Hydrazine

Die Synthese von purin-ähnlichen biheterocyclischen Ringsystemen wird beschrieben und insbesondere der Aufbau von verschieden substituierten Pyrazolo[3.4-d] pyrimidinen ausgehend von Pyrazolen oder Pyrimidinen besprochen. Synthesewege für Pyrazolo[3.4-c] pyridazine und Pyrazolo[3.4-b] pyridine ausgehend von Pyridazinen und Pyridinen und von Pyrazolo[3.4-b] pyrazinen und Pyrazolo[3.4-d] triazinen ausgehend von Pyrazolen werden angegeben. Als biheterocyclisches Ringsystem mit zwei kondensierten 6-Ringen werden die Pyrimido[4.5-d] pyrimidine erwähnt.

Syntheses of pyrazolo [3,4-d]pyrimidines with an amino group in 3- or 4-position are described. For the preparation of the 3-amino derivatives a 4-chloro-5-cyano-pyrimidine is condensed with various hydrazines. The 4-amino-pyrazolo [3,4-d]pyrimidines are obtained by reacting 3-amino-4-carbethoxy-pyrazoles with formamide, chlorinating thc 4-hydroxy-pyrazolo [3,4-d]pyrimidines, and substituting the halogen by amino groups. Some of the compounds show diuretic and cardiac activity, others inhibit tumor-growth.

The preparation of the paraxanthine, theobromine and theophylline isomers 1,5-; 2,5- and 1,7-; 2,7- and 5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro-pyrazolo[3,4-d]-pyrimidines is described and their structure established. A structurally specific synthesis of the caffeine and isocaffeine isomers 1,5,7- and 2,5,7-trimethyl-4,6- dioxo-4,5,6,7-tetrahydro-pyrazolo [3,4-d]pyrimidines has been realized.

The preparation of the caffeine isomers 1,5,7- and 2,5,7-trimethyl-4, 6-dioxo-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidines is described and their structures established. The compounds exhibit diuretic and cardiac activity.

Various monosubstituted hydrazines have been reacted with ethoxymethylenemalononitrile to yield the corresponding l-substituted-5-amino-4-cyanopyrazolcs (IV). Treatment of IV with concentrated sulfuric acid gave the corresponding l-substituted-5-aminopyr~zole-4carbosmides (XVI). The structure of 5-amino-1-phenylpyrazole-4-carbosamidewas established by an unambiguous synthesis. The preparation of 1-alkyl- and l-argl-l-aminoayrazolo[3,4-d]pyriniidineshas been accomplished by treating the corre- sponding 1-alkyl(or aryl)-5-amino-4-cyanopyrazole (IV) with boiling formamide.

Conrad and Zart' treated ethyl cyanoacetate with phenylhydrazine, using sodium alcoholate as a condensing agent, and obtained a colorless compound of the composition C9H9N30and the m. p. 219". This, they assumed to be l-phenyl-3- hydroxy-5-pyrazolone-imide,I. However, the reaction between ethyl cyanoacetate and phenyl- hydrazine could also lead to the isomeric l-phenyl- 3-amino-5-pyrazolone, 11.

This review describes the synthesis and reactions of cyanoacetic acid hydrazide as building block for the synthesis of polyfunctionalized heterocyclic compounds with pharmacological interest.

In the first paper of this series it was shown that the compound synthesized by Conrad and Zart and called 1-phenyl-3-hydroxy-5-pyrazoloinmeide is in fact the isomeric l-phenyl-3-amino-5-pyrazlone I. The real l-phenyl-3-hydroxy-5-pyrazolone imide I1 has now been prepared. Phenylhydrazine was condensed with cyanoacetyl chloride to give 0-cyanoacetylphenylhydrazine 111. In- stead of the acid chloride, cyanoacetazide3can be used, giving a somewhat higher yield. I11 is a colorless well-crystallizing substance.

This invention relates to a new pyrazolo-pyrimidines and a process for their preparation. More particularly the invention concerns hydro-pyrazolo (3,4-d) pyrimidines having the nucleus of the formula

-

which contain at least one of the positions 4 and 6 an oxo group and are alkylated, oxyalkylated, e.g. oxyethylated or cycloalkylated at at leats one ring nitrogen atom, their tautomeric forms and salt thereof.