- COMPOUNDS WITH COPPER- OR ZINC-ACTIVATED TOXICITY AGAINST MICROBIAL INFECTION
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Heterocyclic compounds with a novel pyrazole thioamide-based NNSN structural motif, having highly effective zinc- or copper-activated toxicity against microbial infections at micromolar or nanomolar minimum inhibitory concentrations (MIC), and methods of making and using same.
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- THERAPEUTIC INHIBITORY COMPOUNDS
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Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting plasma kallikrein. Furthermore, the subject compounds and compositions are useful for the treatment of diseases wherein the inhibition of plasma kallikrein inhibition has been implicated, such as angioedema and the like.
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Paragraph 00314
(2018/03/26)
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- Optimization and biological evaluation of 2-aminobenzothiazole derivatives as Aurora B kinase inhibitors
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A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase. Molecular modeling indicated that compound 15g bound well to the active site of Aurora B kinase and formed the essential hydrogen bonds. The potent compounds, 15g and 15k, were selected, and their biological effects were evaluated using HeLa cell lines. It was found that these compounds inhibited the phosphorylation of histone H3 at Ser10 and induced G2/M cell cycle arrest. We suggest that the reported compounds have the potential to be further developed as anticancer therapeutics.
- Lee, Eun,An, Ying,Kwon, Junhee,Kim, Keun Il,Jeon, Raok
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p. 3614 - 3622
(2017/06/13)
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- ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
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Compounds of formula (I) or (II) wherein Rx, Rz, R9, R10, R14, R14′, R15, R15′, A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
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Page/Page column
(2015/05/06)
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- 4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
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The present invention relates to novel 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl-amine derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease or dementia associated with beta-amyloid.
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Paragraph 0101; 0102
(2013/07/31)
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- ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
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Compounds of formula (I) wherein Rx, Rz, R9, R10, R14, R14', R15, R15', A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
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Page/Page column 62
(2012/11/07)
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- 4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
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The present invention relates to novel 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl- aminederivativesas inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretaseis involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associatedwith stroke, dementia associated with Parkinson's disease or dementia associated with beta- amyloid.
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Page/Page column 32-33
(2012/04/10)
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- COMPOUNDS FOR TREATING MUSCULAR DYSTROPHY
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Compounds of formula (I): wherein X, L1, R1, L2, R2, R3, and R4 are as defined herein, are useful in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
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Page/Page column 47
(2010/12/29)
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- CALCIUM RECEPTOR MODULATING AGENTS
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The present invention relates generally to novel calcimimetic compounds and pharmaceutical compositions comprising them. The invention also relates to methods of treating of diseases or disorders related to the function of the calcium sensing receptor using the compounds represented in Formula I.
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Page/Page column 40
(2009/05/28)
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- PROCESSES FOR THE PREPARATION OF PYRAZOLE DERIVATIVES USEFUL AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR
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The present invention relates to processes for preparing pyrazole derivatives of Formula (I) and salts and pharmaceutical compositions of the salts thereof, useful as modulators of 5-HT2A serotonin receptor activity. The present invention also relates to intermediates used in the processes, and their preparation. The present invention also relates to salts of compounds of Formula (I) and pharmaceutical compositions thereof
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Page/Page column 52
(2009/10/30)
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- Effects of introduction of hydrophobic group on ribavirin base on mutation induction and anti-RNA viral activity
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One of the possible mechanisms of antiviral action of ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, 1) is the accumulation of mutations in viral genomic RNA. The ambiguous incorporation of 5′-triphosphate of ribavirin (RTP, 8) by a viral RNA-dependent RNA polymerase (RdRp) is a key step of the mutation induction. We synthesized three ribavirin analogues that possess hydrophobic groups, 4-iodo-1-β-D- ribofuranosylpyrazole-3-carboxamide (7a), 4-propynyl-1-β-D- ribofuranosylpyrazole-3-carboxamide (7b), and 4-phenylethynyl-1-β-D- ribofuranosylpyrazole-3-carboxamide (7c), and the corresponding triphosphates (9a, 9b, and 9c, respectively). Steady-state kinetics analysis of the incorporation of these triphosphate analogues by a poliovirus RdRp, 3D pol, revealed that while the incorporation efficiency of 9a was comparable to RTP, 9b and 9c showed lower efficiency than RTP. Antipolioviral activity of 7a and 7b was much more moderate than ribavirin, and 7c showed no antipolioviral activity. Effects of substituting groups on the incorporation efficiency by 3Dpol and a strategy for a rational design of more active ribavirin analogues are discussed.
- Moriyama, Kei,Suzuki, Tetsuya,Negishi, Kazuo,Graci, Jason D.,Thompson, Corinne N.,Cameron, Craig E.,Watanabe, Masahiko
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p. 159 - 166
(2008/09/18)
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- N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase
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Human neutrophil elastase (NE) plays an important role in the pathogenesis of pulmonary disease. Using high-throughput chemolibrary screening, we identified 10 N-benzoylpyrazole derivatives that were potent NE inhibitors. Nine additional NE inhibitors were identified through further screening of N-benzoylpyrazole analogues. Evaluation of inhibitory activity against a range of proteases showed high specificity for NE, although several derivatives were also potent inhibitors of chymotrypsin. Analysis of reaction kinetics and inhibitor stability revealed that N-benzoylpyrazoles were pseudoirreversible competitive inhibitors of NE. Structure-activity relationship (SAR) analysis demonstrated that modification of N-benzoylpyrazole ring substituents modulated enzyme selectivity and potency. Furthermore, molecular modeling of the binding of selected active and inactive compounds to the NE active site revealed that active compounds fit well into the catalytic site, whereas inactive derivatives contained substituents or conformations that hindered binding or accessibility to the catalytic residues. Thus, N-benzoylpyrazole derivatives represent novel structural templates that can be utilized for further development of efficacious NE inhibitors.
- Schepetkin, Igor A.,Khlebnikov, Andrei I.,Quinn, Mark T.
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p. 4928 - 4938
(2008/03/13)
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- Novel nonprostanoid prostacyclin (PGI2) mimetics with heterocyclic moiety
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Structural modification of [2-(2-benzhydryloxyiminopentyl)-1,2,3,4-tetrahydro-5-naphthyloxy]acetic acid (4), previously identified as a PGI2 agonist without a PG skeleton, was examined. Conversion of the oxime moiety in 4 to the pyrazole led to [2-(4-benzhydrylpylazoyl)methyl-1,2,3,4-tetrahydro-5-naphthyloxy]acetic acid (34) which strongly inhibited ADP-induced aggregation of human platelets in vitro.
- Nagao, Yuuki,Takahashi, Kanji,Torisu, Kazuhiko,Kondo, Kigen,Hamanaka, Nobuyuki
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p. 517 - 523
(2007/10/03)
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- Design and synthesis of heterocyclic carboxamides as natural nucleic acid base mimics
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A series of heterocyclic carboxamides have been designed as mimics for the natural nucleic acid bases. The nucleosides 1-(2'-deoxy-β-D-ribofuranosyl)imidazole-4-carboxamide (1), 1-(2'-deoxy-β-D-ribofuranosyl)pyrazole-3-carboxamide (2), and 1-(2'deoxy-β-D-ribofuranosyl)pyrrole-3-carboxamide (3) were synthesized and their structures confirmed by spectroscopic and analytical means.
- Bergtrom,Bergstrom, Donald E.,Zhang,Zhang, Peiming,Johnson,Travis Johnson
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- 4-Methoxybenzyl (PMB), a versatile protecting group for the regiospecific lithiation and functionalization of pyrazoles
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The use of 4-methoxybenzyl (PMB) protecting group for the regiospecific metallation/functionalisation of pyrazole is reported.
- Subramanyam
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p. 761 - 774
(2007/10/02)
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- Evolution thermique et photochimique des triazolines resultant de l'addition des diazocomposes aux esters d'oximino-malonodinitriles, oximino-cyanoacetates et oximino-malonates de methyle
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Thermolysis of 1,2,3-triazolines 4,5,6 leads to the corresponding aziridines only when X=Y=CO2Me, and then with a very low yield.However, photolysis or evolution in the presence of trifluoroacetic acid gives good results when carried out at sufficiently low temperature.The thermolysis study of 4-6 shows a new route to 1,2,3-triazoline decomposition that has not yet been mentioned in the literature.The easy elimination of the paratoluenesulfonate or benzoate group explains this particular behaviour.
- Perrocheau, Jacques,Carrie, Robert,Fleury, Jean-Pierre
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p. 2458 - 2467
(2007/10/02)
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- Convenient synthesis of vinyldiazomethanes from α-diazo-β-keto esters and related systems
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A series of vinydiazomethanes were readily prepared by sodium borohydride reduction of α-diazo-β-ketoesters followed by phosphorus oxychloride induced by dehydration of the resulting α-diazo-β-hydroxyesters.
- Davies,Hougland,Cantrell Jr.
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p. 971 - 978
(2007/10/02)
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- Effect of Electron-withdrawing Groups on the Thermal Ring Opening of 3H-Pyrazoles to Diazoalkenes
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3-Cyano-3H-pyrazoles, bearing a cyano, a p-chlorophenyl, or a p-chlorobenzyl group at C-3, generated from elimination reaction of the corresponding dihydropyrazoles with a leaving group such as a chlorine or p-chlorobenzoyloxy group, gave diazolkene derivatives, resulting from the ring-opening of the 3H-pyrazoles.However, 3-methoxycarbonyl-3H-pyrazoles bearing a methoxycarbonyl, a p-chlorophenyl, or p-chlorobenzyl group at C-3, prepared in a similar manner, gave mainly 1-methoxycarbonyl-1H-pyrazole derivatives, resulting from migration of the 3-methoxycarbonyl group to the adjacent nitrogen within the generated 3H-pyrazoles.Treatment of 3H-pyrazoles (8a and 29b) and 5-substituted 1-methoxycarbonyl-1H-pyrazoles (10a and 31b) with triethylamine gave 3-substituted 1-methoxycarbonyl-1H-pyrazoles, resulting from migration of the methoxycarbonyl group to the remote nitrogen.
- Nakano, Yoshihiko,Ilamaguchi, Masashi,Nagai, Toshikazu
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p. 1701 - 1757
(2007/10/02)
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- REACTIONS OF TETRAFLUOROETHENE OLIGOMERS. PART XII. CYCLOADDITION REACTIONS OF 3,3,4,4,4-PENTAFLUORO-2-PENTAFLUOROETHYL-2-TRIFLUOROMETHYLDIAZOBUTANE. A NOVEL SYNTHESIS OF PYRAZOLES
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The title diazoalkane (1) reacts smoothly with a variety of electron deficient alkenes to give, unexpectedly, the corresponding pyrazole derivatives.Thus, reaction with methyl or ethyl propenoate affords the methyl and ethyl esters of pyrazole-3-carboxylic acid (2) and (3).Reaction with diethyl maleate yields 3,4-bis-(ethoxycarbonyl)pyrazole (4), and dimethyl maleate gives the corresponding dimethyl ester (5).Treatment of (1) with propenonitrile afforded 3-cyanopyrazole (6), and with propenoic acid the corresponding pyrazole-3-carboxylic acid (7) was obtained.In all of these reactions two side products were isolated, namely perfluoro-(3-methylpent-2-ene) (8) and 3H-3-trifluoromethyldecafluoropentane (9).A mechanistic rationale for these unusual and potentially useful reactions is given.
- Coe, Paul L.,Cook, Michael I.
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p. 323 - 330
(2007/10/02)
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- N,N'-LINKED BIAZOLES. PART 5. SYNTHESIS OF PYRAZOLYL DIMERS BY THE REACTION OF 3-METHOXYCARBONYL-2-PYRAZOLINE WITH LEAD TETRAACETATE
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Contrary to a previous report by Akhrem et. al. (Tetrahedron Lett. 1973, 2655), the reaction of 3-methoxycarbonyl-2-pyrazoline with lead tetraacetate affords not only 3-methoxycarbonyl-1-(3-methoxycarbonyl-2-pyrazolin-1-yl)pyrazole (8) and 3-methoxycarbonyl-1-(1-methoxycarbonyl-1-cyclopropyl)pyrazole (9), but a complex mixture of pyrazoles and pyrazolines depending on the reaction conditions (LTA/pyrazoline ratio and temperature).The structures of all compounds have been established, and a new mechanism is proposed for the reaction.The oxidation of 8 with N-bromosuccinimide gave the symmetrical 3,3'-dimethoxycarbonyl-1,1'-bipyrazole (17).
- Mendoza, Javier de,Gonzales-Muniz, M. Rosario,Martin, M. Rosario,Elguero, Jose
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p. 2619 - 2628
(2007/10/02)
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