- Biophysical models as an approach to study passive absorption in drug development: 6-fluoroquinolones
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A preliminary study attempting to assess and explain the intestinal absorption of a series of antibacterial 7-piperazinyl-6-fluoroquinolones is presented. The synthesis, n-octanol partition coefficients, intrinsic rat gut in situ absorption rate constants, and in vitro antibacterial activity data found for these homologous compounds are described. A fluorimetric, reverse- phase HPLC method was performed for the quantification of the quinolones in absorption and partition samples. Equations based on two classic biophysical absorption models are given for predicting the intrinsic absorption features of the series according to the partition data or merely single structural parameters. In situ absorption rate constants were found to increase by a factor of 9.7-13.5 for moderately lipophilic derivatives relative to the simplest compound, while antibacterial activity decreased only by a factor of 4. In vivo absorption tests with two representative members of the series were carried out and the results showed a good accordance with those found in situ. This makes these compounds or related ones with similar partition features excellent candidates for further pharmacokinetic and pharmacological testing. The study can serve as an example of how to prevent potential absorption problems associated with the development of new drugs.
- Merino,Freixas,Del Val Bermejo,Garrigues,Moreno,Pla- Delfina
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- Synthesis and structure of C17H22FN3O32+ · CuCl42-
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A new compound C17H22FN3O32+ · CuCl42- [pefloxacindium tetrachlorocuprate(II)], C17H20FN3O3 - 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-3-quinoline carboxylic acid (pefloxacin, PefH) is synthesized and characterized by single crystal X-ray diffraction technique. The crystal structure of the compound contains one PefH32+ cation and one CuCl42- anion. The supramolecular architecture of the crystal is determined.
- Vasiliev,Golovnev
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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; 9-10
(2009/04/24)
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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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- 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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- Process for the preparation of quinolonecarboxylic acid esters
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A process for the preparation of quinolone-carboxylic acid esters of the formulae I and II STR1 in which A represents nitrogen or =C--R4, R4 represents hydrogen, fluorine, chlorine, nitro or methyl, B represents halogen, nitro, alkoxy, alkylsulphonyloxy or the radical STR2 and B additionally represents STR3 if R1 does not denote cyclopropyl, and R5 represents a branched or unbranched alkyl group which has 1 to 4 carbon atoms and which can optionally be substituted by a hydroxyl or methoxy group, R6 represents hydrogen, methyl or phenyl, R7 represents hydrogen or methyl, R8 represents dialkylamino having 1 or 2 carbon atoms in the alkyl group or dialkylaminomethyl having 1 or 2 carbon atoms in the alkyl group, or aminomethyl R1 represents hydrogen, optionally substituted alkyl having 1 to 3 carbon atoms, optionally substituted cycloalkyl, 2-fluoroethyl, vinyl, methoxy or 4-fluorophenyl, R2 represents optionally substituted alkyl having 1 to 6 carbon atoms and also cyclohexyl and benzyl, R3 represents hydrogen, methyl or ethyl, and Z represents oxygen, nitrogen which is substituted by methyl or phenyl, and =CH2, characterized in that quinolonecarboxylic acids of the formulae III and IV STR4 in which A, B, Z, R1 and R3 have the meanings indicated above, are reacted with chloroformic acid esters of the formula V in which R2 has the meaning indicated above.
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- Synthesis of Novel Quinolone-Chemotherapeutics. V. Methodical Investigations on the Synthesis of Quinolone Chemotherapeutics
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The synthesis of 6,7-dihalogen-N-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acids (3a,b) from 3,4-dihalogen-anilines is a three-step processes: (a) N-ethylation, (b) reaction with orthoformic ester and Meldrum's acid, (c) intramolecular cyclization.An increase of the total yields in comparison with known methods is mainly connected with the third step.Here the Meldrum's method allows reactions in solution at temperatures 100 deg C.With application of special Lewis acids the 6,7-dihalogen-substituted products are formed in relatively high yields (6,7-difluoro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (3a): 71percent; 7-chloro-6-fluoro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (3b): 60percent) without impurities of the corresponding 5,6-dihalogen substituted isomers.Anhydrides (5) of 4-oxo-1,4-dihydro-quinolone-3-carboxylic acids with dibromo- and difluoro-boric acid were synthesized and shown to facilitate the aromatic nucleophilic substitution.The kinetics of two reactions (5a -> 6 and 3b -> 7) were determined and relative reaction rates established.
- Jordis, Ulrich,Sauter, Fritz,Burkart, Michael,Henning, Hans-Georg,Gelbin, Anke
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p. 267 - 279
(2007/10/02)
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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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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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- 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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