- Tunable Electrosynthesis of Anthranilic Acid Derivatives via a C-C Bond Cleavage of Isatins
-
A facile and direct electrocatalytic C-C bond cleavage/functionalization reaction of isatins was developed. With isatins as the amino-attached C1 sources, a variety of aminobenzoates, and aminobenzamides were synthesized in moderate to good yields under mild conditions.
- Qian, Peng,Liu, Jiaojiao,Zhang, Yan,Wang, Zhiyong
-
p. 16008 - 16015
(2021/07/31)
-
- Unsymmetrically substituted dibenzo[b,f][1,5]-diazocine-6,12(5H,11H)dione—A convenient scaffold for bioactive molecule design
-
A novel approach for the synthesis of unsymmetrically substituted dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones has been developed. This facile three-step method uses variously substituted 1H-benzo[d][1,3]oxazine-2,4-diones (isatoic anhydrides) and 2-aminobenzoic acids as a starting materials. The obtained products were further transformed into N-alkyl-, N-acetyl- and dithio analogues. Developed procedures allowed the synthesis of unsymmetrical dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones and three novel heterocyclic scaffolds: benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)dione, pyrido[3,2-c][1,5]benzodiazocine-5,11(6H,12H)-dione and pyrazino[3,2-c][1,5]benzodiazocine-6,12(5H,11H)dione. For 11 of the compounds crystal structures were obtained. The preliminary cytotoxic effect against two cancer (HeLa, U87) and two normal lines (HEK293, EUFA30) as well as antibacterial activity were determined. The obtained dibenzo[b,f][1,5]diazocine(5H,11H)6,12-dione framework could serve as a privileged structure for the drug design and development.
- Bieszczad, Bartosz,Garbicz, Damian,Trzybiński, Damian,Mielecki, Damian,Wo?niak, Krzysztof,Grzesiuk, El?bieta,Mieczkowski, Adam
-
-
- Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer
-
Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.
- Wang, Lei,Fang, Kun,Cheng, Junfei,Li, Yu,Huang, Yahui,Chen, Shuqiang,Dong, Guoqiang,Wu, Shanchao,Sheng, Chunquan
-
p. 696 - 713
(2020/02/04)
-
- Oxidative ring-opening of isatins for the synthesis of 2-aminobenzamides and 2-aminobenzoates
-
An efficient and practical isatin-based oxidative domino protocol has been developed for the facile synthesis of 2-aminobenzamides and 2-aminobenzoates. The robust nature of this reaction system is reflected by accessible starting materials, room temperature and high-yield gram-scale synthesis.
- Wang, Yu-Wei,Zheng, Lei,Jia, Feng-Cheng,Chen, Yun-Feng,Wu, An-Xin
-
p. 1497 - 1503
(2019/02/13)
-
- Tuning a robust system: N,O zinc guanidine catalysts for the ROP of lactide
-
Non-toxic, highly active and robust complexes are the holy grail as ideal green catalysts for the polymerisation of biorenewable and biodegradable polylactide. Four new zinc guanidine complexes [ZnCl2(TMG4NMe2asme)], [ZnCl2(TMG5Clasme)], [ZnCl2(TMG5Measme)] and [ZnCl2(TMG5NMe2asme)] with different electron-donating and electron-withdrawing groups on the ligand's aromatic backbone have been synthesised. Ligands are derived from low-cost commercially available compounds and have been converted by a three- or four-step synthesis process into the desired ligand in good yields. The compounds have been fully characterised and tested in the ROP of rac-LA under industrially relevant conditions. The complexes are based on the recently published structure [ZnCl2(TMGasme)] which has shown high activity in the polymerisation of lactide at 150 °C. Different substituents in the para-position of the guanidine moiety significantly increase the polymerisation rate whereas positioning substituents in the meta-position causes no change in the reaction rate. With molecular weights over 71000 g mol-1 being achievable, the best system produces polymers for multiple industrial applications and its polymerisation rate approaches that of Sn(Oct)2. The robust systems are able to polymerise non-purified lactide. The initiation of the polymerisation is suggested to occur due to impurities in the monomer.
- Sch?fer, Pascal M.,McKeown, Paul,Fuchs, Martin,Rittinghaus, Ruth D.,Hermann, Alina,Henkel, Johanna,Seidel, Sebastian,Roitzheim, Christoph,Ksiazkiewicz, Agnieszka N.,Hoffmann, Alexander,Pich, Andrij,Jones, Matthew D.,Herres-Pawlis, Sonja
-
p. 6071 - 6082
(2019/05/17)
-
- NONMUSCLE MYOSIN II INHIBITORS FOR SUBSTANCE USE RELAPSE
-
The invention can provide compounds, analogs of blebbistatin, effective and selective inhibitors of nonmuscle myosin II relative to cardiac myosin II. Compounds can be used in the method of treating a disease, disorder, or medical condition in a patient, comprising modulating myosin II ATPase, such as treatment of substance abuse relapse disorder, or of renal disease, cancer and metastasis, benign prostate hyperplasia, hemostasis or thrombosis, nerve injury including retinal damage, lung fibrosis, liver fibrosis, arthrofibrosis, wound healing, spinal cord injury, periodontitis, glaucoma and immune-related diseases including multiple sclerosis; or wherein the disease, disorder, or medical condition comprises addiction including abuse of or addiction to anything classified as a Substance-Related or Addictive Disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM), such as, but not limited to, cocaine, opioids, amphetamines, ethanol, cannabis/marijuana, nicotine, and activities including gambling Compounds are of general formula (I) with substituents as defined herein.
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Page/Page column 56-57
(2020/01/08)
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- En Route to 2-(Cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole
-
A six-step synthetic route from 4-chloro-2-methylaniline to 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1) has been reported. Compound 1a is a key impurity of reverse transcriptase inhibitor efavirenz, an important anti-HIV/AIDS drug. Synthetic challenges, dead ends, and detours are discussed.
- Gazvoda, Martin,Krivec, Marko,?asar, Zdenko,Ko?mrlj, Janez
-
p. 2486 - 2493
(2018/02/23)
-
- AMINATION AND HYDROXYLATION OF ARYLMETAL COMPOUNDS
-
In one aspect, the present disclosure provides methods of preparing a primary or secondary amine and hydroxylated aromatic compounds. In some embodiments, the aromatic compound may be unsubstituted, substituted, or contain one or more heteroatoms within the rings of the aromatic compound. The methods described herein may be carried out without the need for transition metal catalysts or harsh reaction conditions.
- -
-
Paragraph 0257
(2018/03/25)
-
- Iodine(III) Reagent-Mediated Intramolecular Amination of 2-Alkenylanilines to Prepare Indoles
-
A variety of 3-substituted and 2,3-disubstituted indoles were synthesized efficiently in good yields through the intramolecular amination of 2-alkenylanilines promoted by readily available iodine(III) reagents in a short reaction time. Mechanistic studies showed that the reaction pathway went through a nitrenium ion and that 3-acetoxy indoline was the key intermediate in the indole formation. The indole product was easily prepared on a gram scale and amination also proceeded smoothly using catalytic 3,5-dimethylphenyl iodine in the presence of mCPBA. Furthermore, the indolo[3,2-a]carbazole scaffold was prepared in good yield in six steps from commercial ortho-iodoaniline. (Figure presented.).
- Zhao, Chun-Yang,Li, Kun,Pang, Yu,Li, Jia-Qing,Liang, Cui,Su, Gui-Fa,Mo, Dong-Liang
-
supporting information
p. 1919 - 1925
(2018/03/28)
-
- Non-deprotonative primary and secondary amination of (hetero)arylmetals
-
Herein we disclose a novel method for the facile transfer of primary (-NH2) and secondary amino groups (-NHR) to heteroaryl-as well as arylcuprates at low temperature without the need for precious metal catalysts, ligands, excess reagents, protecting and/or Erecting groups. This one-pot transformation allows unprecedented functional group tolerance and it is wellsuited for the amination of electron-rich, electron-deficient as well as structurally complex (hetero)arylmetals. In some of the cases, only catalytic amounts of a copper (l) salt is required.
- Zhou, Zhe,Ma, Zhiwei,Behnke, Nicole Erin,Gao, Hongyin,Kürti, László
-
supporting information
p. 115 - 118
(2017/05/16)
-
- An efficient one-pot oxidative esterification of aldehydes to carboxylic esters using B(C6F5)3-TBHP
-
A simple and efficient protocol for oxidative esterification of diverse aldehydes with alcohols was accomplished with tert-butyl hydroperoxide and 1 mol % of tris(pentafluorophenyl)borane [B(C6F5)3] to generate the corresponding esters in good to excellent yields. The present protocol represents compatibility with wide range of functional groups as well as exceptional tolerance toward acid labile protecting groups such as TBDPS, TBDMS, acetonide, and Boc.
- Guggilapu, Sravanthi Devi,Prajapti, Santosh Kumar,Babu, Bathini Nagendra
-
supporting information
p. 889 - 892
(2015/02/05)
-
- Tandem C-O and C-N Bonds Formation Through O-Arylation and [3,3]-Rearrangement by Diaryliodonium Salts: Synthesis of N-Aryl Benzo[1,2,3]triazin-4(1H)-one Derivatives
-
Metal-free O-arylation and [3, 3]-rearrangement have been shown as an efficient strategy to construct new C-O and C-N bonds in one-pot reactions. The method was used to prepare N-aryl benzo[1,2,3]triazin-4(1H)-one derivatives in good yields from N-hydroxy benzo[1,2,3]triazin-4(3H)-one and diaryliodonium salts. The reaction was tolerated a variety of sensitive functional groups such as iodine, nitro, ester, and aldehyde groups. A rational mechanism was proposed based on the experimental results, and the reaction was easily up to gram scale.
- Shi, Wei-Min,Ma, Xiao-Pan,Pan, Cheng-Xue,Su, Gui-Fa,Mo, Dong-Liang
-
p. 11175 - 11183
(2015/11/18)
-
- PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES
-
The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
- -
-
-
- Discovery of novel bacterial RNA polymerase inhibitors: Pharmacophore-based virtual screening and hit optimization
-
The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ70 and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
- Hinsberger, Stefan,Hüsecken, Kristina,Groh, Matthias,Negri, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
-
p. 8332 - 8338
(2013/12/04)
-
- PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES
-
The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
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-
-
- NOVEL 3,3-DIMETHYL TETRAHYDROQUINOLINE DERIVATIVES
-
A compound of formula (I) as well as pharmaceutically acceptable salt thereof, wherein R1 to R5 have the significance given in claim 1, can be used as a medicament.
- -
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Page/Page column 187
(2011/11/01)
-
- NOVEL 3,3-DIMETHYL TETRAHYDROQUINOLINE DERIVATIVES
-
A compound of formula (I) as well as pharmaceutically acceptable salt thereof, wherein R1 to R5 have the significance given in claim 1, can be used as a medicament.
- -
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Page/Page column 69
(2011/10/31)
-
- Synthesis of new 1,2,3-triazolo[1,5-a]quinazolinones
-
(Chemical Equation Presented) Synthesis of novel 3-substituted-1,2,3- triazolo[1,5-a]quinazolinones in high yields was performed via anionic hetero-domino reaction of appropriate substituted 2-azidobenzoates prepared from isatines and acetonitriles activated by 1,3-thiazole, 1,3-benzothiazole, 1,3,4-oxadiazole, and 1,2,4-oxadiazole rings. It was shown that acetonitriles exhibited high reactivity and were convenient methylenic compounds for such reactions providing rapid structural variation.
- Pokhodylo, Nazariy T.,Matiychuk, Vasyl S.
-
scheme or table
p. 415 - 420
(2010/06/16)
-
- An efficient selective reduction of aromatic azides to amines employing BF3·OEt2/NaI: Synthesis of pyrrolobenzodiazepines
-
A selective and facile method for the reduction of aromatic azides to amines by employing borontrifluoride diethyl etherate and sodium iodide. This methodology has been applied towards the preparation of biologically important imine-containing pyrrolobenzodiazepines and their dilactams through intramolecular reductive-cyclization process. In this protocol the reagent systems are amenable for the generation of solution-phase combinatorial synthesis. Georg Thieme Verlag Stuttgart.
- Kamal, Ahmed,Shankaraiah,Markandeya,Reddy, Ch. Sanjeeva
-
experimental part
p. 1297 - 1300
(2009/04/06)
-
- 2-AMINO-4-PHENYLQUINAZOLINE DERIVATES AND THEIR USE AS HSP90 MODULATORS
-
New phenylquinazoline derivatives of the formula (I) in which R1, R2, R3, R4 and R5 are as defined in claim 1 are HSP90 inhibitors and can be used for manufacturing a medicinal product for the treatment of diseases where the inhibition, regulation and/or modulation of HSP90 plays a part.
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Page/Page column 57
(2010/11/24)
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- Efficient synthesis of 3-substituted 2,3-dihydroquinolin-4-ones using a one-pot sequential multi-catalytic process: Pd-catalyzed allylic amination-thiazolium salt-catalyzed Stetter reaction cascade
-
We developed an efficient method for the synthesis of 3-substituted 2,3-dihydroquinolin-4-ones using a one-pot sequential multi-catalytic process: Pd-catalyzed allylic amination-thiazolium salt-catalyzed Stetter reaction cascade. Measurement of the initial rate of the developed sequential process revealed a significant increase in the reaction rate of the Stetter reaction in the presence of Pd(OAc)2 and AcOH·i-Pr2NEt, the constituents of the first Pd catalysis.
- Nemoto, Tetsuhiro,Fukuda, Tomoaki,Hamada, Yasumasa
-
p. 4365 - 4368
(2007/10/03)
-
- 4-Hydroxy-2-quinolones. 90.* Synthesis and antitubercular activity of 4-methyl-2-thiazolylamides of halo-substituted 4-hydroxy-2-oxo-1,2-dihydro-3- quinolinecarboxylic acids
-
Several variants were studied for the synthesis of esters of halogen derivatives of 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acids, whose reaction with 2-amino-4-methylthiazole gives the corresponding hetarylamides. Results are given for a study of the antitubercular activity of these products. 2006 Springer Science+Business Media, Inc.
- Ukrainets,Sidorenko,Petrushova,Gorokhova
-
-
- FIBROSIS INHIBITOR
-
Medicament being useful as a fibrosis inhibitor for organs or tissues, which comprises a compound of the formula (I): wherein Ring Z is optionally substituted pyrrole ring, etc.; W2 is -CO-, -SO2-, optionally substituted C1-C4 alkylene, etc.; Ar2 is optionally substituted aryl, etc.; W1 and Ar1 mean the following (1) and (2):(1) W1 is optionally substituted C1-C4 alkylene, etc.; Ar1 is optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms:(2) W1 is optionally substituted C2-C5 alkylene, optionally substituted C2-C5 alkenylene, etc.; and Ar1 is aryl or monocyclic heteroaryl, which is substituted by carboxyl, alkoxycarbonyl, etc. at the ortho- or meta-position thereof with respect to the binding position of W1, or a pharmaceutically acceptable salt thereof.
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-
-
- THERAPEUTIC USE OF ARYL AMINO ACID DERIVATIVES
-
The compounds of formula (I) are useful in the treatment of faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, neuropathological disorders and sleep disorders. Processes for the preparation of the final products and intermediates useful in the process are included. Pharmaceutical compositions containing one or more of the compounds are also included.
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Page/Page column 35
(2010/02/06)
-
- Pyrrole derivatives
-
Pyrrole derivatives represented by the following formula: wherein Ring Z is an optionally substituted pyrrole ring, etc.; W2 is —CO—, —SO2—, an optionally substituted C1-C4 alkylene, etc.; Ar2 is an optionally substituted aryl, etc.; W2 and Ar1 mean the following (1) and (2): (1) W1 is an optionally substituted C1-C4 alkylene, etc.; Ar1 is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms: (2) W1 is an optionally substituted C2-C5 alkylene, an optionally substituted C2-C5 alkenylene, etc.; and Ar1 is an aryl or monocyclic heteroaryl, which are substituted by carboxyl, an alkoxycarbonyl, etc. at the ortho- or meta-position thereof with respect to the binding position of W1, or a pharmaceutically acceptable salt thereof These compounds are useful as medicaments such as a fibrosis inhibitor for organs or tissues.
- -
-
-
- Synthesis and Pharmacological Evaluation of Fenamate Analogues: 1,3,4-Oxadiazol-2-ones and 1,3,4-Oxadiazole-2-thiones
-
A series of fenamate pyridyl or quinolinyl analogues of 1,3,4-oxadiazol-2-ones 5a-d and 6a-r, and 1,3,4-oxadiazole-2-thiones 5e-g and 6s-v, respectively, have been synthesized and evaluated for their analgesic (hot-plate), antiinflammatory (carrageenin induced rat's paw edema) and ulcerogenic effects as well as plasma prostaglandin E2 (PGE 2) level. The highest analgesic activity was achieved with compound 5a (0.5, 0.6, 0.7 mmol/kg b.wt.) in respect with mefenamic acid (0.4 mmol/kg b.wt.). Compounds 6h, 61 and 5g showed 93, 88 and 84% inhibition, respectively on the carrageenan-induced rat's paw edema at dose level of 0.1mmol/kg, b.wt, compared with 58% inhibition of mefenamic acid (0.2mmol/kg b.wt.). Moreover, the highest inhibitory activity on plasma PGE2 level was displayed also with 6h, 61 and 5g (71, 70, 68.5% respectively, 0.1mmol/kg b.wt.) compared with indomethacin (60%, 0.01 mmol/kg b.wt.) as a reference drug. In addition 6i, 6k, 6p, 6r, 6t and 6v were devoid of any ulcerogenicity.
- El-Azzounyl, Aida A.,Maklad, Yousreya A.,Bartsch, Herbert,Zaghary, Wafaa A.,Ibrahim, Waleed M.,Mohamed, Mosaad S.
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p. 331 - 356
(2007/10/03)
-
- Synthesis of substituted 1,2-dihydroquinolines and quinolines using ene-ene metathesis and ene-enol ether metathesis
-
We describe a novel and convenient method for quinoline synthesis using ring-closing olefin metathesis (RCM), ene-ene metathesis, and ene-enol ether metathesis. We also report the first example of enol silyl ether-ene metathesis to produce cyclic enol silyl ether. Using this method, versatile substituted quinoline derivatives were readily prepared in excellent yield from anthranilic acid derivatives.
- Arisawa, Mitsuhiro,Theeraladanon, Chumpol,Nishida, Atsushi,Nakagawa, Masako
-
p. 8029 - 8033
(2007/10/03)
-
- Ring-substituted 11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides with similar patterns of cytotoxicity to the dual topo I/II inhibitor DACA
-
A series of ring-substituted analogues of the topoisomerase inhibitor 11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides was prepared and evaluated. The compounds were prepared by Pfitzinger reaction of the appropriate isatin-7-carboxylic acids and 1-indanones, followed by selective thermal decarboxylation of the resulting tetracyclic diacids, subsequent oxidation of the methylene group with alkaline permanganate under carefully controlled conditions, and 1,1'-carbonyldiimidazole-induced amidation. The compounds were evaluated in a panel of cell lines in culture. The largest increases in cytotoxicity (five to tenfold) were shown by 4-substituted analogues, with the 4-Cl derivative having an IC50 of 8nM against the Lewis lung carcinoma. Copyright (C) 1999 Elsevier Science Ltd.
- Deady, Leslie W.,Desneves, Jose,Kaye, Anthony J.,Thompson, Michelle,Finlay, Graeme J.,Baguley, Bruce C.,Denny, William A.
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p. 2801 - 2809
(2007/10/03)
-
- 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist
-
We previously reported a series of benzazepine derivatives as orally active nonpeptide arginine vasopressin (AVP) V2 receptor antagonists. After the lead structure OPC-31260 was structurally evaluated and optimized, the introduction of the 7-Cl moiety on the benzazepine and 2-CH3 on the aminobenzoyl moiety enhanced its oral activity. The new AVP-V2 selective antagonist OPC-41061 was determined to be a potent and orally active agent. Copyright (C) 1999 Elsevier Science Ltd.
- Kondo, Kazumi,Ogawa, Hidenori,Yamashita, Hiroshi,Miyamoto, Hisashi,Tanaka, Michinori,Nakaya, Kenji,Kitano, Kazuyoshi,Yamamura, Yoshitaka,Nakamura, Shigeki,Onogawa, Toshiyuki,Mori, Toyoki,Tominaga, Michiaki
-
p. 1743 - 1754
(2007/10/03)
-
- Practical and efficient chlorination of deactivated anilines and anilides with NCS in 2-propanol
-
Deactivated anilines and anilides were efficiently monochlorinated with NCS in 2-propanol. The described method was applicable to a large scale synthesis.
- Zanka, Atsuhiko,Kubota, Ariyoshi
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p. 1984 - 1986
(2007/10/03)
-
- Pyridazinedione compounds useful in treating neurological disorders
-
The present invention relates to pyridazino[4,5-b]quinolines, and pharmaceutically useful salts thereof, which are excitatory amino acid antagonists and which are useful when such antagonism is desired such as in the treatment of neurological disorders. The invention further provides pharmaceutical compositions containing pyridazino[4,5-b]quinolines as active ingredient, and methods for the treatment of neurological disorders.
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-
- Synthesis and structure-activity relationships of 1,2,3,4- tetrahydroquinoline-2,3,4-trione 3-oximes: Novel and highly potent antagonists for NMDA receptor glycine site
-
A series of 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes (QTOs) was synthesized and evaluated for antagonism of NMDA receptor glycine site. Glycine site affinity was determined using a [3H]DCKA binding assay in rat brain membranes and electrophysiologically in Xenopus oocytes expressing 1a/2C subunits of cloned rat NMDA receptors. Selected compounds were also assayed for antagonism of AMPA receptors in Xenopus oocytes expressing rat brain poly-(A)+ RNA. QTOs were prepared by nitrosation of 2,4- quinolinediols. Structure-activity studies indicated that substitutions in the 5-, 6-, and 7-positions increase potency, whereas substitution in the 8- position causes a decrease in potency. Among the derivatives evaluated, 5,6,7-trichloro-QTO was the most potent antagonist with an IC50 of 7 nM in the [3H]DCKA binding assay and a K(b) of 1-2 nM for NMDA receptors expressed in Xenopus oocytes. 5,6,7-Trichloro-QTO also had a K(b) of 180 nM for AMPA receptors in electrophysiological assays. The SAR of QTOs was compared with the SAR of 1,4-dihydroquinoxaline-2,3-diones (QXs). For compounds with the same benzene ring substitution pattern, QTOs were generally 5-10 times more potent than the corresponding QXs. QTOs represent a new class of inhibitors of the NMDA receptor which, when appropriately substituted, are among the most potent glycine site antagonists known.
- Cai, Sui Xiong,Zhou, Zhang-Lin,Huang, Jin-Cheng,Whittemore, Edward R.,Egbuwoku, Zizi O.,Lü, Yixin,Hawkinson, Jon E.,Woodward, Richard M.,Weber, Eckard,Keana, John F. W.
-
p. 3248 - 3255
(2007/10/03)
-
- Improved synthesis of 2-amino-5-chlorophenyl-2'-pyrrylketone, a key intermediate in the synthesis of HIV Tat-antagonists
-
The reaction of a 2-phenylbenzoxazinone with pyrryl Grignard reagent is very efficient compared with that of a 2-methylbenzoxazinone. The title compound was prepared from 5-chloroanthranilic acid via the 2-phenylbenzoxazinone in 92% overall yield. This method was also successfully applied to the synthesis of 2-aminobenzophenones.
- Okabe,Sun
-
p. 1861 - 1866
(2007/10/02)
-
- 3-Acyl-4-hydroxyquinolin-2(1H)-ones. Systemically Active Anticonvulsants Acting by Antagonism at the Glycine Site of the N-Methyl-D-Aspartate Receptor Complex
-
Most full antagonists at the glycine site of the NMDA receptor contain a carboxylic acid, which we believe to be detrimental to penetration of the blood-brain barrier.By consideration of a pharmacophore, novel antagonists at this site have been designed in which the anionic functionality is a vinylogous acid, in the form of a 4-hydroxyquinolin-2(1H)-one.In this series, a 3-substituent is necessary for binding, and correct manipulation of this group leads to compounds such as the 3-(3-hydroxyphenyl)propargyl ester 24 (L-701,273), with an IC50 for displacement of -L-689,560 binding of 0.17 μM and Kb against NMDA in the cortical slice of 1.39 μM.Compounds were tested for their ability to prevent audiogenic seizure in DBA/2 mice; the most potent compound in this series is the cyclopropyl ketone 42 (L-701,252), with an ED50 of 4.1 mg/kg ip.A model is proposed for binding to the glycine site, in which an important interaction is of a putative receptor cation with the ?-system of the 3-substituent.
- Rowley, Michael,Leeson, Paul D.,Stevenson, Graeme I.,Moseley, Angela M.,Stansfield, Ian,et al.
-
p. 3386 - 3396
(2007/10/02)
-
- Benzimidazole derivatives and their use
-
Novel imidazole derivatives of the formula (I): STR1 wherein R1 is an optionally substituted alkyl group, R2 and R3 are independently a group capable of forming an anion or a group which can be changed thereinto, ring A is a benzene ring optionally having, besides the group shown by R2, further substituents, and X shows linkage of phenylene group and phenyl group directly or through a spacer whose atomic length is not more than 2 and a salt thereof, show antagonistic actions to angiotensin II, thus being useful as therapeutics for cardiovascular diseases.
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- 4H-3,1-BENZOXAZIN-4-ONES AND RELATED COMPOUNDS AND USE AS ENZYME INHIBITORS
-
Novel 2-amino-4H-3,1-benzoxazin-4-ones represented by the formula wherein R 1, R 2, R 3 and X are defined herein are useful as enzyme inhibitors in animals.
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- Synthesis of 3-Amino-4-(3H)-quinazolinones from N-(2-Carbomethoxyphenyl) Imidate Esters
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Novel difunctional aromatic synthons consisting of N-(2-carbomethoxyphenyl) imidate esters were synthesized by treatment of methyl anthranilate esters with aliphatic ortho esters.Treatment of the imidates with hydrazine, methylhydrazine, and phenylhydrazine yielded only quinazolinones and not isomeric 1,3,4-benzotriazepin-5-ones.The type of products obtained gave information relevant to elucidation of the mechanism of cyclization and the relative reactivities of the ester and imidate groups.
- Leiby, Robert W.
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p. 2926 - 2929
(2007/10/02)
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- Succinimido azo dyestuffs
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The invention relates to water-insoluble azo dyestuffs of the formula SPC1 In which A represents the residue of a diazo component of the azobenzene series, R1 a hydrogen atom or an alkyl group which may be substituted which may be substituted, R2 an alkyl group which may be substituted, R3 represents a divalent organic residue which together with the grouping EQU1 may form a 5- to 7-membered heterocycle, and X represents a hydrogen atom or an alkyl, alkoxy, aryloxy or arylmercapto group. The dyestuffs dye polyester fibre in orange, red or blue shades with good fastness: the use of such succinimido containing azo dyestuffs in imparting blue to red color to fibers or fabrics of wool, cellulose triacetate, polyamides and polyesters. The dyeings display excellent fastness to light, sublimation and abrasion on polyester fibers.
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- 4-Carbamoyl-1-benzazepines as antiinflammatory agents
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4-Arylcarbamoyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-diones, e.g. those of the fromula SPC1 R = h, alkyl or aralkyl Ar = iso- or heterocyclic aryl R',r" = h, alkyl, alkanoyl, alkoxy, halogen or CF3 alkali metal or acid addition salts thereof are antiinflammatory agents.
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