441715-25-9

Downstream Products

• 793669-62-2 trans-4-((2S,4S)-1-{2,5-dichloro-4-[(1-methylindol-3-yl)carboxamido]phenyl}acetyl-4-methoxypyrrolidin-2-yl)methoxycyclohexane-1-carboxylic acid ethyl ester 
• 871979-10-1 3-[2-[1-[2,5-dichloro-4-(1-methyl-3-indolylcarbonylamino)phenylacetyl]-(4S)-methoxy-(2S)-pyrrolidinyl]-5-oxazolyl]propionic acid methyl ester 

Relevant academic research and scientific papers

Discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido) phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: An orally active, selective very late antigen-4 antagonist

We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3- indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-( 2S)-pyrrolidinylmethoxy] cyclohexanecarboxylic acid (14e) with potent activity (IC50 = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

PROCESS FOR PRODUCING PHENYLACETIC ACID DERIVATIVE

The present invention provides an advantageous process for producing an intermediate which is useful for producing a compound which exhibits excellent VLA-4 inhibitory effect and safety. Intermediates (III) and (XIII) are produced through conversion throu

METHOD FOR PRODUCING PYRROLIDINE DERIVATIVE

The present invention provides an advantageous method for producing an intermediate which is useful for production of a compound which exhibits excellent VLA-4 inhibitory effect and safety. An intermediate (14) is produced through the following reaction s

PROCESS FOR PRODUCING PYRROLIDINE DERIVATIVE

This invention provides an industrially useful process for producing 1,4-transcyclohexanecarboxylic acid derivative (1) which has excellent VLA-4 inhibitory action and safety, and an intermediate which is useful in such method. More particularly, this inv