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ON THE QUANTITATIVE RELATIONS BETWEEN STRUCTURE AND ANTIAGGREGATION ACTIVITY OF omega-ARYL-omega-OXOALKANOIC ACIDS

A series of omega-aryl-omega-oxoalkanoic acids, I-IV, has been prepared and investigated for dissociation constants in 80percent methylcellosolve, retention characteristics in thin-layer partition chromatography and partition coefficients P in the system octanol-water.Also evaluated were their anti-inflammatory efficacy and inhibitory effect on the platelet aggregation induced by collagen.Analysing the relations between structure and antiaggregation effect, we obtained a non-linear, quadratic dependence of this effect on lipophilicity, the optimum being at log P = 3.The antiaggregation effect increased with shortening the chain between the carbonyl and the carboxyl, and with increasing acidity.It was also diminished by the presence of a methyl group on the interlinking chain.To assess the role of lipophilicity we used the RM values of partition chromatography.The relation between anti-inflammatory efficacy and structure was assessed only qualitatively.In this aspect, too, the nature of the chain between the carbonyl and carboxyl proved to have a marked influence.The anti-inflammatory activity proved considerably enhanced by the presence of another aromatic ring in omega-oxoalkanoic acids derived from biphenyl.

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Reactions of Trialkylsilyl Trifluoromethanesulfonates, VIII. – Synthesis of O-(Trimethylsilyl)ketene O,N-Acetals, 2,5-Bis(trimethylsiloxy)pyrroles, -furans, and -thiophenes

Ketene O,N-acetals 3, 4, 6, 8 are obtained from N,N-diarylcarboxamides and N-acetylheterocycles 5, 7 by silylation with trimethylsilyl triflate (2) in the presence of triethylamine.Analogous reactions of carboxamides 9 and N-acyllactams 11 yield the ketene O,N-acetals 10, 12.Succinimides 13, succinic anhydrides 20, and succinic thioanhydrides 22 are doubly silylated by 2 to give the 2,5-bis(trimethylsiloxy)heterocycles 14, 21, 23. 2,5-Bis(trimethylsiloxy)furan (21a) reacts with aldehyde acetals and orthoesters 24 catalyzed by 2 to yield 2,3-disubstituted succinic anhydrides 25.

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Application of a double Mannich reaction using bis(aminol) ethers in the synthesis of AE ring analogues of methyl lycaconitine

An efficient method for the construction of azabicyclo[3.3.1]nonanes and azabicyclo[3.2.1]octanes is reported via double Mannich reaction of cyclic ketoesters with bis(aminol) ethers. This method is applied to the synthesis of AE ring analogues of methyl lycaconitine.

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On the regioselectivity of Wittig reactions with unsymmetrically substituted succinic anhydrides

Phosphorane ylids react readily with succinic anhydrides to give enol-lactones.With highly substituted succinic anhydrides, condensation occur at the less substituted carbonyl group, suggesting that the reaction is sterically controlled.This, however, is not the case in monosubstituted anhydrides where effects other than steric become dominant.Condensation of phosphorane 1a with methoxysuccinic anhydride occurs selectively at the carbonyl group adjacent to the substituent.Stabilization of the transition state through complexation between the oxygen atom of the substituent and an electron-deficient phosphorus of the ylid is proposed.Key words: cyclic anhydrides; Wittig reaction, regioselectivity; stabilized ylid.

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Synthesis and vasodilatory activity of some amide derivatives of 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone

Synthesis and vasodilatory activity of some amide derivatives of 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone are reported. An effect of substitution at 2-position of pyridazinone ring on vasodilatory potential has also been explored. The most active compound 6-[4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)phenyl]-2-(4-fluorophenyl)-4,5-dihydropyridazin-3(2H)-one (11) exhibited vasodilating activity in nanomolar range (IC50 = 0.051 muM).

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Succinimide derivatives. II. Synthesis and antipsychotic activity of N- [4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]1,2-cis- cyclohexanedicarboximide (SM-9018) and related compounds

Cyclic imides bearing omega-(4-benzisothiazol-3-yl-1-piperazinyl)alkyl moieties were synthesized and tested for antipsychotic activity. The in vitro binding affinities of these compounds were examined for dopamine 2 (D2) and serotonin 2 (5-HT2) receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, N-[4-[4-(1,2- benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis-cyclohexanedicarboximide (SM-9018), was found to be more potent and more selective in vivo than tiospirone in its antipsychotic activity. SM-9018 (17) is currently undergoing clinical evaluation as a selective antipsychotic agent.

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Application of olefin metathesis to the synthesis of ABE ring analogues of methyllycaconitine

The synthesis of four novel ABE ring analogues of methyllycaconitine (MLA) is reported, employing olefin metathesis as the key step for appending the seven-membered B ring onto an AE bicyclic ring system. This strategy allows the stereodivergent synthesis of ABE ring analogues in which the stereochemistry of the AB ring junction is well defined. The compounds are designed as ligands to study binding and function of the alpha7-nAChR.

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Tetrahydrofuran – Wikipedia,
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CYCLOALKYL-FUSED TETRAHYDROQUINOLINES AS CRTH2 RECEPTOR MODULATORS

The invention provides certain cycloalkyl-fused tetrahydroquinolines of the Formula (I), and their pharmaceutically acceptable salts and esters, wherein R1, R2, R7, R8, R8a, E, Y, Z, n, u, and t are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions associated with uncontrolled or inappropriate stimulation of CRTH2 function.

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Quantitative Measurements of Polymer Hydrophobicity Based on Functional Group Identity and Oligomer Length

A combined experimental and computational investigation revealed a hydrophobicity trend for oxygen-containing functional groups commonly encountered in monomers and polymers. Based on solvatochromatic dye experiments, HPLC retention times, and theoretical LogP values, the arrangement of the three oxygen atoms in carbonates results in more hydrophobicity than other permutations like anhydrides. Another trend emerged for functional groups with two oxygen atoms (acetals > esters). Overall, when comparing aliphatic polymers with similarly sized monomers, hydrophobicity decreased as follows: carbonates > acetals > esters > anhydrides. These trends have important implications for degradation, conductivity, and many other applications.

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Effect of Ligand on Ring Contraction of Six-Membered Nickel-Containing Cyclic Esters, , to Their Five-Membered-Ring Isomers, . Kinetic and Thermodynamic Control of Asyammetric Induction by Chiral Diphosphines in the Ring Contraction

Ring contraction of (1) to (2) is accelerated by coordination of bulky ligands: coordination of a bulky diphosphine like 1,2-bis(diphenylphosphino)ethane (dpe) causes an extensive ring contraction to afford (dpe).Use of a chiral diphosphine affords a mixture of unequal amounts of diastereomers (chiral diphosphine)-(R) ((R)-2) and (chiral diphosphine)-(S)- ((S)-2).When (S,S)-chiraphos is used, (R)-2 is kinetically favored, but it isomerizes to thermodynamically favored (S)-2 obeying the first-order kinetics.The equilibrated reaction mixture after the isomerization contains ((S,S)-chiraphos) in 54percent diastereomer excess at 24 deg C, and the kinetic and thermodynamic parameters for the R to S isomerization are as follows: DeltaH = 93 +/- 2 kJ/mol, DeltaS = -8 +/- 6 J/(K mol), DeltaG = 95 kJ/mol, DeltaH = 13 +/- 2 kJ/mol, DeltaS = 54 +/- 6J (K mol), and DeltaG = -3.0 kJ/mol at 24 deg C.Use of (R,R)-dipamp gives a result opposite to that of (S,S)-chiraphos concerning the kinetically and thermodynamically favored species.Data obtained by use of (R)-prophos, trans-cypenphos, and trans-renorphos are also given.The kinetic and thermodynamic control of the asymmetry can be explained by considering the effects of arrangement of two phenyl groups bonded to each phosphorous atom of the diphosphine ligands on the metallacycle entity.

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Tetrahydrofuran – Wikipedia,
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