258331-10-1

Upstream product

• 75-65-0 tert-butyl alcohol 
• 614-75-5 2-Hydroxyphenylacetic acid 
• 115-11-7 isobutene 
• 24424-99-5 di-tert-butyl dicarbonate 
• 70340-04-4 (2-hydroxybenzyl)triphenylphosphonium bromide 
• 95-56-7 2-hydroxybromobenzene 
• 51656-70-3 (2-tert-butoxy-2-oxoethyl)zinc(II) bromide 

Downstream Products

• 258330-89-1 tris(phenyl-2-acetic acid) trimesate 

Relevant academic research and scientific papers

Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach

The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1′ pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

AMIDOMETHYL-BIARYL DERIVATIVES COMPLEMENT FACTOR D INHIBITORS AND USES THEREOF

The present invention provides a compound of formula (I): (I) a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

AMINOMETHYL-BIARYL DERIVATIVES AS COMPLEMENT FACTOR D INHIBITORS AND USES THEREOF

The present invention provides a compound of formula (I), a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical com

Palladium-catalyzed α-arylation of zinc enolates of esters: Reaction conditions and substrate scope

The intermolecular α-arylation of esters by palladium-catalyzed coupling of aryl bromides with zinc enolates of esters is reported. Reactions of three different types of zinc enolates have been developed. α-Arylation of esters occurs in high yields with i

PYRROLIDINE-2-CARBONITRILE DERIVATIVES AND THEIR USE AS INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV (DPP-IV)

The present invention relates to compounds of formula (I), (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, b-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.

Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)

The present invention relates to compounds of formula (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, β-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.

Palladium-catalyzed α-arylation of esters and amides under more neutral conditions

Two procedures for the ∞-arylation of carbonyl compounds under conditions that are more neutral than those of reactions of aryl halides with alkali metal enolates are reported. The first procedure rests upon the development of catalysts bearing the hindered pentaphenylferrocenyl di-tert-butylphosphine (Q-phos) and the highly reactive dimeric Pd(I) complex {P(t-Bu)3]PdBr}2. By this procedure, zinc enolates prepared from ∞-bromo esters and amides react with aryl halides to form ∞-aryl esters and amides in high yields under mild conditions with 1-2 mol % catalyst and with remarkable functional group tolerance. By the second procedure, silyl ketene and silyl ketimine acetals react with aryl bromides in the presence of substoichiometric zinc fluoride, 1 mol % Pd(dba)2, and 2 mol % P(t-Bu)3 in DMF solvent at 80 °C. Reactions of zinc tert-butyl acetate and propionate enolates and trimethylsilyl ketene acetals of tert-butyl propionate and methyl isobutyrate with aryl bromides bearing electron-donating and potentially reactive, base-sensitive electron-withdrawing groups and with pyridyl bromides are reported. In addition, the diastereoselective coupling of phenyl bromide with an imide enolate bearing the Evans auxiliary is reported, and this study shows that racemization of base-sensitive stereocenters does not occur during the coupling process under these more neutral conditions. Copyright

Mechanism of Site-Directed Protein Cross-Linking. Protein-Directed Selectivity in Reactions of Hemoglobin with Aryl Trimesates

Site-directed cross-linking of hemoglobin has become an efficient way to produce a structurally defined altered protein with desirable functional properties. The reagent trimesoyl tris(3,5-dibromosalicylate) (1) introduces a bis amide cross-link derived from the ∈-amino groups of the side chains of the two β-Lys-82 residues in human hemoglobin. The basis of its specificity was investigated using a set of analogues of 1 (2-12). There are marked differences in the reaction patterns of these compounds with amino groups in hemoglobin compared to reactions with n-propylamine. The compounds that effectively modify the protein contain a carboxyl group ortho to the phenolic oxygen of the ester, while materials with meta or para carboxyl groups give little or no reaction. In contrast, the reactions with n-propylamine are slowest with the ortho carboxyl materials. Addition of the unreactive compound 5 to a solution containing hemoglobin reduces the ability of 1 to modify the protein, showing that the unreactive compound binds but does not react. On the basis of these observations and the known reaction patterns of salicylates, it is clear that the environment in the protein controls the reaction, regardless of the inherent reactivity of the reagent. We propose that the carboxyl group positions the reagent critically within the protein. Only the ortho arrangement permits transfer of the acyl function to the nucleophile.

Orally active β-lactam inhibitors of human leukocyte elastase. 2. Effect of C-4 substitution

The effect of changing the C-4 substituent of 3,3-diethyl-1- [(benzylamino)carbonyl]-2-azetidinone on inhibition of HLE and in a model of HLE-induced lung damage in hamsters was explored. Substituents at this position do not appear to interact strongly with HLE with the most potent compounds having k(obs)/[I] = 6900 M-1 s-1. However, substituents at this position had a marked effect on in vivo activity. The greatest oral activity in the lung hemorrhage assay was achieved with C-4 aryl carboxylic acid ethers (60-85% inhibition at 30 mg/kg po). Based upon the established mechanism of inhibition by these compounds, the C-4 substituent would be released, and therefore, the pharmacological potential of these C-4 substituents was of considerable concern. Fortunately, compounds containing 4-hydroxybenzoic acid and 4-hydroxyphenylacetic acid ethers at C-4 were among the most active analogs. These phenolic acids are also found as urinary metabolites in healthy humans. Other heteroaryls at C-4 were also orally active in this model despite relatively modest enzyme activity.