- Preparation method of (2-(1H-imidazole-4-yl)phenyl)methanol
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The invention belongs to the technical field of medicinal chemistry, and particularly discloses a preparation method of (2-(1H-imidazole-4-yl)phenyl)methanol. Amino of 4-iodine-1H-imidazole is protected by a triphenylmethyl protecting group and reacts wit
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Paragraph 0031-0046
(2021/01/04)
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- DIARYLTHIOHYDANTOIN COMPOUND AS ANDROGEN RECEPTOR ANTAGONIST
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The present application belongs to the field of medicine. In particular, the present application relates to a diarylthiohydantoin compound as an androgen receptor antagonist or a pharmaceutically acceptable salt thereof, a preparation method of the same, a pharmaceutical composition comprising the compound, and a use thereof in treating a cell proliferative disease mediated by androgen. The compound of the present application has good antagonistic effect on androgen receptor and exhibits excellent antitumor effect.
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Paragraph 0826-0828
(2020/07/07)
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- Design and synthesis of indoleamine 2,3-dioxygenase 1 inhibitors and evaluation of their use as anti-tumor agents
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Indoleamine 2,3-dioxygenase (IDO) 1 is the key enzyme for regulating tryptophan metabolism and is an important target for interrupting tumor immune escape. In this study, we designed four series of compounds as potential IDO1 inhibitors by attaching various fragments or ligands to indole or phenylimidazole scaffolds to improve binding to IDO1. The compounds were synthesized and their inhibitory activities against IDO1 and tryptophan 2,3-dioxygenase were evaluated. The cytotoxicities of the compounds against two tumor cell lines were also determined. Two compounds with a phenylimidazole scaffold (DX-03-12 and DX-03-13) showed potent IDO1 inhibition with IC50 values of 0.3–0.5 μM. These two IDO1 inhibitors showed low cell cytotoxicity, which indicated that they may exert their anti-tumor effect via immune modulation. Compound DX-03-12 was investigated further by determining the in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that DX-03-12 had satisfactory properties in mice, with rapid absorption, moderate plasma clearance (~36% of hepatic blood flow), acceptable half-life (~4.6 h), and high oral bioavailability (~96%). Daily oral administration of 60 mg/kg of compound DX-03-12 decreased tumor growth by 72.2% after 19 days in a mouse melanoma cell B16-F10 xenograft model compared with the untreated control. Moreover, there was no obvious weight loss in DX-03-12-treated mice. In conclusion, compound DX-03-12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.
- Wen, Hui,Liu, Yuke,Wang, Shufang,Wang, Ting,Zhang, Gang,Chen, Xiaoguang,Li, Yan,Cui, Huaqing,Lai, Fangfang,Sheng, Li
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- OGA INHIBITOR COMPOUNDS
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The present invention relates to O-GIcNAc hydrolase (OGA) inhibitors of formula (I). 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 inhibition of OGA is beneficial, such as tauopathies in particular Alzheimer's disease or progressive supranuclear palsy; and neurodegenerative diseases accompanied by a tau pathology, in particular amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C90RF72 mutations.
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Page/Page column 87
(2020/01/11)
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- Fused imidazole compounds with indoleamine 2,3-dioxygenase inhibition activity
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The invention relates to fused imidazole compounds, and a preparation method and application thereof. The structure of the compounds is shown in a general formula I, wherein the definitions of each group are as described in the specification. The compounds are capable of selectively inhibiting indoleamine 2,3-dioxygenase (IDO). The compounds provided by the invention can be used as IDO inhibitorsfor the treatment and/or prevention of diseases with the pathological characteristics of IDO mediated tryptophan metabolism pathways, such as cancer, eye diseases, autoimmune diseases, psychological disorders, depression, anxiety and other diseases.
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Paragraph 0142; 0143; 0144; 0145
(2018/07/10)
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- SUBSTITUTED [5,6]CYCLIC-4(3H)-PYRIMIDINONES AS ANTICANCER AGENTS
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The present invention relates to novel substituted [5,6]cyclic-4(3H)-pyrimidinone compounds of formula (I) and their preparation methods. (I) In particular, the present invention relates to novel substituted [5,6]cyclic-4(3H)- pyrimidinone compounds useful as inhibitors of protein kinases, specifically CDC7 (cell division cycle 7) inhibitors.
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Page/Page column 40-41
(2018/12/13)
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- Discovery of imidazoleisoindole derivatives as potent IDO1 inhibitors: Design, synthesis, biological evaluation and computational studies
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Indoleamine-2,3-dioxygenase-1 (IDO1) is an attractive target for cancer immunotherapy. Herein, a series of novel imidazoleisoindole derivatives were prepared and evaluated for their ability to inhibit IDO1. Among these, derivative 11r was the most active compound with nanomolar potency in the Hela cell-based assay, while showed negligible cellular toxicity. UV-visible spectra study demonstrated that compounds 11p and 11r bound to IDO1 and coordinated with the heme iron. Furthermore, they could significantly promote T cell proliferation, increase IFN-γ production, and reduce the numbers of Foxp3+ regulatory T cells. Finally, induced fit docking (IFD) and quantum mechanics/molecular mechanics (QM/MM) calculation were performed to understand the interactions of these compounds to IDO1 protein, which provided a comprehensive guide for further structural modification and optimization.
- Zou, Yi,Wang, Fang,Wang, Yan,Sun, Qirui,Hu, Yue,Li, Yuezhen,Liu, Wen,Guo, Wenjie,Huang, Zhangjian,Zhang, Yihua,Xu, Qiang,Lai, Yisheng
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p. 293 - 304
(2017/10/05)
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- Imidazo isoindole IDO1 inhibitor as well as preparation method and application thereof
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The invention belongs to the field of medicine, and particularly relates to an imidazo isoindole IDO1 compound with structural characteristics of the formula (I) shown in the description as well as a three-dimensional isomer or a pharmaceutically acceptable salt thereof, a preparation method thereof and application thereof as an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor. An experiment result shows that the compound of the invention has a significant inhibition effect for the activity of IDO1, can effectively promote the proliferation of cells T, prevents initial cells T from being differentiated into adjustable cells T, can invert IDO1 mediating immunosuppression, can be used for treating relevant diseases with pathological features of an IDO1 mediating kynurenine metabolic way including cancers, virus infection, neurodegenerative diseases, cataracts, organ transplant rejection, depression, autoimmune diseases and the like.
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Paragraph 0085; 0086; 0091; 0092
(2018/01/11)
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- Imidazole-containing condensed tricyclic compound and application thereof
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The invention discloses an imidazole-containing condensed tricyclic compound adopting the structure as shown in the formula (I) or pharmaceutically acceptable salts, stereisomers or prodrug molecules thereof. The imidazole-containing condensed tricyclic compound has the IDO1 activity regulation function, can enhance T-cell activation through blocking immune checkpoints IDO1, is used for treating IDO1-mediated immunosuppression, and therefore, can become an effective medicine for treating malignant tumors. When used together with checkpoint protein anti-body drugs or other anti-cancer drugs, the imidazole-containing condensed tricyclic compound can enhance the anti-cancer effect. Meanwhile, the imidazole-containing condensed tricyclic compound has the potential of effectively treating IDO1 abnormity related immunosuppressive diseases and has a high application value.
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Paragraph 0112
(2018/03/01)
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- Novel Compounds as Autotaxin Inhibitors and Pharmaceutical Compositions Comprising the Same
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The present invention relates to a novel autotaxin inhibitor compound for preventing and treating disease or symptoms due to an increase in concentration of lysophosphatidic acid or activation of autotaxin. The present invention further relates to a pharmaceutical composition containing the same. The novel compound of the present invention is an autotaxin inhibitor which inhibits production of lysophosphatidic acid, and thus is useful for treating or preventing cardiovascular disease, cancer, metabolic disease, kidney disease, liver disease, inflammatory diseases, nervous disease, respiratory disease, desmoid disease, eye disease, cholestatic symptoms, other types of chronic pruritus or acute, or chronic rejection of transplanted organs.COPYRIGHT KIPO 2017
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Paragraph 1139-1142
(2018/05/17)
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- COMPOUNDS FOR THE INHIBITION OF INDOLEAMINE-2,3-DIOXYGENASE
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The present invention relates to compounds, and pharmaceutically acceptable compositions thereof, useful as antagonists of IDO, and for the treatment of IDO-related disorders.
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Paragraph 0216-0217
(2016/04/09)
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- 6,7-HETEROCYCLIC FUSED 5H-PYRROLO[1,2-C]IMIDAZOLE DERIVATIVES AND THEIR USE AS INDOLEAMINE 2,3-DIOXYGENASE (IDO) AND/OR TRYPTOPHAN 2,3-DIOXYGENASE (TD02) MODULATORS
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This invention relates to novel compounds of formula (I) wherein 'A' is a 5 or 6 membered heteroaryl group, unsubstituted or substituted with 1, 2 or 3 groups as defined in claim 1; X is a bond or -(CRA1RB1)n-; Y is selected from: a bond, -(CRDRE)m-, -O-, -NRF, -S-, -C(O)-, -C(NRF) -, -C(ORF)Rc-, -C(NRFRG)RC-, -C(O)NRF, -NRFC(O)-, -NRFC(O)NRG-, - NRFSO2NRG-, -SO2-, -SO2NRF-, -NRFSO2-, -OC(O)- and -C(O)O-; Z is a bond or -(CRA2RB2)k-; wherein m, n and k are each independently selected from 1, 2, 3 and 4; R1 is H or a 3 to 16 membered fully saturated, partially unsaturated or aromatic mono-, di- or tri-cyclic moiety, which optionally may include 1, 2 or 3 heteroatoms selected from O, N and S, and which is unsubstituted or substituted with 1 to 5 substituents as defined in claim 1; R2 is selected from: H, halo, C1-4alkyl, C1-4 haloalkyl, -ORA4 and C1-4alkyl substituted with -ORA4; and R3 and R4 are each independently selected from: H, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, -ORA4, -NRA5RB4, -CN, -SRAS and C1-4alkyl substituted with -ORA5; and pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3- dioxygenase (TD02) modulators (e.g. IDOl, and ID02 and/or TD02 inhibitors).
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Paragraph 00200; 00201
(2016/11/07)
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- N-PYRIDINYL ACETAMIDE DERIVATIVES AS INHIBITORS OF THE WNT SIGNALLING PATHWAY
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This invention relates to compounds. More specifically, the invention relates to compounds useful as inhibitors of the Wnt signalling pathway. Specifically, inhibitors of Porcupine (Porcn) are contemplated by the invention. In addition the invention contemplates processes to prepare the compounds and uses of the compounds. The compounds of the invention may therefore be used in treating conditions mediated by the Wnt signalling pathway, for example treating cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia; or enhancing the effectiveness of an anti-cancer treatment.
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Paragraph 00231
(2016/05/02)
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- RADIOACTIVE HALOGEN LABELED COMPOUNDS OR SALTS THEREOF, AND PHARMACEUTICALS CONTAINING THE SAME
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PROBLEM TO BE SOLVED: To provide: radioactive halogen labeled compounds which have high selectivity for aldosterone synthase (CYP11B2) over steroid 11β-hydroxylase (CYP11B1) and high accumulation selectivity in the adrenal gland compared to the surroundin
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Paragraph 0057; 0058
(2016/12/22)
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- ALDOSTERONE SYNTHASE INHIBITOR
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PROBLEM TO BE SOLVED: To provide a compound having aldosterone synthase inhibition effect useful for treatment of primary aldosteronism causing hypertension or hypokalemia by overproduction of aldosterone, and a pharmaceuticals containing the compound. SOLUTION: There are provided an imidazole compound including 4-[5-(2-fluoroethyl)-1H-imidazole-1-ylmethyl]-3-iodobenzonitrile, 1-(3-bromo-4-cyanobenzyl)-1H-imidazole-5-carboxylic acid methyl, 1-(2-iodo-4-nitrobenzyl)-1H-imidazole-5-carboxylic acid methyl, 1-(3,5-di-tert-butylphenyl)-1H-imidazole-5-carboxylic acid methyl, 1-(2H-chromene-2-on-6-ylmethyl)-1H-imidazole-5-carboxylic acid methyl and 1-(2H-chromene-2-on-6-ylmethyl)-5-iodo-1H-imidazole as examples, and pharmaceuticals containing the compound. COPYRIGHT: (C)2015,JPOandINPIT
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Paragraph 0016; 0100; 0101
(2018/10/10)
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- ALDOSTERONE SYNTHASE INHIBITOR
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PROBLEM TO BE SOLVED: To provide a novel metomidate derivative compound having increased selectivity for CYP11B2 over CYP11B1. SOLUTION: This invention provides a compound represented by a predetermined general formula or salt thereof. COPYRIGHT: (C)2015,
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Paragraph 0016; 0078; 0079
(2018/12/01)
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- TRIAZINE COMPOUNDS AS KINASE INHIBITORS
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The present invention relates to triazine compounds that are useful as kinase inhibitors. More particularly, the present invention relates to morpholino substituted triazines, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumours and cancers as well as other disorders or conditions related to or associated with mTOR kinases or PI3 kinases. The compounds are of the formula (I)
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Page/Page column 96
(2009/09/05)
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- 4-Benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists
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Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in s
- Wijtmans, Maikel,Celanire, Sylvain,Snip, Erwin,Gillard, Michel R.,Gelens, Edith,Collart, Philippe P.,Venhuis, Bastiaan J.,Christophe, Bernard,Hulscher, Saskia,Van Der Goot, Henk,Lebon, Florence,Timmerman, Henk,Bakker, Remko A.,Lallemand, Bénédicte I. L. F.,Leurs, Rob,Talaga, Patrice E.,De Esch, Iwan J. P.
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supporting information; experimental part
p. 2944 - 2953
(2009/04/11)
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- Preparation and diels-alder chemistry of 4-vinylimidazoles
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(Chemical Equation Presented) Various 4-vinylimidazole derivatives have been prepared from the corresponding 4-iodoimidazoles or from urocanic acid. Several methods for the elaboration of these vinylimidazoles and their Diels-Alder reactions are reported. All of the vinylimidazoles prepared in the course of this study react with N-phenylmaleimide quite readily with mild thermal activation providing a single cycloadduct, in most cases the initial, nonaromatic adduct. With more electron rich substrates, there is a tendency for these initial cycloadducts to undergo aromatization, ene reaction, and oxidation although this can be circumvented to a large extent by the choice of reaction conditions. Limited reactions were observed with other dienophiles, providing the expected cycloadducts in most cases, although an abnormal adduct was obtained in one case with dimethyl acetylene dicarboxylate. These substrates also participate in regioselective Diels-Alder reactions with monoactivated dienophiles, but require fairly forcing conditions, thus only providing the aromatized cycloadducts in modest yields. An investigation of substituent effects at the 2-position of the imidazole moiety was undertaken, in which electron-donating and weakly electron-withdrawing substituents are tolerated. In addition, several substrates with terminally substituted vinyl moieties have been investigated.
- Lovely, Carl J.,Du, Hongwang,Sivappa, Rasapalli,Bhandari, Manojkumar R.,He, Yong,Dias, H. V. Rasika
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p. 3741 - 3749
(2008/02/04)
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- NOVEL TUBULIN POLYMERISATION INHIBITORS
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The present invention relates to compounds of general formula (I) as tublin polymerisation inhibitors and methods for preparing such compounds.
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Page/Page column 66
(2008/06/13)
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- PYRIDYL SUBSTITUTED KETOLIDE ANTIBIOTICS
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Antimicrobial macrolide and ketolide compounds are provided having formulas (XII), as well as pharmaceutically acceptable salts, esters or prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.
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- NOVEL KETOLIDE DERIVATIVES
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Antimierobial ketolide compounds are provided having the formula (A), as well as pharmaceutically acceptable salts, esters or prodrugs thereof, pharmaceutical compositions comprising such compounds, methods of treating bacterial infections by the administration of such compounds, and processes for the preparation of the compounds.
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- C12 Modified erythromycin macrolides and ketolides having antibacterial activity
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Antimicrobial macrolide compounds are provided having formulas II: as well as pharmaceutically acceptable salts, esters or prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.
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- Substituted phenyl farnesyltransferase inhibitors
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Compounds of formula (I) or pharmaceutically acceptable salts thereof, inhibit farnesyltransferase. Methods for making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds are disclosed.
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- 3-Azabicyclo[3.1.0]hexane derivatives useful in therapy
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Compounds of formula (I), their salts and prodrugs thereof, where the substituents are as defined herein are disclosed as opiate binding agents useful in the treatment of opiate-mediated conditions. Also described are processes for making such substances.
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- PYRAZINONE, PYRIDINONE, PIPERIDINE AND PYRROLIDINE THROMBIN INHIBITORS
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A compound which inhibits human thrombin and where has the structure and pharmaceutically acceptable salts thereof, wherein such as STR1 which are useful for inhibiting formation of blood platelet aggregates in blood in a mammal.
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- Medetomidine analogs as α2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine
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A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their α-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for α2-adrenoceptors and behaved as a partial α1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was α1-selective and behaved as a potent α1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at α1- vs α2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the α-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the α2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with α2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.
- Zhang, Xiaoyan,Yao, Xiao-Tao,Dalton, James T.,Shams, Gamal,Lei, Longping,Patil, Popat N.,Feller, Dennis R.,Hsu, Fu-Lian,George, Cliff,Miller, Duane D.
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p. 3001 - 3013
(2007/10/03)
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- Synthesis of 4,4'-biimidazoles
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The palladium(0) catalysed coupling reaction of 4-iodo-1-triphenylmethylimidazole (7) or its 2-methyl analogue 8 afforded the 4,4'-biimidazoles 9 and 10, respectively. Treatment of these compounds with 60% aqueous trifluoroacetic acid gave 4,4'-biimidazole and 2,2'-dimethyl-4,4'-biimidazole as their bistrifluoroacetate salts 11 and 12, respectively.
- Cliff,Pyne
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p. 681 - 682
(2007/10/02)
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- 4-Lithio-1-tritylimidazole as a Synthetic Intermediate. Synthesis of Imidazole-4-carboxaldehyde
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Reaction of 4-iodo-1-tritylimidazole with n-butyllithium at -79 deg, followed by rapid quenching of the reaction mixture with DMF, gives good yields of 1-tritylimidazole-4(5)-carboxaldehyde, the isolation of which demonstrates the intermediacy of 4-lithio-1-tritylimidazole.This species should be destabilized by repulsive interaction of the negative charge on C-4 with the adjacent lone pair electrons on N-3 (the ALP effect).The isolation of 1-tritylimidazole-4(5)-carboxaldehyde in good yield and the versatility of the aldehyde functionality make 4-lithio-1-tritylimidazole a useful synthetic intermediate.
- Kirk, Kenneth L.
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