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WO1986005784A1 - Antibiotiques et preparation les contenant - Google Patents

Antibiotiques et preparation les contenant Download PDF

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Publication number
WO1986005784A1
WO1986005784A1 PCT/JP1985/000160 JP8500160W WO8605784A1 WO 1986005784 A1 WO1986005784 A1 WO 1986005784A1 JP 8500160 W JP8500160 W JP 8500160W WO 8605784 A1 WO8605784 A1 WO 8605784A1
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WIPO (PCT)
Prior art keywords
group
reaction
compound
tan
heavy water
Prior art date
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PCT/JP1985/000160
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English (en)
Japanese (ja)
Inventor
Hiroshi Shimadzu
Susumu Shinagawa
Isao Minamida
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Takeda Chemical Industries, Ltd.
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Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1985/000160 priority Critical patent/WO1986005784A1/fr
Priority to JP61063737A priority patent/JPS61257973A/ja
Publication of WO1986005784A1 publication Critical patent/WO1986005784A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/08—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/08—Bridged systems

Definitions

  • the present invention relates to a novel ansamycin antibiotic having an antibacterial activity and a preparation containing the same.
  • Damavaricin D is known [Journal of Antibiotics, Vol. 29, No. 201]. ⁇ 203 (1976)].
  • the tansamycin antibiotic TAN-528A is produced and accumulated by culturing Streptomyces sp.
  • the present inventors synthesized various derivatives using the antibiotic TAN-528A as a raw material, and examined the pharmacological action thereof. As a result, they found that the derivatives had excellent antibacterial activity.
  • the present invention relates to (I) a compound represented by the general formula: [1]
  • R 1 and R 2 are the same or different and are each a hydrogen or carbon atom or
  • R 5 represents a divalent group via two carbon atoms which may have a substituent; This indicates that A— is bonded to the para-position of the 1 ⁇ 0 group of the benzene ring, and that Reiichi is bonded to the meta-position of the R group of the benzene ring in Formula [1].
  • R 6 is a group which can be derived from carboxy, carboxyl, or a group which can be derived from a 7- or 13-position mono-OH. That 0 H taractones may be formed, Y is one CO— or one? One (where
  • R 7 indicates that R 1 forms a 5-membered ring with one OR 1 where an organic residue through a carbon atom. )).
  • R 1 and R 2 are hydrogen, R 6 is methoxycarbonyl and Y is — C 0 —
  • X is not when R 1 is methyl and R 2 is hydrogen and R 6 is
  • X is when ,,, and are methoxycarbonyl and Y is —C 0—
  • organic residue via the carbon atom represented by R 1 or R 2 those having a molecular weight of up to 400 are preferable, and examples thereof include, for example, alkyl, alkenyl, alkynyl, aralkyl, acyl, and alkyloxy groups.
  • Luponyl and the like which may have 1 to 3 substituents.
  • one having a molecular weight of up to 300 is preferable, and for example, for example, a compound of the formula R 3 —S 0 2 — ( Wherein R 3 represents an alkyl, aryl or heterocyclic ring; These may have 1 to 3 substituents. ).
  • organic residue via the carbon atom represented by those having a molecular weight of up to 200 are preferable, and examples thereof include alkyl, alkenyl, alkynyl, acyl, alkoxycarbonyl, and acylboxycarbonyl. And these may have 1 to 3 substituents.
  • organic residue via the nitrogen atom represented by R 4 those having a molecular weight of up to 300 are preferable, and examples thereof include, for example, amino, secondary amino, and tertiary amino rings. Tertiary amino, etc., which may have 1 to 3 substituents.
  • secondary amino examples include monoalkylamino, dicycloalkylamino, monoarylamino, monoalkylamino, and the like.
  • tertiary amino examples include dialkylamino, dicycloalkylamino, diarylamino, diaralkylamino, X-alkyl-1: ⁇ : — arylamino, —alkiryl N-aralkylamino, and the like. No.
  • tertiary amino forming the ring examples include morpholino, pyrrolidino, piperazino, hexamethyleneimino and the like.
  • These primary amino, secondary amino, tertiary amino, and tertiary amino forming a ring may have 1 to 3 substituents.
  • organic residue via the oxygen atom represented by R 4 those having a molecular weight of up to 200 are preferable, and examples thereof include, for example, alkoxy, acyloxy, alkyloxycarbonyloxy, and aralkyloxy. Carbonyloxy, alkylsulfonyloxy, arylsulfonyloxy, etc. These may have 1 to 3 substituents.
  • R 3 ′ -S (O) n- (wherein, R 3 ′ represents alkyl, aryl, aralkyl, heterocycle, or heterocyclic alkyl, which has 1 to 3 substituents. N represents an integer of 0 to 2. Examples of the group include: In the above formula, examples of the halogen represented by R + include fluorine, chlorine, bromine, and iodine.
  • the divalent group via two carbon atoms which may have a substituent represented by R 5 is preferably a group having a molecular weight of up to 300, and is preferably a group having a molecular weight of up to 300 via the two carbon atoms.
  • Examples of the divalent group include ortho-to-phenylene, ortho-naphthylene, vinylene, ethylene and the like, and these may have a 1-3 value substituent.
  • ester examples include an alkyl ester, an aryl ester, an aralkyl acetyl, an alkoxyalkyl ester, an acyloxy alkyl ester, and the like. These have 1 to 3 substituents. b good 0
  • amides examples include ammonia, monoalkylamine, dialkylamin, penoarylamine, diallylamine, penoaralkylamine, dialkylamine, N-alkyl-N-arylamine, and N-alkyl.
  • Amides with amines such as N-aralkylamine and cyclic amine, which may have 1 to 3 substituents.
  • R 1 ′ is, for example, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclohexyl, phenyl, benzyl, etc.
  • R 7 ′ is, for example, acetyl or acetyl. Examples include propionyl, benzoyl, nitrile, ethoxycarbonyl, methoxycarbonyl, ethylsulfonyl, methylsulfonyl, phenylsulfonyl, tolynisulfonyl, a nitro group, and carboxy.
  • alkyl refers to alkyl in alkoxy, alkyl in alkyloxy, alkyl in alkoxy, alkyl in carbonyl, alkyl in alkylsulfonyloxy, alkyl in monoalkylamino, alkyl in dialkylamino, N— Alkyl-N-arylamino and N-alkyl-alkyl in N-aralkylamino, alkyl in alkyl esters, alkyl in alkoxyalkyl esters, alkyl in monoalkylamines, alkyl in dialkylamines, N-alkyl-N- Alkyl in arylamine, N-alkyl-alkyl in N-alkylalkylamine is preferably, for example, one having 1 to 20 carbon atoms.
  • the alkyl may be straight-chain or branched. Specific examples of the alkyl include, for example, methyl, ethyl, propyl, isopropyl, and petit. , Isobutyl, sec-butyl, te-butyl, pentyl, hexyl, heptyl, octyl, nonyl, 2-ethylhexyl, decyl, pendecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl, Nonadecyl and eicosyl are examples.
  • alkenyl preferably has 2 ⁇ 6 carbon atoms.
  • Specific examples of the alkenyl include, for example, vinyl, aryl, isopropyl, methallyl, 1,1-dimethylaryl, 2-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl and the like.
  • alkynyl having 2 to 6 carbon atoms is preferable, and specific examples thereof include ethynyl, propargyl, 2-butyn-11-yl, and 3-butyn-11-yl.
  • 3 butin 1 -yl, 1 —pentin 1 -yl, 3 —pentin 1 -yl, 4 —pentin 2 -yl, 3 —hexine 1 -yl
  • cycloalkyl preferably has 3 to 3 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • acyl or in acyloxycarbonyl as acyl or in acyloxycarbonyl: as acyl in acyloxy, acyl in acyloxy, or acyl in acyloxyalkyl ester, for example, alkyl or alkenyl corresponding to R 1 or R 2
  • alkyl or alkenyl corresponding to R 1 or R 2 examples include phenyl, alkynyl, and aryl corresponding to R 3 (described below), and an acyl group obtained by introducing a carbonyl group or an oxycarbonyl group into a heterocyclic ring, and acetyl, propionyl, and butyryl.
  • Heterocyclic carbonyls such as alkylcarbonyl, such as carbonyl, hexanoyl, heptanyl, octanoyl, and decanol; arylcarbonyl, such as benzoyl and naphthoyl; thiophenecarbonyl, furancarbonyl, and pyridinecarbonyl.
  • Alkoxycarbonyl groups such as, methoxycarbonyl and ethoxycarbonyl; Wenoki Examples include aryloxycarbonyl groups such as cyclocarbonyl and naphthyloxycarbonyl, and arylalkoxycarbonyl groups such as benzyloxycarbonyl.
  • aryl in arylsulfonyloxy, aryl in monoarylamino, aryl in diarylamino, aryl in N-alkyl-1 aryl in N-arylamino, aryl in aryl ester.
  • aryl in monoarylamine, aryl in diarylamine, and aryl in N-alkyl-N-arylamine include, for example, phenyl and naphthyl. And the like.
  • examples of the heterocyclic ring represented by R 3 include phenyl, furyl, pyridyl and the like.
  • the heterocyclic ring represented by R 3 ′ or the heterocyclic ring in the heterocyclic alkyl includes, for example, chenyl, furyl, pyridyl, and an oxygen atom, a sulfur atom, and a heteroatom such as a nitrogen atom.
  • 5- to 8-membered rings or bonding rings having a bond on a carbon atom such as 2 — or 3 — pyrrolyl, 2 — or 3 — furyl, 2 — or 3 — phenyl, 2 — Or 3—pyrrolidinyl, 2—, 3— or 4-pyridyl, N—one oxide 2—, 3—or 4—pyridyl, 2—, 3— or 4-piperidinyl, 2—, 3— Or 4-pyranyl, 2-, 3- or 4-thioviranyl, pyrazinyl, 2-, 4-one or 5-thiazolyl, 2-, 4-one or 5-oxazolyl, 3-, 4_ or 5-isothiazolyl, 3 —, 4 mono or 5 — iso Oxazolyl, 2—, 4— or 5— imidazolyl, 3—, 4— or 5—pyrazolyl, 3— or 4 monopyridazinyl, N—oxydoh 3— or 4—pyrida
  • aralkyl is defined as aralkyl in aralkyloxycarbonyl, aralkyl in N-alkyl-N-aralkylamine, aralkyl in diaralkylamino, aralkyl in diaralkylamino, and N-aralkyl-1N.
  • aralkyl in aralkylamino, aralkyl in aralkyl ester, aralkyl in monoaralkylamine, and aralkyl in diaralkylamine include, for example, benzyl, 2-phenethyl and the like. Examples thereof include morpholino, pyrrolidino, piperazino, hexamethyleneimino and the like.
  • the formed tertiary amine may have a substituent.
  • substituents include a hydroxyl group, a C 3 -cycloalkyl group (which may have a substituent), C B - 1 0 ⁇ Li - Le group, C + alkoxy group, C 3 (which may have a substituent.) - + alkoxy group, C 3 - 6 cycloalkyl Ruokishi group, C s-i.
  • G 7 — 12 aralkylthio, amino, mono C + alkylamino, di
  • Examples include a heterocyclic thio group, a heterocyclic oxy group, and a heterocyclic amino group.
  • alkyl, alkenyl, alkynyl and aryl groups which may be substituted on the cycloalkyl group, aryl and heterocyclic groups may be, for example, a hydroxyl group.
  • Examples of the groups which may be substituted on the above-mentioned alkoxy, alkoxycarbonyl, alkoxycarbonyloxy, acyloxycarbonyl, acyloxy, alkyl ester, alkylsulfonyloxy, alkoxyalkyl ester and acyloxyalkyl ester include: For example, a hydroxyl group, C t - 4 ⁇ Rukokin, C alkylthio group, Amino group, mono C ⁇ Arukiruamino group, di C t - + Arukiruamino group, ⁇ 6 - 1 0 ⁇ Li - Ruamino group, C 7 - 1 2 Ararukiru Amino Group, nitro group, halogen atom, carboxy group, C-alkoxy-propanol group, C-alkynyl group, Ci-5-alkyloxy group, sulfo group, lbamoyl group, substitution rubamoyl group,
  • diaralkylamine, N-alkyl-aralkyl in N-aralkylamine, a heterocyclic ring represented by R 3 ′, and a group which may be substituted by a heterocyclic alkyl heterocyclic ring include, for example, a hydroxyl group, an alkyl group group (which may have a substituent), (which may have a substituent) C 8 one 1 0 Ariru group, C 3 - s consequent opening alkyl group Roh, androgenic atom, a carboxyl group, a sulfo group , ⁇ alkoxy groups, C alkylthio group, two preparative port groups, C t-+ alkoxy - carboxymethyl group, an amino group, a mono C - 4 alkylamino amino group, di C - 4 alkylamino groups, C Rukanoiruami de group, ⁇ 8 - 1 0 ⁇ Li - Ruokishi group, 0 7 - 1 2 Araru kill
  • Examples of the divalent substituent may have the groups represented by R 5, was example, if hydroxyl Bruno, androgenic, C ie alkyl group, 0 3 - 6 consequent opening alkyl, Ce-io ⁇ Li 'Lumpur group , C alkoxy, C t -alkylthio, amino, mono C + alkylamino, di C alkylamino, azide, ditro, cyano, carboxy, C 4 alkoxy-carbonyl, C alkyl I le group, C 2 one 5 Arca noisy Ruo alkoxy group, a sulfo group, a force Rubamoiru group, Cal Bamoiruokishi group, C t-+ Al force Noiruami de group, etc. Okiso group like et be.
  • Examples of the C- 4 alkyl group as a substituent include methyl, ethyl, propyl; isopropyl, butylisobuty), sec-butyl, tert-butyl, and the like.
  • C 3 - beta for example cyclopropyl cycloalkyl group, Shikuropuchi Le, cyclopentyl, cyclohexylene, etc. cyclohexyl force
  • C 0 aryl groups examples include phenyl and naphthyl.
  • the Ararukiru group such as benzyl, 1 Fuenechiru, 2-phenethyl, 1 - Fuwenirupuropiru, 2 Fuwenirupuropiru, 3-phenylene pulp outlet pills,
  • C alkoxy groups include methoxy, ethoxy.propoxy, isopropoxy, butoxy and tert-butoxy.
  • aryloxy groups include phenoxy and naphthoxy.
  • CL- + alkylthio groups include methylthio, ethylthio, propylthio, and butylthio.
  • C 3 - 6 cycloalkylthio The group e.g. cyclopropylthio, such as cyclohexylthio to shea click port,
  • the 2 Ararukiruchio group e.g. benzylthio and mono C Arukiruami amino group as, for example Mechiruami Bruno, Echirua amino, propylamino, Puchiruamino like,
  • dialkylamino group examples include dimethylamino, getylamino, dipropylamino, dibutylamino, and the like.
  • C G -t 0 arylamino groups include, for example, anilino,
  • the C 7 one 1 2 Ararukiruamino groups such Benjiruamino, such as 2-Hue Nechiruami Bruno is,
  • halogen atoms include fluorine, chlorine, bromine, and iodine.
  • C alkoxy-carbonyl groups include methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, and the like.
  • aryloxycarbonyl groups include phenoxycarbonyl, C 3 - 6 consequent opening alkyl O carboxymethyl
  • Examples of the C 7 -L 2 aralkyloxycarbonyl group include benzyloxycarbonyl and the like.
  • d-5 alkanoyl groups include, for example, formyl, acetyl, propionyl, butyryl phenol, pivalyl, etc.
  • Alkanoyloxy groups include, for example, formyloxy, acetoxy, butyryloxy, bivaloyloxy and the like.
  • substituent groups include N-methylcarbamoyl,, N-dimethylcarbamoyl, N-ethylcarbamoyl, N-phenylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl and the like. But,
  • substituted thiolvamoyl groups include —methylthio lvamoyl.
  • substituent groups include N-methylcarbamoyloxy, N, -dimethylcarbamoyloxy, and M-ethylcarbamoyloxy.
  • Examples of the C + alkanoylamide group include formylamino, acetoamide, propionamide, and butyrylamide.
  • Examples of the C alkoxy-carbonylamino group include methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylamino, and the like.
  • C 7 - 1 such as 2 ⁇ Lal Kill O carboxymethyl
  • the carbonylamino group for example benzyl Ruo alkoxycarbonyl ⁇ Mino is,
  • Examples of the optionally substituted C alkyl group include, for example, methoxymethyl , 2-Methoxyxetil, hydroxymethyl, fluoromethyl, trifluoromethyl, difluoromethyl, carboxymethyl, ethoxycarbonylmethyl, potassium benzyl, cyanoethyl, acetylmethyl, etc.
  • heterocyclic group examples include a cyclic group containing one to four nitrogen atoms, one oxygen atom and one sulfur atom, such as pyrrolidino, 2-pyrrolyl, 3-pyrrolidinyl,
  • 3 pyrazolyl, 2 — imidazolyl, 2 — furyl, 2 — phenyl, 2- oxosazolyl, 3 — isoxazolyl, 4 — isothiazolyl, 4-thiazolyl, piperidino, 2 — pyridyl, 3 — pyridyl Jill, 4—pyridyl, piperazino, 2—pyrimidinyl, 5—pyrimidinyl, 2—viranyl, 2—tetrahydropyranil, 2—tetrahidrofril, 3—indrillyl, 2—quinolyl, 1 , 3,
  • R include, for example, hydrogen, hydroxy, halogen, and methyl.
  • 2-Etoquinol-Lupirylethylthio 2-Acetoxicetylthio, 2-Sulphoethylthio, 2-Lubamoylethylthio, 2-Dimethylcarbamoylthio, 2-Lubamoyloxethylthiol, 2 -Dimethylcarbazyloxy, 2-acetamidoethylthio, 2-ethoxycarbonylaminoethylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl , Tert-butylsulfinyl, benzylsulfinyl, phenylsulfinyl, naphthylsulfinyl, furylsulfinyl
  • R 5 specifically, for example, 1,2-phenylene, 4-methyl-1,0-l, 2-phenylene, 5-methyl-11,2-phenylene, 4-ethylene
  • R 8 specifically, for example carboxy, main butoxycarbonyl, ethoxycarbonyl, propyl O alkoxycarbonyl, butyl O propoxycarbonyl two , Methoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 1-methoxyethoxycarbonyl, methylthiomethoxycarbonyl, 2-methylthioethoxycarbonyl, acedoxymethoxycarbonyl, 1-acetomethoxycarbonyl, 1-ethoxy Quincarbonyloxyethoxycarbonyl, ethoxycarbonyloxymethoxycarbonyl, bivaloyloxymethoxycarbonyl, 1-pivaloyloxyethoxycarbonyl, aryloxycarbonyl, 2,2,2—tricycloethylethylo Xycarbonyl, phenoxycarbonyl, 4-methoxyphenyloxycarbonyl, 2,4-dimethoxyphenyloxycarbonyl, 412-nitrophenyloxycarbonyl
  • T A — 528 A carboxylic acid
  • the compound [1] of the present invention can be produced, for example, by the method described below5.
  • the compound [3] when the organic residue via the carbon atom is an alkyl, alkenyl, or alkynyl which may have a substituent, the compound [3] may be subjected to a reaction known per se, 2 performed by reaction with a reagent or basic reagent
  • Examples of the acidic reagent used include pentahydrohalic acids such as hydroiodic acid and hydrobromic acid, Lewis acids such as anhydrous trimethylsilane, anhydrous aluminum chloride, boron trifluoride and boron tribromide.
  • a basic reagent Is a power such as lithium iodide, magnesium iodide, sodium or lithium thiolate, lithium thiophenolate or the like, or a magnesium salt, especially Lewis acid, especially anhydrous Aluminum chloride is preferred.
  • the reaction is preferably carried out in a solvent
  • the solvent may be a halogenated hydrocarbon such as dichloromethane, an ether such as ether or tetrahydrofuran, or an aromatic hydrocarbon such as benzene, toluene, or xylene.
  • a halogenated hydrocarbon such as dichloromethane
  • an ether such as ether or tetrahydrofuran
  • an aromatic hydrocarbon such as benzene, toluene, or xylene.
  • the reaction temperature is appropriately selected from the range of about ⁇ 70 ° C. to 150 ° C.
  • the reaction temperature is selected from the range of about 50 ° C. to 120 ° C. Is good.
  • the reaction time is about 0.1 to 10 hours.
  • the compound [3] is converted to an acid [eg, Mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and strong organic acids such as trifluor ⁇ -acetic acid, toluenesulfonic acid, methanesulfonic acid, etc. or bases [(row, sodium carbonate, calcium carbonate) , Sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, etc.] or tert-butoxy potassium, lithium iodide, lithium propyl.
  • an acid eg, Mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and strong organic acids such as trifluor ⁇ -acetic acid, toluenesulfonic acid, methanesulfonic acid, etc. or bases [(row, sodium carbonate, calcium carbonate) , Sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide,
  • the base When the base is used as the reaction reagent, if the reaction is performed in an anhydrous solvent, if necessary, add water to the reaction solution or transfer the reaction solution to water. After opening, acid (eg, Acid, and collecting the product After the neutralized or acidified with, etc. ⁇ acid).
  • acid eg, Acid
  • the solvent examples include lower alcohols such as methanol and ethanol, polar nonprotonic solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphorotriamide, or a mixture thereof.
  • a mixed solvent of water is frequently used.
  • the reaction temperature is not about -10 and 100 ° C, preferably about 1-5 It is not 7 0 '.
  • R 1 is also a carbon atom in the general formula: 1] properly: or - S 0 2 - compound is an organic residue through a [4], R 1 of the general formula [1] is hydrogen, Y is -
  • the compound can be produced by introducing an organic residue via a carbon atom or 1 S 0 2 — into a compound [5] that is CO— and, if necessary, subjecting the obtained compound to a cyclization reaction.
  • the introduction reaction include an alkylation reaction, an alkenylation reaction, an alkynylation reaction, an acylation reaction, and a sulfonylation reaction.
  • the alkylation, alkenylation or alkynylation reaction can be carried out by a method known per se or a method analogous thereto.
  • the alkyl, alkenyl or alkynylating agent to be used in the reaction the corresponding alkyl, alkenyl or alkynyl halide (eg, chloride, bromide, oxide, etc.) is most preferred, but other than that.
  • the amount of the alkyl, alkenyl or alkynylating agent to be used depends on the reactivity and the like, but is usually in the range of about 1 to 100 moles per mole of the compound: 5; High halides (eg, benzyl halide, phenacylharadono, ⁇ -genoketone, logenog, acid, arylaryl, propargylhalide, which generally has substituents, generally alk; le, alkenyl, or alkynylyo 5 to 10 times mol in the case of amide, etc., about 10 to 20 times when bromide is used, and about 10 to 50 times when chloride is used. Molar amounts are used. '
  • the solvent used in the alkyl, alkenyl or alkynylation reaction is not particularly limited as long as it can dissolve the reaction reagent in a relatively good manner.
  • examples thereof include alcohols such as methanol and ethanol, and dimethyl ether. Tell, Ethers such as tetrahydrofuran and dimethoxetane; ketones such as acetone and methylethylketone; amides such as dimethylformamide and dimethylacetamide; dimethylsulfoxide and sulfolane;
  • Examples include halogenated hydrocarbons such as sulfoxides and sulfones, dichloromethane, chloroform, and aromatic hydrocarbons such as benzene, toluene, and xylene. Of these, methanol is preferred.
  • the reaction temperature may be about ⁇ 10 ° C. to 50, and the reaction time may be about 1 to 24 hours.
  • silver salts such as silver oxide and bases (eg, inorganic bases such as carbonated lime, alkali metal alcohols such as sodium methylate and lithium methylate, triethylamine, pyridine, dimethylamide)
  • bases eg, inorganic bases such as carbonated lime, alkali metal alcohols such as sodium methylate and lithium methylate, triethylamine, pyridine, dimethylamide
  • the reaction rate can be increased and the yield can be improved by coexisting an amine such as pyridine.
  • crown ethers eg, 18-crown-6
  • quaternary ammonium salts eg, tetraethylammonium chloride, benzyltri'methylammonium chloride, cetyltrimethylammonium chloride
  • the reaction may be carried out not only in the above-mentioned solvents but also in a mixed two-phase system of these solvents and water.
  • an iodide ion source such as potassium iodide or sodium iodide to the reaction system.
  • the alkylation reaction can also be performed using a diazoalkane such as diazomethane as a reaction reagent.
  • the reaction is carried out in a solvent such as alcohols (eg, methanol), ethers (eg, getyl ether, tetrahydrofuran, etc.), and ester solvents (eg, ethyl citrate).
  • a solvent such as alcohols (eg, methanol), ethers (eg, getyl ether, tetrahydrofuran, etc.), and ester solvents (eg, ethyl citrate).
  • boron trifluoride, fluoroboron or the like may be added as a reaction accelerator.
  • the reaction is—20 ° C to 30 ° C. Performed at a temperature of C.
  • the alkylation reaction can also be carried out with 0-alkyl-X, -disubstituted isourea (eg,
  • 0- methyl, 0- Echiru, 0- benzyl -: ⁇ , ⁇ '- dicyclohexyl Kishiruiso urea, etc. can also be a carried out as a reaction reagent.
  • the solvent include ethers (eg, tetrahydrofuran, didioxane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), esters (eg, ethyl acetate, etc.), aromatic hydrocarbons Hydrogen (eg, benzene, toluene, xylene, etc.) is used.
  • the reaction temperature is about 40 ° C to 150 ° C.
  • the alkylation and alkenylation reaction can also be carried out by reacting a compound [5] with a reactive reagent having an unsaturated bond [eg, argens (eg, isobutylene, methyl acrylate, ethyl acrylate, acrylate).
  • a reactive reagent having an unsaturated bond eg, argens (eg, isobutylene, methyl acrylate, ethyl acrylate, acrylate).
  • the reaction can also be performed by reacting lonitrile, methacrylonitrile, etc.), or alkyne granules (eg, methyl propiolate, cyanoacetylene, etc.).
  • the reaction is carried out in a solvent [eg, ether (eg, diethyl ether, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbon (eg, dichloromethane, etc.)], acid (eg, sulfuric acid, etc.), Bases [eg, alkali metal alkoxides (eg, sodium methylate, etc.), tertiary amines (eg,. ⁇ '-Methylmo,' refolin, etc.), quaternary ammonium salts (eg, benzyltrimethyl) Such as ammonium hydroxide).
  • a solvent eg, ether (eg, diethyl ether, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbon (eg, dichloromethane, etc.)]
  • acid eg, sulfuric acid, etc.
  • Bases eg, alkali metal alkoxides
  • acylating agent used in the acylation reaction acyl halide is preferable.
  • the amount of the acylating agent to be used is preferably an equimolar amount or more, and more preferably i.
  • the solvent used for the acylation reaction is not particularly limited as long as it can dissolve the compound [5] and the acylating agent, but is preferably a solvent such as methylene chloride, chloroform, tetrahydrofuran, and dioxane. And so on.
  • the reaction temperature is about --30 to 25 ° C and the reaction time Is about 0.1 to 3 hours.
  • coexisting amines such as triethylamine. Pyridine and dimethylamino pyridine in the present reaction system, side reactions can be suppressed and the yield can be improved.
  • Y is a group represented by the formula C— (where R 7 is as defined above)
  • the compound [6] which is a group represented by the formula (1) is a compound [4] wherein Y is —CO— and R 1 is an ⁇ -keto group—nitrile group, and —alkoxycarbonyl group, , Or an alkyl group having a monosulfonyl group or a carboxy group (which may be further substituted but has at least one hydrogen atom) [7] by intramolecular aldol condensation. it can.
  • the intramolecular aldol condensation reaction can proceed only by dissolving it in an organic solvent, especially benzene, phenol, and dichloromethane.
  • the catalyst is accelerated by using a catalytic amount of a base such as triethylamine or benzylamine as a catalyst. Is done. Silica gel or molecular sieve may be used as a catalyst.
  • the reaction is advantageously carried out at room temperature, the reaction time depending on the starting material: 7] and the structure of the base, but generally requires about Q.24 to 24 hours.
  • the compound [8] in which R 2 is a carbon atom or an organic residue via —S 0 2 — in the general formula [1] is different from the compound [9] in which R 2 is hydrogen in the general formula [1] by a carbon atom or — It can be produced by reacting a compound capable of introducing an organic residue via —SO 2 —.
  • the introduction reaction include an alkylation reaction, an alkenylation reaction, an alkynylation reaction, an acylation reaction, and a sulfonylation reaction.
  • the reaction reagent, reaction conditions, and the like in the introduction reaction are the same as those in the production of compound [4] from compound [5] described above, but more severe conditions are often required. In that case Use excessive amounts of reagents, raise the reaction temperature, and increase the reaction time.
  • the oxidizing agent meta-chloro ⁇ -perbenzoic acid, sodium metaperiodide, etc. are used.
  • a solvent for the reaction a solvent which dissolves the compound [10] and the oxidizing agent is desirable.
  • methachloroperbenzoic acid usually, dichloromethane, chloroform, ethyl acetate, methanol and the like are used. It is preferably used.
  • sodium metaperiodate is used as the oxidizing agent, a mixed solvent with water is preferable.
  • reaction time is about 0.1 to 24 hours.
  • the progress of the reaction can be monitored by thin layer chromatography (TLC) or the like.
  • the compound [1 2] in which R + is hydrogen in the general formula [1] is obtained by subjecting the compound [1 1] (supra) in which R + is -S— in the general formula [1] to a desulfurization reaction.
  • a desulfurization reaction It can be manufactured by the following.
  • the desulfurizing agent include organic compounds such as Raney Nigel and triptyl hydride and trivalent organic phosphorus compounds such as triphenylphosphine, trimethylphosphite and triethylphosphite.
  • the amount of desulfurizing agent used is about 1 equivalent or more when using an organic tin compound or a trivalent organic phosphorus compound. When Raney-Nigel is used, the amount used depends on its activity.
  • a desirable method is to observe the reaction status by TLC while introducing a small amount of Raney nickel into the reaction system, and if the raw material remains, add Raney nickel further, and do not use excess Raney nickel. is there.
  • a solvent used in the desulfurization reaction for example, when Raney nickel is used, methanol, ethanol and the like are used, and when an organic tin and an organic phosphorus compound are used, acetone, benzene, toluene and the like are preferably used. used.
  • the reaction temperature in the desulfurization reaction is about 30 to 100 ° C, and the reaction time is about 0.5 to 24 hours.
  • the compound [13] in which R + is hydroxy is, for example, a by-product when the dehydration reaction and the substitution reaction at the 25-position proceed in the same system, or as a compound [ 11] with sodium borohydride.
  • the amount of sodium borohydride is about 1 to ⁇ -fold molar amount, and tetrahydrofuran and dioxane are used as solvents. Etc. are preferably used.
  • the reaction temperature is generally about 25 ° to 100 ° C., and the reaction time is often about 0.1 to 3 hours.
  • Compound [14] in which R + is a halogen in general formula [1] can be produced by subjecting compound [12] in which R 4 is H in general formula [1] to a halogenation reaction. it can.
  • the lower alkyl of -4 includes, for example, methyl, ethyl, ⁇ -propyl, isopropyl, ⁇ -butyl, isoptyl, t-butyl, etc., as the ring formed by ⁇ 8: ⁇ Lysine, ⁇ Hexamethyleneimine and the like.
  • the amount of the methylene salt and manganese dioxide used is excessive, usually about 2 to 1 ⁇ m.
  • a solvent used for the halogenation for example, acetonitrile is used in the reaction with methyleneimmonium salt, and in the reaction with manganese dioxide, for example, dichloromethane or the like is used.
  • the reaction temperature is about 50 to 100 ° C for the reaction with the former, the reaction time is about G.5 to 10 hours, and those for the reaction with the latter are about —10 ° to 30 °. About 1 to 24 hours at C.
  • R 4 is an organic residue via a carbon atom in the general formula [1].
  • [15] can be produced by subjecting a compound [12] in which R + is hydrogen in the general formula [1] to an organic residue introduction reaction via a carbon atom.
  • a methyleneimmonium salt represented by Reaction.
  • an excess amount usually about 2 to 10 times, is used, and acetonitrile is often used as a solvent.
  • the reaction temperature is about 50 to 100 ° C, and the reaction time is often about 0.5 to 10 hours.
  • the thus obtained amino-substituted methyl derivative can be easily converted to a hydroxy-substituted methyl derivative if desired.
  • Mannich reaction When the Mannich reaction is used, it can be carried out in the same manner as a technique known in the field of rifamycin. Such techniques include those described in N. Maggi, V. Arioli and P. Sensi, Journal of Medicinal Chemistry, 8_790 (1965). .
  • the compound [I 6] in which R is an organic residue group via a nitrogen atom is a compound [12] in which R 4 is hydrogen in the general formula [1]. It can be produced by subjecting to a residue introduction reaction.
  • the reaction for introducing an organic residue also via the nitrogen atom can be carried out in the same manner as in the art known in the field of rifamycin and its analogous compound tribomycin. Examples of the technology include the technology described in the following document.
  • the compound [17] in which R + is an organic residue through an oxygen atom in the general formula [1:] is a compound [13] in which R + is a hydroxyl group in the general formula [1] is an organic residue through an oxygen atom.
  • the reaction for introducing an organic residue via an oxygen atom includes an alkylation reaction, an acylation reaction, a sulfonylation reaction, and an alkyloxycarbonylation reaction.
  • the alkylation reaction, acylation reaction and sulfonylation reaction can be carried out under the same conditions as those for the conversion reaction from compound [5] to compound [4].
  • a diazo compound can also be used as an alkylating agent.
  • the alkyloxycarbonylation reaction can be carried out under the same conditions by using an alkyloxycarbonyl compound instead of the aryl halide used in the acylation reaction.
  • Compound [18] is a compound represented by the general formula [
  • R 5 has the same meaning as described above.
  • the compound can be produced by subjecting the obtained compound to a reduction reaction, if necessary.
  • the reaction of the compound [10] with the compound [19] is a cyclization reaction in which a dehydration condensation reaction at the 24 position and a substitution reaction at the 25 position occur simultaneously.
  • the reaction reagent used in the reaction is a compound having an amino group and a thiol group at two adjacent carbon atoms in the molecule.
  • the amount of the reaction reagent is generally used in excess, and is often used in an amount of about 1 to 10 moles per mole of the compound [10].
  • Examples of the solvent used in the reaction include dichloromethane, chloroform and the like.
  • the reaction temperature is about 130 ° to 50 ° C, and the reaction time is about 0.5 to 10 hours.
  • the reduction reaction is performed by bringing compound [18] into contact with a reducing agent.
  • a reducing agent for example, high Dorosarufuai preparative sodium (Na 2 S 2 0 4) , such as Asukorubin acid and the like, which normally excess is used.
  • the solvent used for the reduction reaction for example, ethyl acetate, ethanol, methanol, tetrahydrofuran, dioxane and the like can be mentioned.
  • the reaction temperature is about 0 to 50 ° C, and the reaction time is about 0.1 to 1 hour.
  • R 6 General formula [1] in R 6 are the 7-position or one 3-position of 0 and rings that are formed one C 0-,
  • Compound [2 0], in the general formula [1] R e is a carboxylic acid ester can be prepared by subjecting a compound [2 1] or the compound R B is a carboxylic acid [2 2] lactone ring formation reaction.
  • the lactone ring formation reaction is an intramolecular dealcoholation reaction when the compound [21] is used, and an intramolecular dehydration reaction when the compound [22] is used.
  • the lactonizing agent used in the reaction includes, for example, mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as methanesulfonic acid and ⁇ -toluenesulfonic acid, inorganic bases such as sodium hydroxide and hydroxide rim, and triethyl acetate.
  • Amin, benzylamine, pyri Examples include organic bases such as gin and piperidine, but in some cases the process proceeds simply by ripening.
  • the amount of the lactonizing agent used may be a catalytic amount or a solvent amount, and the solvent used in the reaction may be, for example, dichloromethane, chloroform, ethanol when using an organic acid or an organic base. When methanol or the like uses a mineral acid or inorganic base, ethanol or methanol
  • the reaction temperature is about 0 ° to 100 °. (The reaction time is about 0.1 to 10 hours.
  • the compound [22] in which R 6 is carboxy in the general formula [1] is a compound [22] in which R B is a carboxylic acid ester in the general formula [1]. 21] to a hydrolysis reaction.
  • the hydrolysis reaction can be carried out under the same conditions as ordinary ester hydrolysis reactions obvious to those skilled in the art.
  • the amount of the base is about 1 to 10 moles, preferably about 1.2 to 4 moles.
  • the reaction temperature and time largely depend on the type of alcohol component in the ester group, but are not about 120 to 70 ° C, respectively, preferably about -5 ° C, -30 and about 0.1 to 24 hours, preferably about 0.1 to 3 hours.
  • R 8 is a group that can be derived from carboxy, for example, a compound [21] which is a carboxylic acid ester, and a compound [23] which is an amide. It can be produced by subjecting it to a transesterification reaction or an amidation reaction in [21]. Alternatively, the lactone compound of compound [20] can be opened with an alcohol and an amine to produce compound [21] and compound [23], respectively.
  • the conversion to [21] can be achieved by (a) condensing compound [22] with the corresponding alcohol component by the action of an acid catalyst or a condensing agent, or (mouth) compound [22] or its carboxyl group.
  • an alkylating agent By reacting the salt in the above with an alkylating agent.
  • the reaction is usually carried out in a solvent.
  • the solvent used include ethers (eg, dimethyl ether, tetrahydrofuran, dimethoxetane), aromatic hydrocarbons (eg, 'benzene, toluene, etc.).
  • Acid catalysts or condensing agents that can be used include hydrochloric acid, sulfuric acid, phosphorus Mineral acids such as acids, organic acids such as benzenesulfonic acid, toluenesulfonic acid, etc., boron trifluoride, ferrous sulfate, Lewis acids such as anhydrous aluminum chloride, thionyl chloride, acetyl chloride, cuprate formate, chlorosulfone Acid, acid chlorides such as toluenesulfonic acid chloride, acid anhydrides such as trifluoroacetic anhydride, 2,2-dimethoxypro And acetal solvents such as dimethylformamide, dimethylacetate, etc.
  • the reaction temperature may be about 110-fold to about 110-fold, and the reaction temperature may be about 120-140 ° C (: preferably about 110-500 ° C). It is.
  • the salt may be a metal salt such as a sodium salt, a potassium salt, a calcium salt, a copper salt, a silver salt, or a triethyl ammonium salt.
  • a metal salt such as a sodium salt, a potassium salt, a calcium salt, a copper salt, a silver salt, or a triethyl ammonium salt.
  • Trialkylamines or quaternary ammonium salts such as pyridinium salts and tetraethylammonium salts are preferred.
  • These salts may be prepared before the esterification reaction, and may be a base corresponding to the solution of compound [22].
  • isonitriles eg, hexyl hexyl isonitrile, etc.
  • the base hydrolysis reaction solution in (a) may be used as it is.
  • those produced in the reaction solution may be used.
  • the alkylation reaction is preferably carried out in a solvent such as water, alcohols (eg, ethanol), ketones (eg, acetone), ethers (eg, methyl ether, tetrahydrogen).
  • amides eg, dimethylformamide, dimethylacetamide, hexamethyl phosphorotriamide, etc.
  • sulfoxides eg, dimethylsulfoxide, etc.
  • aromatics examples include hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (clean, dichloromethane, etc.), and these may be used alone or mixed to form a homogeneous or heterogeneous reaction system.
  • alkylating agent to be used include alkyl halides which may have a substituent (eg, chlorine, bromine, iodine, etc.
  • halogens eg, methyl iodide, benzyl chloride, benzyl chloride, benzyl chloride, hexyl chloride).
  • Trityl bromide, phenacyl bromide, etc. dialkyl sulfates (eg, dimethyl sulfate, getyl sulfate, etc.), trialkyl phosphinates (eg, trimethyl phosphate), trialkyl oxodimethyl salts (eg, triethyl) Oxonium tetrafluoroborate, etc.), phenol ethers (eg, butyl isopropenyl ether, etc.)
  • -Acetates eg, vinyl acetate, etc.
  • isobutylene with catalyst And sulfuric acid is preferred
  • diazoalkanes eg, diazomethane. Phenyldiazomethane, diphenyldiazomethane, etc.
  • the amount of the base used relative to the starting carboxylic acid is in the range of about 1 to 100 molar equivalents, preferably about 1 to 25 molar equivalents, and the alkylating agent (here, alkyl halide, dialkyl sulfate, etc.) is correspondingly used. Is used in an amount of about 0.8 to 120 molar equivalents, preferably about 1 to 30 molar equivalents.
  • the alkylation reaction may be carried out by adding a quaternary anidium compound as a so-called phase transfer catalyst (for example, the same as described above).
  • a carboxylic acid (compound [22] is selected as the starting material.
  • the alkylating agent is the compound [22]
  • the reaction may be carried out at room temperature, but the reaction proceeds at room temperature. Temperature, or a catalyst (eg, sulfuric acid, toluenesulfonic acid, acetic acid [mercury, tert-ethylamine], etc.) may be added.
  • the progress of the reaction can be controlled by an appropriate method (eg, thin-layer chromatography), since the diazoalkane itself may be unstable in the reaction solvent. It is advisable to use reagents that are necessary and sufficient for the reaction while tracing with various colors.
  • the reaction proceeds well at a temperature of about 0 to 30 ° C, but if necessary, it may be heated or heated (up to about 40-50 ° C) or a catalyst (eg, methanol, triethanol, etc.). (For example, boron fluoride).
  • the target compound [21] can also be obtained by transesterification of a certain compound [21].
  • an acid catalyst inorganic acids such as hydrobromic acid and sulfuric acid and perchloric acid, and organic acids such as benzenesulfonic acid, toluenesulfonic acid and methanesulfonic acid are preferred.
  • the reaction is carried out at room temperature to 200 ° C. (preferably at room temperature to 130 ° C.).
  • the amidation reaction of an ester form (compound [21]) or a lactone form (compound [20]) is carried out according to the general amidation of an ester, to a compound [21] or a compound [20].
  • the desired amino compound ie, ammonia (which can be introduced into the reaction system in the form of gaseous ammonia, concentrated aqueous ammonia, ammonia solution, ammonium chloride and bases) or amines, (Eg, methanol, ethanol, etc.), ethers (eg, tetrahydrofuran, etc.), sulfoxides (eg, dimethylsulfoxide, etc.) polar solvents or mixed solvents containing these solvents It is preferable to carry out the reaction by medium reaction.
  • base catalysts such as aluminum chloride, sodium methoxide, dimethylaminopyridine, and DBU (1,8-diazabicyclo [5,4,0] -7-indene) can be used.
  • the addition promotes the progress of the reaction and is sometimes preferred.
  • the reaction proceeds at a temperature within the range from room temperature to the boiling point of the solvent.
  • the amines may be ripened to a temperature of about 180 using amines themselves as a reaction medium. .
  • X is represented by the formula (wherein, R + has the same meaning as described above.
  • R has the same meaning as described above.
  • As a reagent for the reduction reaction ascorbic acid
  • the compound can be produced under the same conditions as in the above-mentioned reaction for producing the reduced form of the compound [18].
  • the target compound [1] thus obtained can be isolated and purified by a method known per se, such as concentration, solvent extraction, chromatography, crystallization, recrystallization and the like.
  • the compound [1] of the present invention may act with a base to form a salt.
  • the base include inorganic bases such as sodium, potassium, lithium, calcium, magnesium, and ammonia, and organic bases such as pyridine, collidine, triethylamine, and triethanolamine. ⁇ .
  • the compound [1] of the present invention When the compound [1] of the present invention is obtained in a free form, it may be formed into a salt using a conventional means, and the compound obtained as a salt may be converted into a free form using a conventional means. .
  • the compound [1] may form an inner salt, which is also included in the present invention.
  • Each of the stereoisomers of the compound [i] can be used alone or in a mixture as a medicament.
  • the compound [1] thus obtained is useful as a medicine, and has antibacterial activity against, for example, certain gram-positive and gram-negative bacteria.
  • Table 1 shows the antibacterial activity against (Mycobacterium tuberculos is H37Rv).
  • the minimum inhibitory concentration (MIC) was measured after 2 weeks of culture at 37 ° C by a dilution method using Kirchina medium supplemented with 5% bovine serum.
  • the toxicity of the compound [1] of the present invention is low.
  • the compound [1] of the present invention or a salt thereof exhibits antibacterial activity against certain gram-positive bacteria and gram-negative bacteria, and is also low in toxicity, thereby causing infection by bacteria. It can be used as a bacterial infection therapeutic or antibacterial agent for the treatment of bacterial infections in mammals (eg, mice, rats, dogs, cows, pigs, humans, etc.).
  • the daily dose of the compound [1: or a salt thereof is about 1200 mg / kg, more preferably about 10 to ⁇ 0 mg / kg of the compound [1: Is administered by mixing the compound [1] or a pharmaceutically acceptable salt thereof with a suitable pharmaceutically acceptable carrier, excipient, or diluent by conventional means. It can be administered orally in the form of granules, capsules, drops, or the like, or it can be formulated by conventional means, for example, into injections, and compounded into sterile carriers manufactured by conventional means. It can be administered orally.
  • a binder eg, hydroxypropyl propyl cellulose, hydroxypropyl methylcellulose, macro Gol, etc.
  • disintegrants eg, starch, carboxymethylcellulose calcium, etc.
  • emollients eg, lactose, starch, etc.
  • lubricants eg, magnesium stearate, talc, etc.
  • isotonic agents eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.
  • preservatives eg, benzyl alcohol, cuprate butanol
  • Para-hydroxybenzoate e.g., benzyl para-benzoate, etc.
  • buffers eg, phosphate buffer, sodium acetate buffer, etc.
  • the antibiotic TAN-528A which is a raw material compound used in the method of the present invention, is obtained by culturing an antibiotic TAN-528A producing bacterium belonging to the genus Streptomyces in a culture medium, and adding the antibiotic TAN-528A to the culture. It can be produced by accumulating and accumulating and collecting it. Specific examples of the producing bacteria include Streptom ces al bolongus C-46366 strain.
  • the microorganism can be obtained from the Fermentation Research Institute ( ⁇ F 0, Osaka, Japan). It was deposited under the accession number IF 0 14280 on August 5, 1983 at 183-85, Jusanhoncho, Yodogawa-ku, Ishikawa.
  • microorganism was submitted to the Research Institute of Microorganisms and Technology (FRI, 1-3-1 Higashi-Yatabe-cho, Tsukuba-gun, Ibaraki, Japan) at the Institute of Industrial Technology, Ministry of International Trade and Industry of Japan in August 1983. Deposited on the 9th as accession number FERM 7—7198.
  • the cells were inoculated with Treptomyces' Arbolongs C-146366 (FERMP-7198, IF014280) and cultured on a reciprocating shaker at 28 ° C for 2 days.
  • 1.5 J2 of the resulting seed culture was transferred to a 50-volume stainless steel tank containing 30 J2 of the same composition as the above seed medium, and cultured at 28 ° C for 2 days with aeration and agitation (aeration of 100 J2; agitation at 280 rpm) Min).
  • 5 Jg of the resulting seed culture was inoculated into a 200 J2 tank containing 100% of the main culture medium consisting of 3% glycerol, 0.5% meat extract, 0.5% NaC, and 0.5% peptone (pH 7.0).
  • Aeration and agitation culture (aeration 100%; agitation 200 revolutions / minute) was performed for 2 days.
  • the resulting culture solution was filtered using Hyflo Supercell (4.5Kg), the filtrate (80.2) was extracted with PH 3 using ethyl acetate (40J2 X 2), and the extract was extracted with 2% hydrogen carbonate. After washing with sodium water (40 ⁇ 2), concentrating the ethyl acetate layer, washing the concentrated solution (820 ml) with water, then concentrating the ethyl acetate layer, adding n-hexane to the concentrate and precipitating, A coarse powder (1.16 g) was obtained. The coarse powder ( ⁇ .9 g) obtained in the same manner was subjected to force ram chromatography on a gel (95 g).
  • TAM-528A TAM-528A (683 mg).
  • This powder was subjected to column chromatography with Sephadex LH-20 (340 ml), and the fraction containing the antibiotic TAN-528A eluted with ethyl acetate was concentrated to give a crystalline powder of the antibiotic TAN-528A. (506 mg) was obtained.
  • the physicochemical properties of the antibiotic TAN-528A obtained above are as follows.
  • the main peaks are as follows.
  • TAN-528A 674 mg was dissolved in 30 ml of dichloromethane, cooled to 0 ° C, 172 mg of m-chloroperbenzoic acid was added, and the mixture was stirred for 30 minutes.
  • Dichloromethane was distilled off under reduced pressure, and the residue was extracted with 100 mL of AcOEt.
  • the AcOEt solution was washed with water, dried over anhydrous Na 2 S 04, concentrated under reduced pressure, and the residue was collected by filtration with hexane to give 660 mg of yellow. A powder was obtained.
  • the eluate fractions from 460 ml to 610 ml were collected by the silylation gel column chromatography in Example 2, and n-hexane was distilled off under reduced pressure.
  • the AcOEt solution was washed with water and dried over anhydrous Na 2 S 0 + .
  • Ac0Et was distilled off under reduced pressure, and the thus-obtained orange crystals were collected by filtration and recrystallized from Ac0Et to obtain 192 mg of the title compound.
  • TAN-528A 223 mg was dissolved in 30 ml of MeOH, cooled to 0 ° C, and 78 mg of m-chloroperbenzoic acid was added, followed by stirring for 2 hours. — The eOH was distilled off under reduced pressure, extracted with 50 ml of AcOEt, washed with water and dried over anhydrous Na 2 S 0 + .
  • TAN-528A 223 mg was dissolved in 10 ml of dichloromethane, cooled to 110 ° C, 57 mg of m-chloroperbenzoic acid was added, and the mixture was stirred for 30 minutes.
  • Dichloromethane 50 ml was added and the mixture was washed with water.
  • the dichloromethane layer was washed with water and dried over anhydrous Na 2 SO 4 , dichloromethane was distilled off under reduced pressure, and the residue was collected with hexane.
  • the AcOEt was distilled off under reduced pressure 'to the residue is dissolved in a small amount of CH C1 3 adsorbed on a column of silica force gel (6 g), and developed with -1% MeO H- CHC 1 3 solvent system, 30 m The eluted fractions from 1 to 55 mi were collected, concentrated under reduced pressure, and the residue was collected by n-hexane. Re-precipitation with Ac0Et-n-hexane gave 109 mg of the title compound.
  • Example 8 TAN—528 A lactone (an isomer having a different lactonization position from that of Example 7; a carboxylic acid at position 10 and a hydroxyl group at position 13 condensed)
  • TAN-528A 297 mg was dissolved in 10 ml of ethanol, cooled to 0 ° C, 2 ml of N-NaOH was added, and the mixture was stirred at room temperature for 40 minutes. Then, 2 ml of N—HC1 was added for neutralization, ethanol was distilled off under reduced pressure, and the mixture was extracted with 50 ml of AcOEt. The AcOEt layer was washed with water, dried over anhydrous Na 2 S 0 + , and AcOEt was distilled off under reduced pressure.
  • Alkylating agent 2-phenolic acid
  • Example 38 In the preparative TLC of Example 37, a band having an Rf value of around 0.1 was scraped off and eluted with 25-demethylthio-1.25-hydroxy TAN-528A to obtain 11.7 mg of the title compound. .
  • This benzothiazino compound was found to have the same melting point and N MR as that obtained in Example 37.
  • the melting point and NMR of this hydroxy compound were the same as those obtained in Example 38.
  • This product was found to be similar to the compound obtained in Example 38 in melting point and NR.
  • Example 47 Preparation of 25-demethylthio-25-ode-TAN-528A: 2 ⁇ -demethylthio-125-hydro-TAN-528 ⁇ li 3.2 mg was dissolved in acetonitrile 6 ml, and the mixture was dissolved in Ethylene Moser. 39 mg of a salt was added, and the mixture was refluxed for 2 hours. An additional 59 mg of the reagent was added, and the mixture was further refluxed for 1 hour. After the reaction product was concentrated to dryness, a mixture of ethyl acetate and water was added, and the mixture was separated. After washing with water, drying and drying, 99.6 mg of a brown solid was obtained.
  • the compound [1] of the present invention or a salt thereof has excellent antibacterial activity and can be used as an antibacterial agent. '

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Abstract

Composés représentés par la formule générale (I) (où R1 et R2, qui peuvent être identiques ou différents, représentent chacun de l'hydrogène ou un résidu organique via un atome de carbone ou bien -SO2-, X représente (II), (III), (IV) ou (V) (où R4 est de l'hydrogène, de l'hydroxy, un halogène, ou un résidu organique via un atome de carbone, d'azote, d'oxygène ou de soufre, R5 représente un groupe bivalent via deux atomes de carbone qui peuvent éventuellement être substitués, $(1,4)$- est lié à la position p du noyau de benzène par rapport à R1O-, et $(1,4)$- est lié à la position m par rapport à R1O-), R6 est du carboxy, un groupe dérivé du carboxy, ou un delta- lactone en combinaison avec -OH en position 7 ou 13, et Y représente -CO- ou (VI) (où R7 forme un moyen à 5 chaînons de concert avec -OR1 lorsque R1 représente un résidu organique via un atome de carbone), à condition que X ne représente pas (VII), lorsque R1 et R2 représentent chacun H, R6 représente du méthoxycarbonyle, et Y représente -CO-, et que X ne représente pas (VIII) lorsque R est du méthyle, R2 de l'hydrogène, R6 du méthoxycarbonyle, et Y est -CO-). Ces composés et leur sels ont une excellente activité antibactérienne et peuvent être utilisés comme agent antibactérien.
PCT/JP1985/000160 1985-04-03 1985-04-03 Antibiotiques et preparation les contenant WO1986005784A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN107540682A (zh) * 2017-08-09 2018-01-05 武汉大学 曲张链丝菌素衍生物及其制备方法和应用

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JPS50160289A (fr) * 1974-06-17 1975-12-25

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JPS50160289A (fr) * 1974-06-17 1975-12-25

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Title
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107540682A (zh) * 2017-08-09 2018-01-05 武汉大学 曲张链丝菌素衍生物及其制备方法和应用
WO2019029408A1 (fr) * 2017-08-09 2019-02-14 武汉大学 Dérivé de streptovaricine, procédé de préparation s'y rapportant et son application

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