WO2004078771A1 - 2-フルオロ-6-o-置換ケトライド誘導体 - Google Patents
2-フルオロ-6-o-置換ケトライド誘導体 Download PDFInfo
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- WO2004078771A1 WO2004078771A1 PCT/JP2004/002829 JP2004002829W WO2004078771A1 WO 2004078771 A1 WO2004078771 A1 WO 2004078771A1 JP 2004002829 W JP2004002829 W JP 2004002829W WO 2004078771 A1 WO2004078771 A1 WO 2004078771A1
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- WIPO (PCT)
- Prior art keywords
- acid
- compound
- fluoro
- test
- erythromycin
- Prior art date
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- 239000003835 ketolide antibiotic agent Substances 0.000 title abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 35
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 abstract description 23
- 229960003276 erythromycin Drugs 0.000 abstract description 12
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- 238000000034 method Methods 0.000 description 4
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- 229960004099 azithromycin Drugs 0.000 description 2
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- 230000003115 biocidal effect Effects 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 239000006161 blood agar Substances 0.000 description 2
- 229960002626 clarithromycin Drugs 0.000 description 2
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- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
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- RVHOBHMAPRVOLO-UHFFFAOYSA-N 2-ethylbutanedioic acid Chemical compound CCC(C(O)=O)CC(O)=O RVHOBHMAPRVOLO-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
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- NGJCUJZBSJGQPY-UHFFFAOYSA-N 3-pyrimidin-2-yl-1,2-oxazole Chemical compound O1C=CC(C=2N=CC=CN=2)=N1 NGJCUJZBSJGQPY-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
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- 239000005711 Benzoic acid Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
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- 241000204031 Mycoplasma Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
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- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to novel derivatives of the antibiotic erythromycin. Background art
- Erythromycin A is an antibiotic that is widely used as a treatment for infections caused by gram-positive bacteria, mycoplasma, and others.
- erythromycin has the disadvantage that its pharmacokinetics are unstable because it is decomposed by gastric acid. Therefore, derivatives with increased acid stability have been studied, and as a result, macrolides with stable pharmacokinetics, such as clarithromycin, azithromycin, and oral xithromycin, have been developed.
- These macrolides, which are used for treatment of exogenous respiratory tract infections need to have strong antibacterial activity against Haemophilus influenzae and pneumococci, which have high frequency of clinical isolation. Furthermore, it is important that macrolide-resistant pneumococci are effectively isolated from middle pneumonia because they are frequently isolated from pneumonia.
- HMR3647 Teithromycin, EP680967
- HMR3647 Teithromycin, EP680967
- et al. -773 Seslomycin, No. 809978
- W002 / 32919 2-fluoroketolide attractant
- 14-membered macrolide antibiotics are known to cause drug interactions. Therefore, it is of course very important that the drug is a macrolide that does not easily cause drug interaction, as well as exerts a sufficient therapeutic effect in clinical practice.
- the drug interaction caused by the 14-membered macrolide antibiotic is caused by the fact that the metabolic species (Cyp3A4) metabolizes the 14-membered macrolide and the metabolized macrolide binds irreversibly to Cyp3A4. Has been triggered. Therefore, it is important to be stable against human Cyp3A4. Disclosure of the invention
- An object of the present invention has excellent antibacterial activity against the Infuruenza bacteria and Erisu port hygromycin highly resistant pneumococci is to provide a new ketolide derivative conductor is stable to human Cy P 3A4 metabolism.
- the present inventors have found that a ketolide derivative in which a propargyl group having a specific condensed heterocyclic group at position 6 has been introduced, and further a fluorine atom has been introduced at position 2, has excellent antibacterial activity. And found to be stable to human Cyp3A4, and completed the present invention.
- the present invention provides a formula
- the compound of the present invention was prepared by the method described in W09921871 and US Pat. No. 6,124,269.
- 5-Polydesosaminyl-3,11 didoxy_2-fluoro-11-amino-3-year-old kiso 6-0-propargylerythronolide
- a 1 1,1 2—Cyclic carbamate is obtained by mixing 5-reaction 3- (2-pyrimidyl) isoxazole, bis (triphenylphosphine) palladium chloride ( ⁇ ), acetonitrile and triethylamine and reacting. be able to.
- a pharmaceutically acceptable salt means a salt used in chemotherapy and prevention of bacterial infection.
- They include, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, cunic acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, dalconic acid, dalcoheptonic acid, benzoic acid, methanesulphonic acid , Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, P-Toluenesulfonic acid, lauryl sulfate, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcystine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid,
- the compound of the present invention is orally or parenterally administered, and is 50 to 1000 mg for treating an adult, and is administered in 2 to 3 times a day. This dosage may be adjusted as appropriate according to the patient's age, weight and condition.
- excipients for oral administration, excipients, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, coloring agents, flavoring agents, etc. are mixed, and powders, granules, capsules
- parenteral administration it is administered as preparations such as injections and infusions.
- a usual formulation method can be used.
- Example 1 Example 1
- test compound was a compound described in Example 23 of WO02 / 32919 (5-O-desosaminyl 3,11-dideoxy-2-fluoro-11-amino-6-0_ [3 — [3- (5-Pyrimidyl) isoxazolyl-5-yl] -1-2-propier] -3-oxoerythronolide A 1 1,12-cyclic power and erythromycin azithromycin as comparative compound 2
- MIC minimum inhibitory concentration
- NCCLS Guidelines for Clinical Laboratory Standards
- MHB Mueller-Hint on broth
- a bacterial solution for inoculation 5 ml of these bacterial solutions were inoculated into a susceptibility test microplate at a concentration of about 5 ⁇ 10 5 CFU / ml in MHB and Haemophilus test medium in which divalent ion concentration was adjusted with the addition of 3% horse lysate. After culturing them at 35 ° C under normal environment for 20 hours, the MIC of each compound was measured.
- the results are shown in Table 1.
- the compound of Example 1 showed strong antibacterial activity against erythromycin-resistant streptococci as the comparative compound.
- Influenza bacteria showed antibacterial activity which was 1/2 that of comparative compound 2 and twice that of comparative compound 1.
- the compounds of the present invention have been shown to be useful against both erythromycin resistant pneumococci and influenza bacteria.
- Test Example 2 Therapeutic effect on pneumonia caused by Haemophilus influenzae
- Haemophilus influenzae pneumonia was evaluated in a mouse pneumonia model caused by Haemophilus influenzae.
- the test compound and Influenza bacteria are the same as in Test Example 1.
- Haemophilus influenzae was cultured overnight at 37 ° C. in Brain Heart Infusion Broth supplemented with 5% horse defibrinated blood, and this was used as an inoculum (about 5.0 ⁇ 10 8 CFU / ml).
- Infection was induced by intraperitoneally inoculating 0.05 ml of the inoculated bacterial solution into anesthetized ICR male mice weighing 18-22 g.
- each test compound was orally administered at 100 mg / kg using an oral probe (5 animals per group). Each test compound was suspended and diluted in a 5% gum arabic solution before use. The control group received only a 5% gum arabic solution. Twenty-four hours after the final administration, the mice were sacrificed, the lungs were removed, and homogenized by adding 2 ml of sterile physiological saline. A 10-fold dilution series was prepared with sterile physiological saline, applied to a chocolate agar medium, and cultured overnight. The number of viable bacteria was calculated from the number of colonies formed. The detection limit is 2.30 l og 10 CFU / ml. Table 2 shows the results.
- the compound of Example 1 of the present invention In the test compound 100 mg / kg administration group, the compound of Example 1 of the present invention, Comparative Compound 1 and Comparative Compound 2 all showed stronger antibacterial activity than the control. Therefore, the compound of the present invention was shown to be useful for treating pneumonia caused by Haemophilus influenzae, like Comparative Compound 1 and Comparative Compound 2. LI Lung bacteria count (loglO CFU / lung)
- the erythromycin-resistant pneumococci used in Test Example 1 were cultured at 37 ° C for several hours in Todd-Hewi 11 Broth supplemented with 30% horse serum, diluted 300-fold with the same medium, and the inoculated bacterial solution (about 5 ⁇ 10 5 CFU / ml). Infection was induced by intranasally inoculating 0.05 ml of the inoculated bacterial solution into anesthetized male CBA / J mice weighing 18-22 g. At 42 and 68 hours after the inoculation of the bacterial solution, 100 mg / kg of each test compound was orally administered using an oral probe (5 mice per group). Each test compound was suspended in a 5% gum arabic solution before use and diluted.
- the control group received only a 5% gum arabic solution. Twenty-four hours after the final administration, the mice were sacrificed, the lungs were removed, and homogenized by adding 2 ml of sterile physiological saline. A 10-fold dilution series was prepared with sterile physiological saline, applied to sheep blood agar medium, cultured overnight at 37 ° C in the presence of 5% carbon dioxide, and the number of viable bacteria was calculated from the number of colonies formed. The detection limit is 1.30 1 ⁇ CFU / lung. Table 3 shows the results.
- Example 1 of the present invention showed as excellent a therapeutic effect as the comparative compound in the 100 mg / kg administration group.
- Pulmonary bacteria count (log 1D CFU / lung)
- Test example 4 Human Cyp inhibition test
- test compound is the same as in Test Example 3. Clarithromycin was used as a control. The results are shown in Table 4.
- the compound of the present invention has excellent antibacterial activity against erythromycin-resistant pneumococci and influenzae bacteria, and also has excellent therapeutic effects using infected animals. Because they are stable against metabolic enzymes, the compounds of the present invention are extremely useful as therapeutic agents for erythromycin-resistant pneumococci and influenzae infections in humans.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2007148772A1 (ja) * | 2006-06-23 | 2007-12-27 | Shionogi & Co., Ltd. | マクロライド系抗生物質の糖類被覆製剤 |
EP3290427A1 (en) | 2005-08-24 | 2018-03-07 | Melinta Therapeutics, Inc. | Triazole compounds and methods of making and using the same |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2001500855A (ja) * | 1996-09-04 | 2001-01-23 | アボツト・ラボラトリーズ | 抗菌活性を有する6―o―置換ケトリド |
JP2001521039A (ja) * | 1997-10-29 | 2001-11-06 | アボット・ラボラトリーズ | 2−ハロ−6−o−置換ケトライド誘導体 |
WO2002032919A2 (en) * | 2000-10-16 | 2002-04-25 | Abbott Laboratories | 6-o-substituted erythromycin derivatives having improved gastrointestinal tolerance |
WO2003050132A1 (en) * | 2001-12-05 | 2003-06-19 | Ortho-Mcneil Pharmaceutical, Inc. | 6-o-acyl ketolide derivatives of erythromycine useful as antibacterials |
-
2004
- 2004-03-05 WO PCT/JP2004/002829 patent/WO2004078771A1/ja active Application Filing
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JP2001500855A (ja) * | 1996-09-04 | 2001-01-23 | アボツト・ラボラトリーズ | 抗菌活性を有する6―o―置換ケトリド |
JP2001521039A (ja) * | 1997-10-29 | 2001-11-06 | アボット・ラボラトリーズ | 2−ハロ−6−o−置換ケトライド誘導体 |
WO2002032919A2 (en) * | 2000-10-16 | 2002-04-25 | Abbott Laboratories | 6-o-substituted erythromycin derivatives having improved gastrointestinal tolerance |
WO2003050132A1 (en) * | 2001-12-05 | 2003-06-19 | Ortho-Mcneil Pharmaceutical, Inc. | 6-o-acyl ketolide derivatives of erythromycine useful as antibacterials |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3290427A1 (en) | 2005-08-24 | 2018-03-07 | Melinta Therapeutics, Inc. | Triazole compounds and methods of making and using the same |
WO2007148772A1 (ja) * | 2006-06-23 | 2007-12-27 | Shionogi & Co., Ltd. | マクロライド系抗生物質の糖類被覆製剤 |
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