Pyrazolo pyridine, structure

As mentioned in <1996CHEC-II(7)283>, there are very few X-ray studies of the various classes of compounds in this chapter. In general, the crystal structures published provide supporting evidence for structure elucidation. For example, the X-ray crystal structure of pyrazolo[4,3-f]pyridine 6 was reported to confirm its structure and that of its analogues (7 and 8) by comparison of other spectral data <2004T933>. 

As reported in <1996GHEC-II(7)283>, no specific study on the mass spectra of these classes of compounds has been reported, although this analytical method has only been used as a tool for structure elucidation or reference without critical analysis. Some examples are reported in <1996GHEC-II(7)283>. Further information on the MS of heterocycles can be found in <2001MI1>. The mass spectral data for imidazopyridines, pyrazolo[3,4- ]pyridines, oxazolo-pyridines, ioxazolopyridines, isothiazolopyridines, 377-1,2-dithiolo[3,4- ]pyridines, and l,3-dithiolo[4,5- ]pyridines were reported in <1996GHEG-II(7)283>, but there have been no further reports in this area. 

A series of pyrazolo[3,4-, pyridazinones 430 and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed ICso values in the range 0.14-1.4 pM. A good activity and selectivity profile versus PDE6 was found for compound 430 (6-benzyl-3-methyl-l-isopropyl-4-phenylpyrazolo[3,4-r/]pyridazin-7(6/7)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position 6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five- and six-membered heterocycles (pyrrole, isoxazole, pyridine, and dihydropyridine), as well as some open-chain models were prepared and evaluated. Besides the pyrazole, the best of the fused systems proved to be isoxazole and pyridine <2002MI227>. 

Pyrazolo[3,4-h]pyridines have received considerable attention as a result of their biological activity. Although much of the early literature on their synthesis is confused, due to erroneous structural assignments, this has been resolved in many cases by the use of spectroscopic techniques. 

The reaction of 1,3-dicarbonyl compounds with 3-amino-5-pyrazolones has been used extensively in the preparation of pyrazolo[3,4-b]pyridines. A number of products are possible, depending on the reagent used and the direction of cyclization. As a consequence, many of the early reports proposed incorrect structures. 

Treatment of 3,4-dibenzoylpyrazole with amines in refluxing ethanol furnished mixtures of 5-substituted pyrazolo[3,4-c]- (117) and 6-substituted pyrazolo[4,3-c]pyridines (118).117 The latter isomer was the major constituent in each case and the structures were assigned, using NMR spectrometry. 

Pyrazolo[4,3-c]pyridines gave 5-methiodides in excellent yield.144 154 A methiodide of pyrazolo[l,5-a]pyridine 199b (R1 = H) was also prepared but its structure was not assigned161 the parent compound 5 quaternized in the 1-position.209 The saturated amide, however, formed a 7a-quaternary salt (263) with benzyl chloride, which was converted to the 1-benzyl derivative via the internal salt 264.209... 

Compound (408), which was prepared by the condensation of the amine (407) with benzaldehyde in the presence of piperidine, upon treatment with phenylhydrazine afforded the orange pyrazolo[3,4-6]pyridin-2-one (410) (69%) (Scheme 45) <9iPS(63)ll9>. The structure (410) was confirmed by an alternative synthesis involving a reversal of the reactants. In this case compound (407) was initially reacted with phenylhydrazine to give compound (409) and subsequent condensation with benzaldehyde gave the product (410). 

The epoxidation of oxazolines with DMD by Adam and Hadjiarapoglou has been mentioned in (93TCC45) (Structure (101)). Epoxidations of pyrimidine and purine derivatives with DMD (93TL6313, 95T7561) as well as pyrazolo[l, 5-a]pyridine derivatives with Mn-TPP and Fe-TPP complexes using NaOCl as oxidant have also been reported (102)-(104) <89CPB1410>. 

The structures of several compounds containing the pyrazolo[l,5-a]pyridine ring system have been established by x-ray crystallography <90CPB2667,91TL4977,94AJC99l>. 

A recently developed related sequence is shown in Scheme 5 <87CPB156>. The structure of the final product was found to be independent of the nature of R (R = Et, Ph, NEtz, OEt, SMe) but to be strongly influenced by the nature of R . The involvement of 1,3,4-thiadiazine intermediates was demonstrated by NMR spectroscopy and, in a few cases, by isolation. Synthesis of the previously inaccessible pyrazolo[l,5-a]pyridine-2-thiols was achieved following this route, by initially protecting the thiol as, for example, the 2-cyanoethylthio group <90CPB2662>. 

The l-aryl-3-trifluorometylpyrazole-5-carboxamide group is present in many of the orally available blood coagulation factor Xa inhibitors. Pinto and co-workers found in their medicinal chemistry program that a fluorinated pyrazole was an optimal five-membered heterocyclic core. Thus, two members of the 3-trifluoromethylpyrazole-5-carboxamide series were advanced to preclinical development (Fig. 2a) [81]. An additional structural modification, the incorporation of an aminobenzisoxazole moiety at N1 instead of the benzylamine group, led to the discovery of razaxaban (Fig. 2b), a potent, selective, and orally bioavailable inhibitor of factor Xa with in vivo efficacy in antithrombotic models [82], The amide hydrolysis observed in vivo could be modulated by introducing bicyclic core variants at the carboxamide portion, such as l/f-pyrazolo[4,3-rf pyrimidin-7(6//)-oneor 1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridine-7-one [83]. 

Interestingly, when 5-amino-3-methylpyrazole reacted with Meldrum s acid and benzaldehydes in aqueous PEG 400, pyrazolo[3,4-fc]pyridines 129 were formed with good yields (Scheme 74) [105]. In the model reaction, it was demonstrated that the solvent can be recycled for up to five nms with limited decrease of yields. The reaction was foxmd to be regioselective and the structure of the products was xmambiguously confirmed by X-ray crystallography of 129 (R=4-OMe). This reaction was also successfully performed using n-butyraldehyde instead of benzaldehydes. 

N.M. Nascimento-Junior, T.C.F. Mendes, D.M. Leal, C.M.N. Correa, R.T. Sudo, G. Zapata-Sudo, E.J. Barreiro, CA.M. Fraga, Microwave-assisted synthesis and structure-activity relationships of neuroactive pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives, Bioorg. Med. Chem. Lett. 20 (2010) 74-77. 

Miscellaneous - As a consequence of the wide-spread search for anti-inflammatory agents several novel structures with a variety of activity-profiles have been discovered. A pyrazolo(3. 4-c) pyridine derivative (Su 15336) (XXI), possessing the partial structure of a family of very potent steroids, has been reported to be one of the most active nonsteroidal agents. 5-n-Butyl-l-cyclohexyl-2, 4, 6-trioxoperhydro-pyrimidine (XXII) (TBA 300) is a moderately active compound comparable to phenylbutazone. 

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