1035224-53-3

Upstream product

• 37622-90-5 4-ethoxycarbonylpyrazole 
• 402-23-3 1-bromomethyl-3-trifluoromethylbenzene 

Downstream Products

• 752222-88-1 1-(3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylic acid 

Relevant academic research and scientific papers

Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: High affinity and selective A2B adenosine receptor antagonists

Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A2B adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A2B AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A 2B AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (Ki = 9 nM) for the A2B AdoR, but it is only 2-fold selective versus the A1 AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A2B AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF3 at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A2B AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and 36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A2B AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A2B AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A2B AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (Ki = 1 nM) A2B AdoR antagonist with high selectivity (990-, 690-, and 1000-) for the human A1, A2A, and A3 AdoRs.

AGONISTS OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR-α

Disclosed are compounds of the formula: (I) And pharmaceutically acceptable salts thereof, wherein the variables are as defined herein, which are useful in activating PP ARa and in treating atherosclerosis hypercholesterolemia, primary hypercholesterolemi

A2B ADENOSINE RECEPTOR ANTAGONISTS

Disclosed are novel compounds that are A2B adenosine receptor antagonists having the following structure (I) wherein R1 and R2 are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, and R4 is an optionally substituted heteroaryl moiety. The compounds of the invention are useful for treating various disease states, including asthma, chronic obstructive pulmonary disorder, pulmonary inflammation, emphysema, diabetic disorders, inflammatory gastrointestinal tract disorders, immunological/inflammatory disorders, cardiovascular diseases, neurological disorders, and diseases related to angiogenesis.