1.2.4- Triazolo phthalazines

Dihydroxypyridazines are readily prepared from the diene 103 and DEAZD or PTAD,159 and the amino acid 104, a constituent of the Monamycin antibiotics, was synthesized from the Diels-Alder adduct of phthalazine-l,4-dione and penta-2,4-dienoic acid.160 These unusual amino acids can also be synthesized from the PTAD and parent HTAD adducts of penta-2,4-dienoic acid,161 and a variety of similar adducts, triazolo-pyridazines 105, has been synthesized from a wide range of 4-substituted 1,2,4-triazole-3,5-diones.162... 

Dichlorophthalazine on condensation with thiosemicarbazide in DMF afforded l,4-bis(thiosemicarbazi-do)phthalazine 444, that undergoes cyclization with carbon disulfide in the presence of potassium hydroxide to give l,4-bis(3, 5 -dithioxy-[l,2,4]triazol-l-yl)phthalazine 445. Compound 445 reacts with monochloric acid in the presence of NaOH to give l,4-bis-(l -thioxy-6 -oxo-[l,2,4]triazolo[3,4-A]-l,3-thiazol-2 -yl]phthalazine 446 (Scheme 51) <2001IJC(B)500>. 

Several applications of established ring-closure methodologies have been applied for the syntheses of the benzo-logues of the triazolopyridazine ring system - all these refer to cyclization to [l,2,3]triazolo[3,4- ]phthalazine derivatives. In Table 13, such products are shown together with yields and literature references. The product in entry 8 is somewhat outstanding in this list these compounds have been synthesized by solid-phase methodology, and the yields refer to the amounts of the crude products mostly of 90% purity. 

Table 13 [1,2,3]Triazolo[3,4-a]phthalazine derivatives obtained by established ring-closure techniques, including yields and literature references...

Since the publication of CHEC(1984) <1984CHEC(2)1>, the use of NMR seriously expanded. The majority of the full papers now published contain NMR spectroscopic data. Unfortunately, this is usually only for characterization of the synthesized compounds and no interpretation of the data is provided. In CHEC-II(1996) <1996CHEC-II(6)1>, a representative and very useful table with assigned shifts of simple pyridazines and pyridazin-3(2/7)-ones was published. Phthalazin-l(27/)-ones were also briefly mentioned. As an extension we here summarize some assigned NMR data of bicyclic derivatives [l,2,4]triazolo[4,3- ]pyridazines and tetrazolo[l,5- ]-pyridazines (Table 2 and Figure 3), and isoxazolo[3,4-, pyridazin-7(6//)-ones (Table 3 and Figure 4). 

Hydrazone formation of pyridazine-3-hydrazines with aldoses, dialdofuranoses, and dialdopyranoses was studied by Stanovnik and co-workers. The respective hydrazones could be cyclized with Bt2 in MeOH or Pb(OAc)4 to j-triazolo[4,3-3]pyridazin-3-yl substituted polyols <1997JHC1115, 1998JHC513>. Similarly, 4-[(dimethylamino)-methylene]-l,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one was reacted with pyridazine-3-hydrazines and the resulting mixtures were subsequently treated with Pb(OAc)4. Besides j-triazolo[4,3-3]pyridazine formation also diazenes were obtained. This can be rationalized by the enehydrazine-hydrazone mixtures observed in the first reaction. For phthalazin-l-hydrazines only diazenes were obtained after oxidation <2005TA2927>. Also cyclizations of... 

An aza analog of phthalazine 240 (pyrido[3,4-r/]pyridazine skeleton) was obtained via intramolecular addition-elimination reaction in azaphthalohydrazide 239 with the loss of hydrazine (Equation 56) <1997T8225>. In a similar approach also the 5,6-dihydro[l,2,3]triazolo[4,5-r/]pyridazin-4,7-dione skeleton was constructed <2002JHC889>. 

A combination EIMS and X-ray study of [l,2,4]triazolo[l,2-b]- and [l,3,4]thiadiazolo[3,4-i>]phthalazines was undertaken [95JHC283], and X-ray crystal structure determinations of 5-(2-chlorobenzyl)-6-methyl-3(2W)-pyridazinone [95AX(C)1834], and on 6-benzyloxy-7,8-dihydro-8-phenyl-3-trifluoromethyl-r-triazolo[4,3-i>]pyridazine and its 5,6-dihydro-6-one derivative [95AX(C)1829] have been performed. Structures of some pharmacologically-active pyridazines previously reported as arylidene-4,5-dihydropyridazines need to be revised to those of aromatic pyridazine tautomers 6-8 based on a combination H NMR nOe and X-ray study [95AJC1601],... 

Disposition in the Body. Readily absorbed after oral administration. It undergoes first-pass acetylation, the extent of which is genetically determined bioavailability 30 to 35% in slow acetylators, 10 to 16% in rapid acetylators. The major metabolites are 3-methyl-l,2,4-triazolo[3,4-a]phthalazine (MTP—the acetylation product) hydralazine pyruvic acid hydrazone (HPH) which is the major plasma metabolite 4-(2-acetylhydra-zino)phthalazin-l-one (A-AcHPZ) which is the major urinary metabolite 3-hydroxymethyl-1,2,4-triazolo[3,4-a]phthalazine (3-OHMTP). About 65% of a dose is excreted in the urine in 24 hours. In rapid acetylators, about 30% is excreted as A-AcHPZ and 10 to 30% as conjugated 3-OHMTP in slow acetylators, about 15 to 20% is excreted as A-AcHPZ and up to 10% as conjugated 3-OHMTP. Other metabolites include phthalazin-1-one (PZ), 1,2,4-triazolo[3,4-fl]phthalazine (TP), 9-hydroxy-MTP, phthalazine, tetrazolo[5,l-a]phthalazine, and hydrazones of hydralazine formed with acetone and a-ketoglutaric acid. About 10% of a dose is eliminated in the faeces. 

JOC3221). Nitration of 6-methyl-[l,2,4]triazolo[3,4-a]phthalazine in fuming nitric acidconcentrated sulfuric acid produced the 8-nitro compound (190). On the other hand, attempted nitration of (17) with copper nitrate-acetic anhydride gave only the 3-acetyl compound. The Vilsmeier formylation failed on (17) (69JOC3221) however, deuterium exchange occurred at C-3. The 3-carbaldehyde (see synthesis section) underwent the benzoin condensation and was oxidized to the 3-carboxylic acid. 

Triazolo[3,4-a ]phthalazine C-Terminal peptide sequencing 78DIS(B)(39)233... 

Under this heading, the synthesis of l,2,4-triazolo[4,3-fe]pyridazines (255) as well as the closely related and medicinally very important 1,2,4-triazolo[3,4-a]phthalazines (256), in addition to l,2,4-triazolo[4,3-( ]-cinnolines (257), will be discussed. 

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