Polymorphism and stability of norfloxacin, (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinil)-3-quinolinocarboxylic acid

Norfloxacin was studied by thermal methods (TG and DSC), X-ray powder diffraction, and by FT-IR, UV-VIS and NMR spectroscopy. The drug substance can be prepared in two different crystalline forms and in amorphous state, depending on the experimental conditions of preparation. DSC examinations were carried out at various heating rates and by cycling the samples in the temperature range 50°–250°C. The unstable crystalline form undergoes two irreversible solid-solid phase transitions at 176.5° and 197.6°C. The polymorph melts in the temperature range 218.5°–220.0°C.

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Zusammenfassung Norfloxacin wurde mittels thermischer Methoden (TG und DSC), weiterhin mittels der Debye-Scherrer-Methode und FTIR-, UV-VIS-und NMR-Spektroskopie untersucht. Je nach den experimentellen Bedingungen bei der Herstellung kann die Wirkstoffsubstanz in zwei verschiedenen kristallinen und in einer amorphen Form hergestellt werden. Die DSC-Untersuchungen wurden bei zahlreichen Aufheizgeschwindigkeiten und durch abwechselnden Temperaturwechsel zwischen Raum- und Schmelztemperatur durchgeführt. Die unstabile kristalline Form unterliegt zwei irreversiblen Feststoff-Feststoff-Umwandlungen bei 176.5° und bei 195.6°C. Das polymorphe Material schmilzt im Temperaturbereich 218.5°–220.0°C.

     

The preparation of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylate

Ethyl 7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid has been prepared by a route involving masking of the C_2,3 double bond through reduction, followed by regioselective deprotonation of the C₅ position and methylation and then regeneration of the C_2,3 double bond via selenation, oxidation, and syn-elimination.     

Absorption Spectra of the 4f Electron Transitions of the Nd, Ho and and Er Complexes with 1-Cyclopyropyl-6-fluoro-1,4-dihydro-7- (4-ethyl-1-piperazinyl)-4-oxo-3-quinoline Carboxylic Acid Hydrochloride in the Presence of TX-100

The tripositive rare earth metal ions show comparatively little tendencies to form complexes with a variety of normally powerful coordinating agents due to their peculiar electronic configurations. However, certain chelating groups, notably the β-diketones1,2 and 8-quinolinols3,4, are capable of overcoming this difficulty through the formation of inner complex compounds. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(4-ethyl-1-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrochloride (NN…     

Derivative Spectrophotometric Determination of Nd, Ho and Er in Rare Earth Mixtures with 1-Ethyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinoline carboxylic acid

 The second derivative spectrophotometric method has been developed as a procedure for the determination of neodymium, holmium and erbium in mixed rare earths. It was found that the 1-ethyl-6, 8-difluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4- dihydro-3-quinoline carboxylic acid forms stable complexes with neodymium, holmium and erbium ions in the pH 9.2–10.5 range. In the second derivative spectra the optimum analytical signals for neodymium, holmium and erbium are at 576.2 (+)−574.5 (−)nm, 444.2 (+) −447.8 (−)nm and 516.0 (+) −517.2(−)nm, respectively. Beer’s law is obeyed from 5.0×10⁻⁵ M to 2.5×10⁻⁴ M of neodymium, holmium and erbium. The quantification limits (10 Sb) were 1.2×10⁻⁵ M for Nd, 9.7×10⁻⁵ M for Ho and 3.0×10⁻⁶ M for Er. Received April 22, 1998. Revision March 8, 1999.     

Synthesis and reactions of 7-substituted 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids as an antibacterial agent

1-Cyclopropyl- and 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives having a sulfinyl or sulfonyl group at C-7 were synthesized from 2,6-dichloro-5-fluoronicotinic acid derivatives by the route involving the Dieckmann-type cyclization. The displacement reactions of these compounds with pyrrolidine and piperidine gave mainly the 7-(1-pyrrolidinyl)- and 7-(1-piperidinyl)-1,8-naphthyridine derivatives 24-27 , respectively. Enoxacin, a potent antibacterial agent, was also synthesized with the analogous route.     

Synthesis and antibacterial activity of new 5-substituted 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids

The 5-hydroxymethyl and the 5-formyl-1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared via a 5-trimethylsilyl group and were tested in vitro as potential antibacterials.     

1-环丙基-6-氟-7-(4-酰基-1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸的合成及其抗菌活性研究

以1-环丙基-6-氟-7-氯-1, 4-二氢-4-氧代喹啉-3-羧酸为原料经过两步反应合成出了16个新的1-环丙基-6-氟-7-(4-酰基-1-哌嗪基)-1, 4-二氢-4-氧代喹啉-3-羧酸, 并利用IR, ¹H NMR, ¹³C NMR, MS谱及元素分析对其结构进行了表征. 初步体外抗菌活性研究表明, 大部分目标化合物对大肠杆菌有一定的抑菌活性, MIC值在0.312～20 g/mL之间, 但活性低于对照物环丙沙星和氧氟沙星; 目标化合物对绿脓杆菌无抑菌活性, 最低抑菌浓度(MIC)均大于20 g/mL.     

Study of the absorption spectra of the 4f electron transitions of the praseodymium complex with ciprofloxacin and its analytical application

Ciprofloxacin (CPFX) is proposed as a reagent for the derivative spectrophotometric determination of praseodymium in mixed rare earths. The absorption spectra of 4f electron transitions of the praseodymium complex with CPFX was studied by normal and derivative spectrophotometry. The stoichiometry of the praseodymium-CPFX complex was calculated by the molar ratio and continuous variations methods. A ratio of Pr to CPFX of 1:3 was found. The absorption bands of the 4f electron transitions of the complex were enhanced markedly. Using the third derivative spectrum. Beer's law was obeyed up to 35 microg cm(-3) of praseodymium. The relative standard deviation is 0.62% for 14 microg cm(-3) of praseodymium. The detection and quantification limits were 0.17 and 0.56 microg cm(-3) of praseodymium, respectively. A method for the direct determination of praseodymium in mixtures of rare earths with good accuracy and selectivity is described.     

1-环丙基-6-氟-7-取代喹诺酮抗HIV活性的定量构效关系

用量子化学AM1法对一系列1-环丙基-6-氟-7-取代-1,4-二氢-4-氧-喹啉-3-羧酸的定量构效关系进行了研究,结果表明该类化合物在对HIV的抑制过程中是一很好的电子给予体,给电子的部位主要是7-位哌嗪基末端氮原子,并进一步提出从抗C^+和G^-菌活性差的喹诺酮中有望筛选出好的抗HIV化合物。     

Synthesis and Characterization of 8-Chloro-7-(4-(3-chloropropanoyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid

A new compound 8-chloro-7-(4-(3-chloropropanoyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(II, C_(20)H_(20)Cl_2FN_3O_4, Mr = 456.08) was synthesized and characterized by 1H NMR, 13 C NMR, HR MS and single-crystal X-ray diffraction. X-ray powder diffraction(XRPD), thermal stabilities, UV-Vis spectrum, photoluminescent properties and absolute quantum yield of compound II were also investigated. The structure demonstrates that the crystal belongs to the triclinic system, space group P1 with a = 7.7339(3), b = 10.2396(5), c = 15.9076(8) ?, α = 76.517(4), β = 77.609(4), γ = 80.320(4)°, V = 1187.22(9) ?3, Z = 2, Dc = 1.514 g/mm3, μ = 4.901 mm-1, F(000) = 556.0, R = 0.0534 and w R = 0.1447(I 2σ(I)). The result reveals that fluoroquionolone moiety in this structure stacks with π×××π interactions to generate an infinite 1D chain, which can stabilize the whole framework of compound II. Delightfully, preliminary antibacterial activity in vitro against 4 cell strains uncovers that compound II has almost equal strong activity in comparison with Clinafloxacin, but stronger than Norfloxacin. These outcomes provide important information for further exploration of the structure-activity relationship(SAR) of compound II derivatives or analogs.     

A regiospecific synthesis of 1-methylamino-6-fluoro-7-(4-methylpiperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

An efficient and regiospecific synthesis of 1-methylamino-6-fluoro-7-(4-methylpiperizin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ( 3 ) via an intramolecular nucleophilic displacement cyclization reaction is reported.     

The synthesis of a series of 7-amino-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acids as potential antibacterial agents

A series of 7-amino-1-cyclopropyl-1,4-dihydro-8-fluoro-4-oxo-1,6-naphthyridine-3-carboxylic acids has been prepared and evaluated for antibacterial activity. These compounds were prepared by the displacement of the chloro substituent from 7-chloro-1-cyclopropyl-1,4-dihydro-8-fluoro-4-oxo-1,6-naphthyridine-3-carboxylic acid employing the requisite nitrogen nucleophile to produce the title compounds. The naphthyridine acid was synthesized in ten steps from ethyl 2,4-dihydroxy-3-nitro-5-pyridinecarboxylate. The key step in the sequence was a Schiemann reaction carried out using the hexafluorophosphate salt of the diazonium ion derived from ethyl 3-amino-2,4-dichloro-5-pyridinecarboxylate.     

1－环丙基－5，7，8取代－6－氟－1，4－二氢－4－氧－3－喹啉羧酸定量构效关系的比较分子力场分析研究

利用３Ｄ－ＱＳＡＲ中的比较分子力场分析法（ＣｏＭＦＡ）研究了标题化合物的定量构效关系。通过不同探针与空间网格点间隙的对比研究，发现以　、空间网格点间隙２０ｎｍ结果为最优。从　值来看，ＣｏＭＦＡ计算得到的模型有很高的预测性。依据ＣｏＭＦＡ系数图设计一些新化合物并预测了它们的活性，结果表明：对抑制革兰氏阳性菌有数种化合物的活性比迄今合成的化合物要高。     

Synthesis,structure elucidation and chemotherapeutic activity of 6-substituted 1-ethyl-1,4-dihydro-7-[(1-imidazolyl)phenylmethyl]- 4-oxo-3-quinolinecarboxylic acids

The synthesis, structure elucidation and chemotherapeutic activity of novel 3-quinolinecarboxylic acid derivatives are reported. These derivatives are characterized by a group (1-imidazolyl)phenylmethyl attached to the 7-position and chloro 10a , fluoro 10b or methoxy 10c appended to the 6-position.     

A new synthetic route to 7-halo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,an intermediate for the synthesis of quinolone antibacterial agents

Starting from m-fluorotoluene, 7-chloro-6-fluoro- and 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxoquino-line-3-carboxylic acids, 3 and 16 were synthesized. Compounds 3 and 16 are useful intermediates for the synthesis of a class of quinolone antibacterial agents. The synthetic route involves two processes; i) construction of the quinoline ring by an intramolecular cyclization accompanied by the elimination of a nitro group and ii) introduction of fluorine atom by replacement of a nitro group with potassium fluoride. 7-(3-Amino-1-pyrroli-dinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (18) was prepared from 3 or 16. The antibacterial activity of 18 compares favorably with that of ciprofloxacin (2) .     

New 7-substituted quinolone antibacterial agents. The synthesis of 1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl and 4-thiazolyl)-3-quinolinecarboxylic acids

A series of 1-ethyl-1,4-dihydro-4-oxo-7-(4-thiazolyl)-3-quinolinecarboxylic acids and 1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl)-3-quinolinecarboxylic acids were prepared. Also prepared was 10-[2-(aminomethyl)-4-thiazolyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. Analogs with basic amine substituents on the thiazole moiety were found to have antibacterial activity.     

Determination of 8[(3S)-3-amino-1-pyrrolidinyl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride and related substances by high performance liquid chromatography

Summary The purity of the investigational antibacterial Abbott-086719.1 (I) which is 8[(3S)-3-amino-1-pyrrolidinyl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride is determined using gradient elution HPLC. The chromatographic separation was optimized and the chromatographic parameters critical to separation are discussed in detail. Most acceptable separations were achieved using an Alltima C18 column (5 μm) measuring 4.6 mm I.D. × 15 cm with 0.01M–0.03M citrate eluents which were modified with acetonitrile or with mixtures of acetonitrile and methanol. Related substances in I were determinable to 0.05 %. Repeatability (RSD values) for determining related substances at levels of 0.50 to 0.06 % ranged from ±1.9 to ±10 %. Determinations of I in 5 % dextrose in water and in hydroxypropyl methylcellulose were made using the same column and a simple isocratic system. The determination of I was stability indicating with precision (RSD values) of ±0.5 % to ±2.0 % and good agreement with theory for formulations containing I at 1.0 to 95 mg/mL concentrations. Recoveries of I from the vehicles were quantitative and linearity of the detector response of I was demonstrated to at least 0.10 mg/mL.