Preparation of tyrosine amide derivatives as Rho-​kinase inhibitors

The invention relates to compds. of formula I and pharmaceutically acceptable salts and solvates thereof (wherein X1 and X2 are independently CH and N; p = 1 - 3; each R when present is halo; R0 and R1 are independently H, halo, CN, etc.; R2 and R3 are independently H, C1-​6 alkyl, C3-​10 cycloalkyl, etc.; R4 and R5 are independently H, C1-​6 alkyl, C1-​6 aminoalkyl, etc.; R6 is H, C1-​6 (halo)​alkyl, etc.;) as Rho kinase inhibitors, methods of prepg. such compds., pharmaceutical compns. contg. them and therapeutic use thereof. Particularly the compds. of the invention may be useful in the treatment of many disorders assocd. with ROCK enzymes mechanisms, such as pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD)​, idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH)​. Example compd. II was prepd. by a multistep procedure (procedure given)​. The invention compds. were evaluated for their ROCK1 and ROCK2 inhibitory activities. From the assay, it was detd. that compd. II exhibited Ki value of < 3 nM

A formal synthesis of (-)-pumiliotoxin C

An asymmetric synthesis of an advanced intermediate in the synthesis of natural (-)-pumiliotoxin C has been achieved in six steps and in 61% overall yield employing as the key step a highly diastereoselective lithium amide 1,4-conjugate addition to a dienoic ester derived from (R)-(+)-pulegone

Dyad beads and the combinatorial discovery of catalysts

Dyad beads, bearing both a substrate and a catalyst, were prepared to enable direct split and mix bead based screening for catalysis

Flexible strategy for the synthesis of pyrrolizidine alkaloids.

A general strategy for the production of pyrrolizidine alkaloids is described, starting from intermediate (+)-9. The key features are diastereoselective dihydroxylation, inversion at the ring junction by hydroboration of an enamine, and ring closure to form the bicyclo ring system. This route is attractive because of its brevity and versatility; four natural products were prepared with differing stereochemistry and substitution patterns. Finally, this work allowed assignment of the absolute stereochemistry of 2,3,7-triepiaustraline and hyacinthacine A 7

Enantioselective partial reduction of 2,5-disubstituted pyrroles via a chiral protonation approach.

[reaction: see text] The partial reduction of 2,5-pyrrole diester 1 followed by enantioselective protonation in situ to furnish synthetically useful building blocks is described. An enantiomeric excess of up to 74% was achieved using (-)-ephedrine and related analogues as chiral proton sources. The pyrroline product obtained could be recrystallized to give enantiomerically pure material

An enzymatic approach to the desymmetrization of disubstituted pyrrolines.

The enzymatic desymmetrization of 2,2- and 2,5-disubstituted pyrroline compounds is reported in a procedure which gives access to both enantiomers in excellent enantiomeric excess and good yield. The enzyme reaction precursors are formed easily from two readily available substituted pyrroles using both ammonia (Na/NH3) and ammonia-free (Li/DBB) Birch reduction conditions

Quinuclidine derivatives binding to mucarinic M3 receptors

Preparation of quinuclidine salts for the treatment of diseases mediated by the muscarinic M3 receptor