3967-19-9

Upstream product

• 3886-08-6 5-tert-butyl N-benzyloxycarbonyl-L-glutamate 
• 64-17-5 ethanol 
• 23632-68-0 4(S)-(2-tert-butoxycarbonylethyl)-5-oxo-oxazolidine 3-carboxylic acid benzyl ester 
• 1609945-67-6 bispicolyl amide γ-tert-butyl Z-L-glutamate 
• 100-51-6 benzyl alcohol 

Downstream Products

• 336190-93-3 ethyl 2(S)-2-{[(benzyloxy)carbonyl]amino}-5-oxo-5-[9-(4-pyridyl)-3,9-diazaspiro [5.5]undec-3-yl]pentanoate 
• 106383-97-5 (4S)-4-{[(4-methylphenyl)sulfonyl]amino}-5-ethoxy-5-oxopentanoic acid 
• 685545-27-1 (S)-2-(n-butoxycarbonylamino)-5-[2-(4-carbamimidoylphenyl)-1-oxo-2,8-diazaspiro[4.5]dec-8-yl]-5-oxopentanoic acid ethyl ester 
• 685544-92-7 (S)-5-{2-[4-(aminohydroxyaminomethyl)phenyl]-1-oxo-2,8-diazaspiro[4.5]dec-8-yl}-2-(n-butoxycarbonylamino)-5-oxopentanoic acid ethyl ester 
• 685544-58-5 (S)-2-(n-butoxycarbonylamino)-5-[2-(4-cyanophenyl)-1-oxo-2,8-diazaspiro[4.5]dec-8-yl]-5-oxopentanoic acid ethyl ester 
• 5672-81-1 (4S)-4-{[(benzyloxy)carbonyl]amino}-5-ethoxy-5-oxopentanoic acid 

Relevant academic research and scientific papers

Efficient Transfer of Chelating Amides into Different Types of Esters and Lactones

We describe a general and versatile approach for the conversion of carboxylic acid amides into their corresponding esters despite the fact that the former are thermodynamically more stable. The transformations are mediated by the coordination of CuI by a chelating entity. The resulting weakening of the amide bond allows for nucleophilic attack by alcoholic hydroxyl functions. The principle is demonstrated for a wide variety of transformations, leading to different kinds of esters and lactones. Due to their high resonance energy, amides are generally very stable towards solvolysis. However, bispicolylamides can be activated for alcoholysis by an unusual metal coordination involving the electron pair of the amide nitrogen. Herein, we widened the scope of the reaction by transforming the amides into a range of esters and lactones.

Discovery of Novel 2,8-Diazaspiro[4.5]decanes as Orally Active Glycoprotein IIb-IIIa Antagonists

In our efforts to develop orally active GPIIb-IIIa antagonists with improved pharmaceutical properties, we have utilized a novel 2,8-diazaspiro[4.5]decane scaffold as a template. We describe here our investigation of a variety of templates including spiropiperidinyl-γ -lactams, spiropiperidinylimide, spiropiperidinylureas, and spiropiperidinylhydantoins. With the appropriate acidic and basic pharmacophores in place, each template yielded analogues with potent GPIIb-IIIa inhibitory activity. One of the compounds, 59 (CT50787), was also used to demonstrate for the first time the use of a pharmacological agent which is αIIbβ3 specific to display biological activity in a lower species such as mouse and to extend bleeding times. Evaluation of the pharmacokinetic properties of selected compounds from each series in rat, dog, and cynomolgus monkey has led to the identification of 22 (CT51464), a double prodrug, with excellent pharmacokinetic properties. It exhibited good pharmacokinetic profile across species (F% = 33 (Cyno), 73 (dog), 22 (rat); t1/2β = 14. 2 h (Cyno), 8.97 h (dog), 1.81 h (rat)). The biologically active form, 23 (CT50728), displayed inhibition of platelet aggregation in platelet rich plasma (PRP) with an IC50 value of 53 nM in citrate buffer, 110 nM in PPACK anticoagulated PRP, and 4 nM in solid-phase GPIIb-IIIa competition binding assay (ELISA). Both 23 and 22 were stable in human liver microsomes, did not inhibit the P450 3A4 isozyme, and had low protein binding (18.22% for 23) and a desirable log P (0.45 ± 0.06 for 22, and -0.91 ± 0.32 for 23). It is predicted that the high oral bioavailability for these compounds in multiple species should translate into lower intra- and intersubject variability in man. The long plasma half-life of the lead is consistent with once or twice daily administration for chronic therapy. Analogue 22 (CT51464) thus appears to be a promising oral GPIIb-IIIa inhibitor with significantly improved pharmacokinetic properties over the previously described clinical candidates and may be found useful in the treatment of arterial occlusive disorders.

Pyridyl-containing spirocyclic compounds as inhibitors of fibrinogen-dependent platelet aggregation

Disclosed are certain substituted or unsubstituted pyridyl-containing spirocyclic compounds substituted with both basic and acidic functionality, which are useful in inhibiting platelet aggregation, inhibiting the binding of fibrinogen to blood platelets, and preventing or treating thrombosis

Spirocyclic nonpeptide glycoprotein IIb-IIIa antagonists. Part 1: Design of potent and specific 3,9-diazaspiro[5.5]undecanes

The synthesis and biological activity of novel glycoprotein IIb-IIIa antagonists containing the 3,9-diazaspiro[5.5]undecane nucleus are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the spirocyclic structures as a central template for nonpeptide RGD mimics.

Cleavage of benzyloxycarbonyl-5-oxazolidinones to α-benzyloxycarbonylamino-α-alkyl esters by alcohols and sodium hydrogen carbonate

The reaction of benzyloxycarbonyl-5-oxazolidinones with alcohols and sodium hydrogen carbonate to afford the corresponding benzyloxycarbonyl esters is described.