- Studies on Prodrugs. 10. Possible Mechanism of N-Dealkylation of N-Masked Norfloxacins Having Several Active Methylene Groups
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As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (1a-f) and studied the cleavage mechanism of the C-N bond of N-masked NFLXs utilizing the following experiments: (1) the oxidation of N-masked NFLXs (1a-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 deg C; (2) the liberation of NFLX from N-masked NFLXs after oral administration in mice.It was found that the chemical oxidative dealkylation of N-masked NFLXs proceeded when anion-stabilizing groups (e.g., CN, COR, COOR) are present on the α carbon of the nitrogen atom.In in vivo experiments, N-masked NFLXs having acidic hydrogens on the α carbon to the nitrogen atom also liberated NFLX (2) after oral administration.
- Kondo, Hirosato,Sakamoto, Fumio,Inoue, Yoshimasa,Tsukamoto, Goro
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Read Online
- A norfloxacin, ciprofloxacin and enrofloxacin synthetic method
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The present invention provides a norfloxacin, ciprofloxacin and enrofloxacin preparation method, which comprises the carboxylic acid and piperazine in the solvent under the catalytic action of the catalyst in the reaction step, the catalyst is AlBr3 , FeBr3 , ZnBr2 , CuBr2 Or SnBr4 , It has high yield, low cost and the advantage of energy saving and emission reduction.
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Paragraph 0006; 0016-0027; 0040; 0041
(2019/07/10)
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- ANTIBIOTIC RESISTANCE BREAKERS
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The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of RA or R1 comprises Ar1, wherein Ar1 is an antibiotic resistance breaker moiety which comprises an optionally substituted C6-10 aryl, C7-13 aralkyl, C5-10 heteroaryl, C6-13 heteroaralkyl, C5-10 heterocyclyl, C6-13 heterocyclalkyl, C3-10 carbocyclyl, C4-13 carbocyclalkyl, -C(=NR')-NR'R'' or –CH2- CH=CH2 group; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.
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Page/Page column 100
(2019/01/05)
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- Developing ciprofloxacin analogues against plant DNA gyrase: A novel herbicide mode of action
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Ciprofloxacin has been shown to exhibit potent herbicidal activity through action against plant DNA gyrase, presenting a novel mode of action. Analogues of ciprofloxacin have been prepared with increased herbicidal activity and diminished antibacterial activity, compared to ciprofloxacin, as demonstrated using model systems.
- Wallace, Michael D.,Waraich, Nidda F.,Debowski, Aleksandra W.,Corral, Maxime G.,Maxwell, Anthony,Mylne, Joshua S.,Stubbs, Keith A.
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supporting information
p. 1869 - 1872
(2018/02/23)
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- A high-efficient environment friendly preparation method of quinolone ciprofloxacin drug (by machine translation)
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The invention discloses a high-efficient environmental protection quinolone ciprofloxacin preparation method of drug, is fluorobenzene formyl ethyl acetate, the original carboxylic acid triethyl amine compound as a raw material, the three raw materials into the reactor at a temperature of 90 - 150 °C reaction under 20 - 30 H prepare get quinolone basic parent ring, then adding piperazine, to aminocapronitrile as the solvent, the temperature of the reflux reaction 20 - 28 of H, continue adding 50% sodium hydroxide solution is carboxyl ester hydrolysis to obtain the target compound. The invention is simple in raw material market can buy price is cheap; multi-step reaction link together a pan operation intermediate does not need to separate operation, the reaction process is efficient labor-saving; the whole process of transformation efficiency is high, the final product does not need chromatographic treatment is simple washing can get the pure compound; safety in the course of reaction, after-treatment does not need the eluent separation only needs to ethyl acetate, petroleum ether and methanol washing and can be recycled can be pollution prevention; green reaction process, only ethanol by-product, the atom economy is high; quinolone compounds and high utility value, is important trovafloxacins antibacterial drug composition structure. (by machine translation)
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Paragraph 0026; 0029; 0030
(2019/01/04)
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- Chemical synthesis method for norfloxacin
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The invention discloses a chemical synthesis method for norfloxacin. The chemical synthesis method comprises the following steps: (1) synthesis of a compound ethyl quinolinate: 3-ethylamino-2-(2,4-dichloro-5-fluorobenzoyl) ethyl acrylate is dissolved in DMF, potassium carbonate is added, the mixture is heated to 50-80 DEG C, reacts and stands overnight, a product is cooled and poured into cold water, produced solids are filtered, solids are washed with a large amount of water, and the product ethyl quinolinate is obtained; (2) synthesis of a compound quinolinic acid: ethyl quinolinate is dissolved in methanol, hydrochloric acid is added in a ratio being 1:1, reflux is performed for 2 h, white solids are precipitated and filtered, a filter product is washed with water and dried in a vacuum oven for 2 h, and the product quinolinic acid is obtained. The design is reasonable, and one novel norfloxacin synthesis method is selected and has good market application value.
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Paragraph 0017
(2018/04/01)
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- A norfloxacin, ciprofloxacin and enrofloxacin preparation method
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The invention discloses a preparation method of norfloxacin, ciprofloxacin and enrofloxacin. The preparation method comprises the following steps: directly reacting 1-ethyl-6-fluoro-7-chlo-4-oxo-1,4-dihydro-quinoline-3-carboxylate or 1-cyclopropyl-6-fluoro-7-chlo-4-oxo-1,4-dihydro-quinoline-3-carboxylate with piperazine (or N-ethyl piperazine); and then, performing after-treatment to prepare a corresponding target product norfloxacin (or ciprofloxacin or enrofloxacin). The preparation method disclosed by the invention is short in reaction step, convenient to operate, less investment and beneficial to industrial production; consumption of piperazine (or N-ethyl piperazine) can be reduced by more than half; under the catalytic action, the reaction temperature is low, the byproducts are less, the yield is high and the cost is low; heavy use of inorganic acid and inorganic alkaline is avoided, so that the pollution is reduced.
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Paragraph 0113-0114
(2017/04/25)
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- Diglyceride prodrug strategy for enhancing the bioavailability of norfloxacin
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Prodrug approach using diglyceride as a promoiety is a promising strategy to improve bioavailability of poorly absorbed drugs and the same was explored in the present work to improve oral bioavailability of norfloxacin; a second generation fluoroquinolone antibacterial. The prodrug was synthesized by standard procedures using dipalmitine as a carrier and the structure was confirmed by spectral analysis. Higher Log P indicated improved lipophilicity. The ester linkage between norfloxacin and dipalmitine would be susceptible to hydrolysis by lipases to release the parent drug and carrier in the body. In vivo kinetic studies in rats indicated 53% release of norfloxacin in plasma at the end of 8 h. The prodrug exhibited improved pharmacological profile than the parent compound at equimolar dose that indirectly indicated improved bioavailability.
- Dhaneshwar, Suneela,Tewari, Kunal,Joshi, Sonali,Godbole, Dhanashree,Ghosh, Pinaki
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experimental part
p. 307 - 313
(2012/01/03)
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- Direct transformation of Baylis-Hillman acetates into N-substituted quinolones through an SN2′→ SNAr→(Δ3,4-Δ2,3 shift)→oxidation sequence
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When subjected to tandem SN2-SNAr cyclization in the presence of alkyl or aralkyl amines, Baylis-Hillman acetates gave the corresponding 1,2-dihydroquinolines, which on simple exposure to light and oxygen afforded the corresponding 4- and 2-quinolones through sensitized oxidation or a 3,4-2,3 shift oxidation cascade. The mechanism of the oxidation step, the stabilities of the 1,2- and 1,4-dihydroquinolines in solution and in the solid state, and the synthetic elaboration of the key intermediates to known therapeutic agents are discussed. Georg Thieme Verlag Stuttgart · New York.
- Napoleon, John Victor,Kannoth Manheri, Muraleedharan
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supporting information; experimental part
p. 3379 - 3388
(2011/11/30)
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- Mechanism and synthesis of pharmacologically active quinolones from Morita-Baylis-Hillman adducts
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The synthesis of quinolones from Morita-Baylis-Hillman (MBH) adducts is reported. The quinolone skeleton is formed via a TFA-mediated cyclization of the MBH adduct, and a mechanism study using ESI(+)-MS(/MS) has indicated the role played by TFA in this key reaction step. The total syntheses of Norfloxacin and a benzyl quinolone carboxylic acid (BQCA) derivative are described. Norfloxacin is a fluoroquinolonic antibacterial drug whereas BQCA is M1 receptor positive allosteric modulator and seem to provide access to new potential drugs for Alzheimer disease, pain, and sleep disorders. The syntheses of these two important quinolones exemplify the versatility and potentiality of the approach.
- Amarante, Giovanni W.,Benassi, Mario,Pascoal, Robert N.,Eberlin, Marcos N.,Coelho, Fernando
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experimental part
p. 4370 - 4376
(2010/07/05)
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- NOVEL METHOD OF SYNTHESIS OF FLUOROQUINOLONES
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The invention relates to a method of preparation of fluoroquinolones of formula (I) from compounds of formula (II): in which R1, R2, R3, R4, R5, R6, R7, and X are as defined in Claim 1.
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Page/Page column 6-7
(2009/04/24)
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- Regioselective synthesis of quinolone antibacterials via borate complex of quinolone carboxylic acid
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1-substituted 7-chloro-6-fluoro-4-oxo-1,2-dihydroquinoline-3-carboxylic acids were converted to borate complexes. These compounds were treated with piperazine in presence of triethylamine to afford ciprofloxacin and norfloxacin in high yields.
- Heravi, Majid M.,Jaddi, Zeinab S.,Oskooie, Hossein A.,Khaleghi, Shahnaz,Ghassemzadeh, Mitra
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p. 578 - 579
(2007/10/03)
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- Convenient one pot synthesis of some fluoroquinolones in aqueous media
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A one pot synthetic strategy for the preparation of fluoroquinolones from 1 is introduced. Product 3 was condensed with piperazine in an aqueous media to produce pharmaceutical grade ciprofloxacin in 86% yield. The method was extended to the synthesis of some other fluoroquinolones with pharmaceutical grade quality.
- Abaee, M. Saeed,Sharifi, Ruhollah,Borhani, Shahin,Heravi, Majid M.,Motahari, Hossein
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p. 415 - 418
(2007/10/03)
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- Methods for the manufacture of quinolone carboxylic acids derivatives and intermediates thereof
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Novel process for the preparation of quinolone carboxylic acid derivatives of general formula I, and intermediates thereof as illustrated in Scheme 1 wherein the key intermediate is a compound of formula IX. STR1
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- Regioselective nucleophilic substitution of halogen derivatives of 1-substituted 4-oxo-1,4-dihydroquinoline-3-carboxylic acids
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The rate of the nucleophilic displacement of the fluoro atom of 7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate could be enhanced either by the introduction of further fluoro atom(s) into position(s) 6 and/or 8, or by the formation of a boron chelate (e.g. 3). The regioselectivity of the nucleophilic substitution of the chloro atom in 1-substituted 6-fluoro-7-chloro-4-oxo-1,4dihydroquinoline-3-carboxylic acids could also be enhanced by the formation of a boron chelate (e.g. 7).
- Hermecz, Istvan,Vasvari-Debreczy, Lelle,Podanyi, Benjamin,Kereszturi, Geza,Balogh, Maria,Horvath, Agnes,Varkonyi, Peter
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p. 1111 - 1116
(2007/10/03)
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- Quinolone antibiotics: Study of reactivity and impurity profile of piperazine with chloro-fluoro-quinolone carboxylic acid in aqueous medium
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The reaction of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,2-dihydroquinoline-3-carboxyli c acid with piperazine in water was studied. The product ciprofloxacin was isolated and the impurity formed in the reaction was isolated and characterized as 1-cyclopropyl-7-chloro-6-piperazinyl-4-oxo-1,2-dihydroquinoline-3-carb oxylic acid. Similarly norfloxacin was also synthesised.
- Kalkote,Sathe,Kharul,Chavan,Ravindranathan
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p. 6785 - 6786
(2007/10/03)
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- Process for preparing piperazinyl quinolone derivatives
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A novel process for preparing piperazinyl quinolone derivatives of the formula (I) is disclosed. The process comprises reacting dihaloquinolones with piperazine derivatives and tetraalkyl ammonium halides in the presence of a polar solvent such as acetonitrile, dimethylformamide, pyridine, sulfolane and dimethyl sulfoxide. STR1
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- Process for the preparation of quinoline carboxylic acids
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The invention relates to a new process for the preparation of compounds of the Formula I STR1 (wherein R stands for hydrogen or methyl) and pharmaceutically acceptable salts thereof which comprises reacting a compound of the Formula V STR2 (wherein R1 and R2 stand for an aliphatic acyloxy group comprising 2-6 carbon atoms and optionally substituted by halogen; or for an aromatic acyloxy group comprising 7-11 carbon atoms) with an amine of the Formula VI STR3 (wherein R has the same meaning as stated above) or a salt thereof and subjecting the compound of the Formula VII STR4 thus obtained (wherein R, R1 and R2 are as stated above) to hydrolysis after or without isolation and if desired converting the compound of the Formula I thus obtained into a salt thereof or setting free the same from its salt. The compounds of the Formula I are known antibacterial agents. The advantage of the process of the present invention is that it makes the desired compounds of the Formula I available in a simple manner, with high yields and in a short reaction time.
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- Process for the preparation of quinoline-carboxylic acid derivatives
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The invention relates to a new and simple process for the preparation of quinoline-carboxylic acid derivatives of the general formula (I) STR1 as well as hydrates and therapeutically acceptable salts thereof. In the formula the meaning of the substituents is as follows: R is hydrogen atom or a formyl group, R1 is a hydrogen atom or a straight or branched chain alkyl group having 1 to 4 carbon atoms, which may be substituted by a hydroxyl group, a halogen atom or an amino group; or a CH3 --NH-group, R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. According to the invention the compound of the general formula (II) STR2 or an acid addition salt thereof is reacted with piperazine in dimethylformamide and--if desired--the compound of the general formula (III) STR3 thus obtained is subjected to an acidic or alkaline treatment, or is reacted advantageously with hydrazine or preferably with hydrazine-hydrate.
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- Substituted quinoline carboxylic acid derivatives
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This invention relates to new compounds of value as antibacterial agents. More particularly, it relates to quinoline carboxylic acid derivatives, the hydrates and the acid or alkali addition salts thereof.
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- Process for the preparation of quinoline carboxylic acid derivatives
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Process for the preparation of useful antimicorbial agents, 1-substituted-6-fluoro-7-(1-piperazinyl or 4-substituted-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acids having the chemical structure [IV], STR1 wherein R1 is ethyl or vinyl group, and R4 is STR2 (R3 is hydrogen atom or lower alkyl group).
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- α-Keto aldehydes as enhancing agents of gastro-intestinal drug absorption
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A method and drug form enhancing the absorption of a rectally or orally administered drug from the rectal compartment into the blood stream of a warm blooded animal. The method includes the steps of preparing a drug form capable of being rectally and orally administered. The drug form comprises a therapeutically effective unit dosage amount of a selected drug of the type which is capable of being absorbed into the blood stream from the gastrointestinal area and an α-keto aldehyde or salts thereof being present in the drug form in a sufficient amount to be effective in enhancing the drug absorption rate, when administering the drug form to warm blooded animals.
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- Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubstituted 1-Alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids
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Previous quantitative and qualitative structure-activity studies in antibacterial monosubstituted 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids prompted us to synthesize the 6,7,8-polysubstituted compounds.In this paper, the preparation and antibacterial activity of the 6,7- and 7,8-disubstituted compounds and their derivatives are described.Among these compounds, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (34) possessed many significant activities and was more active than oxolinic acid (84) against Gram-positive andGram-negative bacteria.Structure activity relationships are discussed.
- Koga, Hiroshi,Itoh, Akira,Murayama, Satoshi,Suzue, Seigo,Irikura, Tsutomu
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p. 1358 - 1363
(2007/10/02)
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- Piperazinyl derivatives of quinoline carboxylic acids
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This invention relates to new compounds of value as antibacterial agent. More particularly, it relates to piperazinyl derivatives of quinoline carboxylic acids, the hydrates, and the acid addition salts thereof.
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