- Design and synthesis of novel pyrimido[5,4-d]pyrimidine derivatives as GPR119 agonist for treatment of type 2 diabetes
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We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC0–2h) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC0–2h at the dose of 300 mg/kg.
- Fang, Yuanying,Xu, Jun,Li, Zhifeng,Yang, Zunhua,Xiong, Lijuan,Jin, Yi,Wang, Qi,Xie, Saisai,Zhu, Wufu,Chang, Sheng
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Read Online
- Multistep Synthesis and Nematicidal Activity of 2-(8-azabicyclo[3.2.1]octan-3-yl)-3-imino-2,3-dihydro-1H-isoindol-1-One Derivatives
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[Figure not available: see fulltext.] Novel 2-(8-azabicyclo[3.2.1]octan-3-yl)-3-imino-2,3-dihydro-1H-isoindol-1-ones derived from 5-HT3 receptor antagonists hexahydroazepinylbenzamides were designed and synthesized through isocyanide insertion reaction. All target compounds were evaluated against pinewood nematodes B. xylophilus and root-knot nematodes M. incognita. Good lethal rate (75%) for 3-(tert-butylimino)-5-chloro-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one and serious nervous curl effect against pinewood nematodes B. xylophilus for 3-(tert-butylimino)-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one were observed at 10 mg/l. The inhibition activities of 3-[(4-methoxyphenyl)imino]-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one against root-knot nematodes M. incognita were 84% at 160 mg/l and 60% at 20 mg/l for in vitro test and test tube test, respectively.
- Xu, Jun,Yang, Tianjiao,Wang, Jiayi,Song, Gonghua
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- HETEROARYL-SUBSTITUTED SULFONAMIDE COMPOUNDS AND THEIR USE AS SODIUM CHANNEL INHIBITORS
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This invention is directed to heteroaryl-substituted sulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.
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Paragraph 1057; 1060; 1061
(2020/03/23)
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- Synthesis and evaluation of novel fused pyrimidine derivatives as GPR119 agonists
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A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16, 19, 26, 28, 42) bearing endo-N-Boc-nortropane amine and fluoro-substituted aniline exhibited better EC50 values (0.27–1.2 μM) though they appeared to be partial agonists.
- Fang, Yuanying,Xiong, Lijuan,Hu, Jianguo,Zhang, Shaokun,Xie, Saisai,Tu, Liangxing,Wan, Yang,Jin, Yi,Li, Xiang,Hu, Shaojie,Yang, Zunhua
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p. 103 - 111
(2019/01/28)
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- 1-(3-AMINOPROPYL) SUBSTITUTED CYCLIC AMINE COMPOUNDS, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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Provided are 1-(3-aminopropyl) substituted cyclic amine compounds as represented by formula (I), pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemates and mixtures thereof, and a method of synthesizing said 1-(3-aminopropyl) substituted cyclic amine compounds by using aromatic heterocyclic formaldehyde as raw material. Said compounds can be used as CCR 5 antagonist for the treatment of HIV infection.
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- SUBSTITUTED PIPERIDINE COMPOUNDS
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The present disclosure provides substituted piperidine compounds having Formula (I), and the pharmaceutically acceptable salts and solvates thereof, wherein R1, B, X, and Z are defined as set forth in the specification. The present disclosure i
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Paragraph 0291
(2016/06/01)
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- ANTIMICROBIAL COMPOSITIONS, METHODS OF USE, AND METHODS OF TREATMENT OF INFECTIONS
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The present disclosure provides compositions including a compound (e.g., compounds A-D), pharmaceutical compositions including the compound, methods of treatment of a condition (e.g., an infection) or disease, methods of treatment using compositions or pharmaceutical compositions, and the like.
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Page/Page column 34
(2016/12/22)
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- INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)
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The present invention provides novel compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g.,leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., cyclin-dependent kinase 7 (CDK7)), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject. (I)
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Paragraph 314
(2015/05/05)
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- CEPHEM COMPOUND HAVING CATECHOL GROUP
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A compound of the formula: wherein X is -N=, -CH=, or the like; W is -CH2- or the like; U is -S- or the like; R1 and R2 are each independently hydrogen, halogen, optionally substituted lower alkyl, or the like; R3/su
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Paragraph 0398; 0399
(2013/03/26)
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- BRIDGED PIPERIDINE DERIVATIVES
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The present invention relates to compounds of formula I hetaryl I, hetaryl II, R1, R2, R3, Y, m, and o or to pharmaceutically active acid addition salts thereof. The present compounds of formula I are modulators for amyloid beta and thus, they may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
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- BRIDGED PIPERIDINE DERIVATIVES
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The present invention relates to compounds of formula (l); hetaryl I is a five or six membered heteroaryl group, containing 1 to 3 heteroatoms, selected from S or N; hetaryl II is a six membered heteroaryl group, containing 1 to 3 heteroatoms, selected from S or N, or is a two membered ring system containing 1 to 4 heteroatoms selected from S, or N, wherein at least one ring is aromatic in nature; R1 is lower alkyl, lower alkoxy, lower alkyl substituted by halogen or halogen; R2 is lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy, cycloalkyl substituted by lower alkyl or lower alkyl substituted by halogen, or is lower alkyl substituted by hydroxy, or is furyl, or is O-benzyl, (CH2)p-phenyl, optionally substituted by halogen, lower alkoxy, lower alkyl substituted by halogen, lower alkyl or by cyano; R3 is hydrogen or lower alkyl; Y is (CH2)n-, -CH2OCH2-, -CH2O-, CH2S-, -CH2SCH2- and is bonded to two of the ring carbon atoms, bonding being to either the ring carbon atoms a and b or the ring carbon atoms c and d; p is 0 or 1; m is 0, 1 or 2; if m is 2 then R1 may be the same or different; -75- n is 2 or 3; o is 0, 1 or 2, if o is 2, then R2 may be the same or different; or to pharmaceutically active acid addition salts thereof. The present compounds of formula I are modulators for amyloid beta and thus, they may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimers disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
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Page/Page column 31-32
(2012/09/21)
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- 8-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDE DERIVATIVE
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Disclosed is a compound represented by formula (1) or a pharmacologically acceptable salt thereof (In the formula, A represents a group that is represented by formula (A-1); R1a and R1b may be the same or different and each independently represents a C1-6 alkyl group which may be substituted by one to three halogen atoms; m and n each independently represents an integer of 0-5; X1 represents a hydroxyl group or an aminocarbonyl group; Z1 represents a single bond or the like; and R2 represents an optionally substituted C1-6 alkyl group, an optionally substituted C6-10 aryl group or the like.)
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Page/Page column 29
(2012/09/11)
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- An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: The discovery of N -{(1 S)-1-(3-fluorophenyl)-3-[(3- endo)-3-(5-isobutyryl-2- methyl-4,5,6,7-tetrahydro-1 H -imidazo[4,5- c ]pyridin-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]propyl}acetamide (PF-232798)
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Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
- Stupple, Paul A.,Batchelor, David V.,Corless, Martin,Dorr, Patrick K.,Ellis, David,Fenwick, David R.,Galan, Sébastien R. G.,Jones, Rhys M.,Mason, Helen J.,Middleton, Donald S.,Perros, Manos,Perruccio, Francesca,Platts, Michelle Y.,Pryde, David C.,Rodrigues, Deborah,Smith, Nicholas N.,Stephenson, Peter T.,Webster, Robert,Westby, Mike,Wood, Anthony
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experimental part
p. 67 - 77
(2011/03/19)
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- Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile
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We recently described (J. Med. Chem. 2008, 51, 6538-6546) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further finetuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).
- Kazmierski, Wieslaw M.,Anderson, Don L.,Aquino, Christopher,Chauder, Brian A.,Duan, Maosheng,Ferris, Robert,Kenakin, Terrence,Koble, Cecilia S.,Lang, Dan G.,Mcintyre, Maggie S,Peckham, Jennifer,Watson, Christian,Wheelan, Pat,Spaltenstein, Andrew,Wire, Mary B.,Svolto, Angilique,Youngman, Michael
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scheme or table
p. 3756 - 3767
(2011/07/30)
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- CARBAMATE AND UREA INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE 1
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This invention relates to novel compounds of the Formula I, II, III, IHa, NIb, IV, IVa, IVb, IVc, IVd, IVe, V, Va, Vb1 Vl, Vla, VIb, VII, Vila, VIIb, VIII, Vllla, VIIIb, IX, IXa, X, and Xa, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11 β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of Cortisol in a cell or the inhibition of the conversion of cortisone to Cortisol in a cell.
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Page/Page column 106
(2009/12/05)
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- NOVEL HETEROCYCLIC CARBOXAMIDES AS M1 AGONISTS
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The present invention relates to novel M1 agonistic compounds of formula (I) and their use in the treatment of cognitive impairment associated i.a. with schizophrenia and in the treatment of other diseases mediated by the muscarinic M1 receptor.
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- Prokinetic agent for bowel preparation
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The invention provides methods of bowel preparation before a diagnostic, surgical or therapeutic procedure, in particular, bowel preparation before a colonoscopy procedure, using a 5-HT4 receptor agonist as a prokinetic agent.
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- Discovery of bioavailable 4,4-disubstituted piperidines as potent ligands of the chemokine receptor 5 and inhibitors of the human immunodeficiency virus-1
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We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the 125I-[MIP-1β] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.
- Kazmierski, Wieslaw M.,Aquino, Christopher,Chauder, Brian A.,Deanda, Felix,Ferris, Robert,Jones-Hertzog, Deborah K.,Kenakin, Terrence,Koble, Cecilia S.,Watson, Christian,Wheelan, Pat,Yang, Hanbiao,Youngman, Michael
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experimental part
p. 6538 - 6546
(2009/11/30)
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- Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives
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The optimization of a series of 1-aryl-3-piperidinyl urea derivatives is described in which incorporation of tropenyl and homotropenyl moieties has led to significant improvements in activity and drug-like properties. Replacement of the central piperidine
- Watson, Robert J.,Allen, Daniel R.,Birch, Helen L.,Chapman, Gayle A.,Galvin, Frances C.,Jopling, Louise A.,Knight, Roland L.,Meier, Dorica,Oliver, Kathryn,Meissner, Johannes W.G.,Owen, David A.,Thomas, Elizabeth J.,Tremayne, Neil,Williams, Sophie C.
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p. 147 - 151
(2008/09/17)
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to novel compounds and compositions thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
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- Chemical compounds
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Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
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Page/Page column 46
(2008/06/13)
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- CARBAMATE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
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The invention provides novel benzoimidazolone-carboxamide-derived carbamate 5-HT4 receptor agonist compounds of formula (I): wherein R1, R2, R3, R4, a, and b are defined in the disclosure. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 7; 16
(2008/06/13)
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- N-ALKYL-AZACYCLOALKYL NMDA/NR2B ANTAGONISTS
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Compounds represented by Formula (I): and/or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof, are effective as NMDA/NR2B antagonists useful for treating conditions such as pain, Parkinson’s disease, Alzheimer’s disease, epilepsy, depression, anxiety, ischemic brain injury including stroke.
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Page/Page column 75
(2008/06/13)
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- Quinolinone compounds as 5-HT4 receptor agonists
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The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 23-24
(2008/06/13)
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- Benzoimidazolone-carboxamide compounds as 5-HT4 receptors agonists
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The invention provides novel benzoimidazolone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 19-20
(2010/11/25)
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- Crystalline form of an indazole-carboxamide compound
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The invention provides crystalline halide salts of 1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide and solvates thereof. The invention also provides pharmaceutical compositions comprising such salts, methods of using such crystalline salts to treat diseases associated with 5-HT4 receptor activity, and processes useful for preparing such crystalline salts.
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Page/Page column 10
(2008/06/13)
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- Crystalline form of a quinolinone-carboxamide compound
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The invention provides a crystalline hydrochloride salt of 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide or a solvate thereof. The invention also provides pharmaceutical compositions comprising such crystalline salt forms, methods of using such crystalline salt forms to treat diseases associated with 5-HT4 receptor activity, and processes useful for preparing such crystalline salt forms.
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Page/Page column 9
(2010/11/24)
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- Quinolinone-carboxamide compounds
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The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 18-19
(2008/06/13)
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- Indazole-carboxamide compounds
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The invention provides novel indazole-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 23
(2008/06/13)
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- 5-HT4 receptor agonist compounds
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The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 21
(2008/06/13)
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- PIPERAZINO DERIVATIVES AS NEUROKININ ANTAGONISTS
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The invention relates to compounds of formula (I) wherein Z, Rc, y, m, u, Ar2, n, X, Rc', l and Ar2 are as described herein. These compounds are neurokinin antagonists. These compounds are useful in the treatment of chronic airway diseases such as asthma.
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Page/Page column 74
(2010/11/08)
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- INDAZOLE-CARBOXAMIDE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
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The invention provides novel indazole-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 39-40
(2010/02/13)
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- IMIDAZOPYRIDINE SUBSTITUTED TROPANE DERIVATIVES WITH CCR5 RECEPTOR ANTAGONIST ACTIVITY FOR THE TREATMENT OF HIV AND INFLAMMATION
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The present invention provides compounds of formula (I) wherein R1 and R2 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.
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Page/Page column 39
(2010/02/11)
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- Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
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The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 16
(2008/06/13)
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- Chemical compounds
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The present invention provides compounds of formula (I) wherein R1 and R2 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.
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Page/Page column 18
(2010/02/13)
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- Tropane derivatives useful in therapy
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The present invention provides compounds of formula (I) wherein X, Y, R1, R2 and R3 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.
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- CHEMICAL COMPOUNDS
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Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
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- CCR5 ANTAGONISTS AS THERAPEUTIC AGENTS
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable derivatives thereof, useful in the treatment or prophylaxis of CCR5-related diseases and disorders, for example, in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
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Page 51 - 52
(2010/02/07)
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- Quinolinecarboxylic acid derivatives
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Quinolinecarboxylic acid derivatives represented by the following formula: STR1 wherein C is hydroxymethyl, methoxy, ethoxy or morpholinyl, or pharmaceutically acceptable salts thereof exhibit a potent action for stimulating a serotonin 4 receptor. The compounds exhibit an action of enhancing the gastrointestinal motor function to improve the gastrointestinal conditions such as heartburn, anorexia, bowel pain, abdominal distension, etc., accompanied by chronic gastritis, diabetes mellitus or postoperative gastroparesis, and are thus effective for the treatment of gastro-esophagal reflux, intestinal pseudo-obstruction and constipation.
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