- PYRIMIDINE-BASED BICYCLES AS ANTIVIRAL AGENTS FOR THE TREATMENT AND PREVENTION OF HIV INFECTION
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This invention relates to pyrimidine derivatives, having HIV replication inhibiting. The present invention provides new pyrimidine compounds, designed for the treatment and prevention of HIV-mediated diseases. The invention further relates to pharmaceutical compositions and drugs contained in them. The invention also relates to the use of abovementioned compounds for the treatment and/or prevention of HIV in subjects with HIV-infection (human immunodeficiency virus) or having risk of getting HIV-infection.
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Page/Page column 66-67; 70
(2021/08/27)
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- Preparation method of tertiary butyl 7-hydroxyhexahydrofuro-[3,2-b] pyridine-4(2H)-carboxylic ester
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The invention relates to a preparation method of (3aR, 7S, 7aR)-tertiary butyl 7-hydroxyhexahydrofuro-[3,2-b] pyridine-4(2H)-carboxylic ester, and mainly solves the technical problem of no method suitable for industrial synthesis currently. The preparatio
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Paragraph 0006; 0007; 0018
(2017/10/09)
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- PYRAZOLO[1,5-A]PYRIMIDINE-5,7-DIAMINE COMPOUNDS AS CDK INHIBITORS AND THEIR THERAPEUTIC USE
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The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain pyrazolo[1,5-a]pyrimidine-5,7- diamine compounds (referred to herein as "PPDA compounds") that, inter alia, inhibit (e.g., selectively inhibit) CDK (e.g., CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, etc.). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CDK; and to treat disorders including: disorders that are associated with CDK; disorders that result from an inappropriate activity of a cyclin-dependent kinase (CDK); disorders that are associated with CDK mutation; disorders that are associated with CDK overexpression; disorders that are associated with upstream pathway activation of CDK; disorders that are ameliorated by the inhibition of CDK; proliferative disorders; cancer; viral infections (including HIV); neurodegenerative disorders (including Alzheimer's disease and Parkinson's disease); ischaemia; renal diseases; and cardiovascular disorders (including atherosclerosis). Optionally, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with a further active agent which is, e.g., an aromatase inhibitor, an anti-estrogen, a Her2 blocker, a cytotoxic chemotherapeutic agent, etc.
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Page/Page column 133; 134
(2015/09/28)
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- The Role of the acidity of N-heteroaryl sulfonamides as inhibitors of Bcl-2 family protein-protein interactions
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Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides t
- Touré, B. Barry,Miller-Moslin, Karen,Yusuff, Naeem,Perez, Lawrence,Doré, Michael,Joud, Carol,Michael, Walter,Dipietro, Lucian,Van Der Plas, Simon,McEwan, Michael,Lenoir, Francois,Hoe, Madelene,Karki, Rajesh,Springer, Clayton,Sullivan, John,Levine, Kymberly,Fiorilla, Catherine,Xie, Xiaoling,Kulathila, Raviraj,Herlihy, Kara,Porter, Dale,Visser, Michael
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supporting information
p. 186 - 190
(2013/04/10)
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- PYRIMIDINYL TYROSINE KINASE INHIBITORS
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The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.
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Paragraph 0102
(2014/01/08)
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- SULFONAMIDES AS INHIBITORS OF BCL-2 FAMILY PROTEINS FOR THE TREATMENT OF CANCER
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The present invention includes novel compound and methods of treating a disease or disorder by antagonizing Bcl-2 family proteins, particularly compounds of Formula (I) or pharmaceutically acceptable salt thereof, as well as methods of treating a disease,
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Page/Page column 40
(2011/04/18)
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- FUSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS
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Disubstituted 3,8-diaza-bicyclo[4.2.0]octane and 3,6-diazabicyclo [3.2.0]heptane compounds are described, which are useful as orexin receptor modulators. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.
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Page/Page column 45
(2011/05/06)
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- FUSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS
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Certain disubstituted 3,8-diaza-bicyclo[4.2.0]octane and 3,6-diazabicyclo [3.2.0]heptane are described, which are useful as orexin inhibitors. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.
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Page/Page column 44
(2011/05/06)
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- PHENYL-HETEROARYL DERIVATIVES AND METHODS OF USE THEREOF
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The present invention provides phenyl-heteroaryl derivatives of Formula (I) and pharmaceutically acceptable salts thereof. These compounds are useful in the treatment of RAGE-mediated diseases such as Alzheimer's Disease. The present invention further relates to methods for the preparation of compounds of Formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds, and the use of such compounds and/or pharmaceutical compositions in treating RAGE-mediated diseases.
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Page/Page column 88-89
(2011/09/19)
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- A novel asymmetric synthesis of cis-(3R,4R)-N-(tert -butoxycarbonyl)-4- methyl-3-(methylamino)piperidine
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cis-(3R,4R)-N-(tert-Butoxycarbonyl)-4-methyl-3-(methylamino)piperidine, a key intermediate for the synthesis of CP-690550 (a potent protein kinase inhibitor), is prepared via an asymmetric approach starting from ethyl 1-benzyl-3-oxopiperidine-4-carboxylat
- Hao, Bao-Yu,Liu, Jin-Qiang,Zhang, Wei-Han,Chen, Xin-Zhi
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experimental part
p. 1208 - 1212
(2011/05/30)
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- Synthesis and in vitro antibacterial activity of 7-(3-Alkoxyimino-4-amino- 4-methylpiperidin-1-yl) fluoroquinolone derivatives
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A series of novel 7-(3-alkoxyimino-4-amino-4-methylpiperidin-1-yl) fluoroquinolone derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cytotoxicity. All of the target compounds have potent antibacterial activ
- Wang, Ju-Xian,Zhang, Yi-Bin,Liu, Ming-Liang,Wang, Bo,Chai, Yun,Li, Su-Jie,Guo, Hui-Yuan
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scheme or table
p. 2421 - 2426
(2011/06/25)
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- PIPERIDINE INHIBITORS OF JANUS KINASE 3
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The present invention relates to a new piperidine inhibitors of Janus Kinase 3 activity, pharmaceutical compositions thereof, and methods of use there-of.
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Page/Page column 60
(2010/11/05)
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- Synthesis and in vitro antibacterial activity of 7-(3-alkoxyimino-4-methyl- 4-methylaminopiperidin-1-yl)-fluoroquinolone derivatives
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A series of novel 7-(3-alkoxyimino-4-methyl-4-methylaminopiperidin-1-yl) fluoroquinolone derivatives were designed, synthesized, and characterized by 1H-NMR, MS, and HRMS. These fluoroquinolones were evaluated for their in-vitro antibacterial activity against representative Gram-positive and Gram-negative strains. Generally, all of the target compounds have considerable antibacterial activity against the tested forty strains, and exhibit exceptional potency in inhibiting the growth of methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) ATCC33591 (MICs: 0.06 to 2 μg/mL). In particular, compounds 14, 19, 28, and 29 are fourfold more potent than ciprofloxacin against MSSA 08-49. Compounds 23, 26, and 27 are twofold more potent than ciprofloxacin against MRSA ATCC33591 and MSSA ATCC29213. In addition, compound 14 exhibits excellent activity (MIC: 0.06 μg/mL) against Acinetobacter calcoaceticus, which is two- to 16-fold more potent than the reference drugs gemifloxacin, levofloxacin, and ciprofloxacin.
- Zhang, Yi-Bin,Feng, Lian-Shun,You, Xue-Fu,Guo, Qiang,Guo, Hui-Yuan,Liu, Ming-Liang
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experimental part
p. 143 - 151
(2010/08/05)
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- MODULATORS OF AMYLOID BETA.
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The present invention relates to novel compounds of formula I and therapeutically acceptable salts thereof, their pharmaceutical compositions, processes for making them and their use as therapeutic methods for treatment and/or prevention of various diseases. In particular the invention relates to compounds, which inhibit the Aβ40 and Aβ42 production, increase the Aβ37 and Aβ38 production and maintain the Notch signaling and will be used for treatment and/or prevention of Aβ-related pathologies such as Alzheimer's disease, Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
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Page/Page column 58; 59
(2010/06/11)
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- INHIBITORS OF UNDECAPRENYL PYROPHOSPHATE SYNTHASE
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The present invention relates to compounds that are selective and/or potent inhibitors of UPPS. In addition to compounds which inhibit UPPS, the invention also provides pharmaceutical compositions comprising these compounds and methods of using these comp
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Page/Page column 92
(2010/01/31)
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- PYRIMIDINONE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to Pyrimidinone Derivatives, compositions comprising a Pyrimidinone Derivative, and methods of using the Pyrimidinone Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of G protein-coupled receptor 119 ("GPR119") in a patient.
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Page/Page column 161; 171
(2008/12/08)
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- PIPERIDINOYL-PYRROLIDINE AND PIPERIDINOYL-PIPERIDINE COMPOUNDS
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The present invention relates to a class of compounds of general formula (I) and the salts, hydrates, solvates, polymorphs and prodrugs wherein n, R6, R7 and R10 are as defined herein and especially to MCR4 agonist compounds of formula (I), to their use in medicine, particularly in the treatment of sexual dysfunction and obesity, to intermediates useful in their synthesis and to compositions containing them.
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Page/Page column 85
(2010/11/25)
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- Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease β-site amyloid precursor protein cleaving enzyme (BACE)
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Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by m
- Hanessian, Stephen,Yang, Gaoqiang,Rondeau, Jean-Michel,Neumann, Ulf,Betschart, Claudia,Tintelnot-Blomley, Marina
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p. 4544 - 4567
(2007/10/03)
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- Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0] octane ligands, potent nicotinic acetylcholine receptor agonists
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A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo-[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (hα4β2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the hα4β2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the hα4β2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.
- Frost, Jennifer M.,Bunnelle, William H.,Tietje, Karin R.,Anderson, David J.,Rueter, Lynne E.,Curzon, Peter,Surowy, Carol S.,Ji, Anquo,Daanen, Jerome F.,Kohlhaas, Kathy L.,Buckley, Michael J.,Henry, Rodger F.,Dyhring, Tino,Ahring, Philip K.,Meyer, Michael D.
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p. 7843 - 7853
(2007/10/03)
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- Substituted diazabicycloalkane derivatives
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Compounds of formula (I) [in-line-formulae]Z-Ar1—Ar2??(I) [/in-line-formulae] wherein Z is a diazabicyclic amine, Ar1 is a 5- or 6-membered aromatic ring, and Ar2 is selected from the group consisting of an unsubstituted or substituted 5- or 6-membered heteroaryl ring; unsubstituted or substituted bicyclic heteroaryl ring; 3,4-(methylenedioxy)phenyl; carbazolyl; tetrahydrocarbazolyl; naphthyl; and phenyl; wherein the phenyl is substituted with 0, 1, 2, or 3 substituents in the meta- or para-positions. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions comprising compounds of formula (I) and methods for using such compounds and compositions.
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Page/Page column 26
(2010/02/11)
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- Substituted diazabicycloakane derivatives
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Compounds of formula (I) Z-Ar1—Ar2??(I) wherein Z is a diazabicyclic amine, Ar1 is a 5- or 6-membered aromatic ring, and Ar2 is selected from an unsubstituted or substituted 5-membered heteroaryl ring; an unsubstituted or substituted 6-membered heteroaryl ring; 3,4-(methylenedioxy)phenyl; and phenyl substituted with 0, 1, 2, or 3 substituents in the meta- or para-positions. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions comprising compounds of formula (I) and methods for using such compounds and compositions.
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Page/Page column 20
(2010/02/11)
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- Design and syntheses of melanocortin subtype-4 receptor agonists. Part 2: Discovery of the dihydropyridazinone motif
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Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed.
- Ujjainwalla, Feroze,Warner, Daniel,Snedden, Christine,Grisson, Ricky D.,Walsh, Thomas F.,Wyvratt, Matthew J.,Kalyani, Rubana N.,MacNeil, Tanya,Tang, Rui,Weinberg, David H.,Van Der Ploeg, Lex,Goulet, Mark T.
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p. 4023 - 4028
(2007/10/03)
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- Enzyme-catalyzed kinetic resolution of piperidine hydroxy esters
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Enantiomers of N-protected piperidine-based cis- and trans-4-hydroxy-3- carboxylates and cis-3-hydroxy-4-carboxylates were prepared through kinetic resolution utilizing lipase AK from Pseudomonas fluorescens and Candida antarctica lipase A. The highly enantioselective (E >200) kinetic resolution of (±)-ethyl cis-(±)-4 and trans-1-(tert-butoxycarbonyl)-4- hydroxypiperidine-3-carboxylate (±)-5 was achieved by Pseudomonas fluorescens lipase-catalyzed asymmetric acylation with vinyl acetate in diisopropyl ether at room temperature. Candida antarctica lipase A-catalyzed asymmetric acylation of (±)-ethyl cis-1-benzyl-3-hydroxypiperidine-4- carboxylate (±)-11 was performed with vinyl propanoate in diisopropyl ether at 3°C, with good enantioselectivity (E = 75).
- Solymar, Magdolna,Forro, Eniko,Fueloep, Ferenc
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p. 3281 - 3287
(2007/10/03)
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- Cyclohexane derivatives and their use as therapeutic agents
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The present invention relates compounds of formula (I), wherein ring A is a phenyl or pyridyl ring; X represents a linker selected from the group consisting of formulae: (a), (b), (c), (d), and (e); and R1, R2, R3, R4, R5, R6, R7, R13, R14, R15, R16, R17, R21a and R21b are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.
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- N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
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The present application describes modulators of CCR3 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.
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- Diazabicyclic central nervous system active agents
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Compounds of formula I pharmaceutical compositions of these compounds, and use of said compositions to control synaptic transmission in mammals.
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- Reagents for assaying central local acetylcholinesterase activity
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The present invention relates to N-alkylpiperidine derivatives represented by general formula (1) or (2); wherein R1represents optionally fluorinated lower alkyl; R2represents lower alkyl; and R3represents alkenyl substituted at the 1-position with hydroxy, lower alkoxy, lower alkoxyalkyloxy, lower alkoxyalkyloxyalkyloxy, or lower alkanoyloxy and substituted at the end with radioactive iodine, or alkenyloxymethyl substituted at the end with a radioactive iodine reagent containing the same for assaying central local AchE activity; a method for assaying the central local AchE activity; and labeled precursors of the above compounds. After easily passing through the blood-brain barrier, these compounds are hydrolyzed specifically by AchE in the brain into alcohols, which are then captured by the brain. In contrast, alcohols formed outside the brain do not migrate into the brain. The compounds of the invention emit γ-rays at an appropriate energy level. These characteristics make the compounds highly useful as tracers for SPECT in assaying the central AchE activity.
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- Synthesis of N-methyl-3-acetoxy-4-(1-hydroxy-3-[123I]iodoprop-2-enyl) piperidine, a novel acetylcholine analog
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Lipophilic acetylcholine analogs (N-methylpiperidine derivatives) have been used to map central acetylcholinesterase (AchE) activity in animals and humans. In the former meeting, we reported synthesis of an analog with 4-acetoxy group and side chain at 3-position labeled with iodine-123 (MHIP4A) which showed moderate metabolic clearance. Now, we have synthesized another analog with higher metabolic clearance, namely, N-methyl-3-acetoxy-4-(1-hydroxy-3-[123I]iodoprop-2-enyl)piperidine (HIP3C3A). Eight isomers of HIP3C3A were isolated by diastereomeric and enantiomeric separation with silica gel chromatography and chiralcel HPLC. Tributylstannyl precursors were used for iodination with peracetic acid as an oxidizing agent. The iodination could be carried out quite easily yielding 50-60%. Of the isomers, one isomer showed extremely high metabolic clearance (4.19 mL/min/g with 84% specificity) and another isomer was hydrolyzed by AchE moderately (0.36 mL/min/g with 95% specificity) in rat cerebral cortical homogenate.
- Ueda,Irie,Fukushi,Ikota,Namba,Shinotoh,Iyo,Tanada,Maeda,Takatoku,Yomoda,Nagatsuka
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p. S762-S764
(2007/10/03)
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- GABA agonists. Synthesis and structure-activity studies on analogues of isoguvacine and THIP
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A series of analogues of the specific GABA receptor agonists isoguvacine, isonipecotic acid, and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) have been synthesized and tested as inhibitors of the binding of 3H-GABA to GABA receptor sites on rat brain membranes in vitro. Introduction of a hydroxy group into the 3- or 4-position of isonipecotic acid results in compounds with considerably reduced receptor affinity. The 7-membered ring analogues of isoguvacine and isonipecotic acid are more than two orders of magnitude weaker than the parent compounds. Replacement of the 3-isoxazolol unit of THIP by related heterocyclic rings also result in dramatic loss of activity. Thus iso-THIP (4,5,6,7-tetrahydroisoxazolo[3,4-c]pyridin-3-ol) is a weak inhibitor of 3H-GABA binding, whereas the 3-pyrazolol THIP analogues are inactive.
- Krogsgaard-Larsen,Roldskov-Christiansen
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p. 157 - 164
(2007/10/04)
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