137415-94-2Relevant academic research and scientific papers
Heterocyclic group transfer reactions with I(iii): N -HVI reagents: Access to N -alkyl(heteroaryl)onium salts via olefin aminolactonization
Tierno, Anthony F.,Walters, Jennifer C.,Vazquez-Lopez, Andres,Xiao, Xiao,Wengryniuk, Sarah E.
, p. 6385 - 6392 (2021)
Pyridinium and related N-alkyl(heteroaryl)onium salts are versatile synthetic intermediates in organic chemistry, with applications ranging from ring functionalizations to provide diverse piperidine scaffolds to their recent emergence as radical precursors in deaminative cross couplings. Despite their ever-expanding applications, methods for their synthesis have seen little innovation, continuing to rely on a limited set of decades old transformations and a limited subset of coupling partners. Herein, we leverage (bis)cationic nitrogen-ligated I(iii) hypervalent iodine reagents, or N-HVIs, as "heterocyclic group transfer reagents"to provide access to a broad scope of N-alkyl(heteroaryl)onium salts via the aminolactonization of alkenoic acids, the first example of engaging an olefin to directly generate these salts. The reactions proceed in excellent yields, under mild conditions, and are capable of incorporating a broad scope of sterically and electronically diverse aromatic heterocycles. The N-HVI reagents can be generated in situ, the products isolated via simple trituration, and subsequent derivatizations demonstrate the power of this platform for diversity-oriented synthesis of 6-membered nitrogen heterocycles.
Synthesis and antimuscarinic properties of some N-substituted 5- (aminomethyl)-3,3-diphenyl-2(3H)-furanones
Kaiser,Spagnuolo,Adams Jr.,Audia,Dupont,Hatoum,Lowe,Prosser,Sturm,Noronha-Blob
, p. 4415 - 4424 (2007/10/02)
In a study aimed toward developing new, selective antimuscarinic drugs with potential utility in the treatment of urinary incontinence associated with bladder muscle instability, a series of N-substituted 5-(aminomethyl)- 3,3-diphenyl-2(3H)-furanones, conformationally-constrained lactone relatives of benactyzine, was prepared. The compounds were examined in several paradigms that measure muscarinic (M1, M2, and M3) receptor antagonist activity. Selected members of the series that displayed potency and/or selectivity in these tests were studied for their effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. These studies revealed that incorporation of the amino functionality into an imidazole or pyrazole ring resulted in some novel, potent, and selective antimuscarinic agents. Appropriate alkyl substitution of position 2 of the imidazole strikingly affected muscarinic, particularly M3, receptor activity and may reflect a complementary site of interaction. Some of the compounds selectively reduced bladder pressure in a cystometrogram (CMG) model without producing concomitant mydriatic and salivary effects. The separate and distinct action of several compounds of this series in these in vivo protocols suggests the possibility of subtypes of muscarinic receptors that may correspond to previously characterized molecular cloned subpopulations. In this article, structure-activity relationships for the series of substituted lactones are discussed. These studies led to the identification of (R)-[(2-isopropyl-1H- imidazol-1-yl)methyl]-4,5-dihydro-3,3-diphenyl-2(3H)-furanone (23) as a clinical candidate for treating urinary bladder dysfunction.
5-(1-(IMIDAZOL)METHYL)-3,3-DISUBSTITUTED-2(3H)FURANONE DERIVATIVES
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, (2008/06/13)
Furanone compounds and compositions having anticholinergic activity are described. The compounds have the formula: STR1 wherein: the dashed line indicates either the 4,5-unsaturated or the 4,5-dihydrofuranone ring;R 1 and R 2 may be the same or different and are hydrogen, thienyl, furanyl, or cycloalkyl (C. sub.3-C 6), benzyl, phenyl, substituted phenyl or substituted benzyl wherein the phenyl or benzyl group may be substituted with halogen, trifluoromethyl, lower alkyl, lower alkoxy or hydroxy;R. sub.3, R 4 and R 5 may be the same or different and are hydrogen, lower alkyl, lower alkyl substituted with a halogen, alkoxy, amino or carboxylic acid group, an alkyl or alkylene bridge between R 4 and R. sub.5 or R 3 and the ring N, trifluoromethyl, nitro, a cycloalkyl group containing 3 to 6 carbons, halogen, benzyl, phenyl, substituted phenyl or substituted benzyl, for which the substituents are the same as those set forth for R 1 and R 2 substituted benzyl or phenyl.R 6 in the dihydrofuranone series is hydrogen or lower alkyl.Also described are the pharmaceutically acceptable quaternary alkyl and acid addition salts of such compounds. The compounds are particularly useful in the treatment of neurogenic bladder disorder and chronic obstructive pulmonary diseases.
