- Design, synthesis, and biological activity evaluation of a series of novel sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia
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Accumulating researches have contributed much effect to discover novel chemotherapeutic drug for leukemia with expeditious curative effect, of which bromodomain-containing protein 4 (BRD4) inhibitor is considered as a eutherapeutic drug which has presented efficient cell proliferation suppression effect. In this study, we disclosed a series of phenylisoxazole sulfonamide derivatives as potent BRD4 inhibitors. Especially, compound 58 exhibited robust inhibitory potency toward BRD4-BD1 and BRD4-BD2 with IC50 values of 70 and 140 nM, respectively. In addition, compound 58 significantly suppressed cell proliferation of leukemia cell lines HL-60 and MV4-11 with IC50 values of 1.21 and 0.15 μM. In-depth study of the biological mechanism of compound 58 exerted its tumor suppression effect via down-regulating the level of oncogene c-myc. Moreover, in vivo pharmacokinetics (PK) study was conducted and the results demonstrated better pharmacokinetics features versus (+)-JQ1. In summary, our study discovers that compound 58 represents as a novel BRD4 inhibitor for further investigation in development of leukemia inhibitor with potentiality.
- Chen, Aiping,Feng, Ziying,Huang, Wenlong,Li, Jieming,Liu, Xinhong,Qian, Hai,Qiu, Qianqian,Shi, Jing,Shi, Wei,Zhang, Wenjie,Zhou, Daoguang
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supporting information
(2021/07/22)
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- DOCK1-INHIBITING COMPOUND AND USE THEREOF
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Provided is a compound that is usable as an active ingredient of an anticancer agent. Preferably provided is a compound that has DOCK1-inhibiting activity and exerts an anticancer effect based on the activity. A compound represented by the following formula (A) or a salt thereof: wherein X represents a carbon atom or a nitrogen atom; Y represents an oxygen atom, a hydroxy group, or a hydrocarbon group; R1 and R2 are different, and each represents a hydrogen atom or a group represented by the following formula (A-1): (wherein R6 represents a pyrrolidino group or a phenyl group, and n2 is 0 or 1) ; R3 represents -CO-R7 (wherein R7 is an alkoxy group, an alkyl group, or an alkylamino group), a 1,3-oxazole group, an alkylhydroxy group, a hydrogen atom, or an oxygen atom; R4 represents a hydrogen atom, an oxygen atom, or a hydrocarbon group in which one or more hydrogen atoms may be replaced by one or more substituents; R5 represents a halogen atom, a halogenated alkyl group, or a halogenated alkylthio group; and n1 is an integer of 0 to 5; and
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Paragraph 0263; 0264
(2021/10/07)
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- Preparation method of 2, 5-dibromopyridine
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The invention discloses a preparation method of 2, 5-dibromopyridine, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: reacting 2-hydroxypyridine serving as a raw material with a bromination reagent to obtain 2-hydroxy-5-bromopyridine; and then reacting with a bromination reagent under the action of a Lewis acid catalyst to obtain 2, 5-dibromopyridine. The method is completed in two steps, an isomer obtained in the first step of reaction does not need to be purified, and a product with the purity of 99.5% or above can be obtained through recrystallization once in the last step.
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Paragraph 0020-0025
(2021/04/21)
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- Identification of an Oxalamide Ligand for Copper-Catalyzed C?O Couplings from a Pharmaceutical Compound Library
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A typical pharmaceutical compound library is stocked with molecular diversity and could provide a platform for the discovery of new ligand structures. Herein, we describe the use of this approach in combination with high throughput screening to identify N,N’-bis(thiophene-2-ylmethyl)oxalamide as a ligand that is generally effective for copper-catalyzed C?O cross-couplings to prepare both biarylethers as well as phenols under mild conditions.
- Chan, Vincent S.,Krabbe, Scott W.,Li, Changfeng,Sun, Lijie,Liu, Yue,Nett, Alex J.
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- PYRIDONE DERIVATIVE COMPRISING HETEROATOMIC RING BUTANE SUBSTITUENT, FOR TREATING FIBROSIS AND INFLAMMATORY DISEASES
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Disclosed is a compound for treating fibrosis-related diseases, and specifically disclosed are the compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
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Paragraph 0113; 0114
(2019/03/08)
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- HETEROCYCLIC COMPOUNDS WITH MICROBIOCIDAL PROPERTIES
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The present disclosure relates to a compound of Formula I, wherein the substituents T, A, W, R2, n, Z, G, Z1 and J are as defined in the description.
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- 2,5-DIBROMOPYRIDINE AND PROCESSES OF PREPARATION
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Provided herein is a process for the preparation of 2,5-dibromopyridine.
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Page/Page column 4-5
(2019/01/08)
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- A highly efficient Suzuki-Miyaura methylation of pyridines leading to the drug pirfenidone and its CD3 version (SD-560)
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Efficient introduction of methyl or methyl-d3 into aromatic and heteroaromatic systems still presents a synthetic challenge. In particular, we were in search of a non-cryogenic synthesis of the 5-CD3 version of pirfenidone (4d, also known as Pirespa, Esbriet or Pirfenex), one of the two drugs approved to date for retarding idiopathic pulmonary fibrosis (IPF), a serious, rare and fatal lung disease, with a life expectancy of 3-5 years. The methyl-deuterated version of pirfenidone (4e, also known as SD-560) was designed with the objective of attenuating the rate of drug metabolism, and our goal was to find a green methylation route to avoid the environmental and economic impact of employing alkyllithium at cryogenic temperatures. The examination of several cross-coupling strategies for the introduction of methyl or methyl-d3 into methoxypyridine and pyridone systems culminated in two green and nearly quantitative Suzuki-Miyaura cross-coupling routes in the presence of RuPhos ligand: the first, using commercially available methyl boronic acid or its CD3 analog and the second, employing potassium methyl trifluoroborate or CD3BF3K, the latter obtained by a new route in 88% yield. This led, on a scale of tens of grams, to the synthesis of pirfenidone (4d) and its d3 analog, SD-560 (4e), at 99% isotopic purity.
- Falb, Eliezer,Ulanenko, Konstantin,Tor, Andrey,Gottesfeld, Ronen,Weitman, Michal,Afri, Michal,Gottlieb, Hugo,Hassner, Alfred
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supporting information
p. 5046 - 5053
(2017/11/09)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
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Page/Page column 56
(2016/05/19)
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- Asymmetric Homogeneous Hydrogenation of 2-Pyridones
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An asymmetric homogeneous hydrogenation of 2(1H)-pyridones has been developed, using a ruthenium complex bearing two chiral N-heterocyclic carbene (NHC) ligands. To the best of our knowledge, the presented reaction is the first example of a homogeneous asymmetric conversion of 2-pyridones into the corresponding enantioenriched 2-piperidones.
- Wysocki, Jedrzej,Schlepphorst, Christoph,Glorius, Frank
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supporting information
p. 1557 - 1562
(2015/06/30)
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- A new synthesis of pyridinyl trifluoromethanesulfonates via one-pot diazotization of aminopyridines in the presence of trifluoromethanesulfonic acid
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The first method for the direct one-pot transformation of aminopyridines into pyridinyl trifluoromethanesulfonates is developed. The procedure involves diazotization of aminopyridines with sodium nitrite in a DMSO paste in the presence of trifluoromethanesulfonic acid.
- Krasnokutskaya, Elena A.,Kassanova, Assiya Zh.,Estaeva, Makpal T.,Filimonov, Victor D.
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p. 3771 - 3773
(2014/07/07)
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- PYRIDINE DERIVATIVES
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The present application provides novel pyridine compounds and pharmaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. These compounds are useful in inhibiting CYP 17 activity by administering a therapeutically effective amount of one or more of the compounds to a patient. By doing so, these compounds are effective in treating conditions associated with CPY17 activity. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer, such as prostate cancer.
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Page/Page column 67
(2013/04/13)
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- IMIDAZOLE DERIVATIVES AS CYP17 INHIBITORS FOR THE TREATMENT OF CANCER
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The present application provides novel imidazole compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in inhibiting CYP 17 activity by administering a therapeutically effective amount of one or more of the compounds to a patient. By doing so, these compounds are effective in treating conditions associated with CPY17 activity. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer, such as prostate cancer.
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Page/Page column 72-73
(2013/04/13)
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- NOVEL PYRIDINONE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2-RECEPTORS
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The present invention relates to novel compounds, in particular novel pyridinone derivat ives according to Formula (I) X R1 N Y (I) R2 R3 wherein all radicals are defined in the application. The compounds according to the invention are positive allosteric modulators of metabotropic receptors-subt ype 2 ("mGluR2") which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved. "
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Page/Page column 80
(2010/10/20)
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- PYRAZINE DERIVATIVES AND PHARMACEUTICAL USE THEREOF
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A pyrazine derivative of the following formula (I): or a salt thereof. The pyrazine compound (I) and a salt thereof of the present invention are adenosine antagonists and are useful for the prevention and/or treatment of depression, dementia (e.g. Alzheimer’s disease, cerebrovascular dementia, dementia accompanying Parkinson’s, disease, etc.), Parkinson’s disease, anxiety, pain, cerebrovascular disease (e.g. stroke), etc.), heart failure and the like.
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Page/Page column 49
(2010/02/11)
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- FUSED PHENYLALANINE DERIVATIVES AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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The present invention is directed to fused phenylalanine derivatives which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. 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 the dipeptidyl peptidase-IV enzyme is involved.
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Page/Page column 40
(2008/06/13)
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- Tetrabutylammonium salt induced denitration of nitropyridines: Synthesis of fluoro-, hydroxy-, and methoxypyridines
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(Chemical Equation Presented) An efficient method for the synthesis of fluoropyridines via the fluorodenitration reaction is reported. The reaction is mediated by tetrabutylammonium fluoride (TBAF) under mild conditions without undue regard to the presence of water. The fluorodenitration is general for 2- or 4-nitro-substituted pyridines, while 3-nitropyridines require attendant electron-withdrawing groups for the reaction to proceed efficiently. Nitropyridines also undergo hydroxy- and methoxydenitration under mild conditions in the presence of the corresponding tetrabutylammonium species.
- Kuduk, Scott D.,DiPardo, Robert M.,Bock, Mark G.
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p. 577 - 579
(2007/10/03)
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- 3-Aryl pyridone derivatives. Potent and selective kappa opioid receptor agonists
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A new series of 3-aryl pyridone based kappa opioid receptor agonists was designed and synthesised, based on an understanding of the classical kappa opioid receptor pharmacophore. The most potent of the new compounds were comparable to U-69,593 in receptor affinity, selectivity and functional agonist effect at the cloned human kappa opioid receptor.
- Semple, Graeme,Andersson, Britt-Marie,Chhajlani, Vijay,Georgsson, Jennie,Johansson, Magnus,Lindschoten, Marcel,Ponten, Fritof,Rosenquist, Asa,Soerensen, Henrik,Swanson, Lars,Swanson, Marianne
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p. 197 - 200
(2007/10/03)
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- Synthesis of melatonin analogues derived from furo[2,3-b]- and [2,3-c]pyridines by use of a palladium-copper catalyst system
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2,3,5-Substituted furo[2,3-b]pyridine was synthesised by palladium-catalyzed reaction of 5-bromo-2-hydroxy-3-iodopyridine and phenylacetylene with (Ph3P)2PdCl2, CuI in Et3N. A carbonylative cyclization of 5-hydroxy-2-methoxy-4-(2-phenylethynyl)pyridine with carbon monoxide in methanol with PdCl2, CuCl2 under basic conditions, has been accomplished to prepare methyl 2,5-substituted furo[2,3-c]pyridine-3-carboxylate.
- Van De Po?l, Hervé,Guillaumet, Gérald,Viaud-Massuard, Marie-Claude
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- Mild regioselective halogenation of activated pyridines with N-bromosuccinimide
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Regioselective mono and dihalogenations of amino, hydroxy and methoxy pyridines (2-, 3-, and 4-substituted) as well as 2,6-dimethoxy pyridine with N-bromosuccinimide in different solvents have been studied. Reactivity of the substrates decreases in the order amino>hydroxy>methoxy and regioselectivity depends on the position of the substituent (2-substituted > 3-substituted). In most of the cases we obtained monobrominated derivatives regioselectively and in high yields. Hydroxy and amino pyridines can also be dibrominated in almost quantitative yield with 2 equivalents of NBS.
- Canibano,Rodriguez,Santos,Sanz-Tejedor,Carreno,Gonzalez,Garcia-Ruano
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p. 2175 - 2179
(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 invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
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- Internal and External Heavy-atom Effects on the Photolysis of 1-Benzyloxy-2-pyridone
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The emission efficiencies of the title compound (BP) are subject to pronounced internal and external heavy-atom effects while the efficiency of its photoreaction is insensitive to these heavy-atom perturbations.This result is explained in terms of the mechanism in which the N-O bond cleavage in a BP molecule takes place from higher vibrational states of the first excited singlet state in competition with vibrational relaxation to the fluorescent state.Further supporting evidence for this mechanism is obtained from temperature effects on the fluorescent and reaction efficiencies of BP.
- Sakurai, Tadamitsu,Obana, Takashi,Inagaki, Tatsuya,Inoue, Hiroyasu
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p. 535 - 538
(2007/10/02)
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- THE REACTIONS OF SOME HALOGENATED PYRIDINES WITH METHOXYDE AND METHANETHIOLATE IONS IN DIMETHYLFORMAMIDE
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The reactions of 2,6- and 2,5-dibromopyridines and of 2,3- and 3,5-dichloropyridines with sodium isopropanethiolate and methanethiolate afforded the products of mono- or of bis-substitution depending on the experimental conditions.The same pyridines reacted with sodium methoxide to give good yields of the mono-substituted products; bis-substitution occurred easily only in the case of the 2,6-dibromo- and of the 3,5-dichloropyridine.The syntheses of some methoxy thiomethoxypyridine, starting from the halogeno methoxypyridines or from the halogeno thiomethoxypyridines are also described.The bis-(alkylthio)pyridines can be fragmented by sodium in HMPA to give the bis(mercapto)pyridines.
- Testaferri, Lorenzo,Tiecco, Marcello,Tingoli, Marco,Bartoli, Donatella,Massoli, Alberto
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p. 1373 - 1384
(2007/10/02)
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- CYCLOHEXYLATION OF N-ETHYL-2-PYRIDONE IN THE PRESENCE OF ALUMINIUM CHLORIDE
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The possibility of direct alkylation of N-ethyl-2-pyridone under Friedel-Crafts conditions was demonstrated.The reaction of N-ethyl-2-pyridone with cyclohexyl chloride in the presence of aluminium chloride took place at positions 3 and 5.
- Saidova, F. M.,Binchkauskas, V. Sh.,Khorev, S. G.,Enikeev, E. Ya.
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p. 353 - 357
(2007/10/02)
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