177945-75-4

Upstream product

• 174610-41-4 2-<5-(1,2,4-triazol-4-yl)-1H-indol-3-yl>ethyl alcohol 
• 177947-69-2 2-iodo-4-(1,2,4-triazol-4-yl)aniline 
• 177947-76-1 (3R)-1-(tert-butoxycarbonyl)-3-[(methane-sulfonyloxy)methyl]pyrrolidine 
• 179636-96-5 (3S)-N-(tert-butyloxycarbonyl)-3-<(N-benzylamino)methyl>pyrrolidine 
• 154594-15-7 N-(4-(4H-1,2,4-triazole-4-yl)phenyl)acetamide 
• 122-80-5 N-acetyl-p-phenylenediamine 
• 52761-74-7 4-(4-aminophenyl)-4H-1,2,4-triazole 
• 99735-47-4 (3R)-1-[(R)-1-phenylethyl]-3-(hydroxymethyl)pyrrolidine 
• 177947-99-8 methanesulphonic acid 2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethyl ester 
• 177947-80-7 (3S)-N(H)-3-<(N-benzylamino)methyl>pyrrolidine 

Relevant academic research and scientific papers

PALLADIUM CATALYZED INDOLIZATION

We have found that 2-unsubstituted indoles of structural formula (IV) can be cost-effectively synthesized in high yield by the palladium-catalyzed coupling/ring closure of a 2-halo or 2-trifluoromethylsulfonyloxy aniline (I) and an acyl silane derivative (II), followed by deprotection of the silyl protecting groups. The process of the present invention is particularly useful to form indoles containing acid-labile substituents such as triazole, acetyl, ketal, cyano, and carbamate, or indoles having a good leaving group in the benzyl position. The advantages of the present process are that it does not require the use of triphenyl phosphine or tetrabutyl ammonium chloride or lithium chloride. When applied to 5-triazolyl substituted indoles, the present process also eliminates the tendency of triazolyl polymerization in the Fischer indole synthesis. Still further, the present invention is also directed to the novel intermediates of structural formulae (V) and (VI).

Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1- yl)ethyl]indoles: Potent agonists for the h5-HT(1D) receptor with high selectivity over the h5-HT(1B) receptor

The design, synthesis, and biological evaluation of a novel series of 3- [2-(pyrrolidin-1-yl)ethyl]-indoles with excellent selectivity for h5-HT(1D) (formerly 5-HT(1Dα)) receptors over h5-HT(1B) (formerly 5-HT(1Dβ)) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT(1D) and h5-HT(1B) receptors. The differential expression of h5-HT(1D) and h5-HT(1B) receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT(1D) subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having 9-fold selectivity for h5-HT(1D) over h5-HT(1B) receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT(1D) receptor and 100-fold selectivity with respect to h5-HT(1B) receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT(1D) subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPγS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT(1D) and h5-HT(1B) receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT(1D) receptor domain which is absent for the h5-HT(1B) receptor. The compounds described herein will be important tools to delineate the role of h5-HT(1D) receptors in migraine.

Azetidine, pyrrolidine and piperidine derivatives

A class of substituted azetidine, pyrrolidine and piperidine derivatives are selective agonists of 5-HT1 -like receptors, being potent agonists of the human 5-HT1Dα receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT1Dα receptor subtype relative to the 5-HT1Dβ subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT1D receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT1D receptor agonists.