- Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies
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Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several comp
- Daelemans, Dirk,De Clercq, Erik,Gao, Ping,Ginex, Tiziana,Huang, Boshi,Jiang, Xiangyi,Kang, Dongwei,Liu, Xinyong,Luque, F. Javier,Pannecouque, Christophe,Zhan, Peng,Zhang, Jian
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p. 13604 - 13621
(2021/09/28)
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- Discovery of novel pyrimidine molecules containing boronic acid as VCP/p97 Inhibitors
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Valine-containing protein (VCP) is a member of the adenosine triphosphate family involved in a variety of cellular activities. VCP/p97 is capable of maintaining protein homeostasis and mediating the degradation of misfolded polypeptides by the ubiquitin–proteasome system (UPS). In this manuscript, a series of novel p97 inhibitors with pyrimidine as core structure were designed, synthesized and biologically evaluated. Based on the enzymatic results, a detailed structure–activity relationship discussion of the synthesized compounds was carried out. Furthermore, cellular activities of the compounds with enzymatic potency of less than 200 nM were investigated by using A549 and RPMI8226 cell lines. Among the screened inhibitors, compound 17 (IC50, 54.7 nM) showed good enzymatic activity. Investigation of cellular activities with non-small cell lung cancer A549 and multiple myeloma (MM) RPMI8226 further confirmed the potency of 17 with the IC50 values of 2.80 μM and 0.86 μM, respectively. Compound 17 is now being developed as a candidate. Finally, docking studies were carried out to explore the possible binding mode between the active inhibitor 17 and p97.
- Zhang, Yonglei,Xie, Xiaomin,Wang, Xueyuan,Wen, Tiantian,Zhao, Chi,Liu, Hailong,Zhao, Bo,Zhu, Yongqiang
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- Synthetic method of medical intermediate cycloalkanopyrimidinedione compound
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The invention provides a synthetic method of a cycloalkanopyrimidinedione compound, and belongs to the technical field of organic synthesis. The method provided by the invention comprises the following steps of: taking a 2-methoxycarbonyl naphthenone comp
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Paragraph 0032-0034
(2020/12/15)
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- Novel, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II α over β
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We disclose a novel class of 6-Amino-Tetrahydroquinazoline derivatives that inhibit human topoisomerase II (topoII), a validated target of anticancer drugs. In contrast to topoII-Targeted drugs currently in clinical use, these compounds do not act as topo
- Ortega, Jose Antonio,Arencibia, Jose M.,Minniti, Elirosa,Byl, Jo Ann W.,Franco-Ulloa, Sebastian,Borgogno, Marco,Genna, Vito,Summa, Maria,Bertozzi, Sine Mandrup,Bertorelli, Rosalia,Armirotti, Andrea,Minarini, Anna,Sissi, Claudia,Osheroff, Neil,De Vivo, Marco
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p. 12873 - 12886
(2020/11/17)
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- PYRIDAZINIUM COMPOUNDS FOR USE IN CONTROLLING UNWANTED PLANT GROWTH
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Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as pesticides, especially as herbicides.
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Page/Page column 51-52
(2020/08/22)
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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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- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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Provided are 2-(piperidin-1-yl)pyrimidin-4(3H)-ones or pharmaceutically acceptable salts thereof, each characterized by having a 1,8-diazaspiro[4.5]deca-3-ene, 1-oxa-8-azaspiro[4.5]deca-3-ene, 2,8-diazaspiro[4.5]deca-3-ene, 2-oxa-8-azaspiro[4.5]deca-3-ene, 2,9-diazaspiro[5.5]undeca-3-ene, 1-oxa-9-azaspiro[5.5]undeca-3-ene, 1,9-diazaspiro[5.5]undeca-4-ene, or 3,9-diazaspiro[5.5]undeca-1-ene structure represented by the following general formula (1):
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-
Paragraph 0183; 0184
(2019/05/16)
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- 4-AMINO-2-PYRIDO-BICYCLIC PYRIMIDINES AND USE THEREOF AS TOPOISOMERASE II INHIBITORS
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The present invention concerns 4-amino-2-pyrido-bicyclic pyrimidines as type II topoisomerase inhibitors and use thereof as medicaments especially in the treatment of cancer. The invention also provides a method for the manufacture of 4- amino-2-pyrido bicyclic pyrimidines.
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Page/Page column 20; 23; 55
(2018/07/29)
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- Octahydropyrrolo[3,4-c]pyrrole derivatives and use thereof
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The invention relates to octahydropyrrolo[3,4-c]pyrrole derivatives and a use thereof. The above compounds and a medicinal composition containing the compounds are used for suppressing an orexin receptor. The invention also relates to a method for preparing the compounds and the medicinal composition, and the use of the compounds and the medicinal composition in the treatment or prevention of orexin receptor related diseases.
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Paragraph 0291-0296
(2020/02/06)
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- 5,6,7,8-Tetrahydroquinazolin-2-amine compounds having inhibitory activity of serotonine 5-HT6
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The present invention relates to a novel 5,6,7,8-tetrahydroquinazolin-2-amine compound having an activity of inhibiting 5-HT6 receptor, one of the serotonin subtypes, and a pharmaceutical composition comprising the compound for preventing or treating central nervous system (CNS) diseases or a diagnosis reagent for central nervous system (CNS) diseases. The novel compound according to the present invention has a binding ability to 5-HT6 receptor and an activity of inhibiting the same, and thus is useful for diagnosing, preventing and treating central nervous system (CNS) diseases, such as Alzheimerandprime;s disease (AD), attention deficit / hyperactivity disorder (ADHD), epilepsy, depression, obesity, schizophrenia, sleep disturbance, pain and anxiety disorder.COPYRIGHT KIPO 2017
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Paragraph 0127; 0144-0145
(2017/06/24)
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- COMPOUNDS AND METHODS FOR TREATING, DETECTING, AND IDENTIFYING COMPOUNDS TO TREAT APICOMPLEXAN PARASITIC DISEASES
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Disclosed herein; are novel compounds for treating apicomplexan parasite related disorders, methods for their use; cell line and non-human animal models of the dormant parasite phenotype and methods for their use in identifying new drugs to teat apicomplexan parasite related disorders, and biomarkers to identify disease due to the parasite and its response to treatment.
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Page/Page column 137
(2017/07/14)
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- BICYCLIC DERIVATIVE CONTAINING PYRIMIDINE RING, AND PREPARATION METHOD THEREFOR
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The present invention provides: a bicyclic derivative comprising a pyrimidine ring, or a pharmaceutically acceptable salt thereof; a preparation method therefor, a pharmaceutical composition comprising the same; and a use therefor. According to the present invention, the bicyclic compound derivative comprising a pyrimidine ring, or a pharmaceutically acceptable salt thereof acts as a 5-HT4 receptor agonist, and thus can be usefully applied to the prevention or treatment of dysfunction in gastrointestinal motility, for example, gastrointestinal diseases such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, diabetic gastric atony and the like.
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Paragraph 0193; 0194
(2016/04/26)
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- Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
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The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin-proteasome system (UPS) mediated protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell death. In tumor bearing mice, oral administration of 71 causes rapid accumulation of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to sustained antitumor activity in in vivo xenograft models of both solid and hematological tumors. 71 has been taken into phase 1 clinical trials in patients with multiple myeloma and solid tumors.
- Zhou, Han-Jie,Wang, Jinhai,Yao, Bing,Wong, Steve,Djakovic, Stevan,Kumar, Brajesh,Rice, Julie,Valle, Eduardo,Soriano, Ferdie,Menon, Mary-Kamala,Madriaga, Antonett,Kiss Von Soly, Szerenke,Kumar, Abhinav,Parlati, Francesco,Yakes, F. Michael,Shawver, Laura,Le Moigne, Ronan,Anderson, Daniel J.,Rolfe, Mark,Wustrow, David
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p. 9480 - 9497
(2016/01/12)
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- Discovery and synthesis of N2,N4-substitued- cycloalkyl[d]pyrimidine-2,4-diamine analogs: The first examples of small-molecular FGFR-1 activator
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A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β, and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.
- Li, Bao-Li,Xiao, Fang,Lu, Wen-Chao,Sun, Yu-Yun,Zhu, Jin,Li, Jian
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p. 989 - 994
(2014/08/18)
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- MK2 INHIBITORS AND USES THEREOF
-
The present invention provides compounds, compositions thereof, and methods of using the same.
- -
-
Paragraph 00687
(2014/10/03)
-
- 1-(Arylmethyl)-5,6,7,8-tetrahydroquinazolline-2,4-diones and Analogs and the Use Thereof
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Disclosed are novel 1-(arylmethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diones and analogs thereof, represented by the Formula I, wherein Ar, A, B, R3-R6 are defined herein. Compounds having Formula I are PARP inhibitors. Therefore, compounds of the invention may be used to treat clinical conditions that are responsive to the inhibition of PARP activity, such as cancer.
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-
Paragraph 0150
(2014/09/30)
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- 1-(ARYLMETHYL)-5,6,7,8-TETRAHYDROQUINAZOLINE-2,4-DIONES AND ANALOGS AND THE USE THEREOF
-
Disclosed are novel 1-(arylmethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diones and analogs thereof, represented by the Formula I, wherein Ar, A, B, R3-R6 are defined herein. Compounds having Formula I are PARP inhibitors. Therefore, compounds of the invention may be used to treat clinical conditions that are responsive to the inhibition of PARP activity, such as cancer.
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- MODULATION OF CHEMOSENSORY RECEPTORS AND LIGANDS ASSOCIATED THEREWITH
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The present invention provides screening methods for identifying modifiers of chemosensory receptors and their ligands, e.g., by determining whether a test entity is suitable to interact with one or more interacting sites within the Venus flytrap domains of the chemosensory receptors as well as modifiers capable of modulating chemosensory receptors and their ligands.
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Page/Page column 66
(2009/01/20)
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- Substituted diazepan orexin receptor antagonists
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The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 20
(2008/12/05)
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- QUINOLINE, TETRAHYDROQUINOLINE AND PYRIMIDINE DERIVATIVES AS MCH ANTAGONIST
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The present invention relates to compounds of the Formula (I) wherein Q is: which act as MCH receptor antagonists. These compositions are useful in pharmaceutical compositions whose use includes prophylaxis or treatment of improving memory function, sleeping and arousal, anxiety, depression, mood disorders, seizure, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, binge eating disorders including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson's disease, epilepsy, and addiction.
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Page/Page column 168
(2010/02/08)
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- Pyrimidine derivatives and processes for the preparation thereof
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The present invention relates to novel pyrimidine derivatives of the formulae (I-1) and (I-2) and pharmaceutically acceptable salts thereof which possess an excellent anti-secretory activity, pharmaceutical compositions containing same as an active ingredient, their novel intermediates, and processes for the preparation thereof: STR1 wherein: R4 and R5, which may be the same or different, are independently hydrogen or a C1 -C3 alkyl group, or jointly form a cyclopentyl or cyclohexyl ring; A is a group of formula(II): STR2 wherein R1 and R2 are, independently of each other, hydrogen or a C1 -C3 alkyl group, and R3 is hydrogen, a C1 -C3 alkyl group or a halogen; and B is 1-(substituted)-1,2,3,4-tetrahydroisoquinolin-2-yl of formula (III-1) or 7-(substituted)-4,5,6,7-tetrahydrothieno?2,3-c!pyridin-6-yl of formula (III-2) STR3 wherein R6 is hydrogen or a C1 -C3 alkyl group.
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-
-
- New procedures for the synthesis of heterocyclic substituted and 2,4-difunctionalized pyrimidines
-
N-Tosyl-2-and -3-acetylpyrrols 1 or N-tosyl-2-pyrrolidone 5 were condensed with cyano compounds in the presence of triflic anhydride (Tf2O) to yield heteroarylpyrimidines. 2,4-Difunctionalized pyrimidines were obtained by reaction of the corresponding 2,4-bis(methylsulfonyl)pyrimidines with nucleophiles.
- Garcia Martinez, Antonio,Herrera Fernandez, Antonio,Moreno Jimenez, Florencio,Munoz Martinez, Pablo J.,Alonso Martin, Cristina,Subramanian, Laksminarayanapuran R.
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p. 7973 - 7982
(2007/10/03)
-
- Cephalosporin compounds
-
The present invention relates to novel cephalosporin compounds, pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates and isomers thereof which possess potent and broad antibacterial activities. The compounds of the present invention have a (4-amino-1-substituted-alkapyrimidinium-4-yl)thiomethyl group in 3-position of the cephem nucleus and is specifically represented by the following formula(I): STR1 wherein: R 1 is a hydrogen atom or a C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or --C(R A)(R B)COOH group wherein R A and R B are independently a hydrogen atom or a C 1-4 alkyl group, or form a C 3-7 cycloalkyl group together with the carbon atom to which they are attached;R 2 is an unsubstituted or substituted amino, C 1-4 alkyl or C 3-7 cycloalkyl group; andn is an integer ranging from 2 to 7.
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-
-
- Synthesis and antiviral study of cyclopentano [d] pyrimidine-2,4-diones and octahydroquinazoline-2,4-diones acyclic nucleosides as potential anti- HIV agents
-
The Vorbruggen and Niedballa's method afforded new cyclopentano [d] pyrimidine-2,4-dione and octahydroquinazoline-2,4-dione nucleosides. Various modifications of these new derivatives enabled us to obtain HEPT related compounds which were tested against H
- Renault,Laduree,Robba
-
p. 891 - 901
(2007/10/02)
-
- Oxidation of substituted 2-thiouracils and pyrimidine-2-thione with ozone and 3,3-dimethyl-1,2-dioxirane
-
Ozone and 3,3-dimethyl-1,2-dioxirane react with substituted 2-thiouracils and pyrimidine-2-thione to afford several interesting desulfurized products. The effect of the solvent, protic as opposed to nonprotic, on the course of oxidation was striking.
- Claudia, Crestini,Mincione, Enrico,Saladino, Raffaele,Nicoletti, Rosario
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p. 3259 - 3272
(2007/10/02)
-
- Novel cephalosporin compounds
-
The present invention relates to novel cephalosporin compounds, pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates and isomers thereof which possess potent and broad antibacterial activities. The compounds of the present invention have a (4-amino-1-substituted-alkapyrimidinium-4-yl)thiomethyl group in 3-position of the cephem nucleus and is specifically represented by the following formula(I): wherein: R1 isa hydrogen atom or, a C1 4 alkyl, C2 4 alkenyl, C2 4 alkynyl or -C(RA)(RB)COOH group wherein RAand RBare independently a hydrogen atom or a C1 4 alkyl group, or form a C3 7 cycloalkyl group together with the carbon atom to which they are attached; R2 isan unsubstituted or substituted amino, C1 4 alkyl or C3 7 cycloalkyl group; and n isan integer ranging from 2 to 7.
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-
-
- Synthesis and antimicrobial activity of novel 3- [(aminopyrimidiniumyl)thio]methyl cephalosporins
-
A series of novel cephalosporin compounds which have 3- [(aminopyrimidiniumyl)thio]methyl substituents was synthesized. They show high antimicrobial activity against various bacterial species including Pseudomonas aeruginosa. Structure-activity relationships with various thiopyrimidines, thiopyrimidiniums, bicyclic thiotriazolopyrimidiniums, and bicyclic thioimidazolopyrimidiniums as 3'-substituents were also studied; cephalosporins with quarternized pyrimidinium moieties have better antimicrobial activities than neuteral pyrimidine cephalosporins, and stabilization of the positive charge on the pyrimidinium moieties is essential for better activity. According to semiempirical PM3 calculations, amino and alkylthio substituents on the pyrimidinium rings play a major role in charge stabilization and delocalization.
- Kim,Lim,Yeo,Bang,Kim,Kim,Woo -,Yang,Oh,Nahm
-
p. 3828 - 3833
(2007/10/02)
-
- Ozonation of substituted 2-thiouracils and pyrimidine-2-thione
-
The ozonation of substituted 2-thiouracils and pyrimidine-2-thione is reported; this provides a new method for the synthesis of several pyrimidine derivatives.
- Crestini, Claudia,Saladino, Raffaele,Nicoletti, Rosario
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p. 1631 - 1634
(2007/10/02)
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- Formation of Ethoxyhydroquinazolinone by Attack of an Estercarbonyloxygen at a Cyano Group
-
By the reaction of ethyl-2-oxocyclohexanecarboxylate with cyan amide 4-ethoxy-hexahydroquinazolin-2-one (12) is formed.Butyl-2-oxo-cyclopentanecarboxylate and cyan amide yield butyl-3-cyanamino-cyclopent-1-en-carboxylate (14). 2-Oxocyclohexane-carboxamide
- Bischoff, Christian,Schroeder, Edith
-
p. 129 - 132
(2007/10/02)
-
- 6-ALKYL AND 5,6-DIALKYL-2-METHOXY-4(3H)-PYRIMIDINONES IN THE TRANSFORMATIONS OF PYRIMIDINES-2 SYNTHESIS AND CONVERSION INTO ALKYLURACILS AND 2-ALKOXY-4(3H)-PYRIMIDINONES
-
The synthesis of 6-alkyl and 5,6-dialkyl-2-methoxy-4(3H)-pyrimidinones 3 is described.Their versatility to be transformed into 6-alkyl and 5,6-dialkyluracils 4(a-h), 6-alkyl and 5,6-dialkyl-3-methyluracils 7(a,e,f) and 6-alkyl and 5,6-dialkyl-2-alkoxy-4(3H)-pyrimidinones 5(a-i) is also shown.
- Botta, M.,Cavalieri, M.,Ceci, D.,Angelis, F. De,Finizia, G.,Nicoletti, R.
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p. 3313 - 3320
(2007/10/02)
-
- Pyrimidine derivatives I. Synthesis of hypoglycemic 2-piperazino-5,6-polymethylenepyrimidines 5,6-polymethylenepyrimidines
-
Synthesis and hypoglycemic activity of 36 novel 2,4-diamino-5,6-polymethylenepyrimidine derivatives are described. Derivatives containing piperazino groups at position 2 showed a potent hypoglycemic activity and concomitantly inhibited platelet aggregation.
- Sekiya,Hiranuma,Kanayama,Hata
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p. 317 - 322
(2007/10/02)
-
