- Transition metal-free one-pot synthesis of 2-substituted 3-carboxy-4-quinolone and chromone derivatives
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A novel one-pot synthesis of the 2-substituted 3-carboxy-4-quinolone/ chromone derivatives from readily available 3-oxo-3-arylpropanoates and amides/acyl chlorides is reported, without any transition metal aid. The Royal Society of Chemistry 2013.
- Lin, Jian-Ping,Long, Ya-Qiu
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supporting information
p. 5313 - 5315
(2013/06/27)
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- 7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as Selective CB 2 cannabinoid receptor ligands: Structural investigations around a novel class of full agonists
-
Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo-[1,4]oxazino[2,3,4-ij] quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB2 receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20, hCB2Ki = 2.5 nM, SI = 166; 21, hCB2Ki = 0.81 nM, SI = 383; 38, hCB2K i = 15.8 nM, SI > 633; 56, hCB2Ki = 8.12 nM, SI > 1231; (R)-58, hCB2Ki = 9.24 nM, SI > 1082). The effect of a chiral center on the biological activity was also investigated, and it was found that the (R)-enantiomers exhibited greater affinity at the CB2 receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as agonists, exhibiting functional activity at the human CB2 receptor.
- Baraldi, Pier Giovanni,Saponaro, Giulia,Moorman, Allan R.,Romagnoli, Romeo,Preti, Delia,Baraldi, Stefania,Ruggiero, Emanuela,Varani, Katia,Targa, Martina,Vincenzi, Fabrizio,Borea, Pier Andrea,Aghazadeh Tabrizi, Mojgan
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experimental part
p. 6608 - 6623
(2012/09/22)
-
- NOVEL 7-SUBSTITUTED 3-CARBOXY-OXADIAZINO-QUINOLONE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS ANTI-BACTERIALS
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A subject of the invention is the compounds of formula (I): in which either R1 represents H, OH, NH2, —(CH2)m—NRaRb(m=0.1 or 2),Ra and Rb represent H, linear, branched or cyclic (C1 -C6) alkyl, (C3-C6) cycloalkyl-(C3-C6)— alkyl, Rc, S(O)2Rc, C(O)Rc, S(O)2Rd or C(O)Rd;or Ra and Rb with N form an Rc radical;Rc represents a saturated, unsaturated or 5- or 6-members aromatic ring, containing 1 to 4 heteroatoms chosen from N, O and S, optionally substituted;Rd represents a linear, branched or cyclic (C1-C6) alkyl, optionally substituted by 1 to 4 halogens;or R1 represents Rc or CHReRc or CHReRd;Re represents H, OH, NH2, NH—(C1-C6)-alk or N-(C1-C6)-alk2, or NH—(C1-C7)-acyl or NHRc;R2 represents H, (CH2)m—NRaRb, Rc, CHReRc or CHReRd, and R′2 represents H; it being understood that R1 and R2 cannot at the same time be H or that R1 and R2 or R2 and R1 cannot be one (CH2)m—NRaRb or Rc or H and the other one OH, or one H and the other one NH2, or one H and the other one (CH2)m—NRaRb in which Ra and Rb represent H or alkyl or C(O)Rd, in which Rd represents an unsubstituted alkyl or cycloalkyl; or R1 has the above definition except H and R2 and R′2 together represent gem dialkyl or alkyl-oxime, or R2 and R′2 represent respectively Rc or Rd and OH, NH2, NHRc or NHRf, Rf being a (C1-C7) acyl radical;or R1 represents H and R2 and R′2 together represent alkyl-oxime or one represents Rc and the other one represents OH, NH2, NHRc or NHRf;n is 0 or 1;R3 and R′3 represent H or (C1-C6) alkyl optionally substituted by 1 to 3 halogens or R3 represents (C1-C6) alkoxy carbonyl and R′3 represents H;R4 represents methyl optionally substituted by halogen;R5 represents H, (C1-C6) alkyl or (C7-C12) arylalkyl;R6 represents H, fluorine, NO2, CF3 or CN;in the form of enantiomers or mixtures, as well as their salts with acids and bases; their preparation and their application as anti-bacterials, in both human and veterinary medicine.
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Page/Page column 52
(2009/09/08)
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- Novel ofloxacin derivatives: Synthesis, antimycobacterial and toxicological evaluation
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Thirty novel 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from mycobacteria. Among the synthesized compounds, 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active compound in vitro with MIC99 of 0.19 μM and 0.09 μM against MTB and MTR-TB, respectively. In the in vivo animal model also the same compound decreased the bacterial load in lung and spleen tissues with 1.91 and 2.91 - log 10 protections, respectively, at the dose of 50 mg/kg body weight. Compound 10-[(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active in the inhibition of the supercoiling activity of DNA gyrase with an IC50 of 10.0 μg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.
- Dinakaran, Murugesan,Senthilkumar, Palaniappan,Yogeeswari, Perumal,China, Arnab,Nagaraja, Valakunja,Sriram, Dharmarajan
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p. 1229 - 1236
(2008/09/20)
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- HYDRAZIDE COMPOUNDS AND USES THEREOF
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This application relates to certain novel polycyclic compounds that interact with quadruplex-forming regions of polynucleotides and thereby inhibit translation of genetic information into polypeptides. These compounds can thus provide anticancer and antibacterial and antiviral effects. The invention includes novel compounds and pharmaceutical compositions, and methods of using them to treat cancer and other conditions.
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Page/Page column 57-58
(2008/12/08)
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- Synthesis of new quinolone antibiotics utilizing azetidine derivatives obtained from 1-azabicyclo[1.1.0]butane
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A series of 3-sulfenylazetidine derivatives 5a-f were synthesized via the ring-opening reactions of 1-azabicyclo[ 1.1.0]butane (ABB, 3) with thiols 4a-f in 50-92% yields. Treatment of ABB (3) with aromatic amines 9a-e and dibenzylamine (9f) in the presence of Mg(ClO4)2 afforded the corresponding 3-aminoazetidine derivatives 10a-f in 24-65% yields. N-Benzyl-3-bromoazetidine (13), which was obtained by the reaction of ABB (3) with benzyl bromide, gave 3-aliphatic amino-substituted azetidine derivatives 15a, b. Novel fluoroquinolones 7a-f, 11a-f, 16a, b and 25a-c were obtained by the introduction of these azetidine derivatives into the C7 position of a quinolone nucleus 6 and N1-heterocyclic quinolones 21a-c in 21-83% yields. Some of them exhibited a greater antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in comparison with that of clinically used fluoroquinolone, levofloxacin (LVFX).
- Ikee, Yoshifumi,Hashimoto, Kana,Kamino, Mai,Nakashima, Masaaki,Hayashi, Kazuhiko,Sano, Shigeki,Shiro, Motoo,Nagao, Yoshimitsu
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p. 346 - 356
(2008/12/22)
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- Inhibition of the signal transducer and activator of transcription-3 (STAT3) signaling pathway by 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid esters
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The JAK-STAT3 pathway regulates genes that are important in cell proliferation and thus is a promising target for cancer therapy. A high-throughput screening (HTS) campaign using an Apo-ONE Homogenous Caspase 3/7 assay in U266 cells identified 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 4 as a potential STAT3 pathway inhibitor. Optimization of this HTS hit led to the identification of the 7-cyano analogue 8, which inhibited STAT3-Y705 phosphorylation with an EC50 of 170 nM. Compound 8 also inhibited cytokine induced JAK activation but did not inhibit BCR-ABL activated STAT5 phosphorylation in K562 cells.
- Xu, Jun,Cole, Derek C.,Chang, Chao-Pei Betty,Ayyad, Ramzi,Asselin, Magda,Hao, Wenshan,Gibbons, James,Jelinsky, Scott A.,Saraf, Kathryn A.,Park, Kaapjoo
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experimental part
p. 4115 - 4121
(2009/05/27)
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- QUINOBENZOXAZINE ANALOGS AND METHODS OF USING THEREOF
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The present invention relates to quinobenzoxazines analogs having the general formula: (I)and pharmaceutically acceptable salts, esters and prodrugs thereof; wherein A, U, W, X, Z, B, L, R1, R3, R4 and R5 are substituents.The present invention also relates to methods for using such compounds.
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Page/Page column 90
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LEVOFLOXACIN HEMIHYDRATE
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The present invention relates to an improved process for preparation of Levofloxacin hemihydrate having single individual impurity not more than 0.1% and free from particulate matter and from the other enantiomer (R-form) which comprises dissolving levofloxacin technical grade in aqueous alkaline solution, treating the resulting solution with activated carbon at room temperature, removing the undissolved particulate matter filtration, bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid, removing the precipitated particulate matter by filtration, acidifying the resulting solution, treating the acidified solution with activated carbon at room temperature, filtering the undissolved particulate matter by filtration, neutralizing the acidic solution, filtering again to remove any particulate matter present and, extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual impurity is less than 0.1% and fee from particulate matter and from the other enantiomer (R-form).
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Page/Page column 16-17
(2008/06/13)
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- Novel benzothiazole compounds and methods of use thereof
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The present invention relates to methods of preparing compounds having formula (1), (2), (5), and ((6A)-(6D)) comprising contacting the corresponding ester, an amine with formula NHR1R2, and a Lewis acid having formula MLn, wherein L is a halogen atom or an organic radical, n is 3-5, and M is a group III elemental atom, a group IV elemental atom, As, Sb, V or Fe, wherein A, B, V, X, Z, W, R1, R2, R5, Z1, Z2, Z3, Z4, Z5, Z6, Z7, and Z8 are substituents. Z4, Z5, Z6, Z7, and Z8 are substituents.
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Page/Page column 5; 10-11
(2010/10/20)
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- ANTIMICROBIAL QUINOLONES, THEIR COMPOSITIONS AND USES
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Compounds of the following formula (I) are effective antimicrobial agents.
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- Novel heterocyclic antibacterial compounds
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The invention provides heterocyclic organic compounds that inhibit bacterial DNA polymerase IIIC and type II bacterial topoisomerase. The invention further provides compounds that are useful as intermediates in the synthesis of such heterocyclic organic compounds. Syntheses and uses of such heterocyclic organic molecules are also described.
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- Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 1
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In an attempt to search for clinically useful antitumor agents, we have discovered that a series of 1,7-disubstituted-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids possessed moderate cytotoxic activity. We investigated the structure-acti
- Tomita, Kyoji,Tsuzuki, Yasunori,Shibamori, Koh-ichiro,Tashima, Masanori,Kajikawa, Fumie,Sato, Yuji,Kashimoto, Shigeki,Chiba, Katsumi,Hino, Katsuhiko
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p. 5564 - 5575
(2007/10/03)
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- Quinobenzoxazine, antineoplastic agents
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Quinobenzoxazine, derivatives of the formula STR1 as well as the pharmaceutically acceptable salts, esters, amides and prodrugs thereof are disclosed, wherein R1 is hydrogen or a carboxy-protecting group, R2 and R3 are substitutents, A is oxygen, Z is a halogen or a nitrogen-containing group, X is hydrogen, halogen or alkyl, and W is hydrogen, alkyl, amino or halogen. The compounds have potent antineoplastic activity.
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- A safe, economical method for the preparation of β-oxo esters
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A high yield, economical method for preparation of β-oxo esters has been developed involving the reaction of acid chlorides with potassium ethyl malonate using a magnesium chloride-triethylamine base system in either acetonitrile or ethyl acetate solvents. The method is suitable for the preparation of high purity β-oxo esters in the laboratory and also in large scale production.
- Clay,Collom,Karrick,Wemple
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p. 290 - 292
(2007/10/02)
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- Pyridinyl-quinolone compounds, their preparation and use
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Fluorinated 1-cyclopropyl-7-(substituted-pyridinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids of the formula STR1 wherein R is hydrogen, R' and R" are hydrogen or fluoro, or other groups and Z is 3- or 4-pyridinyl substituted by alkyl groups or substituted alkyl groups, are superior antibacterial agents. They are prepared via a coupling reaction between the corresponding esters (R=alkyl) having a halo group in the 7-position and a substituted (trialkylstannyl)pyridine.
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- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents
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Novel naphthyridine-, quinoline- and benzoxazinecarboxylic acids as antibacterial agents are described as well as methods for their manufacture, formulation, and use in treating bacterial infections including the description of certain novel intermediates used in the manufacture of the antibacterial agents.
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- 7-cycloalkyl naphthyridines
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The present invention includes compounds represented by the formula: STR1 wherein R1 is a hydroxy, a C1 to C6 alkoxy, benzoxy, or an alkylcarbonyloxymethoxy group, or R3 together with R1 forms a group
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- Tricyclic-pyridinylquinoline compounds, their preparation and use
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Fluorinated 10-(2,6-dimethyl-4-pyridinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acids and -benzothiazine-6-carboxylic acids of the formula STR1 wherein R is hydrogen, R' is hydrogen or fluoro, R" is alkyl of 1-3 carbon atoms and X is O or S are superior antibacterial agents.
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- 1-Substituted 7--1-pyrrolidinyl>-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic Acids. New Quantitative Structure-Activity Relationships at N1 for the Quinolone Antibacterials
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A series of 18 1-substituted 7--1-pyrrolidinyl>-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (N1 analogues of CI-934) was synthesized and evaluated for antibacterial activity and DNA-gyrase inhibition.Correlations between the inhibition of DNA gyrase and antibacterial potency were established.A quantitative structure-activity relationship (QSAR) was derived by using the antibacterial potency of each of 11 strains of bacteria and the Gram-negative mean.The equations indicated that antibacterial potency was strongly dependent on STERIMOL length and width and the level of unsaturation of the N1 substituent.Some strains also showed a dependence on the presence of heteroatoms (O, N, S) in the N1 group.No significant correlations between gyrase inhibition and correlations of these parameters were found.These QSAR results are discussed in conjunction with the conformational analyses from molecular modeling studies.The substituent that most enhanced the activity of the quinolone in all regards was the cyclopropyl group.This analogue, 1-cyclopropyl-7--1-pyrrolidinyl>-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (PD 117558), demonstrated outstanding broad spectrum activity both in vitro and in vivo when compared to relevant standards.
- Domagala, John M.,Heifetz, Carl L.,Hutt, Marland P.,Mich, Thomas F.,Nichols, Jeffry B.,et al.
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p. 991 - 1001
(2007/10/02)
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- Process for tetrafluorobenzoic acid
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An improved process for the preparation of 2,3,4,5-tetrafluorobenzoic acid is described which involves decarboxylation of tetrafluorophthalic acid in the presence of a base catalyst. Also described is an improved method for preparing tetrafluorophthalic acid and, in turn, a one-pot process for tetrafluorobenzoic acid using the combination of the two improvements.
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- Antibacterial agents
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Novel quinoline-carboxylic acids as antibacterial agents are described as well as methods for their manufacture, formulation, and use in treating bacterial infections including the description of certain novel intermediates used in the manufacture of the antibacterial agents.
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- Cycloaracylation of Enamines, I. - Synthesis of 4-Quinolone-3-carboxylic Acids
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Starting with o-halobenzoyl chlorides 4 and open-chain secondary enamines 5, a new synthesis of 4-quinolone-3-carboxylic acids 12 is described.The reaction of 7-haloquinolone-3-carboxylic acids 12a-k with aliphatic amines 14 produces highly active antibacterial 7-aminoquinolone-3-carboxylic acids 15.The main product of the 1-cyclopropyl series, "ciprofloxacin" (15a), is being developed as a broad-spectrum chemotherapeutic agent.
- Grohe, Klaus,Heitzer, Helmut
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- Antibacterial 1,7-diamino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids
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Antibacterially effective 1,7-diamino-1,4-dihydro-4-oxo-3-(aza)quinolinecarboxylic acids of the formula STR1 in which A is nitrogen or C--R1, R1 is nitro or halogen, R2 and R3 each independently is C1
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- Synthesis and Structure-Activity Relationship of 1-Aryl-6,8-difluoroquinolone Antibacterial Agents
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A series of new arylfluoroquinolones has been prepared.These derivatives are characterized by having fluorine atoms at the 6- and 8-positions, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position.The in vitro antibacterial potency is greatest when the 1-substituent is 2,4-difluorophenyl and the 7-substituent is a 3-amino-1-pyrrolidinyl group. 1-(4-Fluorophenyl)-6,8-difluoro-7-piperazin-1-yl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (22) was found to possesss excellent in vitro potency and in vivo efficacy.
- Chu, Daniel T. W.,Fernandes, Prabhavathi B.,Maleczka, Robert E.,Nordeen, Carl W.,Pernet, Andre G.
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p. 504 - 509
(2007/10/02)
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- Antibacterial agents
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Novel naphthyridine-, quinoline- and benzoxazine-carboxylic acids as antibacterial agents are described as well as methods for their manufacture, formulation, and use in treating bacterial infections including the description of certain novel intermediates used in the manufacture of the antibacterial agents.
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- 1-cyclopropyl-6,7-dihalo-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and their esters, useful as intermediates for preparing the 7-amine substituted naphthyridines
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1-cyclopropyl-6,7-dihalo-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and their esters, which are useful as intermediates for the preparation of compounds which are useful as anti-bacterial agents.
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- 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinolinecarboxylic acid antibacterial agents
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Novel antibacterially active 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinolinecarboxylic acids of the formula STR1 in which R1 is hydrogen, methyl or ethyl, and R2 is hydrogen or fluorine, and pharmaceutically tolerable hydrates and salts thereof.
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- 7-(3-aryl-1-piperazinyl)- and 7-(3-cyclohexyl-1-piperazinyl)-3-quinolonecarboxylic acid antibacterials
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Novel 1-cyclopropyl-4-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid antibacterials of the formula STR1 in which R1 is hydrogen, alkyl with 1 to 4 carbon atoms and optionally substituted by hydroxyl, methoxy, amino, dimethylamino, halogen, cyano or alkoxycarbonyl having 1 or 2 carbon atoms in the alkyl moiety, or is oxoalkyl having up to 4 carbon atoms, phenacyl, or acyl having 1 to 4 carbon atoms, phenacyl, or acyl having 1 to 4 carbon atoms, R2 is phenyl or cyclohexyl optionally substituted up to three times by halogen, methyl, phenyl, cyano, hydroxyl, methoxy, benzyloxy, amino, methylamino, dimethylamino, piperidino or nitro, or is methylenedioxyphenyl, methylenedioxycyclohexyl, furyl, tetrahydrofuryl or thienyl, and X1 is hydrogen or fluorine, or pharmaceutically ultizable hydrates, acid addition salts, alkali metal salts or alkaline earth metal salts thereof.
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- 7-substituted amino-1-aryl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids and derivatives thereof as antibacterial agents
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Novel 1-aryl or heteroaryl-6,8-difluoro-1,4-dihydro-7-(3-aminomethyl)pyrrolidinyl- or 7-spiroamino-4-oxo-3-quinolinecarboxylic acids and acid derivatives thereof as antibacterial agents are described as well as methods for their manufacture, formulation a
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- Antibacterial agents
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Novel naphthyridine-, quinoline- and benzoxazine-carboxylic acids as antibacterial agents are described as well as methods for their manufacture, formulation, and use in treating bacterial infections including the description of certain novel intermediates used in the manufacture of the antibacterial agents.
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- Antibacterial agents III
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Novel 1-amino-naphthyridine- and quinoline-carboxylic acids as antibacterial agents are described as well as methods for their manufacture, formulation, and use in treating bacterial infections.
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