- Synthesis of fused indazole ring systems and application to nigeglanine hydrobromide
-
The single-step synthesis of fused tricyclic pyridazino[1,2-a]indazolium ring systems is described. Structural details revealed by crystallography explain the unexpected reactivity. The method is applied to the gram scale synthesis of nigeglanine hydrobro
- Sather, Aaron C.,Berryman, Orion B.,Rebek, Julius
-
supporting information; experimental part
p. 1600 - 1603
(2012/06/05)
-
- The effects of ring substituents and leaving groups on the kinetics of SNAr reactions of 1-halogeno- and 1-phenoxy-nitrobenzenes with aliphatic amines in acetonitrile
-
Rate constants are reported for the reactions of a series of 1-chloro-, 1-fluoro- and 1-phenoxy-nitrobenzenes activated by CF3 or CN groups or by ring-nitrogen with n-butylamine, pyrrolidine or piperidine in acetonitrile. The results are compar
- Crampton, Michael R.,Emokpae, Thomas A.,Isanbor, Chukwuemeka
-
p. 1378 - 1383
(2008/09/18)
-
- Repaglinide and related hypoglycemic benzoic acid derivatives
-
The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethylpiperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5- fluoro, and the α-methyl residue were replaced by a 2-piperidino, a 5- hydrogen, and a larger α-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)- enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 μg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known - the acidic group (COOH; S02NH) and the amidic spacer (CONH; NHCO) - the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.
- Grell, Wolfgang,Hurnaus, Rudolf
-
p. 5219 - 5246
(2007/10/03)
-