- Synthesis of N-heteroaroyl aminosaccharide derivatives as fibroblast growth factor 2 signaling modulators
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Fibroblast growth factor 2 (FGF2) signaling plays an important role in angiogenesis. Heparin/heparan sulfate (HS) is required for FGF2 signaling but heparin mimics either promotes or inhibits FGF2 signaling. To take advantage such properties of heparin mimics, a series of N-heteroaroyl aminosaccharide derivatives were designed and synthesized as FGF2 signaling modulators. The bioactivity was determined in a FGF2 and heparin-dependent cell proliferation assay using FGFR1c expressing BaF3 cells. We found that most of the compounds inhibited heparin- and FGF2-dependent BaF3 cell proliferation while three compounds promoted the cell proliferation. These results suggest that the small molecular heparin mimics approach might be useful in developing novel anti-angiogenic agents.
- Dong, Jin,Yao, Shuowei,Zhou, Xiaodong,Zhang, Lijuan,Xu, Yungen
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Read Online
- Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment
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Human dihydroorotate dehydrogenase (hDHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as hDHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited hDHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t. Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of hDHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.
- Chen, Qiang,Gou, Kun,Li, Chungen,Liu, Huan,Liu, Xiaocong,Luo, Youfu,Luo, Yuan,Tao, Lei,Yang, Xiaowei,Yang, Xinyu,Zeng, Ting,Zhao, Yinglan,Zhong, Xi,Zhou, Xia,Zhou, Yue
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p. 18175 - 18192
(2021/12/27)
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- Novel imidazole derivatives having FLT3-inhibitory activity and use thereof
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The present invention relates to a novel benzoimidazole derivative having fms-like tyrosine kinase 3 (FLT3) inhibitory activity, and a use thereof. The novel benzoimidazole derivative or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent inhibitory activity on FLT3, thereby being expected for target treatment through further fundamental approach in preventing or treating acute myeloid leukemia (AML).COPYRIGHT KIPO 2020
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Paragraph 0388-0391
(2020/04/22)
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- Synthesis and in vivo antifibrotic activity of novel leflunomide analogues
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Novel Leflunomide analogues were synthesized and evaluated in vivo against thioacetamide (TAA) induced liver fibrosis in rats. All the animals which were treated with the new analogues showed improved or comparable survival rates to those treated with Leflunomide. Animals which were treated with compounds 8d, 8e, 9 and 11 have shown improved liver parameters than Leflunomide treated animals. Histopathology of the liver has shown that compound 8a is the most active compound, which decreases fibrosis to a minimal level and compounds 8c, 8e and 11 are active compounds with fibrosis score 2-3 which is better than that of Leflunomide.
- Hamdi, Abdelrahman,Said, Eman,Farahat, Abdelbasset A.,El-Bialy, Serry A.A.,Massoud, Mohammed A.M.
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p. 912 - 920
(2016/10/31)
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- SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
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Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
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Page/Page column 677
(2016/04/10)
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- N-(5-arylamido-2-methylphenyl)-5-methylisooxazole-4-carboxamide deravative, pharmaceutical acceptable salt thereof, method for preparation thereof and FMS kinase inhibitor comprising the same
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The present invention relates to a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same. The compound according to the present invention exhibits FMS kinase inhibitory activity, and thus can be used as a pharmaceutical composition for preventing or treating diseases related FMS kinase activity. In the chemical formula 1, the definition of R1 and R2 is the same as defined in the specification.COPYRIGHT KIPO 2016
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Paragraph 0091-0094
(2017/01/05)
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- A NOVEL PROCESS FOR THE PREPARATION OF TERIFLUNOMIDE
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The present invention provides a process for the preparation of Teriflunomide (Formula-I). The present invention describes the synthesis of Teriflunomide without isolating the intermediate Leflunomide. Teriflunomide is prepared from 5-Methyl isoxazole-4-carboxylic acid by converting to its acid chloride and coupling with 4-trifluoromethyl aniline to obtain Leflunomide (which is not isolated) followed by ring opening reaction using aq. Sodium Hydroxide to form Teriflunomide. In other words, the process is telescoped from 5- methylisoxazole-4-carbonyl chloride.
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Page/Page column 14; 19
(2017/01/02)
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- Discovery of 4-arylamido 3-methyl isoxazole derivatives as novel FMS kinase inhibitors
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A series of 4-arylamido 3-methyl isoxazoles were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Most compounds showed selective antiproliferative activity toward the U937 cell line and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide 5a-b, 6a-o and urea 7a-n, 8a-g with hydrophobic moieties, and one of the most potent inhibitor 6a, 5-methyl-N-(2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)isoxazole-4-carboxamide was found to be very potent inhibitor of FMS kinase (GI50 Combining double low line 0.016 μM, IC50 Combining double low line 9.95 nM) with excellent selectivity profiles and is a promising candidate for further development in therapeutics for cancer.
- Im, Daseul,Jung, Kyungjin,Yang, Songyi,Aman, Waqar,Hah, Jung-Mi
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p. 600 - 610
(2015/09/08)
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- CuCF3: A [18F]trifluoromethylating agent for arylboronic acids and aryl iodides
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Positron emission tomography has emerged as the leading method for medical imaging with fluorine-18 as the most widely used radioactive isotope. Here we report a semi-automated method for the preparation of valuable [ 18F]trifluoromethylcopper, as well as its use for the radiosynthesis of [18F]trifluoromethylarenes and heteroarenes. Mild conditions of [18F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [18F] trifluoromethylarenes and heteroarenes. 18F Radiochemistry: A semi-automated method for the fast preparation of radiolabelled (trifluoromethyl)copper is reported (see scheme), thus making [ 18F]CuCF3 almost as accessible as [18F]fluoride itself for the preparation of radiolabelled trifluoromethylated probes. It can be used for the preparation of radiolabelled trifluoromethylarenes from arylboronic acids and aryliodides. This methodology is clean, efficient and consistent with the specific requirements of radiochemistry.
- Ivashkin, Pavel,Lemonnier, Gerald,Cousin, Jonathan,Gregoire, Vincent,Labar, Daniel,Jubault, Philippe,Pannecoucke, Xavier
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supporting information
p. 9514 - 9518
(2014/08/18)
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- Copper-promoted sandmeyer trifluoromethylation reaction
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A copper-promoted trifluoromethylation reaction of aromatic amines is described. This transformation proceeds smoothly under mild conditions and exhibits good tolerance of many synthetically relevant functional groups. It provides an alternative approach for the synthesis of trifluoromethylated arenes and heteroarenes. It also constitutes a new example of the Sandmeyer reaction.
- Dai, Jian-Jun,Fang, Chi,Xiao, Bin,Yi, Jun,Xu, Jun,Liu, Zhao-Jing,Lu, Xi,Liu, Lei,Fu, Yao
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supporting information
p. 8436 - 8439
(2013/07/19)
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- COMPOUNDS FOR TREATING RESPIRATORY SYNCYTIAL VIRUS INFECTIONS
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The present invention relates to compounds of formula (I), its salts, isomers or prodrugs thereof useful in the treatment of viral infections, in particular respiratory syncytial virus (RSV) infections. The present invention also relates to processes for preparing the compounds and intermediates used in their preparation.
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Page/Page column 77
(2011/09/14)
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- Synthesis and fungicidal activities of 1-(5-Methylisoxazoyl-4-carbonyl)-4- arylsulfonyl thiosemicarbazides
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1-(5-Methylisoxazoyl-4-carbonyl)-4-arylsulfonyl thiosemicarbazides, which were prepared by treatment of arylsulfonyl hydrazine with 5-methylisoxazole-4- carbonyl isothiocyanate in good yields. The structures of all compounds were confirmed by 1H NMR, MS and elemental analyses. The preliminary bioassays indicated that some compounds are comparable to the commercial fungicides. Some of these compounds also exhibit moderate fungicidal activities.
- Ye, Dong-Ju
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p. 1503 - 1506
(2012/04/10)
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- Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases
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Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUTLeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.
- Davies, Matthew,Heikkil?, Timo,McConkey, Glenn A.,Fishwick, Colin W. G.,Parsons, Mark R.,Johnson, A. Peter
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supporting information; experimental part
p. 2683 - 2693
(2010/01/16)
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- Preparation of leukotriene B4 inhibitory active 2- and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives and their growth inhibitory activity on human pancreatic cancer cells
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A series of 2-(2-aminothiazol-4-yl)benzo[b]furan and 3-(2-aminothiazol-4- yl)benzo[b]furan derivatives were prepared, and their leukotriene B4 inhibitory activity and growth inhibitory activity in cancer cell lines were evaluated. Several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT1 and BLT2 receptors and growth inhibition to human pancreatic cancer cells MIA PaCa-2. 3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl] -5-methoxybenzo[b]furan 8b showed the most potent and selective inhibition for the human BLT2 receptor, and its IC50 value was smaller than that of the selected positive control compound, ZK-158252. 3-(4-Chlorophenyl)-2-[2-[(dimethylamino)methyleneamino]-5-(2- hydroxyethyliminomethyl)thiazol-4-yl]-5-methoxybenzo[b]furan 9a displayed growth inhibitory activity towards MIA PaCa-2. The Royal Society of Chemistry.
- Kuramoto, Mari,Sakata, Yoko,Terai, Kumi,Kawasaki, Ikuo,Kunitomo, Jun-Ichi,Ohishi, Takahiro,Yokomizo, Takehiko,Takeda, Seiichi,Tanaka, Shuichi,Ohishi, Yoshitaka
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experimental part
p. 2772 - 2781
(2009/02/02)
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- Pyrazine Derivatives
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The present invention relates to compounds of the formula and pharmaceutically acceptable salts and solvates thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds for the treatment of pain.
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Page/Page column 26-27
(2008/06/13)
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- BENZOFURAN COMPOUND AND MEDICINAL COMPOSITION CONTAINING THE SAME
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The present invention relates to a benzofuran compound of the formula (I) wherein each symbol is as defined in the description, a pharmaceutically acceptable salt thereof and the like. The compound of the present invention has superior leukotriene inhibitory action, BLT2 competitive inhibitory action, BLT2 blocking action, action for the prophylaxis or treatment of allergy, action for the prophylaxis or treatment of asthma and action for the prophylaxis or treatment of inflammation, and is useful as an agent for the prophylaxis or treatment of diseases such as allergic disease, asthma, inflammation and the like, and other diseases.
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Page/Page column 46
(2008/06/13)
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- Syntheses of 3-acetoacetylaminobenzo[b]furan derivatives having cysteinyl leukotriene 2 receptor antagonistic activity
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Novel 3-acetoacetylaminobenzo[b]furan derivatives having a modified triene system at the 3-position were synthesized starting with 3-aminobenzo[b]furans. The enol isomers, 3-[(3-hydroxybul-2-enonyl)amino]benzo[b]furans (1), of the 3-acetoacetylaminobenzo[b]furans were obtained as stable isomers owing to formation of a hydrogen bonding between the enol hydroxyl group and the amidocarbonyl group. The planarity of the C-2 substituent through the C-3 side chain suggested the existence of a modified conjugational triene system in the enol compound. Cysteinyl leukotriene 1 and 2 receptor antagonistic activities for these compounds were evaluated. 2-(4-Cyanobenzoyl or ethoxycarbonyl)-3-[(2-cyano-3-hydroxybut-2-enonyl)amino]benzo[e]furans (15g, 15o, 15u) were moderately active.
- Ando, Kumiko,Tsuji, Eriko,Ando, Yuko,Kuwata, Noriko,Kunitomo, Jun-Ichi,Yamashita, Masayuki,Ohta, Shunsaku,Kohno, Shigekatsu,Ohishi, Yoshitaka
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p. 625 - 635
(2007/10/03)
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- Process for preparing 5-methylisoxazole-4-carboxylic- (4'-trifluoromethyl)-anilide
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A process for preparing 5-methylisoxazole-4-carboxylic-(4′-trifluoromethyl)-anilide comprising: (a) reacting ethylacetoacetate, triethylorthoformate, and acetic anhydride at a temperature of from about 75° C. to about 150° C., to form ethyl ethoxymethyleneacetoacetic ester; (b) combining the ethyl ethoxymethyleneacetoacetic ester with sodium acetate or a salt of trifluoroacetic acid in the presence of hydroxylamine sulfate at a temperature of from about ?20° C. to 10° C., to form ethyl-5-methylisoxazole-4-carboxylate; (c) reacting the ethyl-5-methylisoxazole-4-carboxylate with a strong acid to form 5-methylisoxazole-4-carboxylic acid; (d) reacting the crystallized 5-methylisoxazole-4-carboxylic acid with thionyl chloride to form 5-methylisoxazole-4-carbonyl chloride; and (e) reacting the 5-methylisoxazole-4-carbonyl chloride with trifluoromethyl aniline and an amine base at a temperature of from about 0° C. to about 50° C. to form 5-methylisoxazole-4-carboxylic-(4′-trifluoromethyl)-anilide. The process of the invention is especially advantageous for preparing 5-methylisoxazole-4-carboxylic-(4′-trifluoromethyl)-anilide, since the process: (1) eliminates or reduces the formation of the by-product 2-cyanoacetoacetic-1-(4′-trifluoromethyl)-anilide (CATA), generally as low as 0.0006%; (2) eliminates or reduces the formation of isomeric impurity ethyl-3-methyisoxazole-4-carboxylate and its corresponding acid as low as 0.1%, (3) produces a high quality of 5-methylisoxazole-4-carboxylic-(4′-trifluoromethyl)-anilide generally having 99.8-100% HPLC potency; and (4) does not require distillation of the isoxazole ester.
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- Method for systhesizing leflunomide
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A process for synthesizing leflunomide from 5-methylisoxazole-4-carboxylic acid and 4-trifluoromethylaniline is provided. Further provided is the leflunomide prepared by the inventive process, which is substantially free of difficult-to-separate impurities often found in leflunomide prepared by known methods, including N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide, 5-methyl-N-(4-methylphenyl)-isoxazole-4-carboxamide and N-(4-trifluoromethylphenyl)-3-methyl-isoxazole-4-carboxamide. The invention further provides pharmaceutical compositions and dosage forms containing highly pure leflunomide and methods of treating disease using the leflunomide.
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- Isoxazole and crotonamide derivatives and their use as pharmaceuticals and diagnostics
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A compound of the formula STR1 where R1 is the radical of the formula II or III STR2 is suitable for the production of a pharmaceutical for the treatment of inflammations, carcinomatous diseases, or autoimmune diseases. A compound of the formula IV STR3 is suitable for the production of specific antibodies against a compound of the formula I for the discovery of specific-binding proteins from cell extracts, serum, blood, or synovial fluids, for the purification of proteins, for the modification of microtiter plates, or for the preparation of chromatography material, in particular of affinity chromatography material, and for use in diagnostics.
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- Pharmaceutical compounds
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Compounds of the following formula have pharmaceutical properties: STR1 in which X is R'(HO)C=C(CN)--, R1 (CO)--CH(CN)-- or STR2 R1 and R2 are each hydrogen or C1-6 alkyl, R3, R4, R5 and R6 are each hydrogen, hydroxy, halogen, nitro, cyano, carboxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy, halo-substituted C1-4 alkylthio, C2-5 alkoxycarbonyl, optionally substituted phenyl, optionally substituted phenoxy, R'R"N-- where R' and R" are each hydrogen or C1-4 alkyl or R'"CONH-- where R'" is C1-4 alkyl, or a group of the formula --CR7 R8 R9 in which R7, R8 and R9 are each C1-6 alkyl, halo-substituted C1-6 alkyl or optionally substituted phenyl, or R7 and R8, together with the carbon atom to which they are attached, form a cycloalkyl group containing 3 to 7 carbon atoms, or R7, R8 and R9 together with the carbon atom to which they are attached, form a bicycloalkyl group containing 4 to 9 carbon atoms, and Y is a 5- or 6-membered heterocyclic ring excluding pyrazole; and salts thereof.
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- 5-Substituted 4-isoxazolecarboxamides with platelet antiaggregating and other activities
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The synthesis of a series of 5-substituted 4-isoxazolecarboxamides by reaction of eight 5-substituted 4-isoxazolecarbonyl chlorides with pyrrolidine, piperidine, morpholine and 4-trifluoromethylaniline is described. Some of these amides showed platelet antiaggregating activity in vitro slightly inferior to that of acetylsalicylic acid, as well weak antiinflammatory, analgesic and antipyretic activities in rats and mice.
- Fossa,Menozzi,Schenone,Filipelli,Russo,Lucarelli,Marmo
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p. 789 - 802
(2007/10/02)
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- N-phenyl amide compounds
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Compounds of the following formula have pharmaceutical properties: STR1 in which X is R1 (HO)C=C(CN)--, R1 (CO)--CH(CN)-- or STR2 R1 and R2 are each hydrogen or C1-6 alkyl, R3, R4 and R5 are each hydrogen, hydroxy, halogen, nitro, cyano, carboxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy, halo-substituted C1-4 alkylthio, C2-5 alkoxycarbonyl, optionally substituted phenyl, optionally substituted phenoxy, R'R"N- where R' and R" are each hydrogen or C1-4 alkyl R'"CONH-- where R'" is C1-4 alkyl, R6, R7 and R8 are each C1-6 alkyl, halo-substituted C1-6 alkyl or optionally substituted phenyl, or R6 and R7, together with the carbon atom to which they are attached, form a cycloalkyl group containing 3 to 7 carbon atoms, or R6, R7 and R8 together with the carbon atom to which they are attached, form a bicycloalkyl group containing 4 to 9 carbon atoms; and salts thereof.
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- Isoxazole-Oxazole Conversion by Beckmann Rearrangement
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A novel base-catalysed isoxazole-oxazole ring transformation was realized in the conversion of ethyl 5-hydroxy-3-(5-methylisoxazol-4-yl)isoxazole-4-carboxylate into 4-cyano-5-methyloxazol-2-ylacetic acid.A new process was developed for the preparation of t-4-amino-c-2-methyl-6-oxotetrahydropyran-r-3-carboxylic acid hydrochloride, a starting material for the synthesis of thienamycin.
- Doleschall, Gabor,Seres, Peter
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p. 1875 - 1880
(2007/10/02)
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- Substituted phenyl-2-cyano-2-thioalkenoic acid esters
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Substituted phenyl-2-cyano-2-thioalkenoic acid esters which are useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease.
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