Preparation of substituted N-phenyl-4-aryl-2-pyrimidinamines as mediator release inhibitors

Abstract

The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.

Synthesis of New N-Arylpyrimidin-2-amine Derivatives Using a Palladium Catalyst

“…The arylation of 2 with different arylbromides to obtain compounds 4a , b and c was much more difficult. The synthesis of compounds 4a and 4b by the condensation of compound 1 with the appropriate substituted guanidine derivatives was reported previously [ 13 ]. In order to prepare these compounds using Buchwald-Hartwig amination protocol [ 16 ], we first tried to carry out the reaction in refluxing toluene under nitrogen atmosphere, using Pd 2 (dba) 3 , 1,3-bis(diphenylphosphino)propane (dppp) as a ligand and sodium tert -butoxide as a base.…”

“…In most of the reported literature, the synthesis of N -arylpyrimidin-2-amines was achieved by condensation of substituted guanidines with enones [ 13 , 14 , 15 ]. This approach however is of restricted use for the preparation of diverse derivatives of N -arylpyrimidin-2-amines because of the limited availability of substituted guanidines.…”

Unlocking the Chemotherapeutic Potential of β‐Aminovinyl Ketones and Related Compounds

“…After examining a large number of these analogues, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2-pyrimidinamine (36) was chosen for toxicological evaluation. [64] In a recent report, [65] aminoquinolizinones 39 were prepared from cyclohexanonyl enaminone 37 and from the corresponding thione derivative 38 in the search for analogues that would serve as anti-HIV agents (Scheme 9). In addition, Al-Omran et al [66] reported the preparation of a benzotriazole derivative 41 by heterocyclocondensation of enaminone 40 and malonitrile dimer to give the pyridopyridone 41 with interesting antimicrobial activity (Scheme 10).…”

Synthesis and SAR of 4-(pyrazol-3-yl)-pyridines as novel c-jun N-terminal kinase inhibitors

“…In the literature, kinase inhibitors with a central pyrimidine core are ubiquitous whereas those containing pyridine cores are far less common [33, 36–41]. With intermediates in hand, we decided to investigate if 4-pyrazole substituted pyridines had any activity against JNK3.…”