cas 31910-18-6, 2,3-DIHYDROXY-6-METHOXYQUINOXALINE

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Novel molecular targeting anti-tumor aza-steroid derivative based on lipid toxicity and preparation and application thereof
The invention provides a novel molecular targeting anti-tumor aza-steroid derivative based on lipid toxicity and a preparation method and application thereof, and belongs to the field of chemical medicines. The derivative is a compound as shown in a formula I, or a salt thereof, or a stereoisomer thereof. The compound is low in toxicity or basically non-toxic to normal cells, has an obvious inhibition effect to tumor cell lines, particularly has good lipid toxicity selectivity to tumor cells such as liver cancer, lung cancer and the like in vivo, and has an obvious inhibition effect; meanwhile, the compound can effectively activate SREBP1 and PPAR gamma, inhibit lipid transport MTTP, cause lipid aggregation in tumor cells and cause lipid toxicity of the tumor cells. The compound can be used for treating liver cancer, lung cancer and the like in a molecular targeting manner, is low in toxicity or even non-toxic, and has a good application prospect.
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Paragraph 0178; 0180; 0181; 0192; 0221

(2021/08/19)

Synthesis and vasorelaxant evaluation of novel 7-methoxyl-2,3-disubstituted-quinoxaline derivatives
An array of novel 7-methoxyl-2,3-disubstituted quinoxaline derivatives was designed, synthesized and their potential antihypertensive activities were examined, in an attempt to discover potent small molecules with vasorelaxant effects. The vasoactivities of these compounds on vascular tone, as well as underlying mechanisms were hereby explored. Results showed that five compounds (7s, 7t, 7v, 7w, 7γ) could induce endothelium-independent relaxation in high extracellular K+- and phenylephrine-precontracted C57 mice aortic rings. These five compounds, unlike other commonly used vasodilators, could slowly but effectively inhibit vasoconstriction.
Gao, Wen-Cong,Li, Xun,Ma, Xin,Pang, Pan-Pan,Peng, Li-Chun,Yang, Liang,Zheng, Chang-Bo
(2021/02/03)

NS3/4A protease inhibitor intermediate as well as synthesis method and application thereof
The invention belongs to the technical field of medicine, and particularly relates to an NS3/4A protease inhibitor intermediate as well as a synthesis method and application thereof. The synthesis method comprises the following steps: taking 4-methoxy-o-p
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Paragraph 0034-0054; 0076; 0078; 0080; 0082; 0084; 0086

(2020/04/22)

A One-pot Facile Synthesis of 2,3-Dihydroxyquinoxaline and 2,3-Dichloroquinoxaline Derivatives Using Silica Gel as an Efficient Catalyst
An efficient one-pot reaction has been developed for the synthesis of 2,3-dichloroquinoxaline derivatives 3a–n. The reaction was performed in two steps via a silica gel catalyzed tandem process from o-phenylenediamine and oxalic acid, followed by addition of phosphorus oxychloride (POCl3). A variety of 2,3-dichloroquinoxalines have been obtained in good to excellent overall yields. Eight known compounds 3a–3h were characterized by IR, 1H-NMR, and mass spectroscopies. Compounds 3i–3n without spectroscopic data were characterized by IR, 1H-NMR, 13C-NMR, and mass spectroscopies.
Zhang, Pei-Ming,Li, Yao-Wei,Zhou, Jing,Gan, Lin-Ling,Chen, Yong-Jie,Gan, Zong-Jie,Yu, Yu
p. 1809 - 1814
(2018/07/25)

HEPATITIS C VIRUS NS3/4A PROTEASE INHIBITORS
The invention provides novel classes of HCV therapeutics that are orally available, safe and effective HCV NS3/4A protease inhibitors and are less susceptible to drug resistance than existing therapeutics. The invention also relates to pharmaceutical composition of these compounds and methods of preparation and use thereof.
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Paragraph 00192

(2019/01/11)

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)
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(2017/03/28)

Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants
A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156, and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC50 values ≤5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance.
Matthew, Ashley N.,Zephyr, Jacqueto,Hill, Caitlin. J.,Jahangir, Muhammad,Newton, Alicia,Petropoulos, Christos J.,Huang, Wei,Kurt-Yilmaz, Nese,Schiffer, Celia A.,Ali, Akbar
supporting information
p. 5699 - 5716
(2017/07/22)

Process and intermediates for preparing macrolactams
The present invention includes compounds useful as intermediates in the preparation of macrolactams, methods for preparing the intermediates, and methods for preparing macrolactams from the intermediates. One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity. HCV NS3 inhibitory compounds have therapeutic and research applications.
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Page/Page column 35

(2016/02/18)

A N-acetyl-acetyl-6-methoxy-7-amino-quinoxalin -2,3-dione method for the preparation of
The invention discloses a preparation method of N-acetoaetyl-6-methoxy-7-aminoqunoxaline-2,3-diketone, which comprises the following steps: adding an ethanol aqueous solution, iron powder and hydrochloric acid, heating to 70-90 DEG C, adding bordeaux base GP under the protection of nitrogen, performing thermal insulation for 4-6h, adjusting the pH value, then adding diethyl oxalate and a catalyst, performing thermal insulation for 8-12h, cooling to 10-45 DEG C, and filtering to obtain off-white solid 1,4-dihydro-6-methoxy-2,3-quinoxalinedione; heating a salpeter solution to 70-90 DEG C, adding 1,4-dihydro-6-methoxy-2,3-quinoxalinedione, performing thermal insulation, then cooling, performing suction filtration and washing to obtain 1,4-dihydro-6-methoxy-7-nitro-2,3-quinoxalinedione, performing catalytic hydrogenation on 1,4-dihydro-6-methoxy-7-nitro-2,3-quinoxalinedione, and adding a catalyst and water for reaction at the pressure of 0.2-2 MPa and temperature of 80-120 DEG C, cooling to 80-90 DEG C after reaction, performing suction filtration, adjusting the pH value, dropwise adding diketene, performing thermal insulation, cooling to 15-40 DEG C, and performing suction filtration to obtain N-acetoaetyl-6-methoxy-7-aminoqunoxaline-2,3-diketone. The total yield of the finished product is more than 82%, and the purity is more than 99.0%.
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Paragraph 0024

(2017/03/14)

MACROCYCLIC AND BICYCLIC INHIBITORS OF HEPATITIS C VIRUS
Compounds of formula (I):or pharmaceutically acceptable salts thereof, wherein the various substituents are defined herein, methods of using said compounds, and pharmaceutical compositions containing said compounds.
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(2014/09/29)

Inhibitors of nedd8-activating enzyme
The invention relates to an administration unit comprising crystalline form I of {(1 S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (I-216) hydrochloride salt and to a packaging comprising the administration unit according to the invention.
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Paragraph 0177

(2014/08/20)

CRYSTAL FORMS OF A HCV PROTEASE INHIBITOR
The present invention relates to different forms of a HCV inhibitory compound.
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Page/Page column 21

(2013/03/26)

Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
Harper, Steven,McCauley, John A.,Rudd, Michael T.,Ferrara, Marco,DiFilippo, Marcello,Crescenzi, Benedetta,Koch, Uwe,Petrocchi, Alessia,Holloway, M. Katharine,Butcher, John W.,Romano, Joseph J.,Bush, Kimberly J.,Gilbert, Kevin F.,McIntyre, Charles J.,Nguyen, Kevin T.,Nizi, Emanuela,Carroll, Steven S.,Ludmerer, Steven W.,Burlein, Christine,Dimuzio, Jillian M.,Graham, Donald J.,McHale, Carolyn M.,Stahlhut, Mark W.,Olsen, David B.,Monteagudo, Edith,Cianetti, Simona,Giuliano, Claudio,Pucci, Vincenzo,Trainor, Nicole,Fandozzi, Christine M.,Rowley, Michael,Coleman, Paul J.,Vacca, Joseph P.,Summa, Vincenzo,Liverton, Nigel J.
supporting information; experimental part
p. 332 - 336
(2012/06/01)

HEPATITIS C VIRUS NS3 PROTEASE INHIBITORS
The present invention relates to macrocyclic compounds of Formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
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(2013/03/26)

FUSED TRICYCLIC COMPOUNDS WITH ADENOSINE A2a RECEPTOR ANTAGONIST ACTIVITY
The present invention relates to certain certain fused tricyclic heteroaryl rings compounds of the Formula (I) (also referred to herein as the "Fused Tricyclic Compounds"), wherein M, Q, U, W, X, Y, Z, R1, R2, and R3, and rings C and D are as herein described. The present invention also provides compositions comprising at least one Fused Tricyclic Compound, and use of such compounds in the treatment of central nervous system diseases or disorders such as Parkinson's disease.
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Page/Page column 38

(2011/06/16)

Design and synthesis of small molecule RhoA inhibitors: A new promising therapy for cardiovascular diseases?
RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of ～200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1-3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a-v, 13a-h, and 14a-j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC50 values of 1.24 to 3.00 μM. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents.
Deng, Jing,Feng, Enguang,Ma, Sheng,Zhang, Yan,Liu, Xiaofeng,Li, Honglin,Huang, Huang,Zhu, Jin,Zhu, Weiliang,Shen, Xu,Miao, Liyan,Liu, Hong,Jiang, Hualiang,Li, Jian
experimental part
p. 4508 - 4522
(2011/09/14)

Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
The present invention relates to macrocyclic a compound of formula (I) and its use as inhibitors of the hepatitis C virus (HCV) NS3 protease, and in treating or preventing HCV infections.
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Page/Page column 7

(2010/03/02)

NIACIN RECEPTOR AGONISTS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT
Compounds of the formula (I): as well as pharmaceutically acceptable salts and solvates are disclosed. The compounds are useful for treating dyslipidemias, and in particular, reducing serum LDL, VLDL and triglycerides, and raising HDL levels. Pharmaceutic
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(2008/06/13)

Synthesis of quinoxaline derivatives bearing the styryl and phenylethynyl groups and application to a fluorescence derivatization reagent
The cross-coupling of 2-chloro-6-methoxycarbonyl-3-methylquinoxaline (2) and 3-chloro-7-methoxy-1-methylquinoxalin-2(1H)-one (7) with phenylacetylene in the presence of Pd(PPh3)4 gave 6-methoxycarbonyl-3-methyl-2- phenylethynylquinoxaline (3) and 7-methoxy-1-methyl-3-(4-methoxycarbonyl)- phenylethynylquinoxalin-2(1H)-one (9), respectively. Compounds (3 and 9) were further converted into the corresponding olefinic compounds, 6- methoxycaybonyl-3-methyl-2-styrylquinoxaline (4) and 7-methoxy- 1-methyl-3- (4-methoxycarbonyl)styrylquinoxalin-2(1H)-one (10), by partial hydrogenation on palladium catalysts such as Lindlar catalyst and Pd/BaSO4-quinoline, but the conformation of the resulting olefins was unexpectedly E-form. These quinoxaline derivatives showed fluorescent emission bands at a range from 398 to 467 nm in MeCN when the excitation wavelength of 353-405 nm was applied. Further, 3-(4-chlorocarbonyl)-phenylethynyl-7-methoxy-1-methylquinoxalin- 2(1H)-one (12) was demonstrated to be applicable to a fluorescence derivatization reagent for amines.
Katoh, Akira,Yoshida, Tohru,Ohkanda, Junko
p. 911 - 920
(2007/10/03)

4-Aminotriazoloquinoxalines. A Novel Class of Potent Adenosine Receptor Antagonists and Potential Rapid-Onset Antidepressants
A series of 4-aminotriazoloquinoxalines has been prepared.Many compounds from this class reduce immobility in Porsolt's behavioral despair model in rats upon acute administration and may therefore have therapeutic potential as novel and rapid acting antidepressant agents.Optimal activity in this test is associated with hydrogen, CF3, or small alkyl groups in the 1-position, with NH2, NH-acetyl, or amines substituted with small alkyl groups in the 4-position, and with hydrogen or 8-halogen substituents in the aromatic ring.Furthermore, many of these 4-aminoquinoxalines bind avidly, and in some cases very selectively, to adenosine A1 and A2 receptors.A1 affinity of these compounds was measured by their inhibition of tritiated CHA (N6-cyclohexyladenosine) binding in rat cerebral cortex membranes and A2 affinity by their inhibition of tritiated NECA (5'-(N-ethylcarbamoyl)adenosine) binding to rat striatal homogenate in the presence of cold N6-cyclopentyladenosine.Structure-activity relationship (SAR) studies show that best A1 affinity is associated with ethyl, CF3, or C2F5 in the 1-position, NH-iPr or NH-cycloalkyl in the 4-position, and with an 8-chloro substituent.Affinity at the A2 receptor is mostly dependent on the presence of an NH2 group in the 4-position and is enhanced by phenyl, CF3, or ethyl in the 1-position.The most selective A1 ligand by a factor of >3000 is 121 (CP-68,247; 8-chloro-4-(cyclohexylamino)-1-(trifluoromethyl)triazoloquinoxaline) with an IC50 of 28 nM at the A1 receptor.The most potent A2 ligand is 128 (CP-66,713; 4-amino-8-chloro-1-phenyltriazoloquinoxaline) with an IC50 of 21 nM at the A2 receptor and a 13-fold selectivity for this receptor.Representatives from this series appear to act as antagonists at both A1 and A2 receptors since they antagonize the inhibiting action of CHA on norepinephrine-stimulated cAMP formation in fat cells and they decrease cAMP accumulation induced by adenosine in limbic forebrain slices.Thus certain members of this 4-aminotriazoloquinoxaline series are among the most potent and A1 or A2 selective non-xanthine adenosine antagonists known.
Sarges, Reinhard,Howard, Harry R.,Browne, Ronald G.,Lebel, Lorraine A.,Seymour, Patricia A.,Koe, B. Kenneth
p. 2240 - 2254
(2007/10/02)

Quinoxaline Derivatives. XII. The Reactions of Quinoxaline 1,4-Dioxides with Acetic Anhydride
Quinoxaline 1,4-dioxide (XIIIa) with acetic anhydride gave 1-acetoxy-2(1H)-quinoxalinone (XIVa) which was prone to facile hydrolysis to yield 1-hydroxy-2(1H)-quinoxalinone (XVa).Both XIVa and XVa were isolated from the reaction mixture.On prolonged heating with acetic anhydride, XIIIa, XIVa and XVa were converted slowly to the same end product, 2,3(1H,4H)-quinoxalinedione (XXa). 6-Ethoxy- (XIIIb), 6-methoxy- (XIIIc), and 6-methylquinoxaline 1,4-dioxide (XIIId) behaved similarly, except that the attack of the reagent took place exclusively on N-oxide para to the electron-donating substituents, and none of the other expected isomeric compounds XVIIb-d were isolated.Whereas 6-chloroqinoxaline 1,4-dioxide (XIIIe) bearing an electron-attracting chloro substituent on the benzene ring gave exclusively the other isomers XVIIe, XVIIIe, and XXe.A mechanism for this novel rearrangement is proposed and discussed.
Ahmed, Yusuf,Qureshi, M. Ikram,Habib, M. Saleem,Farooqi, M. Amir
p. 1145 - 1148
(2007/10/02)

Method of using [1,2,4]triazolo[4,3-a]quinoxaline-4-amine derivatives as antidepressant and antifatigue agents
A series of novel [1,2,4]triazolo[4,3-a]quinoxaline-4-amine derivatives wherein the amine group is optionally substituted with lower alkyl, phenylalkyl having up to three carbon atoms in the alkyl moiety or alkanoyl having from two to five carbon atoms, or the amine group alternatively completes a piperazino ring, the quinoxaline ring is optionally substituted with fluorine, chlorine, bromine or methoxy, and the triazolo ring is optionally substituted with lower alkyl, lower perfluoroalkyl or phenyl are disclosed. These novel compounds are useful for treatment of symptoms associated with depression. Also disclosed are pharmaceutical compositions containing the novel compounds of this invention and a method of using the compounds in the treatment of depression and fatigue.
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(2008/06/13)

Method of using [1,2,4]triazolo[4,3-a]quinoxaline-4-amine derivatives as antidepressant and antifatigue agents
A series of novel [1,2,4]triazolo[4,3-a]quinoxaline-4-amine derivatives wherein the amine group is optionally substituted with lower alkyl, phenylalkyl having up to three carbon atoms in the alkyl moiety or alkanoyl having from two to five carbon atoms, or the amine group alternatively completes a piperazino ring, the quinoxaline ring is optionally substituted with fluorine, chlorine, bromine or methoxy, and the triazolo ring is optionally substituted with lower alkyl, lower perfluoroalkyl or phenyl are disclosed. These novel compounds are useful for treatment of symptoms associated with depression. Also disclosed are pharmaceutical compositions containing the novel compounds of this invention and a method of using the compounds in the treatment of depression and fatigue.
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(2008/06/13)