- Dependence of the γ Carbon-13 Shielding Effect on Electronegativity
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Three γ effects on 13C shielding in 3,3-dimethyltetracyclohexanes as a function of the hetero-atom X have been examined.The γ-anti effect on the equatorial 3-methyl group is small in absolute magnitude but strongly dependent on the polar properties of X.The plot of the 13C shielding of this carbon vs the electronegativity of X is linear, with a slope of -5.8 ppm/electronegativity unit.The γ-gauche effects on the axial 3-methyl group and on the 4-carbon are large in absolute magnitude but have quite different dependences on the polar properties of X.Whereas the shielding of the 4-carbon exhibits a linear dependence on electronegativity (slope -3.5), the axial 3-methyl group shows little dependence (slope crudely -0.7), even though the geometric relationship between X and either carbon is almost the same.Neither gauche carbon shielding appears to be related to the steric properties of X.The polar component of both the γ-anti effect and the γ-gauche effect is interpreted as arising from overlap of appropriately positioned parallel orbitals.For the anti case, the pathway is the familiar zigzag arrangement of bonds.For the gauche case, the pathway may be either through space (the orbitals would be only on X and C-α; for the 4-carbon, this interaction would be through the center of the ring) or through bonds (there are parallel axial orbitals on all four atoms).The absence of a significant polar effect for the axial 3-methyl group suggests that the gauche interaction requires a rigid pathway.The polar component of the general γ-gauche effect is superimposed upon a larger contribution that is essentially independent of the nature of X and may be associated with the removal of the hydrogen on the β-carbon and replacement with the γ-X group.
- Lambert, Joseph B.,Vagenas, Adelia R.
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- A multireceptorial binding reinvestigation on an extended class of σ ligands: N-[ω-(indan-1-yl and tetralin-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine reveal high affinities towards σ1 and EBP sites
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New 1-[ω-(2,3-dihydro-1H-inden-1-yl)- and (2,3-dihydro-5-methoxy-1H-inden-1-yl)alkyl]- and 1-[ω-(1,2,3,4-tetrahydronaphthalen-1-yl)- and (6-methoxy- or 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine were synthesized, as homologous compounds of an existing series of σ ligands, in order to carry out σ receptor subtypes structure-affinity relationships. The new compounds and some of their related analogues, already reported, were tested in new multireceptorial radioligand binding assays. As reference compounds, the known σ1 ligands SA 4503, BD 1008 and NE 100 were also prepared and tested. All reported compounds showed high σ1 affinity assayed by (+)-[3H]-pentazocine on guinea-pig brain (apparent Ki=1.75-72.2 nM) and moderate or low σ2 affinity by [3H]-DTG on rat liver, in contrast with previous results. One tertiary amine function spaced by a five-membered chain from a phenyl group is the structural feature shared by the most active compounds 26 and 43 and some reference σ1 ligands. The reported σ1 ligands, including reference compounds, also demonstrated a high affinity towards EBP (Δ8-Δ7 sterol isomerase) site (apparent Ki=0.48-14.8 nM) and some of them (37 and 44) were good ligands at L-type Ca++ channel. 1-[4-(2,3-Dihydro-1H-inden-1-yl)butyl]-3,3-dimethylpiperidine (26) was the best mixed σ1 and EBP ligand (apparent Ki=1.75 and 1.54 nM, respectively) with a good selectivity versus σ2 receptor (138- and 157-fold, respectively).
- Berardi, Francesco,Ferorelli, Savina,Colabufo, Nicola Antonio,Leopoldo, Marcello,Perrone, Roberto,Tortorella, Vincenzo
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- Development of the route of manufacture of an oral H1-H 3 antagonist
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A new route to an H1-H3 antagonist was developed to address scalability and environmental and cost of goods issues associated with the initial route.
- Harling, Sandra J.,Herbal, Karim,Langlade, Nathalie,Sanganee, Mahesh,Strachan, John B.,Turner, Peter G.,Whiting, Matthew P.,Bret, Guillaume,Loft, Mike,Negus, Alan,Shanahan, Steve
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p. 112 - 122
(2011/10/13)
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- 3- (4-{ [4-(4-{ [3-(3, 3-DIMETHYL-1-PIPERIDINYL) PROPYL] 0XY} PHENYL) -1-PIPERIDINYL] CARBONYL }-1-NAPHTHALENYL) PROPANOIC OR PROPENOIC ACID AS H1 AND H3 RECEPTOR ANTAGONISTS FOR THE TREATMENT OF INFLAMMATORY AND/OR ALLERGIC DISORDERS
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The present invention relates to a compound of formula (I), or a salt thereof wherein the naphthalene ring can be substituted in the 2, 3, 4, 5, 6, 7 or 8 position by R1, and R1 represents -CH2CH2COOH or -CH=C(CH3)COOH, and to processes for their preparation, to compositions containing them and to their use in the treatment of various diseases such as allergic rhinitis.
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Page/Page column 40-41
(2008/06/13)
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