- Design, synthesis, and evaluation of dioxane-based antiviral agents targeted against the Sindbis virus capsid protein
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Dioxane-based antiviral agents targeted to the hydrophobic binding pocket of Sindbis virus capsid protein were designed by computer graphics molecular modeling and synthesized. Virus production using SIN-IRES-Luc and capsid assembly were monitored to eval
- Kim, Ha Young,Patkar, Chinmay,Warrier, Ranjit,Kuhn, Richard,Cushman, Mark
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- Meso-Tetra(dioxanyl)porphyrins: Neutral, low molecular weight, and chiral porphyrins with solubility in aqueous solutions
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The synthesis of the low-molecular weight, meso-Tetra(dioxan-2-yl)porphyrin with considerable solubility in aqueous solution is described. The key intermediate dioxan-2-carbaldehyde is accessible in either racemic or in stereo-pure forms from commercially available starting materials in three steps. Using 4 × 1 or 2 + 2-Type syntheses provide the porphyrin in modest yields. While the racemic aldehyde created an intractable mixture of diastereomers, the enantiopure aldehyde created a single enantiomer of the target porphyrin. The porphyrin was spectroscopically characterized. As its free base or zinc complex, it showed excellent solubility properties in organic and aqueous solvents, though free water-solubility was not achieved. The work expands on the availability of chiral porphyrins and neutral porphyrins with considerable solubility in aqueous solution.
- Brückner, Christian,Damunupola, DInusha,Jiang, Xu-Liang
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p. 734 - 740
(2021/07/02)
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- CONDENSED HETEROCYCLES AS BCL-2 INHIBITORS
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The disclosure includes compounds of Formula (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11, h, j, m, n, k, v, s, g, V, W, L, Z1 Q1, Q2, Q3, Q4, Q5, Q6, and Q7, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.
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Page/Page column 226
(2021/04/10)
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- 1H-PYRROLO[2,3-B]PYRIDINE DERIVATIVES AS BCL-2 INHIBITORS FOR THE TREATMENT OF NEOPLASTIC AND AUTOIMMUNE DISEASES
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The present invention relates to lH-pyrrolo[2,3-b]pyridine derivatives and related compounds as BCL-2 inhibitors for treating neoplastic, autoimmune or neurodegenerative diseases. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 162 to 233; examples 1 to 8; table; compound examples cpd-1 to cpd-135; biological examples 1 to 4).
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Page/Page column 153-154
(2021/07/02)
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- HOT MELT EXTRUDED SOLID DISPERSIONS CONTAINING A BCL2 INHIBITOR
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A pro-apoptotic solid dispersion comprises, a Bcl -2 family protein inhibitory compound of Formula A as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier, and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises subjecting to elevated temperature the compound of Formula A, the water-soluble polymeric carrier, and the surfactant to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; and cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier, and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl -2 family proteins, for example cancer or an immune or autoimmune disease.
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Page/Page column 40
(2021/09/04)
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- Method for Producing Diarylpyridine Derivatives
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The present invention relates to a novel method for producing diarylpyridine derivatives, and the object of the present invention is to provide a novel, industrially useful method. The present inventors developed a novel method for synthesizing pyridine r
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Paragraph 0077-0078
(2021/06/26)
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- BCL-2 INHIBITORS
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The disclosure includes compounds of Formula (A), (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11, h, j, m, n, k, v, s, g, V, W, L, Z1, Q1, Q2, Q3, Q4, Q5, Q6, and Q7, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.
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Page/Page column 191
(2020/03/15)
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- BCL-2 INHIBITORS
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The disclosure includes compounds of Formula (I), (I) wherein Z, Q1, Q3, Q4, Q5, Q6, Q7, R0, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, g, k, m, n, s, v, j, L, Z1, and, W are defined herein. Also disclosed is a method for treating a neoplastic disease and autoimmune disease with these compounds.
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Page/Page column 53
(2020/07/15)
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- 1,3-THIAZOL-2-YL SUBSTITUTED BENZAMIDES
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The present invention relates to 1,3-thiazol-2-yl substituted benzamide compounds of general formula (I) as described and defined herein, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neurogenic disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 233
(2016/07/05)
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- QUINAZOLINE DERIVATIVES, COMPOSITIONS THEREOF, AND USE AS PHARMACEUTICALS
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Disclosed herein are protein kinase inhibitors, more particularly novel quinazoline derivatives and pharmaceutical compositions thereof,and method of use thereof.
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Page/Page column 28-29
(2015/02/02)
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- INHIBITORS OF BETA-SECRETASE
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The present invention relates to spirocyclic acylguanidines and their use as inhibitors of the β-secretase enzyme (BACE1) activity, pharmaceutical compositions containing the same, and methods of using the same as therapeutic agents in the treatment of neurodegenerative disorders, disorders characterized by cognitive decline, cognitive impairment, dementia and diseases characterized by production of β-amyloid aggregates.
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Paragraph 0294; 0295
(2014/03/24)
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- Discovery of a 5 H-benzo[4,5]cyclohepta[1,2-b ]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer
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c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5] cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.
- Katz, Jason D.,Jewell, James P.,Guerin, David J.,Lim, Jongwon,Dinsmore, Christopher J.,Deshmukh, Sujal V.,Pan, Bo-Sheng,Marshall, C. Gary,Lu, Wei,Altman, Michael D.,Dahlberg, William K.,Davis, Lenora,Falcone, Danielle,Gabarda, Ana E.,Hang, Gaozhen,Hatch, Harold,Holmes, Rachael,Kunii, Kaiko,Lumb, Kevin J.,Lutterbach, Bart,Mathvink, Robert,Nazef, Naim,Patel, Sangita B.,Qu, Xianlu,Reilly, John F.,Rickert, Keith W.,Rosenstein, Craig,Soisson, Stephen M.,Spencer, Kerrie B.,Szewczak, Alexander A.,Walker, Deborah,Wang, Wenxian,Young, Jonathan,Zeng, Qinwen
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supporting information; experimental part
p. 4092 - 4108
(2011/08/06)
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- PYRIMIDINE COMPOUNDS AND METHODS OF MAKING AND USING SAME
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Disclosed herein are pyrimidinyl compounds that are contemplated to be modulators of cystic fibrosis transmembrane regulators (CFTR), and methods of making and using same. Also provided are pharmaceutical compositions and methods of treating disorders associated with cystic fibrosis transmembrane regulators, such as airway inflammation, cystic fibrosis, and the like.
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Page/Page column 70
(2010/07/02)
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- Process development and large-scale synthesis of a c-Met kinase inhibitor
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A highly convergent synthesis of c-Met kinase inhibitor 1 has been demonstrated on a multikilogram scale using three key fragments: dihalotricyclic core 2, chiral sulfamide side chain 3, and pyrazole boronic ester 4. The chirality in sulfamide side chain 3 was installed using the cheap and readily available starting material (S)-epichlorohydrin. A total of 2.71 kg of 1 were isolated in seven steps (the longest linear sequence).
- Stewart, Gavin W.,Brands, Karel M. J.,Brewer, Sarah E.,Cowden, Cameron J.,Davies, Antony J.,Edwards, John S.,Gibson, Andrew W.,Hamilton, Simon E.,Katz, Jason D.,Keen, Stephen P.,Mullens, Peter R.,Scott, Jeremy P.,Wallace, Debra J.,Wise, Christopher S.
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experimental part
p. 849 - 858
(2011/03/20)
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- Tyrosine kinase inhibitors
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This invention relates to salt forms of the compound N-[(2R)-1,4-dioxan-2-ylmethyl]-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide, an inhibitor of tyrosine kinases, in particular the receptor tyrosine
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Page/Page column 15
(2009/07/25)
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- OXIM DERIVATIVES AS HSP90 INHIBITORS
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The invention relates to HSP90 inhibiting compounds consisting of the formula: (I) wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.
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Page/Page column 155-156
(2009/09/05)
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- Heterocylic antiviral compounds
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This invention relates to piperidine derivatives of formula I wherein R1, R2, R3 and R4 are as defined herein useful in the treatment of a variety of disorders, including those in which the modulation of CCR5 re
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Page/Page column 35
(2008/12/08)
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- Benzimidazole compound
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An object of the present invention is to provide a novel chemical compound useful as a therapeutic or prophylactic agent for acid-related diseases, having an excellent inhibitory effect against gastric acid secretion, an excellent effect of maintaining the inhibitory effect against gastric acid secretion, thereby maintaining intragastric pH high for a long time, and having more safety and appropriate physicochemical stability. Provided is a compound represented by where R1 and R3 may be the same or different and each represent a hydrogen atom or a C1-C6 alkyl group; R2 represents (5,5-dimethyl-1,3-dioxan-2-yl)methoxy group, 5,7-dioxaspiro[2.5]oct-6-ylmethoxy group, 1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy group, or (2,2-dimethyl-1,3-dioxan-5-yl)methoxy group; R4, R5, R6 and R7 represent a hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group or C1-C6 haloalkoxy group; and W1 represents a single bond, methylene or ethylene group, a salt thereof or a solvate of these.
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Page/Page column 80
(2008/06/13)
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- Synthesis of dioxane-based antiviral agents and evaluation of their biological activities as inhibitors of Sindbis virus replication
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The crystal structure of the Sindbis virus capsid protein contains one or two solvent-derived dioxane molecules in the hydrophobic binding pocket. A bis-dioxane antiviral agent was designed by linking the two dioxane molecules with a three-carbon chain ha
- Kim, Ha Young,Kuhn, Richard J.,Patkar, Chinmay,Warrier, Ranjit,Cushman, Mark
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p. 2667 - 2679
(2008/02/07)
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- 2-Hydroxymethyl-1,4-dioxane: Synthesis, resolution and determination of the absolute configurations of the enantiomers
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2-Hydroxymethyl-1, 4-dioxane 3 was resolved via salt formation between its hydrogen phthalate and (R)- or (S)-1-phenylethylamine, selective crystallization of the resultant diastereomeric mixtures and subsequent recovery of its enantiomers by saponification. The progress of the resolution was followed by chiral HPLC and the absolute stereochemistry of the two enantiomers determined by comparison of their specific rotations with that of (R)-3 synthesized from enantiomerically pure (R)-1-O-benzylglycerol. The results of the synthesis of 3 and of its resolution are discussed and compared with those previously obtained for 1,2-isopropylidene glycerol evaluating the consequences of replacement of ispropylidene with an ethylene bridge.
- Pallavicini, Marco,Valoti, Ermanno,Villa, Luigi
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p. 267 - 273
(2007/10/03)
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- Syntheses of All Four Stereoisomers Which Are Conformationally Constrained 1,4-Dioxanyl Analogs of the Antineoplastic Ether Lipid ET-18-OCH3
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The syntheses of each of the four nearly optically pure stereoisomers of oxy>phosphocholine (2,3,2',3') were performed by two parallel divergent sequences.Phosphocholines 2 and 3 were prepared via the corresponding 5-heptadecyl-2-(hydroxymethyl)-1,4-dioxanes 21 and 23, respectively, from the completely regiospecific mixed-hydride reductions of (1R,4S,5S)-4-heptadecyl-3,6,8-trioxabicyclooctane (19) and (1R,4R,5S)-4-heptadecyl-3,6,8-trioxabicyclooctane (20), respectively.The two 4-heptadecyl-3,6,8-trioxabicyclooctanes 19 and 20 were the two separable products from an intramolecular cyclization reaction.By a parallel divergent sequence from the enantiomeric starting material, 3-O-benzyl-sn-glycerol (16'), the other two diastereomeric oxy>phosphocholines 2' and 3' were prepared.These four monocyclic oxy>phosphocholines (2,3,2',3') are conformationally constrained analogs of the antineoplastic and immunomodulatory ether lipid rac-2-O-methyl-1-O-octadecylglycero-3-phosphocholine (rac-1) (rac-ET-18-OCH3, rac-Edelfosine).
- Duclos, Richard I.,Makriyannis, Alexandros
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p. 6156 - 6163
(2007/10/02)
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- Alkylation of active methylene compounds with 2-chloromethyl-1,4-dioxane
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The alkylation of some active methylene compounds with 2-chloromethyl-1,4-dioxane was investigated.It was shown that malonic ester gives mono- and dialkylation products, depending on the conditions.The alkylation of acetoacetic ester gives a mixture of C- and O-alkylation products.Acetylacetone is not alkylated under the given conditions but condenses fully, being converted into 2,4-dimethyl-6-hydroxyacetophenone.
- Krasavtsev I. I.,Basalkevich E. D.,Lozinskii M. O.
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p. 1632 - 1634
(2007/10/02)
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