Synthesis and Muscle Relaxant Properties of 3-amino-4-arylpyrazoles

Abstract

A new synthesis of 3-amino-4-arylpyrazoles involving the acetic acid catalyzed reaction of hydrazine with aformylarylacetonitriles is described. Seventeen new pyrazoles in this series are reported, as well as thirteen new N-substituted derivatives of 3-amino-4-phenylpyrazole. While a number of these compounds exhibited muscle relaxant activity, 3-amino-4-phenylpyrazole was the most active. Structure-activity relationships are discussed.In connection with an investigation of the synthesis and pharmacologic action of muscle relaxants, it was necessary to prepare a number of 3-aminopyrazoles unsubstituted in the 1-position. Although numerous synthetic routes for the formation of the pyrazole ring system have been described in the literature,2 relatively few convenient methods for the preparation of 3-aminopyrazoles are described. Thus, reduction of 3-phenyl-azopyrazoles3 and 3-nitropyrazoles,4 hydrolysis of bispyrazolyl formamidines,5 and modification of a carboxylic acid derivative in the 3-position via the Curtius or Hoffman rearrangements43•6 have been used.A more direct route to 3-aminopyrazoles was suggested by the reaction of hydrazine with an a-substituted-/3-ketonitrile to give a 3-amino-4,5-disubstituted derivative.7 When the enol ether of an a-cyanoketone8 or an -cyanoaldehyde9 was used, similar products were obtained. The preparation of 3aminopyrazoles by the direct reaction of hydrazine with an -cyanoaldehyde has not been reported, presumably because of the well known reaction between aldehydes and hydrazine to give excellent yields of azine. Treatment of -formylphenylacetonitrile (B) with hydrazine did, in fact, generate the azide (D). However, small yields of 3-amino-4-phenylpyrazole (C) could be obtained by using excess hydrazine. Furthermore, yields of up to 88% of the pyrazole (C) could be obtained by adding an amount of acetic acid in excess of that required to neutralize the hydrazine. This was found to be a quite general reaction, and the compounds in Table I were prepared using the same procedure and the appropriate a-formylarylacetonitriles.The -formylarylacetonitriles were prepared by a modification of the method of Walther and Schickler10 in which the corresponding arylacetonitriles wrere (1) To whom all inquires concerning pharmacology should be sent.(2) T. L.

Influences of temperature and threshold effect of NaCl concentration on Alpias vulpinus OCT

“…It is a protein well preserved during evolution in different species [11][12][13][14]. The enzyme (M w 120,000) has a trimeric structure composed of identical subunits, catalyzes the synthesis of citrulline from ornithine and carbamoyl phosphate with the release of orthophosphate during the first step in the de novo biosynthesis of arginine [13]. In our work we analyze the thermodynamic stability and molecular structure of Alopias vulpinus OCT in function of salts concentration, in the range of temperature from 60 to 70 • C. Further elucidations have also been monitored by UV-vis and CD spectroscopy.…”

α‐Cyano‐β‐styrenyl esters for amide bond formation

“…a-Cyano-6-styrenol is easily prepared by the Claisen condensation of benzyl cyanide and ethyl formate (2). We have observed that it readily reacts with symmetrical anhydrides of amino acids, e.9.…”

“…---a-Cyapp:@:-kyrepris: l a was prepared as reported (2) except that NaH dispersion in oil was substituted for NaOMe: yield 77%. The known p-C1 (4) and p-trifluoromethyl derivative (5) (lb and lc) were similarly synthesized in 90 and 85 % yield respectively.…”

Stabilization effects of kosmotrope systems on ornithine carbamoyltransferase

“…We have investigated the ornithine carbamoyltransferase (OCTase) which catalyzes the carbamoylation of l-ornithine to form citrulline in the sixth step of the arginine biosynthesis pathway [6][7][8]. OCTase has a trimeric structure composed of identical subunits and catalyzes the synthesis of citrulline from ornithine and carbamoyl phosphate with the release of orthophosphate during the first step in the de novo biosynthesis of arginine.…”