-l,2,3,4-tetrahydro-8//-pyrido[l,2-a]pyrazin-8-one with 37% formaldehyde solution gave a tetracyclic tetrahydroprotoberberine analogue in a Mannich-type reaction (78AJC187). Reactions of 2,3,4,4a,5,6-hexahydro-l//-pyrazino[l,2-a]-quinolines with 1 W-pyrrolo[2,3-h]pyridine in the presence of 37% aqueous CH20 and AcONa in AcOH, and with 3-dimethylaminomethyl-l //-pyrrolo[2,3-h]pyridine afforded 3-[(l//-pyrrolo[2,3-h]pyridin-3-yl)methyl] derivatives (94MIP6 96USP5576319). 

Methods for preparing hexahydro-l,3,5-triazine analogues are provided (2) and illustrated in Eq. 2 ... 

Hexahydro-5-methylene-pyrimides, (IV), have also been prepared and converted into the 6-membered analogue of the current invention (3) as illustrated in Eq. 3. 

The preparation of 4-(2,3-dichlorophenyl)-1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-1,7-naphthyridine-3-carboxylic acid 2-methoxy-2-phenylethyl ester, (I), and other Step 5 condensation analogues of the current invention are described (2) and illustrated in Eq. 1 ... 

The cyclopentyl Step 5 analogue, N-(5-bromo-2,3-dioxo-2,3,4,7,8,9-hexahydro-lH-cyclopenta[f]quinoxalin-8-yl)acetamide, (I), has been prepared and is described (2). 

Another Step 5 analogue, 9-[(4-chlorophenyl)acetyl]-1,4,7,8,9,lO-hexahydro-6-nitropyrido[(3,4-f]quinoxaline-2,3-dione, (II), has also been prepared and is discussed (3). 

A large number of hexahydro-2,3a,7-triazacyclopenta[c]pentalene-l,3-diones analogues should be achievable using commercially available M1-M5 monomers ... 

Compounds 38 and 39 were synthesised as possible bioisosteric analogues for PHNO (27a) or one of its analogues. After changing the structure of the hexahydronaphthoxazines (27a, 75, 76) to the hexahydrothianaphthoxazines (38, 39) the position of the sulfur atom would suggest that the hexahydrothianaphthoxazines are bioisosteric analogues for tra s-7-hydroxy-4- -propyl-2,3,4a,5,6,1 Ob-hexahydro--///-naphth[l,2A][1,4]oxazine (75) which is not a potent dopamine... 

The discovery of the anthelmintic activity of the pyrazinoisoquinolines [25,31,32] initiated the synthesis of a variety of substituted pyrazinoisoquinolines. Praziquantel was picked up from more than 400 l,2,3,6,7,llb-hexahydro-4H-pyraz-ino[2,l-a]isoquinolin-4-ones and related compounds, because of its potent and broad spectrum biological activity [26]. The structure activity relationship in the analogues of praziquantel would indicate that positions 2 and 4 are the most critical positions, which govern the cestodicidal as well as antischistosomal activities in the pyrazinoisoquinolines. 

Acetylation of ll-(2,4-dichlorophenyl)-2,3,4,5,10,ll-hexahydro-3,3-dimethyl-lH-dibenzo[fr,e][l,4]diazepin-l-one and its analogues with acetic anhydride gave a series of N-acetyl derivatives, which were evaluated for their HCV inhibitory activity (07WOP196). 

The methylation of 7-phenyl-2,3,4,5-tetrahydro-l/f-l,4-diazepin-5-one (82) with dimethyl sulfate under phase-transfer conditions gave the 4-methyl analogue in modest yield. Activated aryl halides (l-fluoro-2,4-dinitrobenzene) furnished the 4-aryl analogues, in neither case was there any reaction at N-1 <93BSB89>. Hexahydro-l,4-diazepine is arylated on both nitrogen atoms with activated haloheterocycles such as 2-chloropyridine on reaction at 100°C under high pressure in the presence of triethylamine <90H(31)1217>. 

Treatment of (82) with either NBS or NCS at room temperature produced the 6-bromo and 6-chloro derivatives, respectively, and these underwent the expected nucleophilic reactions with sodium methoxide <93BSB89>. Bromination of l-ethoxycarbonyl-hexahydro-l,4-diazepin-5-one (83) with two equivalents of bromine in the presence of phosphorous pentachloride gave the 6,6 -dibromo compound, which was reduced to the monobromo analogue on hydrogenation <91TL2469>. 

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