22410-94-2

Upstream product

• 22388-54-1 Ethyl-γ-(o-hydroxybenzamido)butyrat 
• 56-12-2 4-amino-n-butyric acid 
• 69-72-7 salicylic acid 
• 5538-51-2 O-acetylsalicyloyl chloride 
• 188578-09-8 4-(3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)butyric acid 

Relevant academic research and scientific papers

Hydroxybenzoyl Chlorides in the Synthesis of Conjugates with Biologically Active Dipeptides

Abstract: Conjugates of hydroxy- and acetoxybenzoic acids with dipeptides based on 4-aminobutanoic acid and glycine were synthesized through hydroxy(acetoxy)benzoyl chlorides and 4-[hydroxy(acetoxy)benzoyl-amino]butanoyl chlorides as intermediate products. Acyl chlorides were prepared by treatment of the corre-sponding acids with oxalyl chloride in the presence of dimethylformamide at a ratio of 1:1.1:0.07 in boiling benzene. The target N-[hydroxy(acetoxy)benzoyl] derivatives of dipeptides were obtained with high yields, and no further purification of the products was necessary. The synthesized compounds were evaluated as potential neuroprotective agents.

Compounds and compositions for delivering active agents

The present invention provides a compound having the formula or a salt thereof which facilitates the delivery of active agents. Compositions and dosage unit forms comprising the compound of the present invention and at least one active agent, such as a peptide, mucopolysaccharide, carbohydrate, or a lipid, are also provided. Methods of administration and preparation of the compounds and compositions of the invention are provided as well.

Studies directed at the use of a parallel synthesis matrix to increase throughput in an in vivo assay

Heparin is the anticoagulant of choice for hospitalized patients, but it is dosed only by injection because it is not absorbed following oral administration. We have discovered and prepared compounds (delivery agents) that facilitate the gastrointestinal absorption of heparin in rats, monkeys, and humans when given orally. We are currently developing a parallel synthesis approach to increase our delivery agent screening throughput in vivo. This approach has been used to produce micromolar quantities of compounds for testing in rats in a 5 x 5 parallel synthesis array. Using an amine benzoylation reaction sequence, 10 mixtures were prepared. These mixtures contained equal weight quantities of five N-substituted, non-α, amino acid delivery agents. Each of these mixtures was orally administered to rats in combination with heparin, and plasma clotting times (APTT) were measured to determine activity. Deconvolution of the data accurately identified the most active individual components. Independent synthesis of these compounds verified their activity. This parallel synthesis approach is an effective tool for the screening of oral heparin delivery agents and has increased screening throughput significantly.

Synthesis and evaluation of compounds that facilitate the gastrointestinal absorption of heparin

A family of novel compounds (delivery agents) that promote the gastrointestinal absorption of USP heparin in rats and primates has been discovered. The delivery agents in combination with heparin were administered either orally or intracolonically in an aqueous propylene glycol solution and caused dramatic increases in both plasma heparin concentrations (anti-Factor Xa) and clotting times (APTT). Using one of the most effective delivery agents in this series, an estimated relative bioavailability of 8% can be achieved following oral administration to cynomolgus monkeys. To establish a correlation between the in vivo data and an in vitro parameter, immobilized artificial membrane (IAM) chromatography was performed. Log relative k' values were correlated to the efficiency of oral heparin delivery.

Synthesis, stability and anticonvulsant activity of two new GABA prodrugs

4-(3,4-Dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)-butyric acid (7) and its ethyl ester 6, two potential γ-aminobutyric acid (GABA) prodrugs, were synthesized and studied to determine their stability in aqueous buffer and their susceptibility to undergo enzymatic hydrolysis in vitro (mouse plasma). Both compounds were fairly stable in aqueous media, (t( 1/4 ) = 68.2 h and 25.7 h, respectively). The 3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazine ring underwent enzymatic hydrolysis (t( 1/4 ) = 5.8 h) in compound 7, whereas in compound 6 it seemed not to be opened by mouse plasma esterases within the observation time (3 h). Both compounds were tested for their anticonvulsant activity in pentetrazole (PTZ) treated mice, and showed significant activity. Compound 7, administered as sodium salt 8, was active at relatively low doses and can be considered a very interesting GABA prodrug.