- Preparation method of lenvatinib
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The invention discloses a preparation method of lenvatinib, which comprises the following steps: by using 4-nitro-2-chlorobenzonitrile as an initial raw material, introducing nitro into molecules forelectron withdrawing, thereby greatly lowering the elect
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- A [...] synthetic method
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The invention provides a method of synthesizing [...]. First of all the invention to 4 - cyano - 3 - hydroxy aniline as the starting material, by dimethyl carbonate methylation, after third acid in the oximation reaction at room temperature, the conditions in the PPA shut-ring forms the 6 - cyano - 7 - methoxy - 4 - quinolinone, in thionyl chloride formed under the action of the 6 - cyano - 7 - methoxy - 4 - [...], under acidic conditions [...] cyano hydrolysis synthesis of one of the intermediates 6 - formamido - 7 - methoxy - 4 - chloroquinolin. Then the 4 - hydroxy - 2 chloroaniline with cyanogen bromide at low temperature 4 - hydroxy - 2 - chloro cyaniding amine, the 4 - hydroxy - 2 - chloro cyaniding amine with bearing-displacement generating Reeth reaction synthesis [...] another key intermediate 1 - (2 - chloro - 4 - hydroxy-phenyl) - 3 - ring propyl urea. Finally the two intermediate 6 - formamido - 7 - methoxy - 4 - chloroquinolin and 1 - (2 - chloro - 4 - hydroxy-phenyl) - 3 - ring propyl urea in the alkaline environment for carrying out the alkylation reaction [...]. This scheme has mild reaction conditions, no highly toxic reagent, environmental protection and the like.
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Paragraph 0043; 0044; 0045; 0053; 0054; 0062; 0063
(2019/05/22)
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- CONDENSED HETEROCYCLIC COMPOUND
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The present invention provides a fused heterocyclic compound having an RORγt inhibitory action. The present invention relates to a compound represented by the formula (I'): wherein each symbol is as defined in the specification, provided that 2-(2-((4-cyanophenyl)amino)-2-oxoethoxy)-N-(9-ethyl-9H-carbazol-3-yl)acetamide and N-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3-methylpentanediamide are excluded, or a salt thereof.
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Paragraph 0484; 0485
(2014/08/06)
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- Synthesis of prenyl- and geranyl-substituted carbazole alkaloids by DIBAL-H promoted reductive pyran ring opening of dialkylpyrano[3,2-a]carbazoles
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The DIBAL-H promoted reductive pyran ring opening of dialkylpyrano[3,2-a] carbazoles provides a direct access to a broad range of prenyl- and geranyl-substituted carbazoles. Formation of a pyran ring followed by reductive ring opening represents a new met
- Hesse, Ronny,Kataeva, Olga,Schmidt, Arndt W.,Knoelker, Hans-Joachim
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supporting information
p. 9504 - 9509
(2014/08/18)
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- Development of 2-thioxoquinazoline-4-one derivatives as dual and selective inhibitors of dynamin-related protein 1 (Drp1) and puromycin-sensitive aminopeptidase (PSA)
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An established inhibitor ot dynamin-related protein 1 (Drp1), 3-(2,4-dichloro-5-methoxyphenyl)- 2- thioxoquinazoline-4-one (mdivi-1), was recently reported also to show potent puromycin-sensitive aminopeptidase (PSA)-inhibitory activity. Herein, we report structural development of mdivi-1 derivatives and structure-activity relationship (SAR) analysis of the synthesized compounds, as well as the structurally related PSA-specific inhibitor 3-(2,6-diethylphenyl)quinazoline-2,4-dione (PAQ-22), with the aim of identifying key structural features for inhibitory activity in order to develop selective inhibitors of Drpl, which is a potential target for treatment of Huntington's disease. Among the synthesized compounds, 3-(4-chloro3methoxyphenyl)-2-thioxoquinazoline-4-one 10g) exhibited more potent Drpl-inhibitory activity than mdivi-1 with high selectivity for Drpl over PSA.
- Numadate, Akiyoshi,Mita, Yusuke,Matsumoto, Yotaro,Fujii, Shinya,Hashimoto, Yuichi
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p. 979 - 988
(2015/02/19)
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- OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS
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Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptors are disclosed.
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Page/Page column 22
(2012/11/13)
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- OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS
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Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptor are disclosed.
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Page/Page column 17; 36-37
(2011/07/07)
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- Cyclic amine compounds
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The present invention relates to pharmaceutical agents which are agents for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis; the pharmaceutical agents frailty suppressants, muscle strength enhance
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Page/Page column 22
(2009/03/07)
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- Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor
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A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
- Winters, Michael P.,Crysler, Carl,Subasinghe, Nalin,Ryan, Declan,Leong, Lynette,Zhao, Shuyuan,Donatelli, Robert,Yurkow, Edward,Mazzulla, Marie,Boczon, Lisa,Manthey, Carl L.,Molloy, Christopher,Raymond, Holly,Murray, Lynne,McAlonan, Laura,Tomczuk, Bruce
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p. 1926 - 1930
(2008/12/22)
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- Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators
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Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.
- Hamann, Lawrence G.,Manfredi, Mark C.,Sun, Chongqing,Krystek Jr., Stanley R.,Huang, Yanting,Bi, Yingzhi,Augeri, David J.,Wang, Tammy,Zou, Yan,Betebenner, David. A.,Fura, Aberra,Seethala, Ramakrishna,Golla, Rajasree,Kuhns, Joyce E.,Lupisella, John A.,Darienzo, Celia J.,Custer, Laura L.,Price, Jennifer L.,Johnson, James M.,Biller, Scott A.,Zahler, Robert,Ostrowski, Jacek
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p. 1860 - 1864
(2008/02/04)
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- Palladium-catalyzed silane/siloxane reductions in the one-pot conversion of nitro compounds into their amines, hydroxylamines, amides, sulfonamides, and carbamates
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A combination of palladium(II) acetate, aqueous potassium fluoride, and polymethylhydrosiloxane (PMHS) facilitates the room-temperature reduction of aromatic nitro compounds to anilines. These reactions tend to be quick (30 min), high-yielding, and tolerate a range of other functional groups. Replacement of PMHS/KF with triethylsilane allows for the reduction of aliphatic nitro compounds to their corresponding hydroxylamines. Depending on the substrate, both conditions can allow for the in situ conversion of the product amines into amides, sulfonamides, and carbamates. Georg Thieme Verlag Stuttgart.
- Rahaim Jr., Ronald J.,Maleczka Jr., Robert E.
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p. 3316 - 3340
(2008/09/17)
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- BENZAMIDE DERIVATIVES
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A compound represented by formula (1): wherein X is a single bond or a substituted or unsubstituted lower alkylene group; Z is a saturated or unsaturated monocyclic hydrocarbon ring group or the like; and each of R1, R2, R3 and R4, which may be the same or different, is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug has inhibitory effect on Rho kinase and hence is useful for treating diseases which are such that morbidity due to them is expected to be improved by inhibition of Rho kinase and secondary effects such as inhibition of the Na+/H+ exchange transport system caused by the Rho kinase inhibition, for example, hypertension.
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- HETEROCYCLIC KINASE INHIBITORS
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Compounds having the formula (I) are useful for inhibiting protein kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
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- Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
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Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.
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- Compounds derived from an amine nucleus and pharmaceutical compositions comprising same
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Compounds having the formula (I), are effective as inhibitors of IMPDH enzyme and/or serine protease Factor VIIa, wherein B is a monocyclic or bicyclic carbocyclic or heterocyclic ring, D is a monocyclic or bicyclic carbocyclic or heterocyclic ring except when A is a heterocyclic ring, then D is a heterocyclic ring system, R is hydrogen or C1-4alkyl, and A, R1, R2and R4are as defined in the specification.
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- Compounds derived from an amine nucleus and pharmaceutical compositions comprising same
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Compounds having the formula (I), are effective as inhibitors of IMPDH enzyme and/or serine protease Factor VIIa, wherein B is a monocyclic or bicyclic carbocyclic or heterocyclic ring, D is a monocyclic or bicyclic carbocyclic or heterocyclic ring except when A is a heterocyclic ring, then D is a heterocyclic ring system, R is hydrogen or C1-4alkyl, and A, R1, R2 and R4 are as defined in the specification.
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- Compounds derived from an amine nucleus that are inhibitors of IMPDH enzyme
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The present invention discloses the identification of the novel inhibitors of IMPDH (inosine-5′-monophosphate dehydrogenase). The compounds and pharmaceutical compositions disclosed herein are useful in treating or preventing IMPDH mediated diseases, such as transplant rejection and autoimmune diseases.
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- Exploiting subsite S1 of trypsin-like serine proteases for selectivity: Potent and selective inhibitors of urokinase-type plasminogen activator
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A nonselective inhibitor of trypsin-like serine proteases, 2-(2-hydroxybiphenyl-3-yl)-lH-indole-5-carboxamidine (1) (Verner, E.; Katz, B. A.; Spencer, J.; Allen, D.; Hataye, J.; Hruzewicz, W.; Hui, H. C.; Kolesnikov, A.; Li, Y.; Luong, C.; Martelli, A.; Radika. K.; Rai, R.; She, M.; Shrader, W.; Sprengeler, P. A.; Trapp, S.; Wang, J.; Young, W. B.; Mackman, R. L. J. Med. Chem. 2001, 44, 2753-2771) has been optimized through minor structural changes on the S1 binding group to afford remarkably selective and potent inhibitors of urokinase-type plasminogen activator (uPA). The trypsin-like serine proteases1 that comprise drug targets can be broadly categorized into two subfamilies, those with Ser190 and those with Ala190. A single-atom modification, for example, replacement of hydrogen for chlorine at the 6-position of the 5-amidinoindole P1 group on 1, generated up to 6700-fold selectivity toward the Ser190 enzymes and against the Alal90 enzymes. The larger chlorine atom displaces a water molecule (H2O1s1) that binds near residue 190 in all the complexes of 1, and related inhibitors, in uPA, thrombin, and trypsin. The water molecule, H2O1s1, in both the Ser190 or Ala190 enzymes, hydrogen bonds with the amidine N1 nitrogen of the inhibitor. When it is displaced, a reduction in affinity toward the Ala190 enzymes is observed due to the amidine N1 nitrogen of the bound inhibitor being deprived of a key hydrogen-bonding partner. In the Ser190 enzymes the affinity is maintained since the serine hydroxyl oxygen Oγser190 compensates for the displaced water molecule. Highresolution crystallography provided evidence for the displacement of the water molecule and validated the design rationale. In summation, a novel and powerful method for engineering selectivity toward Ser190 proteases and against Ala190 proteases without substantially increasing molecular weight is described.
- Mackman,Katz,Breitenbucher,Hui,Verner,Luong,Liu,Sprengeler
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p. 3856 - 3871
(2007/10/03)
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