- Picazoplatin, an azide-containing platinum(II) derivative for target analysis by click chemistry
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Despite the broad use of platinum-based chemotherapeutics, identification of their full range of cellular targets remains a significant challenge. In order to identify, visualize, and isolate cellular targets of Pt(II) complexes, we have modified the chemotherapeutic drug picoplatin with an azide moiety for subsequent click reactivity. The new compound picazoplatin readily binds DNA and RNA oligonucleotides and undergoes facile post-labeling click reactions to alkyne-fluorophore conjugates. Pt-fluorophore click reactions in rRNA purified from drug-treated Saccharomyces cerevisiae demonstrate its potential for future in vivo efforts.
- White, Jonathan D.,Osborn, Maire F.,Moghaddam, Alan D.,Guzman, Lindsay E.,Haley, Michael M.,DeRose, Victoria J.
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Read Online
- An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials
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The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we des
- ?eren, Mario,Aithani, Laksh,Anderson, Mark,Cardoso-Silva, Jonathan,Cincilla, Giovanni,Conduit, Gareth J.,Galushka, Mykola,Guan, Davy,Hallyburton, Irene,Irwin, Benedict W. J.,Kirk, Kiaran,Lehane, Adele M.,Lindblom, Julia C. R.,Lui, Raymond,Matthews, Slade,McCulloch, James,Motion, Alice,Ng, Ho Leung,Robertson, Murray N.,Spadavecchio, Vito,Tatsis, Vasileios A.,Todd, Matthew H.,Tse, Edwin G.,Van Hoorn, Willem P.,Wade, Alexander D.,Whitehead, Thomas M.,Willis, Paul
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supporting information
p. 16450 - 16463
(2021/11/24)
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- Ruthenium-catalyzed ester reductions applied to pharmaceutical intermediates
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Ruthenium pincer complexes were synthesized and used for catalytic ester reductions under mild conditions (～5 bar of hydrogen). An experimental design approach was used to optimize the conditions for yield, purity, and robustness. Evidence for the catalytically active ruthenium dihydride species is presented. Observed intermediates and side products, as well as time-course data, were used to build mechanistic insight. The optimized procedure was further demonstrated through scaled-up reductions of two pharmaceutically relevant esters, both in batch and continuous flow.
- Shaalan, Youssef,Boulton, Lee,Jamieson, Craig
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supporting information
p. 2745 - 2751
(2020/11/30)
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- Iron catalysed selective reduction of esters to alcohols
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The reaction of (dppBIAN)FeCl2 with 3 equivalents of n-BuLi affords a catalytically active anionic Fe complex; the nature of the anionic complex was probed using EPR and IR experiments and is proposed to involve a dearomatized, radical, ligand scaffold. This complex is an active catalyst for the hydrosilylation of esters to afford alcohols; loadings as low as 1 mol% were employed.
- Tamang, Sem Raj,Cozzolino, Anthony F.,Findlater, Michael
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supporting information
p. 1834 - 1838
(2019/02/20)
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- HETEROCYCLIC INHIBITORS OF PCSK9
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This application relates to chemical compounds which may act as inhibitors of, or which may otherwise modulate the activity of, PCSK9, or a pharmaceutically acceptable salt, solvate, prodrug or polymorph thereof, and to compositions and formulations comprising such compounds, and methods of using and making such compounds. Compounds include compounds of Formula (I): (I) wherein A, D and Q are described herein.
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Page/Page column 100; 101; 102
(2018/10/24)
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- Modular Route to Azaindanes
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A convergent radical based route to azaindanes is described, relying on the degenerative addition transfer of various substituted S-(pyridylmethyl)-O-ethyl dithiocarbonates (xanthates) to functional alkenes followed by radical cyclization onto the pyridine ring activated by protonation with trifluoroacetic acid. In one case, a richly decorated cyclohepta[b]pyridine could be assembled swiftly by allowing the first adduct to N-phenylmaleimide to undergo addition to N-allylphthalimide prior to cyclization.
- Huang, Qi,Zard, Samir Z.
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supporting information
p. 3895 - 3898
(2017/07/26)
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- P2X3 AND/OR P2X2/3 COMPOUNDS AND METHODS
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The present application provides novel compounds and methods for preparing and using these compounds. In one embodiment, the compounds are of the structure of formula (I), wherein R1-R4 are defined herein. In a further embodiment, these compounds are useful in method for regulating one or both of the P2X3 or P2X2/3 receptors. In another embodiment, these compounds are useful for treating pain in patients by administering one or more of the compounds to a patient.
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- PROTEIN KINASE INHIBITORS
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The present invention relates to a novel family of inhibitors of protein kinases. In particular, the present invention relates to inhibitors of the members of the Tec and Src protein kinase families.
- -
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Paragraph 0181
(2015/07/15)
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- SPIROHYDANTOIN COMPOUNDS AND THEIR USE AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
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The present invention relates to a compound of formula (1-1 ) in free form or in pharmaceutically acceptable salt form in which the substituents are as defined in the specification; to its preparation, to its use as a medicament and to medicaments comprising it. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
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- PROTEIN KINASE INHIBITORS
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The present invention relates to a novel family of inhibitors of protein kinases. In particular, the present invention relates to inhibitors of the members of the Tec and Src protein kinase families.
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Page/Page column 58-59
(2014/01/07)
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- SUBSTITUTED N-(1H-INDAZOL-4-YL)IMIDAZO[1,2-a]PYRIDINE-3-CARBOXAMIDE COMPOUNDS AS TYPE III RECEPTOR TYROSINE KINASE INHIBITORS
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Compounds of Formula I: and pharmaceutically acceptable salts thereof in which R1, R2, R3, R4, R5 and R6 have the meanings given in the specification, are inhibitors of cFMS and are useful in the treatment of fibrosis, bone-related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, pain and burns in a mammal
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Page/Page column 129
(2012/06/30)
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- ALPHA, ALPHA - DI SUBSTITUTED GLYCINE ESTER DERIVATIVES AND THEIR USE AS HDAC INHIBITORS
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Compounds selected from the following group and their salts are inhibitors of HDAC activity, useful in the treatment of, inter alia, cell proliferative disease and inflammation: Cyclopentyl 1 -[({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-2- yl}methy)amino]cyclopropanecarboxylate; Cyclopentyl 1 -[({5-[(1E)-3-(hydroxyamino)-3- oxoprop-1-en-1-yl]pyridin-2-yl}methy)amino]cyclobutanecarboxylate; Cyclopentyl 1-[({5- [(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-2yl}methyl)amino]- cyclopentanecarboxylate; Cyclopentyl 1-[({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1- yl]pyridin-2-yl}methyl)amino]cyclohexanecarboxylate; Cyclopentyl 4-[({5-[(1E)-3- (hydroxyamino)-3-oxoprop-1 -en-1 -yl]pyridin-2-yl}methyl)amino]tetrahydro-2H-pyran-4- carboxylate; Cyclopentyl 4-[({6-[(1E)-3-{[1 -(2-methylpropoxy)ethoxy]amino}-3-oxoprop-1 - en-1 -yl]pyridin-3-yl}methyl)amino]tetrahydro-2H-pyran-4-carboxylate; Cyclopentyl 1 -({4- [(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]-2-methylbenzyl}amino)- cyclohexanecarboxylate; Cyclopentyl 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]- 2-methylbenzyl}amino)cyclopentanecarboxylate; Cyclopentyl 1-({4-[(1E)-3- (hydroxyamino)-3-oxoprop-1-en-1-yl]-2-methylbenzyl}amino)cyclobutanecarboxylate; Methylcyclopentyl 4-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3- yl}methyl)amino]tetrahydro-2H-pyran-4-carboxylate; Cyclopentyl 4-{[1 -({6-[(1E)-3- (hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)piperidin-4-yl]amino}tetrahydro- 2H-pyran-4-carboxylate; Cyclopentyl 4-{[1-({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1- yl]pyridin-2-yl}methyl)piperidin-4-yl]amino}tetrahydro-2H-pyran-4-carboxylate; Cyclopentyl 4-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)tetrahydro- 2H-pyran-4-carboxylate; Cyclopentyl 4-({3-[(1E)-3-(hydroxyamino)-3-oxoprop-1 -en-1 - yl]benzyl}amino)tetrahydro-2H-pyran-4-carboxylate; and (3R)-Tetrahydrofuran-3-yl N-{4- [(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-2-methyl-D-leucinate.
- -
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Page/Page column 22
(2012/03/26)
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- Convenient and improved protocols for the hydrogenation of esters using Ru catalysts derived from (P,P), (P,N,N) and (P,N,O) ligands
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An improved protocol where a pre-cursor, [Ru(Cl)2(NBD)(Py) 2], is treated with ligands to form [RuCl2(bidentate ligand)(diamine)] pre-catalysts for ester hydrogenation is reported. This family of catalysts, as well as a range of ruthenium complexes of tridentate P^N^X (X = NR2, OH) ligands have been investigated in the hydrogenation of aromatic esters. A range of aromatic esters can be hydrogenated in high yields at temperatures between 30 °C and 100 °C.
- Carpenter, Ian,Fuentes, Jose A.,Clarke, Matthew L.,Eckelmann, Susan C.,Kuntz, Michael T.,France, Marcia B.
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p. 10136 - 10140,5
(2012/12/11)
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- Convenient and improved protocols for the hydrogenation of esters using Ru catalysts derived from (P,P), (P,N,N) and (P,N,O) ligands
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An improved protocol where a pre-cursor, [Ru(Cl)2(NBD)(Py) 2], is treated with ligands to form [RuCl2(bidentate ligand)(diamine)] pre-catalysts for ester hydrogenation is reported. This family of catalysts, as well as a range of ruthenium complexes of tridentate P^N^X (X = NR2, OH) ligands have been investigated in the hydrogenation of aromatic esters. A range of aromatic esters can be hydrogenated in high yields at temperatures between 30 °C and 100 °C.
- Carpenter, Ian,Eckelmann, Susan C.,Kuntz, Michael T.,Fuentes, Jose A.,France, Marcia B.,Clarke, Matthew L.
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p. 10136 - 10140
(2013/01/14)
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- FUSED TETRACYCLIC PYRIDO[4,3-B]INDOLE AND PYRIDO[3,4-B]ONDOLE DERIVATIVES AND METHODS OF USE
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This disclosure is directed to fused tetracyclic pyrido[4,3-b]indoles and pyrido[3,4- b]indoles. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.
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Page/Page column 227
(2011/09/19)
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- ENZYME INHIBITORS
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Compounds of formula (I), inhibit HDAC activity: wherein A, B and D independently represent =CH- or =N-; W is-CH=CH- Or -CH2CH2-; R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R2 and R3 are selected from the side chains of a natural or non-natural alpha amino acid, provided that neither R2 nor R3 is hydrogen, or R2 and R3, taken together with the carbon to which they are attached, form a 3-6 membered saturated cycloalkyl or heterocyclyl ring; Y is a bond, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(=O)NR'-, -C(=S)-NR', -C(=NH)NR' or -S(=O)2NR - wherein R' is hydrogen or optionally substituted C1-C6 alkyl; L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p- wherein m, n, p, Q, AIk1 and AIk2 are as defined in the claims; X1 represents a bond; -C(=O); or -S(=O)2-; -NR4C(=O)-, -C(=O)NR4-,- NR4C(=O)NR5-, -NR4S(=O)2-, or -S(=O)2NR4- wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; and z is 0 or 1.
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Page/Page column 34-35
(2010/09/17)
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- COMPOUNDS WHICH POTENTIATE THE AMPA RECEPTOR AND USES THEREOF IN MEDICINE
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Compounds of formula (I) and salts thereof are provided: wherein n is 0, 1, 2 or 3; R1 is selected from phenyl and pyridyl, each of which is optionally substituted by one or two groups independently selected from C1-4alkyl and haloge
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Page/Page column 33
(2009/07/25)
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- AMIDE COMPOUNDS, COMPOSITIONS AND USES THEREOF
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Compounds are provided according to formula (1 ) : where A, B, W, X', L, R1, R3, R4b, and m' are as defined herein. Provided compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, cognitive disorders, anxiety, depression, and others.
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Page/Page column 62-63
(2009/10/22)
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- NEW COMPOUNDS V
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The present invention relates to new compounds of formula (I), to pharmaceutical compositions comprising these compounds and to the use of these compounds as leptin receptor modulator mimetics in the preparation of medicaments against conditions associate
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Page/Page column 24
(2009/12/28)
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- HDAC INHIBITORS
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Compounds of formula (I) inhibit HDAC activity, wherein A, B and D independently represent =C- or =N-; W is a divalent radical -CH=CH- or CH2CH2-; R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R2 is the side chain of a natural or non-natural alpha amino acid; z is 0 or 1; and Y, L1, and X1 are as defined in the claims.
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Page/Page column 26-27
(2008/06/13)
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- Triazolopyridine cannabinoid receptor 1 antagonists
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The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents, and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the following general formula: including all prodrugs, solvates, pharmaceutically acceptable salts and stereoisomers, wherein R1, R2, R3, R4 and R5 are described herein.
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Page/Page column 81-82
(2008/06/13)
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- Triazolopyrimidine cannabinoid receptor 1 antagonists
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The present application describes compounds according to both Formulas I and II, pharmaceutical compositions comprising at least one compound according to either Formula I or II and optionally one or more additional therapeutic agents, and methods of treatment using the compounds according to Formulas I and II both alone and in combination with one or more additional therapeutic agents. The compounds have the following general formulas: including all prodrugs, solvates, pharmaceutically acceptable salts and stereoisomers, wherein R1, R2, R3, R4 and R5 are described herein.
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Page/Page column 46
(2010/11/25)
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- Alpha-substituted arylalkyl phosphonate derivatives
-
The present invention relates to novel α-substituted arylalkylphosphonate derivatives and their uses for lowering plasma levels of apo (a), Lp(a), apo B, apo B associated lipoproteins (low density lipoproteins and very low density lipoproteins) and for lo
- -
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Page/Page column 7
(2010/02/11)
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- HIV protease inhibiting compounds
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A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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Page/Page column 103
(2010/02/12)
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- 2-IMINOPYRROLIDINE DERIVATES
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A 2-iminopyrrolidine derivative represented by the formula: {wherein ring B represents a benzene ring, pyridine ring, etc.; R101 - R103 represent hydrogen, halogen, C1-6 alkyl, etc.; R5 represents hydrogen, C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, etc.; R6 represents hydrogen, C1-6 alkyl, C1-6 alkyloxycarbonyl, etc.; Y1 represents a single bond, -CH2-, etc.; Y2 represents a single bond, -CO-, etc.; and Ar represents hydrogen, a group represented by the formula: [wherein R10-R14 represent hydrogen, C1-6 alkyl, hydroxyl, C1-6 alkoxy, etc.; and R11 and R12 or R12 and R13 may bond together to form a 5- to 8-membered heterocyclic ring], etc.}, or a salt thereof.
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- Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino- pyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure-activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists
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We previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo-[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF1 receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26h exhibited good binding affinity at the human CRF1 receptor with a Ki value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF1 receptor (IC50 = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC50 = 20 nM). 26h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26h was orally bioavailable and able to penetrate into the brain. 26h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF1 receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26h was developed into a clinical compound and exhibited efficacy in patients with major depression.
- Chen, Chen,Wilcoxen, Keith M.,Huang, Charles Q.,Xie, Yun-Feng,McCarthy, James R.,Webb, Thomas R.,Zhu, Yun-Fei,Saunders, John,Liu, Xin-Jun,Chen, Ta-Kung,Bozigian, Haig,Grigoriadis, Dimitri E.
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p. 4787 - 4798
(2007/10/03)
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- Potentiators of glutamate receptors
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The present invention relates to potentiators of metabotropic glutamate receptor function and specifically provides compounds of formula I, compositions thereof and methods of using the same.
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- BENZAZEPINE DERIVATIVE, PROCESS FOR PRODUCING THE SAME, AND USE
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The present invention provides a novel benzazepine derivative represented by formula : wherein, R1 is a 5- or 6-membered aromatic ring, R2 is lower alkyl group, etc., Y is an optionally substituted imino group, ring A and ring B are independently an optionally substituted aromatic ring, W is formula -W1-X2-W2- (W1 and W2 are independently S(O)m1 (m1 is 0, 1 or 2), etc., and X2 is an optionally substituted alkylene groupetc. ), a preparation method and use thereof.
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- ANDROGEN RECEPTOR ANTAGONISTS
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The present invention provides an androgen receptor antagonistic agent and a superior prophylactic or therapeutic agent for hormone-sensitive cancer, which contain a compound of the formula: wherein, R1 is a hydrogen atom, a group binding through a carbon atom, a group binding through a nitrogen atom, a group binding through an oxygen atom or a group binding through a sulfur atom; R2 is a hydrogen atom, a group binding through a carbon atom, a group binding through a nitrogen atom, a group binding through an oxygen atom or a group binding through a sulfur atom, R3 is a hydrogen atom, a hydrocarbon group which may have substituent (s) , an acyl group or a heterocyclic group which may have substituent(s), R4 is a hydrogen atom, a group binding through a carbon atom, a group binding through a nitrogen atom, a group binding through an oxygen atom or a group binding through a sulfur atom, and R5 is a cyclic group which may have substituent(s); or a salt thereof, or its prodrug.
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- Synthesis of (E)-5-(2-arylvinyl)-2-(hetero)arylpyridines, (E)-2-(2-arylvinyl)-5-methoxycarbonylpyridines and (E,E)-2,5-bis(2-arylvinyl)pyridines as polarity and pH probes
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In this report we describe the synthesis photophysical properties (E)-5-(2-arylvinyl)-2-(hetero)-and of various arylpyridines 7a-f, (E)-2-(2-arylvinyl)-5-methoxycarbonylpyridines 14a,b and (E,E)-2,5-bis(2-arylvinyl)pyridines 13a,b. The fluorescence spectr
- Van der Eycken, Erik,Jidong, Zhang,Kilonda, Amuri,Compernolle, Frans,Toppet, Suzanne,Hoornaert, Georges,Van der Auweraer, Mark,Jackers, Carine,Verbouwe, Wouter,De Schryver, Frans C.
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p. 928 - 937
(2007/10/03)
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- Protease inhibitors
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The present invention provides compounds of formula (I) which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia or malignancy; and metabolic bone disease therewith.
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- REMEDIES FOR PAIN
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The present invention provides a pain control agent, which contains, as an active ingredient, a compound having both μ opioid receptor agonist activity and dopamine D2 receptor antagonist activity. The compound having both of these activities exerts a potent morphine-like analgetic effect and causes no psychological dependence, and even regulates side effects. In particular, a novel compound represented by general formula (I) or a pharmacologically acceptable salt thereof has both μ opioid receptor agonist activity and dopamine D2 receptor antagonist activity, and is useful as pain control agent with regulated side effects.
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- Identification of MK-944a: A second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors
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Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of α1 acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
- Dorsey,McDonough,McDaniel,Levin,Newton,Hoffman,Darke,Zugay-Murphy,Emini,Schleif,Olsen,Stahlhut,Rutkowski,Kuo,Lin,Chen,Michelson,Holloway,Huff,Vacca
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p. 3386 - 3399
(2007/10/03)
-
- Synthesis and biological activity of metabolites of the antidiabetic, antihyperglycemic agent pioglitazone
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Pioglitazone (5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzyl)-2,4- thiazolidinedione, 2) is a prototypical antidiabetic thiazolidinedione that had been evaluated for possible clinical development. Metabolites 6-9 have been identified after dosing of rats and dogs. Ketone 10 has not yet been identified as a metabolite but has been added to the list as a putative metabolite by analogy to alcohol 6 and ketone 7. We have developed improved syntheses of pioglitazone (2) metabolites 6-9 and the putative metabolite ketone 10. These entities have been compared in the KKA(y) mouse model of human type-II diabetes to pioglitazone (2). Ketone 10 has proven to be the most potent of these thiazolidinediones in this in vivo assay. When 6-10 were compared in vitro in the 3T3-L1 cell line to 2, for their ability to augment insulin-stimulated lipogenesis, 10 was again the most potent compound with 6, 7, and 9 roughly equivalent to 2. These data suggest that metabolites 6, 7, and 9 are likely to contribute to the pharmacological activity of pioglitazone (2), as had been previously reported for ciglitazone (1).
- Tanis, Steven P.,Parker, Timothy T.,Colca, Jerry R.,Fisher, Roberta M.,Kletzein, Rolf F.
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p. 5053 - 5063
(2007/10/03)
-
- Studies on antidiabetic agents. XII. Synthesis and activity of the metabolites of (±)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4- thiazolidinedione (pioglitazone)
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The metabolites of (±)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4- thiazolidinedione (1, pioglitazone), which is a representative insulin- sensitizing agent, were synthesized to confirm their structures and for studies of their pharmacological properti
- Sohda,Ikeda,Meguro
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p. 2168 - 2172
(2007/10/03)
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- Thiazolidinedione derivatives, production and use thereof
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A thiazolidinedione compound of the formula STR1 wherein X,Q are as defined in the specification. The compounds are used for treating diabetes.
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- Optionally substituted pyrido[2,3-d]pyridine-2,4(1H,3H)-diones and pyrido[2,]pyrimidine-2(1H,3H)-ones
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The present invention relates to optionally substituted pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones or optionally substituted pyrido[2,3-d]pyrimidine-2(1H,3H)-ones, i.e., compounds of Formula I: STR1 wherein: Y is --CH2 -- or --C(O)--; R1 is hydrogen or --(CH2)n --R7, wherein: R7 is aryl or heteroaryl, and n is 1 or 2, provided that when Y is --C(O)--, R7 is heteroaryl; and R2, R3, R4, R5 and R6 are hydrogen, or one is selected from lower alkyl, halo, carboxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, di-methylcarbamoyl, methylcarbonyl, methylthio, methylsulfinyl, methylsulfonyl, hydroxymethyl, amino, trifluoromethyl, cyano or nitro; or R2, R3, R4 and R5 are independently selected from hydrogen, lower alkyl, nitro, chloro, fluoro, methoxycarbonyl or methylcarbonyl, provided at least one is hydrogen, and R6 is hydrogen; or a pharmaceutically acceptable ester, ether or salt thereof.
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- Pyridine compounds, process for the preparation thereof and pharmaceutical composition containing the same
-
The present invention relates to novel pyridine compounds having antiallergic activity mainly through 5-lipoxygenase inhibitory activity, antihistamine activity and/or inhibiting activity against chemical mediator release
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- Acrylamide derivatives as antiallergic agents. 2. Synthesis and structure-activity relationships of N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acrylamides
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A new series of 3-(3-pyridyl)acrylamides 16, 17, 19, and 26, and 5-(3-pyridyl)-2,4-pentadienamides 20-25 were prepared and evaluated for their antiallergic activity. Several of these compounds exhibited more potent inhibitory activities than the parent compounds 1a [(E)-N-[4 [4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acrylamide] against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase. Particularly, 4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(6-methyl-3-pyridyl)acrylamide (17p) showed an ED50 value of 3.3 mg/kg po in the rat PCA test, which was one-fifth of ketotifen and oxatomide. As compared with ketotifen and oxatomide, compound 17p (AL-3264) possessed a better balance of antiallergic properties due to inhibition of chemical mediator release, inhibition of 5-lipoxygenase, and antagonism of histamine.
- Nishikawa,Shindo,Ishii,Nakamura,Kon,Uno
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p. 583 - 593
(2007/10/02)
-
- A General Synthesis of Substituted Fluorenones and Azafluorenones
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Twenty-one variously substituted fluorenones and azafluorenones have been synthesized via photochemical Pschorr cyclizations of 2-diazoniodiaryl ketones as the key ring-forming step.Direct, (bipy)3RuII-, or (bipy)3RuII/CuII-photosensitized conditions were used, depending on the system to be cyclized.Where selectivities were possible in the ring closure, the isomer ratios obtained were in accord with an aryl radical as the reactive intermediate.The precursor aminodiaryl ketones were obtained from the sequence ortho lithiation of an arylpivalamide, reaction withan aryl aldehyde to give a 2-pivalamidodiarylcarbinol, oxidation to give a 2-pivalamidodiaryl ketone, and hydrolysis to give the 2-aminodiaryl ketone.
- Kyba, Evan P.,Liu, Shiuh-Tzung,Chockalingam, Kannappan,Reddy, B. Raghava
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p. 3513 - 3521
(2007/10/02)
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- ω-(3-pyridyl)alkenamide derivatives and anti-allergenic pharmaceutical compositions containing same
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Compounds of the formula: STR1 wherein X is alkylene or --(CR6 =CR7)r -- wherein R6 is H, alkyl or phenyl, R7 is H, alkyl, cyano or phenyl, and r is 1 or 2; A is alkylene or alkylene interrupted by at least one double bond; R1 is H, halogen, alkyl, alkoxy, alkylthio, cycloalkyloxy, cycloalkylthio, alkoxycarbonyl, carboxy, phenyl, phenoxy, phenylthio, 3-pyridyloxy or 3-pyridylthio; R2 is H, hydroxy, alkanoyloxy or alkoxycarbonyloxy, or adjacent R1 and R2 may combine to form tetramethylene or --CH2 OCR8 R9 O-- (R8 and R9 are alkyl); R3 is H, alkyl or hydroxyalkyl; R4 is H or alkyl; R5 is phenyl, heteroaryl or --(CH2)m --CHR10 R11 (R10 is H or phenyl, R11 is phenyl or pyridyl and m is 0 to 2); p is 0 or 1; and q is 2 or 3; the phenyl group or moiety being optionally substituted, and a salt thereof, process for the preparation thereof, and pharmaceutical composition containing the same. Said compounds and salts thereof show excellent antiallergic activity mainly through 5-lipoxygenase inhibiting activity, antihistamine activity and/or inhibitory activity against chemical mediator release and useful for treatment of allergic diseases.
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- Mercaptoalkylpyridine disulfides
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Mercaptoalkylpyridines carrying an ethenyl or ethynyl substituent are prepared from known pyridine compounds, principally pyridoxine, by known chemical procedures, and are useful in the treatment of rheumatoid arthritis and related inflammatory diseases.
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