- Fused tricyclic derivative as FGFR4 inhibitor
-
The present invention provides a fused tricyclic derivative that is the selective inhibitor of fibroblast growth factor receptor 4 (FGFR4), a pharmaceutical composition containing the compound, a method of making the compound and a method of treating cell proliferative diseases, such as cancer, using the compounds of the invention.
- -
-
Paragraph 0597; 0603-0607
(2021/05/12)
-
- Method for synthesizing 4-methoxy-2-nitroaniline by adopting continuous flow reactor
-
The invention relates to the technical field of organic synthesis, and discloses a method for synthesizing 4-methoxy-2-nitroaniline by using a continuous flow reactor. The method comprises the following steps: S1, respectively adding a 4-methoxyaniline solution and acetic anhydride into a continuous flow reactor I, and carrying out an acetylation reaction to obtain a reaction solution I containing4-methoxyacetanilide; S2, respectively adding a nitration reagent and the reaction solution I into a continuous flow reactor II, and carrying out a nitration reaction to obtain a reaction solution IIcontaining 4-methoxy-2-nitroacetanilide; S3, respectively adding hydrolysate and the reaction solution II into a continuous flow reactor III, and carrying out a hydrolysis reaction to obtain a reaction solution III containing 4-methoxy-2-nitroaniline; and S4, carrying out post-treatment on the reaction solution III to obtain 4-methoxy-2-nitroaniline. The method is high in reaction speed, small inamount of byproduct 4-methoxy-3-nitroaniline, high in heat and mass transfer efficiency, high in reaction safety, high in selectivity, high in yield and purity and convenient in after-treatment.
- -
-
-
- Sodium persulfate-promoted site-selective synthesis of mononitroarylamines under transition-metal-free conditions
-
A practical preparation of nitroarylamines from protected arylamines was herein disclosed. In this system, sodium nitrite acted as a nitration reagent in the presence of sodium persulfate without any transition-metal catalysts. This efficient site-selective protocol took place at room temperature for a short time through a free radical pathway.
- Xie, De-Xun,Yu, Hui-Juan,Liu, Hui,Xue, Wei-Cai,Qin, Yuan-Shou,Shao, Guang
-
p. 1157 - 1165
(2019/01/24)
-
- A O-nitro to the preparation method of the anisidine
-
The invention relates to a O-nitro to anisidine preparation method. Characterized in that to the anisidine as raw materials, by acetylation, mixed acid nitration to obtain the 4 - methoxy - 2 - nitro acetanilide, and hydrolyzed to from 2 - nitro - 4 - methoxybenzene elimination and to acetaminophen as raw materials, by methylation, antirust, the reduction reaction of the nitro to synthetic O-anisidine.
- -
-
-
- NOVEL FYN KINASE INHIBITORS
-
The present invention relates to the novel therapies to treat neurodegenerative diseases such as Parkinson's disease (PD). The present invention relates to novel small molecule inhibitors of Fyn Kinase and for testing activity against Parkinsons's disease models compounds that inhibit Fyn kinase having the following formula. (I)
- -
-
-
- Salicylic Acid-Catalyzed One-Pot Hydrodeamination of Aromatic Amines by tert-Butyl Nitrite in Tetrahydrofuran
-
A significant acceleration in the hydrodeamination of in situ formed diazonium salts (from aromatic amines) has been observed in the presence of 10-mol% salicylic acid, using tetrahydrofuran as the hydrogen donor. The reaction proceeds efficiently at 20 °C for a wide range of substituted anilines, even at 10-mmol scale, without any other additive. The same protocol has been adapted to the selective deuterodeamination of some aromatic amines. Control experiments clearly show that aryl radicals are involved in the reaction mechanism. (Figure presented.).
- Felipe-Blanco, Diego,Alonso, Francisco,Gonzalez-Gomez, Jose C.
-
p. 2857 - 2863
(2017/08/23)
-
- Palladium(II)-catalyzed, heteroatom-directed, regioselective C-H nitration of anilines using pyrimidine as a removable directing group
-
A new palladium-catalyzed, heteroatom-directed strategy for C-H nitration of anilines is described. This C-H functionalization reaction is highly ortho-selective and results in very good yields. The highlight of the work is the use of pyrimidine as the removable directing group. This approach constitutes one of the rare methods of ortho-nitration of anilines, a reaction that is normally very difficult to achieve via traditional approaches.
- Pawar, Govind Goroba,Brahmanandan, Abhilashamole,Kapur, Manmohan
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p. 448 - 451
(2016/02/18)
-
- Indole and indazole compounds as an inhibitor of cellular necrosis
-
The present invention refers to a formula (1) compounds of, pharmaceutically acceptable salts or isomers thereof thereof, and characterized by by containing as active ingredients-associated diseases, cell death and method for the prevention or treatment of relates and compositions. [Formula 1] In formula said R 1, R 2, R 3, R 4, R 5, R 6, A, X, n and m to equal the specification.
- -
-
Paragraph 0339; 0344-0346; 0349
(2016/10/08)
-
- Copper-catalyzed mild nitration of protected anilines
-
A practical copper-catalyzed direct nitration of protected anilines, by using one equivalent of nitric acid as the nitrating agent, has been developed. This procedure features mild reaction conditions, wide structural scope (with regard to both N-protecting group and arene substitution), and high functional-group tolerance. Dinitration with two equivalents of nitric acid is also feasible. Practical and reliable: A Cu-catalyzed selective nitration of para- and ortho-substituted aniline derivatives by using one equivalent of HNO3 has been developed that produces water as the only stoichiometric byproduct (see scheme; PG=protecting group). This method is compatible with strongly electron-deficient substrates, enabling dinitration (by using 2.0 equiv of HNO3). This method allows for a rapid access to relevant nitrogen-containing heterocyclic architectures.
- Hernando, Elier,Castillo, Rafael R.,Rodríguez, Nuria,G?mez Arrayás, Ram?n,Carretero, Juan C.
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supporting information
p. 13854 - 13859
(2016/02/18)
-
- Cyclometalated iridium(III) bipyridyl-phenylenediamine complexes with multicolor phosphorescence: Synthesis, electrochemistry, photophysics, and intracellular nitric oxide sensing
-
We present a new class of phosphorescent cyclometalated iridium(III) bipyridyl-phenylenediamine complexes [Ir(N^C)2(bpy-DA)](PF 6) (bpy-DA=4-(N-(2-amino-5-methoxyphenyl)aminomethyl)-4′- methyl-2,2′-bipyridine; HN^C=2-(2,4-difluorophenyl)pyridine (Hdfppy) (1-a), 2-phenylpyridine (Hppy) (2-a), 2-phenylquinoline (Hpq) (3-a), 2-phenylcinchoninic acid methyl ester (Hpqe) (4-a)) and their triazole counterparts [Ir(N^C)2(bpy-T)](PF6) (bpy-T=4-((6- methoxybenzotriazol-1-yl)methyl)-4′-methyl-2,2′-bipyridine; HN^C=Hdfppy (1-b), Hppy (2-b), Hpq (3-b), Hpqe (4-b)). Upon photoexcitation, the diamine complexes exhibited fairly weak green to red phosphorescence under ambient conditions whereas the triazole derivatives emitted strongly. The photophysical properties of complexes 2-a and 2-b have been studied in more detail. Upon protonation, the diamine complex 2-a displayed increased emission intensity, but the emission properties of its triazole counterpart complex 2-b were independent on the pH value of the solution. Also, complex 2-a was found to be readily converted into complex 2-b upon reaction with NO under aerated conditions, resulting in substantial emission enhancement of the solution. The reaction was highly specific toward NO over other reactive oxygen and nitrogen species (RONS) as revealed by spectroscopic analyses. The lipophilicity and cellular uptake efficiency of the diamine complexes have been examined and correlated to their molecular structures. Also, cell-based assays showed that these complexes were noncytotoxic toward human cervix epithelioid carcinoma (HeLa) cells (at 10 μM, 4 h, percentage survival ≈80-95-%). Additionally, the diamine complexes have been used to visualize intracellular NO generated both exogenously in HeLa cells and endogenously in RAW 264.7 murine macrophages by laser-scanning confocal microscopy. Visualizing NO: Phosphorescent cyclometalated iridium(III) bipyridyl-phenylenediamine complexes have been designed as intracellular NO sensors. They react selectively with NO over other reactive oxygen and nitrogen species and are converted into their triazole counterparts, resulting in significant emission enhancement. The diamine complexes show low cytotoxic activity and are capable of sensing intracellular NO generated exogenously in HeLa cells and endogenously in RAW 264.7 murine macrophages.
- Law, Wendell Ho-Tin,Leung, Kam-Keung,Lee, Lawrence Cho-Cheung,Poon, Che-Shan,Liu, Hua-Wei,Lo, Kenneth Kam-Wing
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p. 1316 - 1329
(2014/06/09)
-
- Rhenium(I) polypyridine diamine complexes as intracellular phosphorogenic sensors: Synthesis, characterization, emissive behavior, biological properties, and nitric oxide sensing
-
We report the development of a series of rhenium(I) polypyridine complexes appended with an electron-rich diaminoaromatic moiety as phosphorogenic sensors for nitric oxide (NO). The diamine complexes [Re(N^N)(CO)3(py-DA)] [PF6] (py-DA=3-(N-(2-amino-5-methoxyphenyl)aminomethyl)pyridine; N^N=1,10-phenanthroline (phen) (1a), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-phen) (2a), 4,7-diphenyl-1,10-phenanthroline (Ph 2-phen) (3a)) have been synthesized and characterized. In contrast to common rhenium(I) diimines, these diamine complexes were very weakly emissive due to quenching of the triplet metal-to-ligand charge-transfer ( 3MLCT) emission by the diaminoaromatic moiety through photoinduced electron transfer (PET). Upon treatment with NO, the complexes were converted into the triazole derivatives [Re(N^N)(CO)3(py-triazole)][PF 6] (py-triazole=3-((6-methoxybenzotriazol-1-yl)methyl)pyridine; N^N=phen (1b), Me4-phen (2b), Ph2-phen (3b)), resulting in significant emission enhancement (I/I0≈60). The diamine complexes exhibited high reaction selectivity to NO, and their emission intensity was found to be independent on pH. Also, these complexes were effectively internalized by HeLa cells and RAW264.7 macrophages with negligible cytotoxicity. Additionally, the use of complex 3a as an intracellular phosphorogenic sensor for NO has been demonstrated. Emission turned ON for NO: A series of rhenium(I) polypyridine complexes functionalized with an electron-rich diaminoaromatic moiety has been developed as a new class of phosphorogenic sensors for NO. Upon treatment with NO, the weakly emissive complexes were converted into the strongly emissive triazole derivatives, resulting in significant emission enhancement (I/I0≈60; see figure). Experiments showed that the diamine complexes can sense NO that is 1) generated exogenously by NOC-7 in HeLa cells and 2) produced endogenously in RAW264.7 macrophages.
- Choi, Alex Wing-Tat,Yim, Vicki Man-Wai,Liu, Hua-Wei,Lo, Kenneth Kam-Wing
-
supporting information
p. 9633 - 9642
(2014/08/18)
-
- Design, synthesis and anticancer activity evaluation of diazepinomicin derivatives
-
A series of diazepinomicin derivatives were synthesized and evaluated in vitro for their growth inhibitory activity against the human carcinoma cell lines. The results indicated the anticancer selectivity of this kind of compounds. Based on the results, preliminary structure-activity relationships were discussed.
- Yu, Yongguo,Wu, Jianbo,Lei, Fan,Chen, Lei,Wan, Weili,Hai, Li,Guan, Mei,Wu, Yong
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p. 369 - 373
(2013/07/26)
-
- Diversified synthesis of novel quinoline and dibenzo thiazepine derivatives using known active intermediates
-
The novel drug development to control resisting infections in conventional drug therapy is a need of today. Few antiulcer relative derivatives developed by approaching convergent synthesis. The derivatives synthesized successfully are dibenzo thiazepine-pyridine (SLN11-SLN15) and benzimidazole-hydroquinoline based derivatives (SLN16-SLN20). It involved the coupling through microwave, sonication and conventional techniques at final step. The efficient technology identified as sonication technique basically time and yield. The reported compounds were structural characterized by elemental analysis and spectral studies such as 1H, 13C NMR and MS.
- Sharada,Satyanarayana Reddy,Sammaiah,Sumalatha
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p. 7959 - 7966
(2013/09/23)
-
- Identification of novel HDAC inhibitors through cell based screening and their evaluation as potential anticancer agents
-
A series of benzimidazole based HDAC inhibitors have been rationally designed, synthesized and screened. The SAR of this new chemotype is described. The lead compound, 11e, showed strong activity in several cellular assays and demonstrated in vivo efficacy in mouse xenograft pancreatic cancer models.
- Wang, Tong,Sepulveda, Mario,Gonzales, Paul,Gately, Stephen
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p. 4790 - 4793
(2013/09/02)
-
- Catalytic reduction of ortho - And para -azidonitrobenzenes via tert -butoxide ion mediated electron transfer
-
The reduction of a range of substituted azidonitrobenzene derivatives to the corresponding aniline is described. The chemoselective reaction proceeds cleanly and in good yield, generating minimal waste products. The process involves a thiazolium salt derived species which is proposed as a radical anion relay, with tert-butoxide as the stoichiometric reductant.
- Burnley, James,Carbone, Giorgio,Moses, John E.
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supporting information
p. 652 - 656
(2013/04/10)
-
- Discovery and optimization of benzotriazine Di-N-oxides targeting replicating and nonreplicating mycobacterium tuberculosis
-
Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 μg/mL against H37Rv and a cytotoxicity (CC 50) against Vero cells of 25 μg/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.
- Chopra, Sidharth,Koolpe, Gary A.,Tambo-Ong, Arlyn A.,Matsuyama, Karen N.,Ryan, Kenneth J.,Tran, Tran B.,Doppalapudi, Rupa S.,Riccio, Edward S.,Iyer, Lalitha V.,Green, Carol E.,Wan, Baojie,Franzblau, Scott G.,Madrid, Peter B.
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p. 6047 - 6060
(2012/09/05)
-
- Organophosphorus-catalysed Staudinger reduction
-
The first Staudinger reduction that is catalytic in phosphine has been developed, showing excellent yields and functional group selectivity. To this end we utilised dibenzophosphole catalysts and mild in situ reduction of the intermediate iminophosphoranes. We could avoid the necessity of water during the reduction, obtained no phosphine oxides as waste and thus enabled facile purification of the product. A range of azides was converted into amines with good to excellent yields and high functional group tolerance. Copyright
- Van Kalkeren, Henri A.,Bruins, Jorick J.,Rutjes, Floris P. J. T.,Van Delft, Floris L.
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experimental part
p. 1417 - 1421
(2012/07/03)
-
- INDOLE AND INDAZOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
-
The present invention relates to indole or indazole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole or indazole compounds as an active ingredient.
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Page/Page column 12
(2010/08/08)
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- INDOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
-
The present invention relates to new indole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole compounds as an active ingredient.
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Page/Page column 18
(2010/08/22)
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- Functionalized alkoxy arene diazonium salts from paracetamol
-
Arene diazonium tetrafluoroborates can be synthesized from aromatic acetamides via a sequence of deacetylation, diazotation and precipitation, induced by anion exchange. The reaction is conducted as a convenient one-flask transformation with consecutive addition of the appropriate reagents. Exchange of solvents or removal of byproducts prior to isolation of the product is not required. The arene diazonium salts are isolated from the reaction mixture by simple filtration. Two complementary protocols are presented, and the utility of the reaction is exemplified for a synthesis of the diarylheptanoid natural product de-O-methyl centrolobine.
- Schmidt, Bernd,Berger, Rene,Hoelter, Frank
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supporting information; experimental part
p. 1406 - 1414
(2010/06/19)
-
- INDOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
-
The present invention relates to new indole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole compounds as an active ingredient.
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Page/Page column 60
(2009/04/25)
-
- INDOLE AND INDAZOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
-
The present invention relates to indole or indazole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole or indazole compounds as an active ingredient.
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Page/Page column 43
(2009/04/25)
-
- Sensitized lanthanide-ion luminescence with aryl-substituted N-(2-nitrophenyl)acetamide-derived chromophores
-
The syntheses of the two tetraazamacrocyclic ligands L1 and L2 bearing a [(methoxy-2-nitrophenyl)amino]carbonyl chromophore, i.e., an N-(methoxy-2-nitrophenyl)acetamide moiety, together with their corresponding lanthanide-ion complexes are described. A combined spectroscopic (UV/VIS, 1H-NMR), structural (X-ray), and theoretical (DFT) investigation revealed that the absorption properties of the chromophores were dictated by the extent of electronic delocalisation, which in turn was determined by the position of the MeO substituent at the aromatic ring. X-Ray crystallographic studies showed that when attached to the macrocycle, both isomeric forms of the N-(methoxy-2-nitrophenyl)acetamide unit can participate in coordination, via the C=O, to an encapsulated potassium cation. Luminescence measurements confirmed that such a binding mode also exists in solution for the corresponding lanthanide complexes (q ca. ≤1), with the para-MeO derivative allowing longer wavelength sensitization (λex 330 nm).
- Andrews, Michael,Ward, Benjamin D.,Laye, Rebecca H.,Kariuki, Benson M.,Pope, Simon J. A.
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scheme or table
p. 2159 - 2172
(2010/03/26)
-
- FARNESOID X RECEPTOR AGONISTS
-
The present invention relates to famesoid X receptors (FXR, NR1H4) FXR is a member of the nuclear receptor class of ligand-activate transcription factors More particularly, the present invention relates to compounds useful as agonists for FXR, pharmaceutical formulations comprising such compounds, and therapeutic use of the same Novel isoxazole compounds are disclosed as part of pharmaceutical compositions for the treatment of a condition mediated by decreased FXR activity, such as obesity, diabetes, cholestatic liver disease, liver fibrosis, and metabolic syndrome
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Page/Page column 205
(2009/03/07)
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- Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof
-
The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (e.g., indazoles and benzothiazoles), which act as ligands for the α7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 68
(2010/11/26)
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- 1 H-INDAZOLES, BENZOTHIAZOLES, 1,2-BENZOISOXAZOLES, 1,2-BENZOISOTHIAZOLES, AND CHROMONES AND PREPARATION AND USES THEREOF
-
The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of -disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (indazoles and benzothiazoles), which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 77
(2010/11/27)
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- Studies in the synthesis of 2-mercapto-5-methoxybenzimidazole
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The compound, 2-mercapto-5-methoxybenzimidazole, is an important intermediate required for the synthesis of omeprazole. It is a proton pump blocker or an inhibitor of the enzyme, H+/K+-ATPase. In the present work, synthesis of this intermediate by three different routes has been discussed and its yields from all the three routes have been compared.
- Mahajan,Nandre
-
p. 1756 - 1758
(2007/10/03)
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- Ammonium nickel sulphate mediated nitration of aromatic compounds with nitric acid
-
Aromatic compounds were efficiently nitrated under mild conditions employing ammonium nickel sulphate and nitric acid as a reagent. This procedure works efficiently at room temperature yielding mononitro derivative in fair to good yield with high regioselectivity.
- Tasneem,Ali,Rajanna,Saiparakash
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p. 1123 - 1127
(2007/10/03)
-
- 8-Aminoquinolines as anticoccidials - Part III
-
Analogues of the antimalarial pentaquine, 1, in which the nature of the side-chain on the 8-amino position was varied, were prepared and evaluated for anticoccidial activity both in vitro and in vivo. Specifically, both the inter-nitrogen distance and the nature of the terminal amino group were investigated. Novel analogues of equal or improved efficacy in vitro and in vivo to pentaquine were discovered.
- Armer, Richard E.,Barlow, Jacqueline S.,Chopra, Narinder,Dutton, Christopher J.,Greenway, David H.J.,Greenwood, Sean D.W.,Lad, Nita,Shaw, Jonothan,Thompson, Adrian P.,Thong, Kam-Wah,Tommasini, Ivan
-
p. 2425 - 2430
(2007/10/03)
-
- A convenient copper-catalyzed direct animation of nitroarenes with 9-alkylhydroxylamines
-
O-Alkylhydroxylamines, particularly O-methylhydroxylamine, aminate nitroarenes in the presence of a strong base and a copper catalyst to give aminonitroarenes in good yields, ortho- or para-Animation with respect to the nitro group takes place, and in some cases the ortho-aminated product is preferentially obtained. With 3-substituted nitrobenzenes where the substituent has a lone pair of electrons, preferential amination occurs at the 2-position to give the sterically most congested 3c-f, 14 and 22g.
- Seko, Shinzo,Miyake, Kunihito,Kavvamura, Norio
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p. 1437 - 1444
(2007/10/03)
-
- Nitroarylamines via the Vicarious Nucleophilic Substitution of Hydrogen: Amination, Alkylamination, and Arylamination of Nitroarenes with Sulfenamides
-
A new reaction of sulfenamides with electrophilic arenes under basic conditions is described. The σ adducts formed from nitroarenes and the anions of sulfenamides undergo elimination of thiol to produce the corresponding o- and/or p-nitroanilines. This reaction is analogous to the known alkylation and hydroxylation of nitroarenes via the vicarious nucleophilic substitution of hydrogen (VNS). The reaction gives access to a wide range of substituted nitroanilines, nitronaphthylamines, and aminoheterocycles. By means of the reaction with N-alkyl- and N-arylsulfenamides, it is possible to obtain N-alkylnitroanilines and nitrodiarylamines. By varying the structure of sulfenamide and the reaction conditions, particularly the nature and concentration of the base, it is possible to control the orientation of animation.
- Makosza, Mieczyslaw,Bialecki, Maciej
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p. 4878 - 4888
(2007/10/03)
-
- Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides
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Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy.Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy.The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells.Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substituents in the 6- and /or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells.Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced.Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxide have reduction potentials significantly more positive than Tirapazamine (Epc -0.90 V).The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine.The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity.Four of the compounds, 6e, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro.In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine.This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.
- Monge, Antonio,Palop, Juan A.,Cerain, Adela Lopez de,Senador, Virginia,Martinez-Crespo, Francisko J.,et al.
-
p. 1786 - 1792
(2007/10/02)
-
- Process for preparing nitroaniline derivatives
-
A process for preparing a nitroaniline derivative comprising a step of reacting an aromatic nitro compound with an O-alkylhydroxylamine or a salt thereof in the presence of a base and optionally a metallic catalyst, which process is industrially advantageous since it provides the nitroaniline derivative from the aromatic nitro compound in a high yield in one step, and the aminating agent used can be obtained from hydroxylamine at a relatively low cost.
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-
-
- Process for the production of 2-aryl-2H-benzotriazoles
-
A process for the production of 2-aryl-2H-benzotriazoles comprises reducing and cyclizing the corresponding o-nitroazobenzenes with hydrogen at a temperature in the range of about 20° C. to about 100° C. and at a pressure in the range of about 15 psia (1 atmosphere) to about 1000 psia (66 atmospheres) in an alkaline medium at a pH over 10 in the presence of a nickel catalyst, preferably molybdenum-promoted Raney nickel. High yields of pure product are obtained directly with a concomitant reduction of undesired by-product and a reduction in effluent pollution problems.
- -
-
-
- Process for the production of 2-aryl-2H-benzotriazoles
-
A process for the production of 2-aryl-2H-benzotriazoles comprises reducing and cyclizing the corresponding o-nitroazobenzenes with hydrogen at a temperature in the range of about 20° C. to about 100° C. and at a pressure in the range of about 15 psia (1 atmosphere) to about 1000 psia (66 atmospheres) in an organic solvent mixture containing an organic amine at a pH over 10 in the presence of noble metal hydrogenation catalyst, preferably palladium. High yields of pure product are obtained with a concomitant reduction of undesired by-products and a reduction in effluent pollution problems.
- -
-
-
- Process for the production of 2-aryl-2H-benzotriazoles
-
A process for the production of 2-aryl-2H-benzotriazoles comprises reducing and cyclizing the corresponding o-nitroazobenzenes with carbon monoxide at a temperature in the range of about 20° C. to about 150° C. and at a pressure in the range of about 15 psia (1 atmosphere) to about 1000 psia (66 atmospheres) in an alkaline medium at a pH over 10 in the presence of a copper-amine complex catalyst. High yields of pure product are obtained with a concomitant reduction of undesired by-products and a reduction in effluent pollution problems.
- -
-
-
- Process for the production of 2-aryl-2H-benzotriazoles
-
An improved process for the production of 2-aryl-2H-benzotriazoles by the reduction of o-nitroazobenzene intermediates with zinc in alkaline medium comprises employing a ratio of moles of alkali to moles of o-nitroazobenzene intermediate in the range of 0.2-1.7/1 in the presence of less than 150 ppm of iron based on zinc used. The improved process results in higher yields of high purity products with a concomitant reduction in the amount of undesired cleavage amine by-products and a reduction in effluent pollution problems. The process is carried out in a polar/non-polar solvent mixture.
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