WO1998040393A1 - Nouveaux derives du mycaminosyltylonolide - Google Patents

Nouveaux derives du mycaminosyltylonolide Download PDF

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Publication number
WO1998040393A1
WO1998040393A1 PCT/JP1998/000954 JP9800954W WO9840393A1 WO 1998040393 A1 WO1998040393 A1 WO 1998040393A1 JP 9800954 W JP9800954 W JP 9800954W WO 9840393 A1 WO9840393 A1 WO 9840393A1
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Prior art keywords
compound
group
silica gel
formula
acid
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PCT/JP1998/000954
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English (en)
Japanese (ja)
Inventor
Tomio Takeuchi
Sumio Umezawa
Osamu Tsuchiya
Toshiaki Miyake
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Microbial Chemistry Research Foundation
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Publication date
Application filed by Microbial Chemistry Research Foundation filed Critical Microbial Chemistry Research Foundation
Priority to AU61210/98A priority Critical patent/AU6121098A/en
Publication of WO1998040393A1 publication Critical patent/WO1998040393A1/fr

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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
    • 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 a novel myosinyltylonolide derivative having antibacterial activity. More specifically, the present invention relates to a novel myosinyltyronolide or 4'-deoxymycinosyltyronolide having antibacterial activity, which is a 3- (1-alkyl (alkyl- or cycloalkyl- or phenylthiomethyl) ) For derivatives. Background technology
  • Tylosin is a macrolide antibiotic produced by Streptomyces flagell NRRL 022 and 273, and has a broad antibacterial spectrum against gram-positive and gram-negative bacteria.
  • Thai mouth synth has a mycaminose attached to the 5th position of a lactone ring called Tylonolide, and a mycinose attached to the 23rd position of the lactone ring. It has a structure having mycarose bonded to the 4-position hydroxyl group of the mycosis moiety (H. Umezawa, Recent Advances in Chemistry and Biochemistrv of Antibiotics, 964, pp. 62-63, and Letters, j No. 34, pp. Pp.
  • Thai mouth sin also inhibits spirochetes, protozoa, etc., and reduces parasitic parasites such as chickens in poultry. It is used as a feed additive because it has inhibitory activity and promotes livestock growth.
  • mycaminosyltylonolide represented by, and 4′-deoxy and 3,4′-dideoxy derivatives of mycaminosyltylonolide have antibacterial activity. (Showa 57-280100). It is also known that a 3-deoxy derivative of myricinosyltylonolide has an antibacterial activity (Japanese Patent Application Laid-Open No. 2-275894).
  • the hydroxyl group at the 3-position of the macrolactone ring has low reactivity and it is difficult to introduce a substituent, and it has not been considered that the introduction of the substituent can enhance the antibacterial activity.
  • acetyl-O— (Bull. Chem. Soc. Jpn., 54 (12), 3837-3845 (1981))
  • Compounds substituted by T-carbonyl-O (J. Antibiot., 39 (12), 1724-1735 (1986)) are known.
  • Japanese Patent Application Laid-Open No. 62-50909 discloses a cladinosyl group as a 3-position substituent.
  • the present inventors have carried out various studies for the purpose of synthesizing new myominosyltylonolide derivatives. As part of these studies, the present inventors have developed an amino acid methyl group, a cycloalkylthiomethyl group, or an arylthiomethyl group at the 3-position hydroxyl group of myosinyl tynonolide ⁇ 4'-dexoximeinylsyltyronolide. Research was conducted to introduce a group.
  • the present inventors have succeeded in newly synthesizing myo-minosyltylonolide (hereinafter sometimes abbreviated simply as ⁇ )) or 4'-deoxymi-nosyltyronolide (hereinafter simply referred to as “4”).
  • ⁇ myo-minosyltylonolide
  • 4'-deoxymi-nosyltyronolide hereinafter simply referred to as “4”.
  • DMT 3- 3- (alkyl- or cycloalkyl- or arylthiomethyl) derivatives have excellent antibacterial activity against certain Gram-positive and Gram-negative bacteria
  • the derivatives are recognized as being useful as fungicides, and their derivatives are expected to have an activity of inhibiting the growth of spirochetes and protozoa and other biological activities.
  • R represents a group CHSR 1 (where R 1 is an alkyl group, a cycloalkyl group or an aryl group), and Me represents a methyl group].
  • R 1 is an alkyl group, a cycloalkyl group or an aryl group
  • Me represents a methyl group.
  • the myominosyltylonolide derivatives of the general formula (I) according to the present invention can be two groups of derivatives represented by the following formulas (Ia) and (Ib), respectively.
  • a 3-O 1 (alkyl-, cycloalkyl-, or arylthiomethyl) derivative of myosinosyltyronolide ie, 3-O — (Alkyl or cycloalkyl mono or arylthiomethyl) myosinosyltylonolide.
  • the alkyl group is a straight-chain or branched ( ⁇ , to ⁇ ,.) Alkyl group, preferably ( C ⁇ CJ alkyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-heptyl group and n-hexyl group
  • the cycloalkyl group is a (C 3 -C 10 ) cycloalkyl group, preferably a (C 4 -C 6 ) cycloalkyl group, for example, a cyclopropyl group, Cycloheptyl group and cycle It can be a mouth hexyl group or the like.
  • the Ariru group, phenyl group, 0 6 ⁇ , ... such as a naphthyl group And a phenyl group.
  • 3-O-substituent—CH 2 SR 1 of the derivative of the general formula (I) according to the present invention include a methylthiomethyl group, an ethylthiomethyl group, an n-propylmethyl group, and an n-hexylthio group.
  • Preferred specific examples of the derivatives of the general formula (I) according to the present invention include the following compounds.
  • MT is an abbreviation for 4'-deoxy maiminosyltyronolide.
  • the method for producing the derivative of the general formula (I), that is, 3-O-substituted mono-aminosyltylonolide or 3-O-substituted 4'-deoxydimycinosyl-minosyltylonolide according to the present invention will be described.
  • the derivative of the general formula (I) can be produced by a six-step method comprising the following steps (a) to (f).
  • the protected myosinyltylonolide 20-dimethyl acetal is produced (see JP-A-57-281100).
  • the corresponding 20-dimethyl acetal is produced by using 4'-deoxymycinosyltylonolide instead of myosynyltylononolide.
  • the compound represented by the formula (III): MT or 4′-DMT 20-dimethyl Selectively protect only the 2'- and 4'-hydroxyl groups (when the raw material is MT) or only the 2'-hydroxyl group (when the raw material is 4'-DMT) of lacetal with an acetyl group (abbreviated as Ac)
  • the compound of formula (III) is reacted with acetic anhydride in acetonitrile anhydride at room temperature.
  • the reaction solution containing the compound of the formula (IV) is concentrated under reduced pressure.
  • the obtained residue is dissolved in toluene, washed with a saturated aqueous solution of sodium hydrogencarbonate, dehydrated, and concentrated to dryness under reduced pressure to obtain a compound of the formula (IV) as a solid.
  • R 1 is an alkyl group, a cycloalkyl group, or a phenyl group
  • the reaction solution containing the compound of the formula (V 1 I) is concentrated under reduced pressure.
  • the obtained syrup-like substance is purified by silica gel single-pressure ram chromatography, the compound of the formula (VII) is obtained as a solid.
  • the reaction solution containing the compound of the formula (IX) is concentrated under reduced pressure.
  • the resulting syrupy substance is purified by silica gel-one column chromatography to isolate the compound of the formula (IX).
  • the reaction solution containing the compound of the formula (I) is made slightly alkaline with an aqueous solution of sodium hydrogen carbonate, and then extracted with chloroform.
  • the port-mouth form extract is dehydrated and further concentrated under reduced pressure.
  • the obtained residue is purified by silica gel single column chromatography (eluent: chloroform-form-methanol-28% aqueous ammonia, eluted with 15: 1: 0.1) to give a compound of the formula (I).
  • the compound of the present invention thus produced can be isolated and purified as a salt, a hydrate, a solvate, or a crystalline polymorph of the compound as free.
  • the salt of the compound (I) of the present invention can also be produced by subjecting the salt to a conventional salt formation reaction.
  • the compound of the present invention forms a salt.
  • it is an acid addition salt with an inorganic acid or an organic acid, and a pharmaceutically acceptable salt is preferable.
  • these salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, With organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, or acidic amino acids such as aspartic acid or glutamic acid Addition salts can be mentioned.
  • the starting compounds of the above-mentioned production methods include novel substances, but they can be produced by applying the production methods described in the examples, methods based on the production methods, or modified methods arbitrarily practicable by those skilled in the art. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Industrial applicability
  • the compounds of the present invention are useful as fungicides, and their derivatives are expected to have activity to inhibit the growth of protozoa and other biological activities.
  • Preparations containing one or more of the compound of the present invention or a salt thereof as an active ingredient are prepared using carriers, excipients and other additives usually used for preparation of preparations.
  • Administration may be oral, such as tablets, pills, capsules, granules, powders, or liquids, or parenteral, such as intravenous or intramuscular injections, suppositories, or transdermals.
  • the dose should be appropriately determined according to the individual case in consideration of the symptoms, age of the subject, gender, etc., and usually about 0.01 to 1 OOOmg / day, preferably 0 to 1 mg / day for an adult in the case of oral administration. 0.1 to 100 mg / day, for parenteral administration, 0.1 to 100 mg / day for adults, preferably about 0.01 to 5 mg / day. ⁇ 4 divided doses.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. , Meta-silicic acid, mixed with magnesium aluminate.
  • the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizers such as lactose. , Glutamic acid or aspartic acid.
  • tablets or pills may be coated with sugar such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose or the like, or with a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as purified diluents. Contains water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
  • Such compositions may also include adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). May be.
  • My Power Minosyltylonolide (MT) 20 Dimethyl acetal (2.183 g, 3.38 mmol I) was dissolved in 4 Om I of acetonitrile anhydride, and 0.96 ml of acetic anhydride (10.14 mmol I) was dissolved. , 3 moI eq.) And stirred for 1.5 hours at room temperature for O-acetylation. After completion of the reaction, the solvent was concentrated under reduced pressure from the reaction solution, and the obtained residue was dissolved in 20 OmI of toluene and washed with saturated aqueous sodium hydrogen carbonate. The toluene solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried to give 2.576 g of the title compound 1 as a yellowish white solid.
  • Main signal 5 (ppm): 2.49 (s, NMe2), 4.83 (s, ⁇ CH2S), 2.13 (s, SMe).
  • Example 6 (c) (Approximately 3: 2 by volume) at 50 ° C in the same manner as in Example 6 (c) in the same manner as in Example 6 (c), except for anhydrous ethyl methylsulfoxide, n-hexylmethylsulfoxide, cyclohexylmethylsulfoxide or phenyl. Reacted with methylsulfoxide.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
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  • Genetics & Genomics (AREA)
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Abstract

L'invention concerne de nouveaux dérivés du mycaminosyltylonolide, représentés par la formule générale (I), dans laquelle X représente un groupe hydroxyle ou un atome d'hydrogène; R représente CH2SR?1 (où R1¿ représente un groupe alkyle, cycloalkyle ou aryle); et Me représente un groupe méthyle; ainsi que leurs sels et des médicaments les contenant. Ces composés ont une excellente activité antimicrobienne contre les bactéries Gram positives et Gram négatives, et sont utiles comme antibiotiques de la famille des macrolides.
PCT/JP1998/000954 1997-03-10 1998-03-09 Nouveaux derives du mycaminosyltylonolide WO1998040393A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61210/98A AU6121098A (en) 1997-03-10 1998-03-09 Novel mycaminosyltylonolide derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/55118 1997-03-10
JP05511897A JP4106104B2 (ja) 1997-03-10 1997-03-10 新規マイカミノシルタイロノライド誘導体

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WO1998040393A1 true WO1998040393A1 (fr) 1998-09-17

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PCT/JP1998/000954 WO1998040393A1 (fr) 1997-03-10 1998-03-09 Nouveaux derives du mycaminosyltylonolide

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JP (1) JP4106104B2 (fr)
AU (1) AU6121098A (fr)
WO (1) WO1998040393A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06238465A (ja) * 1993-02-19 1994-08-30 Honda Motor Co Ltd チップドレッサの刃具

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5944398A (ja) * 1982-08-02 1984-03-12 フアイザ−・インコ−ポレ−テツド 抗菌性マイコサミノシルタイロノライド及び関連マクロライド誘導体
WO1993014101A1 (fr) * 1992-01-14 1993-07-22 Zaidan Hojin Biseibutsu Kagaku Kenkyukai Derive de 3,4'-didesoxymycaminosyltylonolide et production de ce compose

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5944398A (ja) * 1982-08-02 1984-03-12 フアイザ−・インコ−ポレ−テツド 抗菌性マイコサミノシルタイロノライド及び関連マクロライド誘導体
WO1993014101A1 (fr) * 1992-01-14 1993-07-22 Zaidan Hojin Biseibutsu Kagaku Kenkyukai Derive de 3,4'-didesoxymycaminosyltylonolide et production de ce compose

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AU6121098A (en) 1998-09-29
JPH10251291A (ja) 1998-09-22
JP4106104B2 (ja) 2008-06-25

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