WO1998018807A1 - Erythromycin a derivatives - Google Patents
Erythromycin a derivatives Download PDFInfo
- Publication number
- WO1998018807A1 WO1998018807A1 PCT/JP1997/003683 JP9703683W WO9818807A1 WO 1998018807 A1 WO1998018807 A1 WO 1998018807A1 JP 9703683 W JP9703683 W JP 9703683W WO 9818807 A1 WO9818807 A1 WO 9818807A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- erythromycin
- acid
- derivative
- compound
- acceptable salt
- Prior art date
Links
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class 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 title claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 208000035143 Bacterial infection Diseases 0.000 claims description 5
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 5
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 9
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 229960003276 erythromycin Drugs 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229930006677 Erythromycin A Natural products 0.000 description 8
- -1 2,3-dihydroxypropyl group Chemical group 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 5
- 101150065749 Churc1 gene Proteins 0.000 description 5
- 102100038239 Protein Churchill Human genes 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- 238000006243 chemical reaction Methods 0.000 description 4
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
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- 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 2
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- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
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- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- 150000007513 acids Chemical class 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- 239000003963 antioxidant agent Substances 0.000 description 1
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- 235000003704 aspartic acid Nutrition 0.000 description 1
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- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
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- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
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- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical class 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)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
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- 229940099563 lactobionic acid Drugs 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 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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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 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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- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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 A.
- Erythromycin A is an antibiotic widely used as a treatment for infectious diseases caused by gram-positive bacteria, mycoplasma, and the like.
- erythromycin A has the disadvantage that it is degraded by acid in the stomach because it is unstable to acid, and its pharmacokinetics is not constant.
- Many erythromycin A derivatives have been produced to date to improve such biological or pharmacodynamic properties.
- a 6-0-methylerythromycin A derivative (US Pat. No. 4,331,803) is reported to have improved acid stability and better in vivo antibacterial activity when administered orally than erythromycin A. Have been.
- An object of the present invention is to provide an erythromycin A derivative or a salt thereof, which is a new macrolide antibiotic having a strong antibacterial activity, and a composition containing the same as an active ingredient.
- Another object of the present invention is to provide a use of the erythromycin A derivative or a salt thereof for the treatment of bacterial infection, which comprises applying an effective amount of the erythromycin A derivative or a salt thereof to a patient. To provide.
- the present inventors have conducted various studies on the antibacterial activity of the erythromycin A derivative, and as a result, have found that a compound having a specific group introduced at the 6-position has strong antibacterial activity, and completed the present invention.
- the present invention provides a compound of the formula (I)
- R represents an alkyl group having 3 to 5 carbon atoms or an alkyl group having 3 to 5 carbon atoms substituted with a hydroxyl group.
- the alkyl group having 3 to 5 carbon atoms is linear or branched, and examples thereof include a propyl group, an isopropyl group, a butyl group, a pentyl group, and an isopentyl group.
- the alkyl group having 3 to 5 carbon atoms substituted by a hydroxyl group is linear or branched and includes a 2,3-dihydroxypropyl group, a 2,3-dihydroxy-3-methylbutyl group, and the like. be able to.
- pharmaceutically acceptable salts refer to salts used in chemotherapy and prevention of bacterial infections.
- acids such as hydrogenic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, penden
- the compound of the present invention can be produced, for example, as follows.
- the method for producing the compound of the present invention is not limited to the method shown below.
- Step (2) The compound (a) is hydrogenated by a conventional method to obtain a compound of the present invention represented by the formula (b) (wherein R 1 is the same as described above).
- Step (3) The compound represented by the formula (c) (where R 'is the same as described above) is obtained by subjecting the compound (a) to a normal diolation reaction using osmium tetroxide. The compounds of the invention can be obtained.
- the erythromycin A derivative of the present invention is administered orally or parenterally, and is 50 to 2000 mg when treating an adult, and is administered in 2 to 3 times a day. This dosage may be adjusted appropriately according to the age, weight and condition of the patient.
- the compound of the present invention can be used in various pharmaceutical forms for the purpose of application due to its pharmacological action.
- the pharmaceutical compositions of the present invention can be prepared by uniformly mixing an effective amount of the compound of the present invention in the form of the free or acid addition salt as an active ingredient with a pharmaceutically acceptable carrier.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- composition of the present invention for oral administration, excipients, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, coloring agents, flavoring agents, etc. are mixed. Preparations include powders, granules, capsules, tablets and the like, and for parenteral administration, preparations such as injections and infusions. When formulating, a usual formulation method can be used.
- Example 1-one Provides professional reerythromycin A
- Step (1) 2 4 "— 0-bis (trimethylsilyl) erythromycin A 9— ⁇ 0— [1- (1-methylethoxy) cyclohexyl] oxime ⁇ (37.8 g, 0.037 mol) and prenyl bromide
- the reaction was carried out in the same manner as in the step (1) of Example 1 using amide (16.36 g) and potassium hydroxide (4.28 g) to obtain 6-0-prenylerythromycin A (10.16 g).
- Step (2) Using the compound (0.30 0.37 ⁇ 01) obtained in the above step (1) and 10% palladium carbon (50! 3 ⁇ 4 wet, 0.06 g), react in the same manner as in step (2) of Example 1. The title compound (0.157 g, crystallized from methanol) was obtained.
- the compound (l.Og, 1.29 dl) obtained in Step (1) of Example 1 was dissolved in tetrahydrofuran (5 ml).
- N-methylmorpholine N-oxide (0.908 g) and osmium tetroxide solution (3.64 ml) were added, and the mixture was stirred at room temperature under a nitrogen stream for 15 hours.
- a saturated aqueous sodium sulfite solution (10 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate.
- the in vitro antibacterial activity of the compound obtained in Example 1 against various test bacteria was measured using a medium for susceptible discs (manufactured by Eiken Chemical Co., Ltd.) according to the MIC assay method of the Japan Society of Chemotherapy did.
- the results were expressed as MIC values (minimum inhibitory concentration of microbial growth / g / m 1) and are shown in Table 1.
- the compound obtained in Example 1 showed strong antibacterial activity.
- the compounds of the present invention have strong antibacterial activity and are useful as antibacterial agents. Therefore, the compounds of the present invention are useful as antibacterial agents for the treatment of bacterial infections in humans and animals (including farm animals).
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Abstract
Erythromycin A derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof having a potent antibacterial activity wherein R represents optionally hydroxylated C3-5 alkyl.
Description
明 細 書 エリス口マイシン A誘導体 技術分野 Description Eris mouth mycin A derivative Technical field
本発明は、 抗生物質ェリスロマイシン Aの新規誘導体に関する。 The present invention relates to novel derivatives of the antibiotic erythromycin A.
背景技術 Background art
エリスロマイシン Aはグラム陽性菌、 マイコプラズマなどに起因する感染症の 治療薬として広く使用されている抗生物質である。 しかし、 エリスロマイシン A は酸に対し不安定であるため胃酸で分解され、 体内動態が一定しないという欠点 があった。 これまで多くのエリスロマイシン A誘導体が、 このような生物学的又 は薬効学的特性の改良を目的に製造されてきた。 例えば 6—0—メチルエリス口 マイシン A誘導体 (米国特許第 4331803号) は酸に対する安定性が改善され、 経 口投与時の生体内抗菌活性がエリス口マイシン Aに比較し優れていることが報告 されている。 Erythromycin A is an antibiotic widely used as a treatment for infectious diseases caused by gram-positive bacteria, mycoplasma, and the like. However, erythromycin A has the disadvantage that it is degraded by acid in the stomach because it is unstable to acid, and its pharmacokinetics is not constant. Many erythromycin A derivatives have been produced to date to improve such biological or pharmacodynamic properties. For example, a 6-0-methylerythromycin A derivative (US Pat. No. 4,331,803) is reported to have improved acid stability and better in vivo antibacterial activity when administered orally than erythromycin A. Have been.
本発明の目的は、 強い抗菌力を有する新たなマクロライド系抗生物質である、 エリスロマイシン A誘導体又はその塩、 及びそれらを有効成分として含有する組 成物を提供することである。 An object of the present invention is to provide an erythromycin A derivative or a salt thereof, which is a new macrolide antibiotic having a strong antibacterial activity, and a composition containing the same as an active ingredient.
本発明の他の目的は、 上記エリス口マイシン A誘導体又はその塩の有効量を患 者に適用することからなる細菌感染症の治療のための上記エリス口マイシン A誘 導体又はその塩の用途を提供するものである。 Another object of the present invention is to provide a use of the erythromycin A derivative or a salt thereof for the treatment of bacterial infection, which comprises applying an effective amount of the erythromycin A derivative or a salt thereof to a patient. To provide.
発明の開示 Disclosure of the invention
本発明者等は、 エリス口マイシン A誘導体の抗菌力について種々検討した結果、 6位にある特定の基を導入した化合物が強い抗菌活性を有することを見出し、 本 発明を完成した。 The present inventors have conducted various studies on the antibacterial activity of the erythromycin A derivative, and as a result, have found that a compound having a specific group introduced at the 6-position has strong antibacterial activity, and completed the present invention.
[式中、 Rは炭素原子数 3— 5のアルキル基、 又は水酸基で置換された炭素原子 数 3— 5のアルキル基を示す。 ] で表されるエリスロマイシン A誘導体又はその 医薬上許容される塩である。 [In the formula, R represents an alkyl group having 3 to 5 carbon atoms or an alkyl group having 3 to 5 carbon atoms substituted with a hydroxyl group. ] The erythromycin A derivative represented by these, or its pharmacologically acceptable salt.
本発明において、 炭素原子数 3— 5のアルキル基とは、 直鎖状又は分枝鎖状で あり、 たとえばプロピル基、 イソプロピル基、 ブチル基、 ペンチル基、 イソペン チル基などを挙げることができる。 水酸基で置換された炭素原子数 3— 5のアル キル基とは、 直鎖状又は分枝鎖状であり、 2, 3—ジヒドロキシプロピル基、 2, 3—ジヒドロキシー 3—メチルブチル基などを挙げることができる。 また、 医薬 上許容される塩とは、 細菌感染症の化学療法および予防において使用される塩を 意味する。 それらは、 たとえば酢酸、 プロピオン酸、 酪酸、 ギ酸、 トリフルォロ 酢酸、 マレイン酸、 酒石酸、 クェン酸、 ステアリン酸、 コハク酸、 ェチルコハク 酸、 ラクトビオン酸、 ダルコン酸、 ダルコヘプトン酸、 安息香酸、 メタンスルホ ン酸、 エタンスルホン酸、 2—ヒ ドロキンエタンスルホン酸、 ベンゼンスルホン 酸、 パラ トルエンスルホン酸、 ラウリル硫酸、 リンゴ酸、 ァスパラギン酸、 グル 夕ミン酸、 アジピン酸、 システィン、 N—ァセチルシスティン、 塩酸、 臭化水素 酸、 リン酸、 硫酸、 ヨウ化水素酸、 ニコチン酸、 シユウ酸、 ピクリン酸、 チオシ ァン酸、 ゥンデ力ン酸、 アクリル酸ポリマー、 力ルボキシビニルポリマ一などの 酸との塩を挙げることができる。 In the present invention, the alkyl group having 3 to 5 carbon atoms is linear or branched, and examples thereof include a propyl group, an isopropyl group, a butyl group, a pentyl group, and an isopentyl group. The alkyl group having 3 to 5 carbon atoms substituted by a hydroxyl group is linear or branched and includes a 2,3-dihydroxypropyl group, a 2,3-dihydroxy-3-methylbutyl group, and the like. be able to. Also, pharmaceutically acceptable salts refer to salts used in chemotherapy and prevention of bacterial infections. They include, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, lactobionic acid, dalconic acid, dalcoheptonic acid, benzoic acid, methanesulphonic acid, ethane Sulfonic acid, 2-hydroquinethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, lauryl sulfate, malic acid, aspartic acid, glutamate, adipic acid, cysteine, N-acetylcystine, hydrochloric acid, bromide Examples include salts with acids such as hydrogenic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, pendenic acid, acrylic acid polymers, and carboxylic acid vinyl polymers. be able to.
本発明の化合物は、 例えば次のように製造することができる。 The compound of the present invention can be produced, for example, as follows.
ただし、 本発明の化合物の製造方法は、 下記に示す方法に限定されるものでは ない。
However, the method for producing the compound of the present invention is not limited to the method shown below.
(i) ¾ェ (i)
£S9£0/L6d£/lDd ん 0881/86 OAV
工程(1) ;米国特許 4990602号記載の 2 ' , 4 " 一 0—ビス (トリメチルシリ ノレ) エリスロマイシン A 9— ( 0 - C 1 - ( 1 一メチルエトキン) シクロへキ シル] ォキシム} を不活性溶媒中、 塩基存在下、 ァリルブロマイドあるいはプレ 二ルブロマイドと- 15 °Cから室温で反応させた後、 低級アルコール中、 酸存在下、 亜硫酸水素ナトリウムを用い、 脱保護と 9位ケトンの再生を同時に行い、 式 (a ) (式中、 R 1 は水素原子又はメチル基を示す。 ) で表される化合物を得る。 ここ で不活性溶媒としては N, N—ジメチルホルムアミ ド又はジメチルスルホキシド あるいはそれらとテトラヒドロフランとの混合溶媒が用いられる。 塩基としては 水酸化力リウム、 水酸化ナトリウム、 水素化力リウム又は水素化ナトリウムなど が用いられる。 低級アルコールとしてはメタノール、 エタノールあるいはイソプ ロパノールなどが用いられる。 £ S9 £ 0 / L6d £ / lDd 0881/86 OAV Step (1): Inactivating 2 ', 4 "10-bis (trimethylsilinole) erythromycin A9- (0-C1- (1-methylethoxyquin) cyclohexyl] oxime} described in US Pat. No. 4,990,602 After reacting with acryl bromide or prenyl bromide in a solvent in the presence of a base at -15 ° C to room temperature, deprotection and regeneration of the 9-position ketone using sodium bisulfite in a lower alcohol in the presence of an acid At the same time to obtain a compound represented by the formula (a) (wherein R 1 represents a hydrogen atom or a methyl group), wherein N, N-dimethylformamide or dimethylsulfoxide is used as the inert solvent. Alternatively, a mixed solvent of them and tetrahydrofuran is used, and as the base, lithium hydroxide, sodium hydroxide, lithium hydride or sodium hydride is used. As the alcohol, methanol, ethanol or isopropanol is used.
工程 (2) ;化合物 (a ) に対し常法により水素添加を行い、 式 (b ) (式中、 R 1 は前記と同じである。 ) で表される本発明の化合物を得ることができる。 工程 (3) ;化合物 (a ) に対して四酸化オスミウムを用いる通常のジオール化 反応を行うことにより、 式 (c ) (式中、 R ' は前記と同じである。 ) で表され る本発明の化合物を得ることができる。 Step (2): The compound (a) is hydrogenated by a conventional method to obtain a compound of the present invention represented by the formula (b) (wherein R 1 is the same as described above). . Step (3): The compound represented by the formula (c) (where R 'is the same as described above) is obtained by subjecting the compound (a) to a normal diolation reaction using osmium tetroxide. The compounds of the invention can be obtained.
本発明のエリスロマイシン A誘導体は、 経口投与または非経口投与され、 成人 を治療する場合で 50〜2000mgであり、 これを 1日 2〜3回に分けて投与する。 こ の投与量は、 患者の年齢、 体重および症状によって適宜増減することができる。 本発明化合物は、 その薬理作用から適用目的に対する各種の製薬形態で使用可 能である。 本発明の製薬組成物は活性成分として遊離又は酸付加塩の形態にある 有効な量の本発明化合物を、 薬理的に許容しうる担体と均一に混合して製造でき る。 この担体は投与に対して望ましい製剤の形態に応じて、 広い範囲の形態をと ることができる。 本発明の製剤形態としては、 経口投与する場合は、 賦形剤、 結 合剤、 滑沢剤、 抗酸化剤、 コーティング剤、 界面活性剤、 可塑剤、 着色剤、 矯味 矯臭剤などを混合して製造される、 散剤、 顆粒剤、 カプセル剤、 錠剤などの製剤 があげられ、 非経口投与する場合は、 注射剤、 点滴剤などの製剤があげられる。 製剤化する際には、 通常の製剤化の方法が使用できる。 The erythromycin A derivative of the present invention is administered orally or parenterally, and is 50 to 2000 mg when treating an adult, and is administered in 2 to 3 times a day. This dosage may be adjusted appropriately according to the age, weight and condition of the patient. The compound of the present invention can be used in various pharmaceutical forms for the purpose of application due to its pharmacological action. The pharmaceutical compositions of the present invention can be prepared by uniformly mixing an effective amount of the compound of the present invention in the form of the free or acid addition salt as an active ingredient with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. As the formulation of the present invention, for oral administration, excipients, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, coloring agents, flavoring agents, etc. are mixed. Preparations include powders, granules, capsules, tablets and the like, and for parenteral administration, preparations such as injections and infusions. When formulating, a usual formulation method can be used.
発明を実施するための最良の形態
次に、 実施例にて本発明を更に詳細に説明する。 BEST MODE FOR CARRYING OUT THE INVENTION Next, the present invention will be described in more detail with reference to examples.
実施例 1 —一。—プロ レエリスロマイシン Aの製造 Example 1-one. —Production of professional reerythromycin A
工程(1) 2* , 4" — 0—ビス (トリメチルシリル) エリスロマイシン A 9一 {0- [ 1 - (1一メチルエトキシ) シクロへキシル] ォキシム 1 (30.0g,0. 027mol) をジメチルスルホキシド一テトラヒ ドロフラン(1:1; 300ml)に溶解し、 氷冷下でァリルプロマイド(9.85g) 、 水酸化カリウム(3.17g) を加え、 氷冷下で 1.5 時間撹拌した。 反応後、 50% ジメチルァミン水溶液 (5ml) を加えて室温で 30 分間撹拌し、 水を加えてへキサンで抽出した。 へキサン層を飽和食塩水で洗浄し、 無水硫酸マグネシゥムで乾燥後溶媒を留去した。 得られた残渣をェ夕ノール(150 ml) に溶解し、 室温で 90% ギ酸 (3.47ml)、 水(150ml) を加えて 1時間加熱還流し た後、 亜硫酸水素ナトリウム(19.8g) を加えてさらに 2時間加熱還流した。 反応 液を濃縮し、 氷冷下 2規定水酸化ナトリウム水溶液で pHllとした後、 水を加えて 酢酸ェチルで抽出した。 酢酸ェチル層を飽和食塩水で洗浄し、 無水硫酸マグネシ ゥムで乾燥後、 酢酸ェチルを留去し、 得られた残渣をシリカゲルカラムクロマト グラフィ一 (溶出溶媒; クロ口ホルム: メタノール: アンモニア水 =94:6:0.6〜 9:1:0.1)で精製後、 クロ口ホルム—イソプロピルエーテルより結晶化を行い、 6 — 0—ァリルエリスロマイシン A (3.56g) を得た。 Step (1) 2 *, 4 "— 0-bis (trimethylsilyl) erythromycin A 9-1 {0- [1- (1-methylethoxy) cyclohexyl] oxime 1 (30.0 g, 0.027 mol) is added to dimethyl sulfoxide After dissolving in tetrahydrofuran (1: 1; 300 ml), arypromide (9.85 g) and potassium hydroxide (3.17 g) were added under ice cooling, and the mixture was stirred for 1.5 hours under ice cooling. An aqueous solution (5 ml) was added, the mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with hexane.The hexane layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in ethanol (150 ml), 90% formic acid (3.47 ml) and water (150 ml) were added at room temperature, and the mixture was heated under reflux for 1 hour. Then, sodium hydrogen sulfite (19.8 g) was added to add 2%. The reaction solution was concentrated under ice cooling and 2N sodium hydroxide. The solution was adjusted to pH 11, water was added, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off. Purification by column chromatography (elution solvent; chloroform: methanol: aqueous ammonia = 94: 6: 0.6 to 9: 1: 0.1), followed by crystallization from chromatoform-isopropyl ether to give 6-0-a Rilerythromycin A (3.56 g) was obtained.
MS(FAB)m/z;774[M+H]+ MS (FAB) m / z; 774 [M + H] +
'Η- N R(CDC13) δ (ppm) ;2.30 (6H, s, N(CH3) 2), 3.33 (3H, s, 0CH3), 3.86, 4.01( 各 1H,各 dd, J=7.4, 11.2Hz, 0CH2CHCH2), 5.16(2H, dd, J=l.5, 17.3Hz, OC^CHC^), 5.90 (1H, dddd, J=l.5, 7.4, 11.2, 17.3Hz, 0CH2CHCH2) 'Η-NR (CDC1 3 ) δ (ppm); 2.30 (6H, s, N (CH 3 ) 2 ), 3.33 (3H, s, 0CH 3 ), 3.86, 4.01 (1H each, dd, J = 7.4 , 11.2Hz, 0CH 2 CHCH 2 ), 5.16 (2H, dd, J = 1.5, 17.3Hz, OC ^ CHC ^), 5.90 (1H, dddd, J = 1.5, 7.4, 11.2, 17.3Hz, 0CH 2 CHCH 2 )
1 C-N R(CDCh) δ (ppm) ;40.22 (Q, N(CH3) 2), 65.97 (T, 0CH2CHCHZ), 116.74 (T, 0CH2CHCH2), 135.91(D, 0CH2CHCH2)。 1 CN R (CDCh) δ (ppm); 40.22 (Q, N (CH 3 ) 2 ), 65.97 (T, 0CH 2 CHCH Z ), 116.74 (T, 0CH 2 CHCH 2 ), 135.91 (D, 0CH 2 CHCH 2 ).
工程 (2) 上記工程(1) で得た化合物 (0.30g,0.39誦 ol)、 10% パラジウムカー ボン(50%湿潤, 0.12g) にェタノール (3ml) を加え、 水素気流下、 室温で 2日間撹 拌した。 反応液をセライ ト濾過し、 溶媒留去後、 シリ力ゲル力ラムクロマトグラ フィー (溶出溶媒; クロ口ホルム: メタノール: アンモニア水 =9:1:0.1) で精製 後、 クロ口ホルム一イソプロピルエーテルより結晶化し、 標題化合物(0.21g) を 得た。
Step (2) Ethanol (3 ml) was added to the compound obtained in step (1) (0.30 g, 0.39 referred to) and 10% palladium carbon (50% wet, 0.12 g), and the mixture was added at room temperature under a stream of hydrogen at room temperature. Stirred for days. The reaction mixture was filtered through celite, the solvent was distilled off, and the residue was purified with silica gel gel chromatography (elution solvent; chloroform: methanol: aqueous ammonia = 9: 1: 0.1). Further crystallization gave the title compound (0.21 g).
'H-NMR(CDC13) 5(ppm);1.80(3H, t, J=7.5Hz, OCzW ^), 1.2-1.5 'H-NMR (CDC1 3) 5 (ppm); 1.80 (3H, t, J = 7.5Hz, OCzW ^), 1.2-1.5
(4H, m, OCsHiCHa), 2.40 (6H, s, N(CH3)2), 3.31(3H, s, 0CH3)。 (4H, m, OCsHiCHa), 2.40 (6H, s, N (CH 3) 2), 3.31 (3H, s, 0CH 3).
実施例 2 6—0—イソペンチルエリスロマイシン Aの製造 Example 2 Production of 6-0-isopentylerythromycin A
工程(1) 2, , 4" — 0—ビス (トリメチルシリル) エリスロマイシン A 9— {0— 〔1一 (1—メチルエトキシ) シクロへキンル] ォキシム} (37.8g, 0. 037mol) と、 プレニルブロマイ ド(16.36g)、 水酸化カリウム(4.28g) を用いて実 施例 1の工程(1) と同様に反応を行い 6— 0—プレニルエリス口マイシン A(10. 16g)を得た。 Step (1) 2,, 4 "— 0-bis (trimethylsilyl) erythromycin A 9— {0— [1- (1-methylethoxy) cyclohexyl] oxime} (37.8 g, 0.037 mol) and prenyl bromide The reaction was carried out in the same manner as in the step (1) of Example 1 using amide (16.36 g) and potassium hydroxide (4.28 g) to obtain 6-0-prenylerythromycin A (10.16 g).
S(FAB)m/z;802[M+H]+ S (FAB) m / z; 802 [M + H] +
'H - NMR(CDC13) 6 ( pm); 1.64, 1.72 ( 各 3H,各 s, 0CH2CHC(CH3)2), 2.30 'H - NMR (CDC1 3) 6 (pm); 1.64, 1.72 ( each 3H, each s, 0CH 2 CHC (CH 3 ) 2), 2.30
(6H, s, N(CH3) 2), 3.31 (3H, s, 0CH3), 3.9-4.0(2H, m, OC^CHC CH 2), 5.21(1H, dd, J= 7.5, 7.5Hz, 0CH2CHC(CH3)2) (6H, s, N (CH 3 ) 2 ), 3.31 (3H, s, 0CH 3 ), 3.9-4.0 (2H, m, OC ^ CHC CH 2 ), 5.21 (1H, dd, J = 7.5, 7.5Hz , 0CH 2 CHC (CH 3 ) 2 )
13C-NMR(CDC13) δ (ppm); 17.95, 25.64 ( 各 Q, 0CH2CHC( H3) 2), 40.30 13 C-NMR (CDC1 3) δ (ppm); 17.95, 25.64 ( each Q, 0CH 2 CHC (H 3 ) 2), 40.30
(Q, N(CH 3 ) 2 ) , 60.87 (T, OCH 2 CHC (CH 3 ) 2 ) , 122.77 (D, OCH 2 CHC (CH 3 ) 2 ) o (Q, N (CH 3) 2 ), 60.87 (T, OCH 2 CHC (CH 3) 2), 122.77 (D, OCH 2 CHC (CH 3) 2) o
工程 (2) 上記工程(1) で得た化合物(0.30 0.37咖01)、 10%パラジウムカー ボン(50!¾湿潤, 0.06g) を用いて、 実施例 1の工程 (2) と同様に反応を行うことに より標題化合物 (0.157g、 メタノ一ルより結晶化) を得た。 Step (2) Using the compound (0.30 0.37 咖 01) obtained in the above step (1) and 10% palladium carbon (50! ¾ wet, 0.06 g), react in the same manner as in step (2) of Example 1. The title compound (0.157 g, crystallized from methanol) was obtained.
MS(FAB)m/z;804[M+H]+ MS (FAB) m / z; 804 [M + H] +
'H- NMR CDC ) S (ppm) ;0.90, 0.91 ( 各 3H,各 d, J=7.5Hz, 0CH2CH2CH(CH3)2), 1.4-1.6(4H, m, OC^C^CHCCHJ 2), 2.29 (6H, s, N(CH3) 2), 3.06(1H, m, 0CH2CH2CH (CH3)2),3.32(3H, s,0CH3) 。 'H- NMR CDC) S (ppm ); 0.90, 0.91 ( each 3H, each d, J = 7.5Hz, 0CH 2 CH 2 CH (CH 3) 2), 1.4-1.6 (4H, m, OC ^ C ^ CHCCHJ 2), 2.29 (6H, s, N (CH 3) 2), 3.06 (1H, m, 0CH 2 CH 2 CH (CH 3) 2), 3.32 (3H, s, 0CH 3).
実施例 3 6— O— (2, 3—ジヒ ドロキシプロピル) エリスロマイシン Aの 実施例 1の工程(1) で得た化合物(l.Og, 1.29議 ol) をテトラヒドロフラン(5ml) に溶解し、 室温で N—メチルモルホリン N—ォキシド(0.908g)、 四酸化ォスミ ゥム ¾溶液 (3.64ml)を加え、 窒素気流下、 室温で 15時間撹拌した。 反応液に飽和 亜硫酸ナトリウム水溶液(10ml)を加えて室温で 30分間撹拌した後、 酢酸ェチルで 抽出した。 酢酸ェチル層を水洗し、 無水硫酸マグネシウムで乾燥後、 酢酸ェチル
を留去して得られた残渣をシリカゲルカラムクロマトグラフィー (溶出溶媒;ァ セトン:へキサン: トリエチルァミン =6 : 10 :0. 2 〜10: 10 :0. 2)で精製し、 標題化 合物 (0. 23g) を得た。 Example 3 6-O— (2,3-dihydroxypropyl) erythromycin A The compound (l.Og, 1.29 dl) obtained in Step (1) of Example 1 was dissolved in tetrahydrofuran (5 ml). At room temperature, N-methylmorpholine N-oxide (0.908 g) and osmium tetroxide solution (3.64 ml) were added, and the mixture was stirred at room temperature under a nitrogen stream for 15 hours. A saturated aqueous sodium sulfite solution (10 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry over anhydrous magnesium sulfate. The residue obtained by distilling off the residue was purified by silica gel column chromatography (elution solvent: acetone: hexane: triethylamine = 6: 10: 0.2 to 10: 10: 0.2), and the title was obtained. Compound (0.23 g) was obtained.
MS(FAB)m/z ;808 [M+H] +。 MS (FAB) m / z; 808 [M + H] < +>.
実施例 4 6—0— ( 2, 3—ジヒ ドロキシー 3 —メチルプチル) エリスロマ イシン Aの製造 Example 4 Preparation of 6-0- (2,3-dihydroxy-3-methylbutyl) erythromycin A
実施例 2の工程(1) で得た化合物(2. 0g, 2. 49瞧 ol) と、 四酸化オスミウム ¾溶 液 (6. 34ml)を用い、 実施例 3と同様の方法により標題化合物(l. Olg) を得た。 Using the compound (2.0 g, 2.49 mol) obtained in step (1) of Example 2 and an osmium tetroxide solution (6.34 ml), the title compound ( l. Olg).
MS(FAB)m/z ;836 [M+H] +。 MS (FAB) m / z; 836 [M + H] < +>.
試験例 (試験管内抗菌活性) Test example (in vitro antibacterial activity)
感受性ディスク用培地 (栄研化学製) を用い、 本発明の化合物の例として、 実施例 1で得られた化合物の各種試験菌に対する試験管内抗菌力を日本化学療法 学会 M I C測定法に準じて測定した。 As an example of the compound of the present invention, the in vitro antibacterial activity of the compound obtained in Example 1 against various test bacteria was measured using a medium for susceptible discs (manufactured by Eiken Chemical Co., Ltd.) according to the MIC assay method of the Japan Society of Chemotherapy did.
その結果を M I C値 (微生物生育最小阻止濃度 / g/m 1 ) で表し、 表 1に 示した。 実施例 1で得られた化合物は強い抗菌活性を示した。 The results were expressed as MIC values (minimum inhibitory concentration of microbial growth / g / m 1) and are shown in Table 1. The compound obtained in Example 1 showed strong antibacterial activity.
表 1 table 1
本発明の化合物は、 強い抗菌活性を有するので、 抗菌剤として有用である。 し たがって、 本発明の化合物はヒト及び動物 (農園動物を含む) における細菌感染 症の治療のための抗菌剤として有用である。
The compounds of the present invention have strong antibacterial activity and are useful as antibacterial agents. Therefore, the compounds of the present invention are useful as antibacterial agents for the treatment of bacterial infections in humans and animals (including farm animals).
Claims
1. 式 ( I ) 1. Formula (I)
[式中、 Rは炭素原子数 3— 5のアルキル基、 又は水酸基で置換された炭素原子 数 3— 5のアルキル基を示す。 ] で表されるエリスロマイシン A誘導体又はその 医薬上許容される塩。 [In the formula, R represents an alkyl group having 3 to 5 carbon atoms or an alkyl group having 3 to 5 carbon atoms substituted with a hydroxyl group. ] The erythromycin A derivative represented by these, or its pharmacologically acceptable salt.
2. 有効量の請求の範囲第 1項に記載のエリスロマイシン A誘導体又はその医 薬上許容される塩を含有する医薬組成物。 2. A pharmaceutical composition comprising an effective amount of the erythromycin A derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
3. 請求の範囲第 1項に記載のエリスロマイシン A誘導体又はその医薬上許容 される塩を有効成分として含有する抗菌剤。 3. An antibacterial agent comprising the erythromycin A derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
4. 請求の範囲第 1項に記載のエリスロマイシン A誘導体又はその医薬上許容 される塩の有効量を患者に適用することからなる細菌感染症の治療方法。 4. A method for treating a bacterial infection, which comprises applying an effective amount of the erythromycin A derivative or a pharmaceutically acceptable salt thereof according to claim 1 to a patient.
5. 細菌感染症の治療のための請求の範囲第 1項に記載のエリスロマイシン A 誘導体又はその医薬上許容される塩の使用。
5. Use of an erythromycin A derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the treatment of a bacterial infection.
Priority Applications (1)
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AU44726/97A AU4472697A (en) | 1996-10-31 | 1997-10-14 | Erythromycin a derivatives |
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JP8289498A JP2000198795A (en) | 1996-10-31 | 1996-10-31 | Erythromycin a derivative |
JP8/289498 | 1996-10-31 |
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WO1998018807A1 true WO1998018807A1 (en) | 1998-05-07 |
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PCT/JP1997/003683 WO1998018807A1 (en) | 1996-10-31 | 1997-10-14 | Erythromycin a derivatives |
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AU (1) | AU4472697A (en) |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999011651A2 (en) * | 1997-09-02 | 1999-03-11 | Abbott Laboratories | 3-descladinose 6-o-substituded erythromycin derivatives |
WO2004039823A1 (en) * | 2002-10-29 | 2004-05-13 | The Kitasato Institute | Novel macrolide derivatives havaing effect of potentiating antifungal activity |
WO2009019868A1 (en) | 2007-08-06 | 2009-02-12 | Taisho Pharmaceutical Co., Ltd. | 10a-azalide compound crosslinked at position-10a and position-12 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS572298A (en) * | 1980-06-04 | 1982-01-07 | Taisho Pharmaceut Co Ltd | Erythromycin derivative |
WO1997042206A1 (en) * | 1996-05-07 | 1997-11-13 | Abbott Laboratories | 6-o-substituted erythromycin compounds and method for making same |
WO1997042204A1 (en) * | 1996-05-07 | 1997-11-13 | Abbott Laboratories | 6-o-substituted erythromycins and method for making them |
-
1996
- 1996-10-31 JP JP8289498A patent/JP2000198795A/en active Pending
-
1997
- 1997-10-14 AU AU44726/97A patent/AU4472697A/en not_active Abandoned
- 1997-10-14 WO PCT/JP1997/003683 patent/WO1998018807A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS572298A (en) * | 1980-06-04 | 1982-01-07 | Taisho Pharmaceut Co Ltd | Erythromycin derivative |
WO1997042206A1 (en) * | 1996-05-07 | 1997-11-13 | Abbott Laboratories | 6-o-substituted erythromycin compounds and method for making same |
WO1997042204A1 (en) * | 1996-05-07 | 1997-11-13 | Abbott Laboratories | 6-o-substituted erythromycins and method for making them |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999011651A2 (en) * | 1997-09-02 | 1999-03-11 | Abbott Laboratories | 3-descladinose 6-o-substituded erythromycin derivatives |
WO1999011651A3 (en) * | 1997-09-02 | 1999-05-06 | Abbott Lab | 3-descladinose 6-o-substituded erythromycin derivatives |
WO2004039823A1 (en) * | 2002-10-29 | 2004-05-13 | The Kitasato Institute | Novel macrolide derivatives havaing effect of potentiating antifungal activity |
WO2009019868A1 (en) | 2007-08-06 | 2009-02-12 | Taisho Pharmaceutical Co., Ltd. | 10a-azalide compound crosslinked at position-10a and position-12 |
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Publication number | Publication date |
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JP2000198795A (en) | 2000-07-18 |
AU4472697A (en) | 1998-05-22 |
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