- Effects of the pyridine 3-substituent on regioselectivity in the nucleophilic aromatic substitution reaction of 3-substituted 2,6-dichloropyridines with 1-methylpiperazine studied by a chemical design strategy
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A chemical design strategy has been used to select 3-substituted 2,6-dichloropyridines for the nucleophilic aromatic substitution reaction with 1-methylpiperazine. The aim was to study the dependency of the regioselectivity in these reactions on the character of the pyridine 3-substituent expressed by their lipophilicity (PI), size (MR), and inductive effect (Ip). Interestingly, the regioselectivity did not correlate with any of these parameters, but in a statistically significant manner with the Verloop steric parameter B1, as indicated by the p value of 0.006 (R2 = 0.45). This implies that bulky 3-substituents close to the pyridine ring induce regioselectivity towards the 6-position. Useful in practical synthesis is the different regioselectivity obtained with a carboxylic acid 3-substituent and precursors or derivatives thereof. Thus, in acetonitrile as solvent, 3-carboxylate and 3-amide substituents were preferred to obtain the 2-isomer (9:1 ratio of the 6-isomer), whereas the 3-cyano and 3-trifluoromethyl substitutents were preferred to obtain the 6-isomer (9:1 ratio of the 2-isomer). Analysis of the regioselectivity Rsel for the pyridine 2-position in the reaction of 2,6-dichloro-3-(methoxycarbonyl)pyridine with 1-methylpiperazine in 21 different solvents showed that Rsel could be predicted by the Kamlet-Taft equation: Rsel = 1.28990 + 0.03992α - 0.59417β - 0.46169π* (R2 = 0.95, p = 1.9 × 10-10). Rsel is thus mainly correlated with the ability of the solvent to function as a hydrogen-bond acceptor, as expressed by the solvatochromic β parameter. Thus, the 16:1 regioselectivity for the 2-isomer in DCM (β = 0.10) could be switched to a 2:1 selectivity for the 6-isomer in DMSO (β = 0.76). Copyright
- Bach, Peter,Marczynke, Michaela,Giordanetto, Fabrizio
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p. 6940 - 6952
(2013/02/22)
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- Substituted nitrogen-containing heteroaryl derivatives useful as modulators of the histamine H4 receptor
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The present invention relates to substituted nitrogen-containing heteroaryl derivatives, pharmaceutical compositions containing them, and methods of using any of these derivatives and compositions for H4 receptor activity modulation and the tre
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Page/Page column 66
(2009/04/24)
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- IMIDAZOPYRIDINE COMPOUND
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A compound represented by the following general formula (1), or a salt or hydrate thereof: wherein R1 represents a C1-C6 alkyl group or C2-C6 alkynyl group which may be substituted, or a phenyl group which may be substituted, R2 represents a hydrogen atom or a C1-C6 alkyl group, R3 represents methyl or ethyl group, R4 represents a C1-C6 alkyl group, R5 represents a hydrogen atom, provided that a compound wherein R1 is a C1-C6 alkyl group unsubstituted or substituted with a halogen atom and R2 is a hydrogen atom is excluded.
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Page/Page column 71-72
(2010/02/14)
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- TRISUBSTITUTED ARYL AND HETEROARYL DERIVATIVES AS MODULATORS OF METABOLISM AND THE PROPHYLAXIS AND TREATMENT OF DISORDERS RELATED THERETO
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The present invention relates to certain trisubstituted aryl and heteroaryl derivatives of Formula (I) that are modulators of metabolism. Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such as, diabetes and obesity.
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Page/Page column 183; 184
(2008/06/13)
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