An efficient conversion of nitriles to amidines

Garigipati, Ravi S.

doi:10.1016/s0040-4039(00)88891-7

Cited by 155 publications

(69 citation statements)

References 6 publications

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“…Reduction of the nitrile and sulfonylation (or acylation) under Schotten-Baumann conditions with the appropriate cyanoarylsulfonyl chloride (or cyanoaryl acid chloride) provided the bisbenzonitriles 4a-f, 5a-f or 6a-f, 7a-f, respectively (39). The use of the GarigapatiWeinreb amidination (40,41) in a sealed tube at high temperature or refluxing in toluene helps to overcome the insolubility of the monoamidine to return the required bisamidines 8-11 in moderate to low yields. Occasionally, the monoamidine intermediates 12 were isolated and tested.…”

Section: Resultsmentioning

confidence: 99%

Potent selective nonpeptidic inhibitors of human lung tryptase

Burgess

Newhouse

Rizzi

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Human lung tryptase, a homotetrameric serine protease unique to mast cell secretory granules, has been implicated in the pathogenesis of asthma. A hypothesis that tethered symmetrical inhibitors might bridge two adjacent active sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure-activity relationship against human tryptase with one series possessing subnanomolar potencies. Additional evidence supporting the concept of active-site bridging is also presented.

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Section: Resultsmentioning

confidence: 99%

Potent selective nonpeptidic inhibitors of human lung tryptase

Burgess

Newhouse

Rizzi

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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“…According to Garigipati's method, 24 the amidines 52a, 52b and 56 were obtained from nitriles by addition of methylchloroaluminum amides 25 generated from trimethylaluminum and ammonium chloride or methylamine hydrochloride.…”

Section: Chemistrymentioning

confidence: 99%

Design and Synthesis of Imidazoline Derivatives Active on Glucose Homeostasis in a Rat Model of Type II Diabetes. 2. Syntheses and Biological Activities of 1,4-Dialkyl-, 1,4-Dibenzyl, and 1-Benzyl-4-alkyl-2-(4‘,5‘-dihydro-1‘H- imidazol-2‘-yl)piperazines and Isosteric Analogues of Imidazoline

et al. 1999

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Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl-4-alkyl-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazines resulted in the identification of 1-methyl-4-(2′,4′-dichlorobenzyl)-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of R 2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties. In such a way, substitution of both piperazine N atoms was first optimized by using various alkyl, branched or not, and benzyl groups. Second, some modifications of the imidazoline ring and its replacement by isosteric heterocycles were carried out, proceeding from PMS 812, to evaluate their influence on the antidiabetic activity. The importance of the distance between the imidazoline ring and the piperazine skeleton was studied third. Finally, the influence of the N-benzyl moiety was also analyzed compared to a direct N-phenyl substitution. The pharmacological evaluation was performed in vivo using glucose tolerance tests on a rat model of type II diabetes. The most active compounds were 1,4-diisopropyl-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazine (41a), PMS 847 (S-22068), and 1,4-diisobutyl-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazine (41b), PMS 889 (S-22575), which strongly improved glucose tolerance without any side event or hypoglycemic effect. More particularly, PMS 847 proved to be as potent after po (100 µmol/kg) as after ip administration and appears as a good candidate for clinical investigations.

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“…16 Previously, it was shown that alkylchloroaluminum amides are useful reagents for the conversion of nitriles to amidines under milder conditions. 16 It was found that 17 addition of alkylchloroaluminum amides, generated conveniently from trimethyl aluminum and ammonium chlorides, to nitriles in warm toluene efficiently afforded the desired amidines in reasonable yields after hydrolysis of aluminum species as shown in Schemes 5 and 6. …”

Section: Amidines From Nitrilesmentioning

confidence: 99%