WO1991017988A1 - Nouvel agent antimicrobien a base de fluoroquinolone - Google Patents

Nouvel agent antimicrobien a base de fluoroquinolone Download PDF

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Publication number
WO1991017988A1
WO1991017988A1 PCT/JP1991/000597 JP9100597W WO9117988A1 WO 1991017988 A1 WO1991017988 A1 WO 1991017988A1 JP 9100597 W JP9100597 W JP 9100597W WO 9117988 A1 WO9117988 A1 WO 9117988A1
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WO
WIPO (PCT)
Prior art keywords
compound
present
acid
antibacterial activity
cyclopropyl
Prior art date
Application number
PCT/JP1991/000597
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English (en)
Japanese (ja)
Inventor
Hiroyuki Nagano
Yasuyuki Katoh
Shuzo Matsubara
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Publication of WO1991017988A1 publication Critical patent/WO1991017988A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel fluoroquinolone compound, specifically, 1-cyclopropyl 16-fluoro-1,4-dihydro 7- (3-methylamino-pipi-lysine-1-inole> __ 8-methoxy-14.
  • the compound of the present invention has a strong antibacterial activity and is useful as a medicine.
  • Fluoroquinolone antibacterial agents also called new quinolone agents, are synthetic antibacterial agents that are not only strong in antibacterial activity and excellent in bactericidal action, but also effective in most bacterial species from Gram-positive bacteria to Gram-negative bacteria. . In addition, it is extremely effective against resistant bacteria that exhibit resistance to so-called beta-lactam agents such as penicillin agents and cephalosporin agents.
  • the present inventors have studied to improve the above-mentioned deficiency of the fluoroquinolone antibacterial agent, and as a result, the formula (I) in which the 7-position of the quinolone ring is substituted with 3-methylaminopyrrolidine. It has been found that the compound shown by the formula (1) has strong antibacterial activity, and that some of the aforementioned side effects are also reduced.
  • the quinoline carboxylic acid derivative of the present invention is characterized in that it has a cyclopropyl group at position 1 and a 3-methylamino-1-pyrrolidyl group at position 7 and a methoxy group at position 8.
  • this compound is not a safe drug in the acute toxicity test in mice, showing hyperacute toxicity that causes tonic convulsions within several hours of administration and death. Also, it can be said that the antibacterial activity is considerably weak as compared with the compound of the present invention.
  • the compound represented by the formula (I) according to the present invention is obtained by solving the respective disadvantages of the compounds represented by the above formulas ( ⁇ ) and ⁇ DI>.
  • the compounds of the present invention may be prepared from existing quinolone antibacterial agents, for example, 1 oX acin (NFLX), Ofl oxacin (OFLX), Cip 1 of 1 oxacin (CPFX), Lomef 1 oxacin (LFLX) and the like. It has also been confirmed to show stronger antibacterial activity.
  • the quinolone compound represented by the formula (I) of the present invention is a novel compound.
  • the compound can be produced by reacting 3-methylaminopyrrolidine with 3_-carboxylic acid.
  • 3-methylaminopyrrolidine as the R-form or the S-form as the raw material used at this time, optical isomers can be produced separately.
  • salts are pharmaceutically usable, and include, for example, inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and oxalic acid, succinic acid, citric acid, fumaric acid, maleic acid, and the like.
  • inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and oxalic acid, succinic acid, citric acid, fumaric acid, maleic acid, and the like.
  • p Organic acids such as toluene sulfonic acid.
  • the compound of the present invention is a superior compound having strong antibacterial activity and having reduced side effects. This was confirmed by the following experimental examples.
  • the antimicrobial activity of the compounds of the present invention was compared with known antimicrobial agents.
  • MIC was measured according to the Japanese Society of Chemotherapy. After test bacteria is 3 7 ° C 1 Yorusei ⁇ culture, 0. And diluted with 0 5% gelatin added PBS, and a 1 0 6 and 1 0 8 cfu 1 (bacterial suspension standard strains only>. Each 5 ⁇ l each of the test bacterial solution was spot-inoculated on a microplater (MIT-type Sakuma Seisakusho) on an agar medium plate containing a two-fold dilution of the drug. The MIC was determined from the presence or absence.
  • BHI-broth In the culture of these strains, the usual gram-positive bacteria are Rainheart Infusionbroth (BHI-broth, Difco), and S. aga 1 actiae, S. pneumoniae, and S. pyogenes are horses. BHI-broth containing 10% defibrinated blood (Japan Biomaterials Center) was used. On the other hand, P. Aeruginosa ⁇ O. In 1% KN 0 3 added M ue I 1 er H intonbroth ( MH- broth), or other Gram-negative bacteria was carried out "preculture Te MH- broth.
  • Tables 1 and 2 show the in vitro antibacterial activity against the standard strain.
  • Table 3 shows the in vitro antibacterial activity of the optical isomers of the compound of the present invention.
  • Enterococcus faecal is CSJ1212 0 .2 3 .1 1 .6 0 .8 0 .4 3.1
  • Bac i 11 us subt ins ATCC6633 ⁇ 0.013 0 .1 0 .05 0 .025 0 • 025 0.1
  • Meal i 8 en es faecal is s IF013111 0.8 .6 1.6 .1 1.6 1.6 .1 1.6
  • Acinetobacler ca 1 coace ticus IF012552 0.2 .3 0.40 • 40.1 0.8.
  • Bac i 1 I us s u b t i I is ATCC6633 0.03 0 .2 0 • 1 0 • 05 0 .025 0.2
  • Enterobacter aerogenes IF013534 0., 1 0.1 0.1 0.025 0.1 0.I
  • ⁇ 1 ca 1 i genes f aeca 1 is IF013111 1.6 .12.5 1.6 .1 .6 3.1 3.1 .1
  • Proteus mi r a b i 1 is IF013300 0.025 0.05 0.025 Serra tia marcescens TO- 101 0.1 0.2 0.1
  • Horgane I 1 a morgan ⁇ i IF03848 0.025 0.05 0.025 Ac i netobacter IF012552 0.2 0.2 0.2 calcoaceticus
  • the compounds of the present invention show stronger activity than known quinolone antibacterial agents. Further, the antibacterial activity of the compound of the present invention is characterized in that it is particularly strong in Gram-positive bacteria such as Staphylococcus aureus.
  • the cytotoxicity and acute mouse toxicity of the compound of the present invention were tested in comparison with the compound of the formula (E) and the compound of the formula (DI).
  • DB AZ2 mouse-derived lymphocytic leukemia cells L 1 2 1 0 IX 1 0 5 1 1 1 are spiked into 10% fetal calf serum-supplemented RPM I — 1640 medium, and 5 ml of the cells are used for cell culture. Dispensed into bottles. Immediately add a fixed dilution of the test drug, and incubate for 2 days in a carbon dioxide incubator.
  • the number of surviving L1210 cells was measured under a microscope by the trypan blue uptake method.
  • the cultured cells were centrifuged, fixed in ethanol, and stained with Providediodide (PI), and the appearance of multinuclei and the effect on cell cycle were analyzed by FACS.
  • PI Providediodide
  • mice Six-week-old d d Y male mice were injected intraperitoneally with a fixed volume of each compound.
  • Table 4 shows the cytotoxicity of each compound and the results of the mouse acute test. In addition, cytotoxicity IC 5. The cell accumulation in the G 2 ZM phase and the appearance of multinucleated cells were also shown.
  • the compounds of the present invention have low cytotoxicity in view of IC S , G 2 ZM phase cell accumulation and appearance of multinucleated cells.
  • 1,4-dihydro-4 4-oxoquinoline-1-3-carboxylic acid-BF2-chelate 2.5 g, 3-methylaminopipalysine 1 g, triethylamine 1 g, methylene chloride 10 mi at room temperature overnight Stir.
  • the precipitated crystals are filtered, suspended in 1 N-sodium hydroxide aqueous solution: methanol (1: 1) 5 O ml, and heated and dissolved by steam heating.
  • the compound of the present invention has strong antibacterial activity and has low side effects, it can be said that it is a useful drug.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveau dérivé d'acide quinolone carboxylique de la formule (I) et son sel, caractérisé par le fait qu'il présente une plus forte activité microbienne et moins d'effets secondaires que les composés analogues connus.
PCT/JP1991/000597 1990-05-11 1991-05-01 Nouvel agent antimicrobien a base de fluoroquinolone WO1991017988A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP12000390 1990-05-11
JP2/120003 1990-05-11

Publications (1)

Publication Number Publication Date
WO1991017988A1 true WO1991017988A1 (fr) 1991-11-28

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/000597 WO1991017988A1 (fr) 1990-05-11 1991-05-01 Nouvel agent antimicrobien a base de fluoroquinolone

Country Status (2)

Country Link
AU (1) AU7770091A (fr)
WO (1) WO1991017988A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071357B2 (en) 2001-07-23 2006-07-04 Wisconsin Alumni Research Foundation Diazaphosphacycles
US7507820B2 (en) 2003-08-06 2009-03-24 Wisconsin Alumni Research Foundation Diazaphosphacycles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62252772A (ja) * 1986-01-21 1987-11-04 Kyorin Pharmaceut Co Ltd 選択毒性に優れた８−アルコキシキノロンカルボン酸およびその塩並びにその製造方法
JPS63198664A (ja) * 1986-03-31 1988-08-17 Sankyo Co Ltd キノロンカルボン酸誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62252772A (ja) * 1986-01-21 1987-11-04 Kyorin Pharmaceut Co Ltd 選択毒性に優れた８−アルコキシキノロンカルボン酸およびその塩並びにその製造方法
JPS63198664A (ja) * 1986-03-31 1988-08-17 Sankyo Co Ltd キノロンカルボン酸誘導体

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071357B2 (en) 2001-07-23 2006-07-04 Wisconsin Alumni Research Foundation Diazaphosphacycles
US7355072B2 (en) 2001-07-23 2008-04-08 Wisconsin Alumni Research Foundation Diazaphosphacycle transition metal complexes
US7355073B2 (en) 2001-07-23 2008-04-08 Wisconsin Alumni Research Foundation Synthesis of diazaphosphacycles
US7737272B2 (en) 2001-07-23 2010-06-15 Wisconsin Alumni Research Foundation Diazaphosphacycle transition metal complexes
US8058429B2 (en) 2001-07-23 2011-11-15 Wisconsin Alumni Research Foundation Diazaphosphacycle transition metal complexes
US7507820B2 (en) 2003-08-06 2009-03-24 Wisconsin Alumni Research Foundation Diazaphosphacycles

Also Published As

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AU7770091A (en) 1991-12-10

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