1-Pyrazolo pyrazines

Pyrazolo[4,3- ]pyrrolo[l,2- ]pyrazines were obtained by cyclodehydration of amide derivatives of pyrrolopyrazoles <2005M217>. 

Several bis-heterocyclopyridines have been previously demonstrated to have various central nervous system effects <1996CHEC-II(8)967>. Pyrrolo[l, 2- ]thieno[3,2-f ]pyrazines have been demonstrated to be high-affinity ligands for 5-HT3 receptors <1996JME2068>. Pyrazolo[4,3- ]pyrrolo[ l,2-tf]pyrazines have moderate antibacterial and antifungal activity <2005M217>. 

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

An efficient one-pot synthesis of some novel azolo[l,5-a]pyrimidines, via enaminonitriles, has been described <00SC1985>. The utility of 3-aminocinnamonitrile in the synthesis of new pyrazolo[l,5-a]pyrimidines has been reported <00ZN(B)321>. The synthesis of novel arylaminopyrazolo[3,4-d]pyrimidin-4-ones has been described <99IJC(B)1075>. The synthesis and properties of a-Thiagra, a substituted 5-(2-thienyl)pyrazolo[4,3-d]pyrimidin-7-one bioisostere of Viagra, have been described <00H(53)2643>. Imidazo[4,5-b]pyrazines are obtained by the reaction of 4-amino- 5-imino-imidazole derivatives with acetophenone dimethylacetal . 

Only two isomeric pyrazolopyrazines are possible 1/f-pyrazolo [3,4- >]pyrazine (59) and pyrazolo[l,5-a]pyrazine (60). Derivatives of both ring systems are known. Annular tautomerism could occur in 59 [cf. 4 f-pyrazolo[3,4-( ]pyrazine (59a) ]. 

Js.JJa.s in these systems is 0.5, indicating appreciable bond length alterations. 74.5 is very similar to 7o of benzene (9 Hz), while 75.6 is only 4.0 Hz. In the pyrazolo[l,5-fl]pyrazine ring system, H-6 and H-7 appeared at low fields (> 8.1 ppm), and Jej is only 5 Hz, indicating that bond order in these systems is less than in benzene (7o = 9 Hz) (74CPB1814). 

The acetyl proton signal of the pyrazolo[3,4-f][l,2,5]oxadiazole 61 resonating at 2.80ppm appears downfield <2000RJ0758> of the corresponding protons in A, A -diacetylbis(l,2,5-oxadiazolo)[3,4-A3, 4 -< ]pyrazine 62 <1997RJ01656>. 

Treatment of 3-(2-methoxy-5-bromophenyl)-l//-pyrazolo[3,4-/ ]pyrazine-6-chloride with 2,4-difluoroanisole affords 3-(2-methoxy-5-bromophenyf)-6-(2,4-difluorophenylammo)-l//-pyrazolo[3,4- ]pyrazine <2006BML262>. 

Pyrazoldiamines were reported in CHEC-II to react with hydroxy ketones to yield pyrazolo[3,4-/ ]pyrazines. Similar to this, pyrazolopyrazines 285 are obtained at room temperature from reaction of 284 with glyoxal (and butane-2,3-dione) in good yield (Equation 39) <2004TL4105>. 

Aminopyrazinium salts (199) with potassium carbonate give the 1-imides (200), which are readily converted into the corresponding pyrazolo[l, 5-Z>]pyrazine (e.g., 204) by DM AD, DEAD, or EP (e.g., 203).330 334 No products corresponding to 201 were detected, aromatiza-... 

The syntheses of some pyrazolo[l,5-a]pyrazines from A-amino-pyrazinium derivatives have been described.345 Treatment of 266 R R2 = H or Me) with base gave 267, which cyclized to 268 with EP or DMAD. The A-imino derivative (270), from the interesting A-amino-pyrazinium A -oxide salt (269) gave 41 % of 271 with EP.345... 

Subsequent development in all industrialized countries was rapid, especially during the period 1945-1975, and led to more than 1000 commercial products by 1989. Almost 400 compounds of distinct chemical structure or composition are registered in the Colour Index. Many of these compounds, including 3 and heterocycles such as imidazolone, dibenzothiophene-5,5 -dioxides, methine derivatives, dihydrocollidine, pyrazine, carbostyrils, pyrazolo[3,4-6]quinolines, and 5,6-benzocoumarins are no longer used and have been replaced by others. 

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