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WO1998018808A1 - Derives de l'erythromycine - Google Patents

Derives de l'erythromycine Download PDF

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Publication number
WO1998018808A1
WO1998018808A1 PCT/JP1997/003684 JP9703684W WO9818808A1 WO 1998018808 A1 WO1998018808 A1 WO 1998018808A1 JP 9703684 W JP9703684 W JP 9703684W WO 9818808 A1 WO9818808 A1 WO 9818808A1
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WO
WIPO (PCT)
Prior art keywords
group
formula
erythromycin
compound
acid
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1997/003684
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English (en)
Japanese (ja)
Inventor
Toshifumi Asaka
Akiko Matsuura
Masato Kashimura
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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 Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Priority to AU44727/97A priority Critical patent/AU4472797A/en
Publication of WO1998018808A1 publication Critical patent/WO1998018808A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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

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. For example, a 6-0-methylerythromycin A derivative (U.S. Pat. No. 4,331,803) has been reported to have improved acid stability and an in vivo antibacterial activity upon oral administration compared to erythromycin A. ing.
  • 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 group at the 6-position has a strong antibacterial activity, and completed the present invention.
  • the present invention provides a compound of the formula (I)
  • R ′ represents a group represented by the formula 10—CO—CH 2 Y (wherein, Y represents a phenyl group, a nitrophenyl group or a pyridyl group) or a cladinosyloxy group; R 2 represents a hydrogen atom, or R 1 and R 2 together represent an oxo group, R 3 represents a hydrogen atom, an acetyl, ethylsuccinyl or nicotinyl group, and R 4 represents a compound of the formula CH 2 CH m A group represented by CH m ,, (where m is 0 or 1 ) ; a group represented by the formula: CH 2 CHC (CH ; 1 ) 2 ; a group represented by the formula: CH 2 CH pupilCH n P h Wherein n is 1 or 2, and Ph represents a phenyl group.
  • R 8 represents a hydrogen atom, a benzyl group or a benzyl group substituted with 1 to 5 halogen atoms.
  • R 6 represents a hydroxyl group
  • R 7 represents a hydroxyl group or a hydrogen atom
  • R 6 and R 7 together represent a cyclic carbonate group.
  • 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, ethyl succinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyquinone Ethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetyl cysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid And salts with acids such as hydroiodic acid, nicotinic acid, o
  • 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 (1) Inactivating 2 ', 4 "10-bis (trimethylsilyl) erythromycin A 9- (0_ [1- (1-methylethoxy) cyclohexyl] oxime ⁇ described in US Pat. No. 4,990,602 In a solvent, in the presence of a base, the formula
  • X represents a chlorine atom, a bromine atom or an iodine atom
  • W represents a hydrogen atom or represents a triple bond together with Z
  • Y represents a hydrogen atom or a methyl group
  • Z represents hydrogen.
  • the inert solvent N, N-dimethylformamide or dimethylsulfoxide, or a mixed solvent thereof with tetrahydrofuran is used.
  • the base potassium hydroxide, sodium hydroxide, lithium hydride or sodium hydride is used.
  • As lower alcohol methanol, ethanol or isopropanol is used.
  • Step (2) reacting the compound (a) with 1N or 2N hydrochloric acid or an acid such as sulfuric acid to remove the sugar at the 3-position, and then reacting it with acetic anhydride in acetone or dichloromethane. After protecting the 'position, an oxidation reaction is performed in an inert solvent such as dichloromethane with activated dimethyl sulfoxide at -78 ° C to 30 ° C to obtain a 3-position ketone.
  • an inert solvent such as dichloromethane with activated dimethyl sulfoxide at -78 ° C to 30 ° C to obtain a 3-position ketone.
  • a base such as sodium bicarbonate may be added here in a lower alcohol or a hydrated lower alcohol, and the reaction is carried out at 0 ° C to 100 ° C to remove the protecting group at the 2′-position, and the formula (b) ( In the formula, W, Y and Z are the same as described above.)
  • the compound of the present invention represented by the following formula: can be obtained.
  • activating agents for dimethyl sulfoxide include acetic anhydride, trifluoroacetic anhydride, oxalyl chloride, phosphorus pentachloride, pyridinesulfonic acid, pyridine trifluoroacetic acid, 1,3-jinclohexylcarbodiimide, and 1- (3 -Dimethylaminopropyl) 1-3-ethylcarbodiimide hydrochloride, etc., and lower alcohols are the same as those used in step (1). The same.
  • Step (3) After protecting compound (b) at the 2′-position in the same manner as in step (2), a reagent such as phosgene dimer or phosgene trimer is reacted with a reagent such as pyridine in an inert solvent such as dichloromethane. After performing 1,1,2-cyclic carbonate using a base, deprotection at the 2'-position is performed by the method shown in step (2), and formula (c) (where W, Y and Z are as defined above) The compound of the present invention represented by the following formula is obtained.
  • Step (4) Hydrogenating the compound (a) by a conventional method to obtain a compound of the present invention represented by the formula (d), wherein W, Y and Z are the same as described above. Obtainable.
  • Step (5) The compound (a) is subjected to a normal diolation reaction using osmium tetroxide to obtain a compound represented by the formula (e) (where W, Y and Z are the same as described above).
  • the compound of the present invention can be obtained.
  • Step (6) Removal of the sugar at position 3 and protection of the compound at position 2 'in the same manner as in step (2) in an inert solvent in the presence of a base such as 4-dimethylaminopyridine.
  • a base such as 4-dimethylaminopyridine. 3
  • monopyridylacetic acid hydrochloride with its activator at -30 ° C to 30 ° C, a 3-position ester is obtained.
  • the ester is subjected to deprotection at the 2'-position in a lower alcohol or a hydrated lower alcohol in the same manner as in the step (2) to obtain a compound represented by the formula (O (where W, Y and Z are the same as described above).
  • the compound of the present invention represented by the following formula can be obtained: 1,3-dicyclohexylcarpoimide, 1,1- (3-dimethylaminopropyl) -13-ethylcarpoid Imide hydrochloride or pivaloyl chloride is used, and as an inert solvent, dichloromethane, dichloroethane, acetone, pyridine, ethyl acetate or tetrahydrofuran is used.
  • Step (8) Compound (g) is reacted with bromofluoromethane in a mixed solvent of dimethylsulfoxide and tetrahydrofuran in the presence of potassium hydroxide to obtain a compound of the formula (h) (where TES is as defined above). And a compound represented by the formula (i) (wherein TES is the same as described above).
  • Step (9) The compound of the present invention represented by the formula (j) can be obtained by subjecting the compound (h) to detriethylsilation by a conventional method.
  • Step (10) The compound (j) is subjected to debenzylation at the 9-position using a conventional catalytic hydrogenolysis condition to obtain the compound of the present invention represented by the formula (k).
  • Step (11) By treating compound (i) in the same manner as in step (9), a compound of the present invention represented by the formula (£) can be obtained.
  • the erythromycin A derivative of the present invention is administered orally or parenterally, and is 50 to 2000 when treating an adult, and is administered in two to three doses a day. This dosage can 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.
  • excipients for oral administration, excipients, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, coloring agents, flavoring agents, etc.
  • examples include preparations such as powders, granules, capsules, and tablets that are manufactured by mixing.
  • parenteral administration examples include preparations such as injections and drops.
  • Listhromycin A 9— ⁇ 1- (1-Methylethoxy) cyclohexyl] oxime ⁇ (22.9 g, 0.022 mol) is dissolved in dimethyl sulfoquindotetrahydrofuran (1: 1; 230 ml) and cooled on ice. Cinnamyl bromide (13.lg) and potassium hydroxide (963 ⁇ 4, 2.59g) were added, and the mixture was stirred under ice cooling for 1.5 hours.
  • the reaction solution was concentrated, adjusted to pH 11 with a 2N aqueous sodium hydroxide solution under ice-cooling, added with water, and extracted with ethyl acetate.
  • the ethyl acetate layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then the ethyl acetate is distilled off.
  • Example 2 The compound (1.67 g, 1.96 mmol) obtained in Example 1 was dissolved in tetrahydrofuran (12 ml), and N-methylmorpholine N-oxide (0.690 g :) and osmium tetroxide solution (4.99 ml) were added at room temperature. The mixture was stirred at room temperature for 15 hours under a nitrogen stream. 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 ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off.
  • Example 2 The compound obtained in Example 1 (7.00 g, 8.23 ml) was dissolved in ethanol (7 ml), 1N hydrochloric acid (70 ml) was added, and the mixture was stirred at room temperature for 3.5 hours.
  • the reaction solution was extracted with chloroform, and the foam layer was washed with dilute hydrochloric acid, washed with an aqueous sodium hydroxide solution, then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was dissolved in acetone (30 ml), acetic anhydride (1.26 g) was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours.
  • Example 5 The compound (0.45 g, 0.65 MIO1) obtained in Example 5 was dissolved in acetone (3.5 ml), acetic anhydride (0.10 g) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off, adjusted to pH 9 with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off.
  • Example 2 Using the compound obtained in Example 2 (1.00 g, 1.30 rec. Ol) and performing 11,12-cyclic carbonate formation by the same reaction as in Example 6, the title compound (0.54 g) was obtained.
  • the title compound (0.54 g) was obtained.
  • Example 2 The title compound (0.31 g) was obtained in the same manner as in Example 5 using the compound (6. OOg, 7.77 country ol) obtained in Example 2.
  • Example 9 Production of 3-Deoxy-1 5-O-desosaminyl 3-oxo-1 6-0-Propargylerythronolide A11,12-Cyclic Carbonate
  • the compound obtained in Example 7 (0.45 g, 0.56 mmol)
  • the title compound (0.145 g) was obtained c
  • Step (2) Dissolve the compound (1.llg, 1.01 fraction) obtained in the above step (1) in dimethyl sulfoxide tetrahydrofuran (1: 1, 10 ml), and add bromofluoromethane (0.1 ml) under ice cooling. 56 g) and potassium hydroxide (96! 3 ⁇ 4, 0.18 g) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with hexane.
  • Step (3) Compound 1 (0.21 g, 0.19 ethoxylate) obtained in the above step (2) is dissolved in tetrahydrofuran (2 ml), and tetra (n-butyl) ammonium fluoride (0.097 g) is added at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, the ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound (0.15 g).
  • Example 1 3 3-0- (3-pyridyl) acetyl 5-0 Desosa miniru 6 1—Manufacture of cinnamyl erythronolide A
  • Step (1) Erythromycin B (10 g, 14.0 country ol) is dissolved in acetonitrile (100 ml), and pyridine hydrochloride (2.42 g, 2L0 mmol) and 1,1,1,3,3,3-hexamethylzine razan (8.84 ml, 41.9 ol) were added and stirred at room temperature for 3 hours. After the reaction, n-hexane (100 ml) was added, and the mixture was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain 2 ', 4 "-10-bistrimethylsilylerythromycin B (12.8 g).
  • Step (2) Using the compound (11.3 g, 13.1 mmol) obtained in the above step (1), a reaction was carried out in the same manner as in the step (2) of Example 10, to obtain a 6-0-fluoromethyl compound.
  • the obtained 6-0-fluoromethinole compound was dissolved in ethanol (50 ml), 99% formic acid (0.99 ml) was added, and the mixture was stirred at room temperature for 5 hours.
  • 10 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, ethanol was distilled off under reduced pressure, and extraction was performed using ethyl acetate.
  • Example 6 Using a medium for sensitive disks (manufactured by Eiken Chemical Co., Ltd.), The in vitro antibacterial activity of the compound obtained in Example 6 against various test bacteria was measured in accordance with the MIC measurement method of the Japanese Society of Chemotherapy. Azithromycin was used as a comparative drug. The result is M l. The values are shown in Table 1 (minimum inhibitory concentration of microbial growth zg / ml) and are shown in Table 1. The compound obtained in Example 6 showed strong antibacterial activity, indicating that it had strong antibacterial activity not only against gram-positive bacteria but also against some erythromycin-resistant bacteria. table 1
  • the compound of the present invention Since the compound of the present invention has strong antibacterial activity against Gram-positive bacteria and some erythromycin-resistant bacteria, it is useful as an antibacterial agent. Therefore, the compounds of the present invention are useful as antibacterial agents for treating bacterial infections in humans and animals (including farm animals).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne des dérivés de l'érythromycine A représentés par la formule générale (I) ou des sels pharmaceutiquement acceptables de ceux-ci, ayant des activités antibactériennes non seulement sur des bactéries gram positif mais également sur certaines bactéries tolérantes à l'érythromycine. Dans ladite formule (I), R1 représente -O-CO-CH¿2?Y (Y représentant phényle, nitrophényle ou pyridyle) ou cladinosyloxy; R?2¿ représente hydrogène ou R1 et R2 forment ensemble oxo; R3 représente hydrogène, acétyle, éthylsuccinyle ou nicotinoyle; R4 représente -CH¿2?CHmCHm+1 (m valant 0 ou 1), -CH2CHC(CH3)2, -CH2CHnCHnPh (n valant 1 ou 2; et Ph représentant phényle), -CH2CH(OH)CH(OH)Ph (Ph étant défini comme ci-dessus) ou fluorométhyle; R?5¿ représente =O ou =NOR8 (R8 représente hydrogène ou benzyle éventuellement substitué par 1 à 5 atomes d'halogène); R6 représente hydroxy; et R7 représente hydroxy ou hydrogène, ou R6 et R7 forment ensemble un carbonate cyclique.
PCT/JP1997/003684 1996-10-31 1997-10-14 Derives de l'erythromycine Ceased WO1998018808A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44727/97A AU4472797A (en) 1996-10-31 1997-10-14 Erythromycin a derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/289497 1996-10-31
JP28949796 1996-10-31

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Publication Number Publication Date
WO1998018808A1 true WO1998018808A1 (fr) 1998-05-07

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011651A3 (fr) * 1997-09-02 1999-05-06 Abbott Lab Derives d'erythromycine 3-descladinose 6-o-substituee
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
JP2003501439A (ja) * 1999-06-07 2003-01-14 アボット・ラボラトリーズ ６−ｏ−カルバメートケトライド誘導体
JP2003523938A (ja) * 1999-04-16 2003-08-12 コーサン バイオサイエンシーズ， インコーポレイテッド マクロライド系抗感染剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS572298A (en) * 1980-06-04 1982-01-07 Taisho Pharmaceut Co Ltd Erythromycin derivative
WO1997042206A1 (fr) * 1996-05-07 1997-11-13 Abbott Laboratories Composes a base d'erythromycine 6-0 substituee et technique de production
WO1997042204A1 (fr) * 1996-05-07 1997-11-13 Abbott Laboratories Erythromycines 6-o substituees et leur procede de preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS572298A (en) * 1980-06-04 1982-01-07 Taisho Pharmaceut Co Ltd Erythromycin derivative
WO1997042206A1 (fr) * 1996-05-07 1997-11-13 Abbott Laboratories Composes a base d'erythromycine 6-0 substituee et technique de production
WO1997042204A1 (fr) * 1996-05-07 1997-11-13 Abbott Laboratories Erythromycines 6-o substituees et leur procede de preparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1999011651A3 (fr) * 1997-09-02 1999-05-06 Abbott Lab Derives d'erythromycine 3-descladinose 6-o-substituee
JP2003523938A (ja) * 1999-04-16 2003-08-12 コーサン バイオサイエンシーズ， インコーポレイテッド マクロライド系抗感染剤
JP2003501439A (ja) * 1999-06-07 2003-01-14 アボット・ラボラトリーズ ６−ｏ−カルバメートケトライド誘導体

Also Published As

Publication number Publication date
AU4472797A (en) 1998-05-22

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