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WO1986003752A1 - Nouveaux derives antibiotiques, leur procede de preparation et leur utilisation - Google Patents

Nouveaux derives antibiotiques, leur procede de preparation et leur utilisation Download PDF

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Publication number
WO1986003752A1
WO1986003752A1 PCT/JP1984/000602 JP8400602W WO8603752A1 WO 1986003752 A1 WO1986003752 A1 WO 1986003752A1 JP 8400602 W JP8400602 W JP 8400602W WO 8603752 A1 WO8603752 A1 WO 8603752A1
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WO
WIPO (PCT)
Prior art keywords
compound
amino
ester
oxo
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/JP1984/000602
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English (en)
Japanese (ja)
Inventor
Koichi Yoshioka
Setsuo Harada
Michihiko Ochiai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries 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 Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to PCT/JP1984/000602 priority Critical patent/WO1986003752A1/fr
Priority to PCT/JP1985/000358 priority patent/WO1987000178A1/fr
Priority to DK558885A priority patent/DK558885A/da
Priority to JP60280139A priority patent/JPH0674275B2/ja
Priority to KR1019850009508A priority patent/KR930001405B1/ko
Priority to CN85109633A priority patent/CN1024668C/zh
Priority to DE8585309197T priority patent/DE3586591T2/de
Priority to IE319885A priority patent/IE59102B1/en
Priority to AT85309197T priority patent/ATE80162T1/de
Priority to ES550040A priority patent/ES8705431A1/es
Priority to EP85309197A priority patent/EP0191989B1/fr
Publication of WO1986003752A1 publication Critical patent/WO1986003752A1/fr
Priority to US07/058,265 priority patent/US4897489A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C07F9/65392—Five-membered rings containing two nitrogen atoms
    • C07F9/65395—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the present invention relates to a novel 2- (4-substituted amino-3-oxo-2-isoxazolidinyl) tetrahydro-5-oxo-12-furancarboxylic acid derivative having excellent antibacterial activity and ⁇ -lactamase inhibitory activity, It concerns the manufacturing method and its use.
  • TAN-88 a new antibiotic TAN-588 showing antibacterial activity against Gram-positive and Gram-negative bacteria from a new species belonging to the genus Endobacter and Rhizobacter isolated from soil. -5 8 8 ”.
  • the present inventors have conducted studies to elucidate the chemical structure of the antibiotic TAN-588.
  • the antibiotic TAN-588 was found to have tetrahydro 5-oxo at the nitrogen atom of the 3-oxo-isoxazoline ring. It was found that it had a unique skeleton to which 2-furancarbonic acid was bound.
  • the present inventors have synthesized a derivative of the antibiotic TAN-588 exhibiting an antibacterial activity, found that the derivative has an excellent antibacterial activity, and as a result of further research, completed the present invention. .
  • the present invention provides: .
  • R 1 represents an organic residue via an amino or nitrogen
  • R 2 represents carboxy or a group derivable therefrom
  • X represents hydrogen, methoxy or formylamino, respectively.
  • R 1 is acetylamino or amino
  • X is hydrogen
  • R 2 is not paranitrobenzyloxycarbonyl or benzhydryloxycarbonyl. Or a salt thereof,
  • R and X have the same meaning as described above. Characterized by reacting the compound represented by the formula (I) with a compound capable of introducing a group capable of bonding to a carbon atom or an oxygen atom of carboxy to form a group derivable from carboquine.
  • R and X have the same meaning as described above. Represents a group that can be derived from carboquine. However, when 'R 1 is acetylamino or amino and X is hydrogen, R is not paranitrobenzyloxycarbonyl or benzhydryloxycarbonyl. Production method of the compound represented by
  • R 1 represents an amino residue or an organic residue via nitrogen
  • R 2 represents carboxy or a group derivable from carboxy.
  • the compound represented by the general formula is subjected to a methoxylation reaction or a formylamination reaction.
  • examples of the organic residue via nitrogen represented by R 1 or R include, for example, acylamino, carbon-substituted amino, alkenylamino, thioamino, silylamino, phosphorylamino, and the like. And a group represented by C0—C0—NH—.
  • acyl in the above acylamino examples include an acyl group substituted for a 6-amino group of a conventionally known penicillin derivative and an acyl group substituted for a 7-amino group of a cephalosporin derivative.
  • acylamino group examples include, for example,
  • R 3 is hydrogen, alkyl ⁇ chi, alkenyl 58, consequent C2 alkyl ⁇ , Ari Le ⁇ , heterocyclic 'chi ⁇ , alkoxy ⁇ chi ⁇ , a Ariruokishi ⁇ , R: or hydrogen, alkyl
  • R + comprises a case forming a R 3 and ring.
  • R 5 is hydrogen, an amino acid residue ⁇ ⁇ , a protecting group for an amino group, or a compound represented by the formula R 7 —
  • R 7 represents a heterocycle, an alkoxy 58 or an amino 85 , and ⁇ represents an integer of 0 to 2.
  • R 8 is a group represented by the formula R 1Q — C— ⁇ where R 1Q is an alkyl 5 ⁇ , a heterocyclic ring or
  • Is aryl, ⁇ , and R 11 is hydrogen, alkyl *, alkenyl ⁇ ⁇ , arylcarbonyl, cycloalkyl *, heterocycle ⁇ or a formula—R 12 —R 13 (where R 12 is alkylene, cyclo alkylene or alkenylene, R 13 is Ariru-, carboxy '55 or an ester or mono- or dialkyl Kiruami de, a group represented by represents respectively.), a group represented by represents respectively ⁇ , JI 3 is a chemical bond or Formula—C 0— ⁇ —CH— (where 13 ⁇ 41 + represents an aralkyl ⁇ ', an aryl ⁇ or a heterocycle *.), Respectively.
  • R 15 is Ariru ⁇ , heterocyclic chi ⁇ or cycloalkenyl
  • R 18 is heat Dorokishi, carboxy, Sulf ⁇ I le, sulfo, Suruhookishi, Ari Le 5 ⁇ - O alkoxycarbonyl or Ashiruokishi ⁇ chi ⁇ Are respectively shown.
  • R 17 -R 18 -CH 2 -C O-H- [wherein, R 17 is an alkyl ⁇ , cyano, aryl *, aryloxy ⁇ , alkenylene ⁇ or heterocycle ⁇ or amino ⁇ ′, and also R 18 Is a chemical bond or one S— is shown respectively.
  • R 17 is an alkyl ⁇ , cyano, aryl *, aryloxy ⁇ , alkenylene ⁇ or heterocycle ⁇ or amino ⁇ ′, and also R 18 Is a chemical bond or one S— is shown respectively.
  • R 13 and R 2 ° are the same or different and represent hydrogen, alkyl 5 ⁇ , aryl ⁇ , heterocycle ⁇ , cycloalkyl, and ⁇ represents 0 or S, respectively.
  • R 10 — C— in R 8 is a synth represented by the formula R 10 — C—
  • Examples of an amino substituted via carbon as an example of an organic residue via nitrogen represented by R 1 above include, for example, a compound of the formula
  • R 21 is alkyl ⁇ chi ⁇ , Ariru 55, alkenyl or heterocyclic ring.
  • R 22 and R 23 are the same or different alkyl ",, Ariru-chi-, shows alkenyl 56 respectively, a case where the R 22 and R 23 form a heterocyclic ring together with the adjacent nitrogen atom Including.
  • R 2+ , R 25 and R 2S are the same or different and each represent alkyl *, aryl or alkenyl, and R 2+ and R 25 or R 28 form a heterocyclic ring together with an adjacent nitrogen atom. Including the case where it is formed.
  • Each of the groups represented by ⁇ ⁇ ⁇ ⁇ is exemplified.
  • alkenylamino as an example of the group represented by R 1 include, for example,
  • R 27 and R 28 the same or different and each represents hydrogen, alkyl 58, ⁇ Li Lumpur "-, cycloalkyl, amino" a-or heterocycle ⁇ , R 27 and This includes the case where R 28 forms a cycloalkyl * or a heterocyclic ring with an adjacent carbon atom.
  • the group represented by] is mentioned.
  • Examples of thioamino as an example of the group represented by R 1 include, for example, a compound of the formula.
  • R 23 represents alkyl, ⁇ , or aryl ⁇ ]
  • ⁇ represents an integer of 0 to 2.
  • Q includes a group represented by
  • silylamino as an example of the group represented by R 1 above include, for example,
  • R 3 °, R 3t and R 32 are the same or different and represent alkyl ⁇ or aryl >>, including the case where these form a cyclic group.
  • R 33 represents hydrogen or silyl.
  • the group represented by] is mentioned.
  • amino phosphinates as examples of groups represented by R 1 above include, for example,
  • R 34 and R 35 same or different, alkyl-chi-, Ariru “ ⁇ , alkoxy” indicates, or Ariruokishi " ⁇ , if R 3 and R 35 form a heterocyclic ring 55 including. ]
  • the group represented by] is mentioned.
  • R 36 -CO-CO- ⁇ - [wherein, R 36 represents hydrogen, alkyl ⁇ , alkoxy *, aryl ⁇ ', aryl ⁇ oxy, heterocycle ⁇ , or amino >>. ]
  • the group represented by] is mentioned.
  • the organic residue via nitrogen represented by R 1 or R is preferably, for example, one having a molecular weight of up to 500.
  • R 37 represents alkyl, alkenyl ⁇ ⁇ , aryl ⁇ ⁇ ⁇ , cycloalkyl, heterocycle ⁇ or silyl ⁇ ⁇ .
  • R 3 3 and R 3 3 are the same or different and are hydrogen, alkyl ⁇ , ⁇ reel "-, cycloalkyl", indicates Arukeniru ⁇ or heterocyclic "-, R 3 8 and R 3 3 Include a heterocyclic ring * with an adjacent nitrogen atom. ], Respectively.
  • the group may be derived from Karubokin represented by R 2 Ah 3 Iba R 2 'may, for example molecular weight is preferably up to 5 0 0.
  • the alkyl in the above is preferably, for example, one having 1 to 6 carbon atoms, such as methyl, ethyl, 11-propyl, isopropyl, ⁇ -butyl, isobutyl, sec-butyl, t-butyl, 1, 1 Monodimethylpropyl, ri-pentyl, isopentyl, n-hexyl, isohexyl and the like.
  • Examples of the substituent which the alkyl group may have include, for example, halogen, nitro, amino (alkyl, alkenyl, cycloalkyl, aryl) may have as a substituent. :), sulfo, cyano, aryl Droxy, carboxine, cycloalkyl, alkoxy (amino, hydroxy, carboxynoperogen, aryl, cycloalkyl, alkoxy may be substituted), aryl (halogen, alkyl, alkoxy, alkylamino, May be substituted with rubamoyl, sulfo, alkylsulfonyl, cyano, hydroxy, carboxy, nitro, asiloxy, aralkyloxy, sulfoxy.
  • Arylcarbonyl optionally having substituents, aryl as defined above Have the same substituent groups Moyoi Ariruokishi, heterocyclic (two Toro, Okiso, Ariru, alkenylene, halogenoalkyl, alkylsulfonyl, Arukiru, alkoxy, alkyl It may have amino, amino, halogen, rubamoyl, hydroxy, cyano, ruboxy, or sulfo as a substituent. :), asil, asiloxy, alkoxyl carbonyl, alkoxyl propylonyloxy, ashyloxy.
  • aralkyl alkyl, alkoxynoperogen, amino, hydroxy, nitro, cyano, alkamoyl, sulfamoyl
  • Aralkyloxy alkyl, alkoxy, alkoxyamino, hydroxy, nitro, cyano, carbamoyl, sulfamoyl may be substituted)
  • alkylsulfonyl alkylsulfinyl
  • alkylthio may be substituted with cyano, halogen, carboxy, alkylamino, imino, or rubamoyl
  • arylthio.heterocyclic group-thio cyano, hydroxy
  • Amino, alkylamino, alkyl, halogen, and oxo may be present as substituents.
  • ⁇ 4 1> tool ⁇ ;: (wherein, R 4., R 4 1 are the same or different, a hydroxyl group, an amino group.) And the like group represented by the.
  • the cycloalkyl or cycloalkyl formed preferably has 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Is mentioned.
  • substituent which the cycloalkyl group may have include, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, oxo and the like.
  • Examples of the cycloalkylene represented by R 12 include those in which the above cycloalkyl further has another bond.
  • RS.FT.R .R .R 13- 17, R 13 - as Ariru in 32, Ariru represented by R 3+ one 33 (aryl), ⁇ reel carbonyl, ⁇ reel O alkoxycarbonyl or Ariruokishi is
  • phenyl, naphthyl, biphenyl, anthryl, indenyl and the like can be mentioned.
  • substituents which the aryl group may have include, for example, halogen, nido, cyano, amino (alkyl, alkenyl, cycloalkyl, aryl) as a substituent. :), Sulfo, hydroxy, sulfoxy, sulfamoyl, alkyl (amino, halogen, hydroxy, cyano may be substituted. :), alkoxy, aralkyloxy, alkyl sulfonamide, methylenedioxy, alkyl sulfonyl, Alkylsulfonylamino and the like. Further, a condensed ring (eg, tetrahydronaphthyl, indanyl, acenaphthyl, etc.) may be formed with cycloalkyl.
  • a condensed ring eg, tetrahydronaphthyl, indanyl, acenap
  • R 3 the alkoxy represented by R 7, R 3+ one 38 is preferably a carbon number from 1 to 6, and examples thereof, for example main butoxy, ethoxy alkoxy, n- Purobokishi, i one Examples include propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, and n-hexyloxy.
  • alkoxy group examples include, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, aryl and silyl (alkyl, aryl and aralkyl as substituents). ) And the like.
  • the alkenyl Le or alkenylene represented by RS.R .R t2, R 17, R 21 one 28. R 37 one 33, for example lay preferred are those of 1 to 4 carbon atoms, examples of which include e.g.
  • Examples of the substituent which the alkenyl group may have include, for example, halogen, nitro, amino, sulfo, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, aryl, and acyl. .
  • RS.RS.lT.R .R .R .R .R 13 -! 28 ' ⁇ as the heterocyclic ring heterocycle or these groups form shown at 33, for example, with one A 5- to 7-membered heterocyclic group containing a sulfur atom, a nitrogen atom or an oxygen atom, a 5- to 6-membered heterocyclic group containing a 2- to 4-valued nitrogen atom, 1-2 nitrogen atoms and 1 sulfur atom or A 5- to 6-membered heterocyclic group containing an oxygen atom is mentioned, and these heterocyclic groups are a 6-membered ring group containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring group containing one sulfur atom. It may be condensed.
  • heterocyclic group examples include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, birazinyl, pyridazinyl, piperazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl.
  • heterocyclic group may have examples, for example, amino (which may have a substituent such as acylno, logen-substituted alkylacyl, phenyl, or alkyl), halogen, nitro, sulfo, cyano, Hydroxy, Power Roxy, Oxo, Toxo, C.
  • Alkyl may have aryloxy, amino, hydroxy.
  • examples of the acyl represented by R 4 include, for example, phthaloyl, succinyl, maleoyl, citraconoyl, daltharyl, and adiboyl which are cyclic with R 3 .
  • substituent which the acyl group may have include, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, and alkoxy.
  • the acyl in the acyloxy represented by R 16 is preferably, for example, those having 1 to 4 carbon atoms, and examples of the cool include formyl, acetyl, propionyl, butyryl, isoptyryl and the like.
  • examples of the substituent of alkyl include alkyl (amino, halogen, cyano, and alkoxy). It may have carboxy, hydroxy, or hydroxy as a substituent. ).
  • the amino acid residue represented by R 5 for example glycyl, Araniruno "Lil, leucyl, isoleucyl, seryl, threonyl, Shisuti alkenyl, Shisuchiru, Mechioniru, one or Asuparagiru, one or ⁇ one glutaminyl mill , Lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptophanyl, prolyl.
  • substituent which the amino acid residue may have include halogen. Hydroxy, sulfo. Carboxy, cyano, alkylamino, aralkyloxycarbonyl, aralkyloxy and guanidino.
  • aromatic acyl groups such as phthaloyl, 4-tritrobenzoyl, 4-tert-butylbenzoyl, 4-tert-butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl, etc., for example, formyl, acetyl, propionyl, mono-sigma acetyl, dicyl Aliphatic acyl groups such as oral acetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl, succinyl, etc., for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, iso
  • O PI Sulfonyl groups such as tylsulfonyl and the like, and, for example, non-acyl groups such as trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, di- or trialkylsilyl, benzyl, and 4-nitrobenzyl.
  • a protecting group for a mino group is not particularly limited in the present invention, but particularly preferred is monochloroacetyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.
  • examples of the cycloalkenyl represented by R 8 and R 15 include cyclohexene, cyclohexene, cycloheptene, cyclopentene, cyclooctene and the like.
  • examples of the substituent in the optionally substituted carboxyl group represented by R 13 and R 16 include, for example, alkyl (having hydrogen, cyano, or hydroxy as a substituent). ), Aryl (alkyl, alkoxy, halogen, hydroxy, acyloquin, sulfo, cyano, sulfamoyl may be substituted), silyl (alkyl, aryl, aralkyl substituted) And heterocyclic rings (amino, alkylamino, sulfamoyl, carbamoyl, halogen, cyano, and nitro may be substituted).
  • examples of the substituent in the amino which may have a substituent represented by R 7 , R 27 , R 28 and R 3e include, for example, amidine, iminomethyl, imino (aryl substituted) methyl, Guanidylcarbonyl, heterocycles (may have the same substituents as the above-mentioned complex rings. :), imino (heterocycle-substituted) methyl, arylcarbonyl, hydroxyalkyl, alkyl, etc. Is mentioned.
  • examples of the substituent in the optionally substituted silyl represented by R 33 and R 37 include alkyl, aryl, aralkyl and the like. Examples of the group in the case where R 3 and R 4 form a cyclic group include 2,2-dimethyl-5-oxo-141-phenylimidazolidin and the like.
  • the R 3 °, R 3 1, R 3 2 may form a R 3 3 and cyclic groups, in the examples For instance, 2, and 5 Jishiriruazashiku port pentyl and the like, which for example, alkyl , Aryl and the like.
  • the halogen as the substituent include chlorine, bromine, fluorine, and iodine.
  • Alkyl in the above description of the substituent is preferably an alkyl having 1 to 10 carbon atoms, more preferably 1 to 6 or 1 to 4 carbon atoms.
  • cycloalkyl those having 3 to 6 carbon atoms are preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclo-hexyl and the like.
  • alkoxy one having 1 to 4 carbon atoms is preferable, and examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, ⁇ -butoxy, i-butoxy, and t-butoxy.
  • aryl examples include phenyl and naphthyl.
  • the heterocyclic those similar to the heterocyclic ring represented by the R 3 and the like.
  • acyl those having 1 to 6 carbon atoms and more preferably 1 to 4 carbon atoms are preferable, and examples thereof include formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, isoparryl, vivaloyl, and hexanoyl.
  • aralkyl examples include benzyl, phenyl, and phenyl loop And the like.
  • alkenyl or alkenylene examples include the same as the alkenyl represented by R 3 described above.
  • the amino acid residues include the same amino acid residue represented by R 5 can be mentioned.
  • the number of substituents in each of the above groups is preferably 1 to 3.
  • I mino groups include, for example, 3- (2,6-dichlorophenyl) -1-methylisoxazo-l-yl 4-ylcarbonylamino, 4-ethyl-12,3-dioxo-1-pipe Radinocarbonyl 7amino, 3-phenyl 5-methylisoxazolu-1-ylcarbonylamino, 3- (2-chlorophenyl) -1-methylisoxazole-4-ylcarbonylamino, .3- (2-Chloro-6-fluorophenyl) -1-5-methylisoxazolu-4-ylcarbonylamino, nicotinylamino.benzoylamino, 4-bromobenzoylamino, 2,6-dimethoxybenzoyl Amino, formylamino, acetylamino, propionylamino, butyrylamino, isoptyrylamino, pivaloylamino, methoxy
  • Examples of the body include, for example, D-alanylamino, benzyl N-caproluvoxy 7-D-glutamyl-D-aralanamino, D-phenylidylyl-D-aralanamino, N-carbobenzoxy-D-aralanamino, ⁇ -lipobenzoxy-D —Phenylglycylamino, D —Aranil D —Fanildaricylamino, D —Glutamyl D —Aranylamino, 2— (4-Ethyl ⁇ "2,3 Dioxo 1-Piperazinocarboxamide) 2-phenylacetylamino, 2- (4-cyclohexyl-2,3-dioxo-1--1-piperazinocarboxamide) -1-phenylphenylamino, 2- (4-ethyl-2-, 3-dioxo-1 2-piperazinocarboxamide) -1- (4-sulfoxypheny
  • acylamino group represented by the formula R 8 — R 3 — C 0— ⁇ ⁇ — include, for example, ⁇ — [2- (2-amino-4-thiazolyl) -12-methoxyiminoacetyl] — D —Aranylamino, ⁇ — [2- (2-amino-4—thiazolyl) -1-2-methoxymininoacetyl] — D —Furgylglycylamino, 2 -— (2-amino-4-thiazolyl) 1-2 — [2- (2-Amino-4-thiazolyl) -1-2-methoxyiminoacetamide] acetylamino, 2— (2—chloroacetamido 4-monothiazolyl) -1-2-methoxyiminoacetylamino, 2- (2-amino-4 1-thiazolyl) 1-methoxyethoxy
  • Rho 1,4-dihydro 4-oxopyridine 1-acetylamino, S-carboxyvinylthioacetylamino, 2- (2-aminomethylphenyl)
  • N—C—N H— Specific examples of the group represented by the formula> N—C—N H— include:
  • rubamoylamino methylaminocarbonylamino, ethylaminocarbonylamino, t-butylaminocarbonylamino, isobutylaminocarbonylamino, dimethylaminocarbonylamino, 2-methylphenylaminocarbonylamino, phenylaminocarbonylamino Nilaminocarbonylamino, 3-chlorophenylaminocarbonylamino, 4-12-trophenylaminocarbonylcarbonyl, 4-promophenylaminocarbonylamino, thiocarbamoylamino, methylaminothiocarbonylamino Ethylaminocarbonylamino, phenylaminothiocarbonylamino, dimethylaminocarbonylamino, and 3-fluorophenylaminocarbonylamino.
  • R 2 1 - Examples of the group represented by NH-, e.g. Mechirua Mino, Echiruamino, Ariruami Roh, Kishiruamino cyclohexane, cyclohexane carboxylate Rumechiruamino, Benjiruamino, 4 one black port Benjiruamino, Fuweniru Amino, 2-imidazolylamino, 1-methyl-2-imidazolylamino, 2- (2-amino-4-thiazolyl) -1-2-methoxyaminothiothioacetylamino, 1-benzyl-4,1-pyrimidine Diaminoamino, 2-acetyl-1-methylvinylamino and the like.
  • dimethylamino getylamino, dipropylamino, dibenzylamino, dicyclohexylamino, N-benzylamino N-methylamino, diarylamino, N-phenyl-1N-methylamino, pyrrolidinyl, pyridinyl, piperidinyl , Morpholinyl and the like.
  • alkylamino group represented by the formula R 25 —, ⁇ — include R 26
  • Examples include trimethylammonium, triethylammonium, tribenzylammonium, benzyldimethylammonium, methylpyrrolidinium, methylpiperidinium and the like.
  • Specific examples of the alkenylamino group represented by the formula ⁇ 2 2 > C N—
  • dimethylaminomethyleneamino 1-dimethylaminoethylideneamino, hexahidraw 1H-azepine-11-ylmethyleneamino, 11- (N-benzyl-N-methylamino) ethylideneamino, 4, dimethylaminobenzylideneamino, p-nitro) benzylideneamino, benzylideneamino and the like.
  • thioamino group represented by the formula R 29 — S On— NH— include, for example, benzenesulfonylamino, 4-methylbenzenesulfonylamino, 4-methoxybenzenesulfonylamino, 2, 4, 6—Trimethyl
  • Is for example, trimethylsilylamino, triethylsilylamino, t-butyldimethylsilylamino, t-butyldifuninylsilylamino, isop- ⁇ -dimethyldimethylsilylamino, triphenylsilylamino, triisopropylsilylamino, triisopropylsilylamino, tribenzylsilylamino
  • Examples include mino, (triphenylmethyl) dimethylsilylamino, 2,2,5,5-tetramethyl-2,5-disilylazacyclopentane. ⁇ 34 0 II
  • Examples include amino dimethyl phosphate, amino getyl phosphate, amino diphenyl phosphate, amino dibenzyl phosphate, and amino 4-diphenylphenyl phosphate.
  • R 3e —CO—CO—NH— examples include, for example, methoxyoxalylamino, ethoxyxalylamino, phenoxyoxalylamino, benzyloxalylamino, methyl Oxalylamino,
  • Formula - C 0- Specific examples of the group represented by N rather 3 3, such as di Mechiruami de, Jechiru - Ami de, Jipuropiruami de, Jibenjiruami de, di
  • reaction in the case of reacting is, for example, acylation, ureidation (H
  • acid halide for example, acid chloride, acid bromide and the like are used.
  • the acid anhydride examples include mixed anhydrides of monoalkyl carbonic acid mixed anhydrides, mixed acid anhydrides of aliphatic carboxylic acids (eg, diacid, piperic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.), and aromatic acids Mixed acid anhydrides composed of aromatic carboxylic acids (for example, benzoic acid and the like), symmetrical acid anhydrides and the like are used.
  • amide compound for example, a compound in which an acyl group is bonded to nitrogen in the ring, such as pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, and benzotriazole is used.
  • examples of the active ester include methyl ester, ethyl ester. Methoxymethyl ester, propargyl ester, 412 trophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methyl ester and the like.
  • esters such as silphenyl esters, esters with 1-hydroxyl 1H-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimid, and the like are used.
  • the active thioester for example, a thioester with a heterocyclic thiol such as 2-pyridylthiol, 2-benzthiazolylthiol or the like is used.
  • a thioester with a heterocyclic thiol such as 2-pyridylthiol, 2-benzthiazolylthiol or the like is used.
  • the various reactive derivatives as described above are appropriately selected depending on the type of the carboxylic acid.
  • the reaction may be carried out in the presence of a base, and examples of the base used include aliphatic tertiary amines (eg, trimethylamine, triethylamine, tripropylamine, tri-n-butylamine, etc.),- Tertiary amines such as methylpiperidine, N-methylbi- ⁇ -lysine, hexyl dimethylamine, and ⁇ -methylperforin, such as di- ⁇ -butylamine, diisobutylamine, and dihexylamine.
  • aliphatic tertiary amines eg, trimethylamine, triethylamine, tripropylamine, tri-n-butylamine, etc.
  • Tertiary amines such as methylpiperidine, N-methylbi- ⁇ -lysine, hexyl dimethylamine, and ⁇ -methylperforin, such as di- ⁇ -butylamine, diisobutylamine, and dihe
  • Dialkylamines such as pyridine; aromatic amines such as pyridine; lutidine and arcolidin; alkaline metals such as lithium, sodium and potassium; alkaline earth metals such as calcium and magnesium; A hydroxide or carbonate is used.
  • a carboxylic acid reactive derivative is usually used in an amount of about 1 mol per 1 mol of the compound (1), and it can be used in excess as long as the reaction is not hindered.
  • the amount of the base used varies depending on the starting compound (DI), the type of the reactive derivative of the carboxylic acid, and other reaction conditions, but is usually about 1 to 30 mol per 1 mol of the compound (IE). Moles, preferably about 1 to 10 moles. This reaction is usually performed in a solvent.
  • the solvent examples include ethers such as dioxane, tetrahydrofuran, getyl ether, diisopropyl ether, propylene oxide, and butylene oxide; esters such as ethyl ethyl diformate and ethyl ethyl formate; Halogenated hydrocarbons such as 1,2-dichloroethane and 1,1,1-trichloroethane, for example, hydrocarbons such as benzene, toluene, and n-hexane, for example, N, N-dimethylformamide, ⁇ , ⁇ -Common organic solvents such as amides such as dimethylacetamide and nitriles such as acetonitrile, alone or in combination Used.
  • ethers such as dioxane, tetrahydrofuran, getyl ether, diisopropyl ether, propylene oxide, and butylene oxide
  • esters such as ethy
  • a liquid base can be used also as a solvent.
  • the reaction temperature is not particularly limited as long as the reaction proceeds, but the reaction is usually carried out at about 150 ° C to 150 ° C, preferably about 130 ° C to 80 ° C.
  • the reaction is usually completed in tens of minutes to tens of hours depending on the starting material, base, reaction temperature and type of solvent used, but sometimes takes several tens of days.
  • R 19 , R 2 ° and Z have the same meaning as described above. This is carried out by reacting a substituted isothiocyanate or a substituted isothiocyanate containing a group represented by the formula (1).
  • the substituted isocyanate include methyl isocyanate, ethyl isocyanate, vinyl isocyanate, p-bromophenocyanate, and the like.
  • the substituted isocyanate include methyl isothiocyanate, For example, phenylisothiocyanate is used.
  • the substituted isocyanate or substituted isothiocyanate is usually used per 1 mol of the compound (II), but it can be used in excess as long as the reaction is not hindered.
  • a solvent to be used for example, tetrahydrofuran, getyl ether, ethyl ethyl ester, chloroform, dichloromethane, toluene, and the like are used.
  • the reaction temperature is about 120 to 50 ° C, and the reaction time is usually about 10 minutes to 5 hours.
  • the reaction of bonding a group bonded via carbon to the amino group of compound (M) is described below as alkylation.
  • the alkylation of the compound (IE) can be produced by reacting the compound (EO) with an alkylating agent containing a group which binds to the nitrogen of the group R 1 via a carbon atom.
  • alkylating agent containing a group which binds to the nitrogen of the group R 1 via a carbon atom.
  • halogenated alkyl compounds such as propyl chloride, butyl chloride, benzyl chloride, butyl bromide, benzyl bromide, aryl bromide, methyl iodide, ethyl iodide, propyl iodide, and the like, for example, dimethyl sulfate, getyl sulfate, etc.
  • Dialkylsulfuric acid compounds such as methyl mesylate, ethyl mesylate, methyl tosylate, ethyl tosylate, and other substituted sulfonic acid ester compounds; alkyl dihalide compounds (eg, 1,5-dioctapentane, 1,4-dichlorobutane, etc.);
  • This reaction is usually performed in a solvent, Examples of the solvent used include water, methanol, ethanol, benzyl alcohol, benzene, dimethylformamide, tetrahydrofuran, acetonitrile, etc.
  • the temperature of this reaction is about 20 ° C or less.
  • the reaction time is about 30 minutes to 50 hours at 200 ° C.
  • This reaction is carried out by changing the reaction conditions, for example, by changing the molar ratio between the compound ( ⁇ ) and the alkylating agent.
  • Compounds, tertiary amine compounds or quaternary amine compounds can be selectively produced, and different substitution groups can be introduced into nitrogen by carrying out the reaction stepwise.
  • the reaction for introducing a group bonded via carbon other than alkyl can also be performed in the same manner as described above.
  • the alkylation can also be carried out by combining the compound (IE) and a carbonyl compound in the presence of a reducing agent.
  • a reducing agent examples include lithium aluminum hydride, sodium cyanoborohydride, sodium borohydride, sodium, sodium amalgam, a combination of zinc and an acid, and the like. It is also carried out by catalytic reduction using palladium, platinum, rhodium or the like as a catalyst.
  • amino group R 2 1 - NH- (imino amino group-substituted alkyl amino group, Arukirui Reaction to convert to a compound represented by amino group-substituted alkylamino or substituted guanidino group):
  • the conversion of an amino group into an imino-substituted alkylamino group or an alkylimino group-substituted alkylamino group is carried out in a solvent such as dioxane, tetrahydrofuran, dimethylformamide, chloroform, acetone, acetonitrile, or water. It is carried out by reacting with imidoesters. Suitable imidoesters include, for example, methylformimidate, ethylformimidate, benzylformimidate, methylacetimidate, ethylacetimidate, methylphenylacetimidate, ethyl.
  • N-methylformimidate, methyl N-ethylformimidate, methyl N-isopropylformimidate, etc. are used.
  • the reaction temperature is around 0 ° to 25 ° C, and the reaction time is usually about 1 to 6 hours.
  • the conversion reaction of the amino group to the guanidino group is carried out in a solvent such as water, dimethylformamide, hexamethylene phosphoroamide, for example, 0-alkyl or 0-arylpsoidurea or S-alkyl.
  • the reaction is carried out by reacting with S-arylpsouidothioureas.
  • Examples of the above pseudoureas include 0-methylpseuidourea, S-methylpsudourea, 0-2,4-dichlorophenylpseudourea, 0 ⁇ , ⁇ -trimethylpsudourea, and the like.
  • As the dothioureas, S- ⁇ -nitrotrophydosidourea and the like are used.
  • the reaction temperature is about 0 ° to about 40, and the reaction time is usually about 1 to 24 hours.
  • the alkenylation (imination) of the compound (1) can be carried out by dehydration condensation of the compound (II) with a carbonyl compound. This reaction can be carried out in a solvent or solvent that proceeds without solvent. Use acid or base as catalyst Sometimes used. Alternatively, the compound (II) and the carbonyl compound can be produced by ripening and refluxing in the presence of a dehydrating agent or by using a dehydrating apparatus such as Dean-Stark.
  • the solvent used in this reaction is, for example, benzene, toluene, dichloromethane, ethanol, etc., the reaction temperature is about 0 ° to 200 ° C., and the reaction time is about 1 hour to 20 hours. is there.
  • Examples of the acid used as the catalyst include benzenesulfonic acid, methanesulfonic acid, sulfuric acid, boron trifluoride, zinc chloride, and the like, and examples of the base include hydroxylated sodium and sodium carbonate.
  • Examples of the dehydrating agent used in this reaction include molecular sieve, silica gel, anhydrous magnesium sulfate, and anhydrous sodium sulfate.
  • the thiolation reaction of compound (IE) is usually carried out by reacting compound (H) with a compound of formula R 29 — SO n—
  • a halogenated thio compound eg, sulfonyl halide, sulfinyl halide, sulfonyl halide
  • a base e.g, a halogenated thio compound
  • the reaction is carried out in a solvent.
  • the solvent used in this reaction is, for example, water.
  • Examples include acetone, dioxane, dimethylformamide, benzene, tetrahydro sigma-furan, dichloromethane methane, or a mixed solvent thereof.
  • the base include organic bases such as pyridine, picoline, triethylamine, diisopropylethylamine and methyl morpholine, and sodium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate and carbonated carbonate.
  • An inorganic base is used. This reaction usually uses about 1 equivalent of a halogenated thio compound and about 1 to 10 equivalents of a base to the compound (III), and the reaction temperature is about 120 to 80 ° C. The time is between 15 minutes and 10 hours.
  • thioanhydride eg, toluene
  • halogenated thio compound e.g, toluene
  • It can also be performed by reacting with a thiolating reagent such as 2,4-triazolide.
  • R 30 formula R 31 ⁇ S i- or R 33 (wherein, R 3 ° one 33 has the same meaning as defined above.)
  • Such bases include, for example, pyridine, picoli
  • Organic bases such as phosphorus are exemplified.
  • the reaction is preferably performed in a solvent ',
  • solvent examples include acetone, dioxane, dimethylformamide,
  • Temperatures should be about 120 ° C to the boiling point of the solvent, or about 120 ° C to 8 ° C.
  • reaction time is about 15 minutes to 20 hours.
  • Chloride eg, dimethyl phosphoric acid chloride
  • Tilulinic acid lip diphenylphosphoric acid lip, dibenzylphosphoric acid lip
  • the reaction is carried out by reacting a base with an equivalent or an excess amount of a base in a solvent.
  • a base an organic base such as pyridine, picolin, triethylamine, N-methylmorpholine, or an inorganic base such as sodium hydroxide, sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, or the like is used.
  • the solvent for example, water, acetone, acetonitrile, dioxane, dimethylformamide, tetrahydrofuran, dichloromethane, or a mixed solvent thereof is used.
  • the reaction temperature is about 120 ° C. to 80 ° C., and the reaction time is i5 minutes to i5 hours.
  • the meth- oxylation of compound (W) can be performed by the 6- or 7-position meth- oxylation method performed in the field of penicillin / cephalosporin.
  • the meth- oxylation of penicillin or cephalosporin is described, for example, by E. M. Gordon, R. B. Sykes, et al., "Chemistry and Biology of ⁇ -Lactam Antiiotics” Vol 1, 199. (1982).
  • the methoxylation reaction of a compound (VT0) is carried out by reacting compound (II) with a metal salt of methanol and a halogenating agent in the presence of methanol.
  • a metal salt of methanol lithium metal is used.
  • the halogenating agent include t-butylpipochloride, N-chlorsuccinimide, N-promosuccinimide, N-chloracetamide, and N-chloracetamide.
  • B Mouth acetoamide, N-chlorobenzenesulfonamide, chlorine, bromine, etc. are used.
  • This reaction is carried out in a solvent, and examples of the solvent include tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, methanol, and dimethylformamide.
  • the compound (W) is dissolved or suspended in the above-mentioned solvent, and an alkali metal of methanol, methanol and a halogenating agent are added and reacted.
  • the reaction proceeds at about 180 ° C to 30 ° C, and the reaction is stopped by making the reaction system acidic. Suitable acids for terminating the reaction include, for example, formic acid, acetic acid and trichloroacetic acid. After completion of the reaction, the excess halogenating agent is removed by treating it with a reducing agent such as sodium thiosulfate or a trialkyl ester of phosphorous acid.
  • Formylamination is performed by converting compound (VI) into a compound of the formula ⁇ i / — ⁇ ()
  • R 1 is a portion other than nitrogen in the organic residue (R) through nitrogen, and R 2 is as defined above.”
  • the nucleophilic derivative of formamide includes, for example, N-silyl, ⁇ -stannyl and ⁇ -phosphorylformamide derivatives, among which preferred ones are ⁇ , ⁇ -bis (trimethylsilyl) formamide
  • the formylamidation reaction is usually carried out in a solvent in an inert atmosphere such as nitrogen or argon.
  • the reaction temperature is about 100 ° C. to 12 ° C. (TC, preferably about 180 ° C. to 150 ° C .; the reaction time is about 10 minutes to 80 ° C.).
  • the time is preferably about 15 minutes to 2 hours, and the solvent used is preferably a non-protonic solvent, such as tetrahydrofuran, dimethylformamide, and hexane.
  • Methyl phosphoramide or dioxane Formylamide group is formed by hydrolysis with acid or base, or treatment with metal ions such as mercury, silver, talium or copper, following the reaction.
  • the imine body is about 100 ° C. to 12 ° C. (TC, preferably about 180 ° C. to 150 ° C .; the reaction time is about 10 minutes to 80 ° C.).
  • the time is preferably about 15 minutes to 2 hours
  • the solvent used is preferably a non-protonic solvent, such as tetrahydrofuran, dimethylformamide, and
  • (W) can be produced by a method similar to the method described in the above-mentioned (methoxylation) E. M. Gordon et al.
  • the reaction may be, for example, esterification or amidation. It is performed by subjecting it to a reaction or the like.
  • the esterification is performed, for example, by the following method.
  • Compound (V) is treated with a diazoalkane, for example, diazomethane, phenyldiazomethane, diphenyldizomethane, etc., and a solvent, for example, tetrahydrofuran, dioxane, ethyl ethyl formate, acetonitrile, etc. at about 0 to reflux temperature. And react for about 2 minutes to 2 hours.
  • a diazoalkane for example, diazomethane, phenyldiazomethane, diphenyldizomethane, etc.
  • a solvent for example, tetrahydrofuran, dioxane, ethyl ethyl formate, acetonitrile, etc.
  • the reaction is carried out at about 0 ° C to reflux temperature for about 15 minutes to 18 hours, and solvents such as chloroform, dic ⁇ ⁇ methane, and dichloroethane are used.
  • the acid anhydride of compound (V) obtained by reacting compound (V) with an acid chloride, for example, ethyl chloride and benzyl chloride, and an acid anhydride such as 3) And under the reaction conditions described in 3).
  • the anhydride can be obtained by reacting compound (V) with an acid chloride in a solvent such as tetrahydrofuran, dichloromethane or the like at 25 ° C. to reflux temperature for about 15 minutes to 10 hours.
  • the amidation of carboxylic acid is carried out by converting compound (V) with an acid chloride, for example, ethyl chloroformate, benzyl chloroformate or acid anhydride, for example, anhydrous acid, trifluoroacetic anhydride and the like.
  • the reaction is carried out by synthesizing an acid anhydride and reacting with ammonia or a selected amine, for example, the above-mentioned alkyl, dialkyl, aralkyl or heterocyclic amide agent.
  • the above reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like at about 0 to about 15 minutes to 16 minutes at reflux temperature.
  • a solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like at about 0 to about 15 minutes to 16 minutes at reflux temperature.
  • the protecting group can be removed as necessary.
  • a method for removing the protecting group a commonly used method such as a method using an acid, a method using a base, a method using hydrazine, a method using reduction, etc., is appropriately selected according to the type of the protecting group.
  • the acid varies depending on the type of the protecting group and other conditions.
  • the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid.
  • acid ion exchange resins and the like are used.
  • the base may be, for example, a hydroxide or carbonate of an alkali metal such as sodium or potassium or an alkaline earth metal such as calcium or magnesium, depending on the type of the protecting group and other conditions.
  • Organic bases such as inorganic bases, metal alkoxides, organic amines, and quaternary ammonium salts, as well as basic ion exchange resins.
  • a solvent is used in the above method using an acid or a base, a hydrophilic organic solvent, water or a mixed solvent is often used.
  • the force varies depending on the type of the protecting group and other conditions.
  • a metal such as tin or zinc or a metal compound such as chromium dichloride or chromium oxychloride and an organic compound such as a fumaric acid or propionic acid or hydrochloric acid.
  • a method using an acid such as an inorganic acid, a method of reducing in the presence of a metal catalyst for catalytic reduction, and the like.
  • the catalyst used in the method of catalytic reduction includes, for example, platinum wire, platinum sponge, Platinum catalysts such as platinum black, platinum oxide, and colloidal platinum; palladium sponge; palladium black; palladium oxide; palladium sulfate barium sulfate;
  • Palladium catalyst such as radium carbonate, palladium carbon, palladium silica gel, colloid palladium, reduced nickel, nickel oxide, Raney ipo Nickel. Nickel Urushibara.
  • a metal such as iron and chromium and an inorganic acid such as hydrochloric acid or an organic acid such as formic acid, phosphoric acid and propionic acid are used.
  • the reduction method is usually carried out in a solvent.
  • alcohols such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, and ethyl sulphate are frequently used.
  • water, acetone and the like are frequently used.
  • the acid is a liquid, the acid itself can be used as a solvent.
  • the reaction temperature in the method using an acid, the method using a base, and the method using reduction is usually performed under cooling or heating.
  • the compound in which R 2 is a carboxyl group in the compound (I ′) is obtained by reacting the compound in which R 2 is a group derivable from a carboxyl group in the compound (I) with the same reaction as the above-described deprotection reaction. In some cases, it can be manufactured.
  • the target compound (I) thus obtained is isolated by a method known per se, for example, concentration. Liquid conversion, phase transfer, solvent extraction, freeze-drying, crystallization, recrystallization, fractionation, chromatography, etc. It can be purified.
  • the target compound (I) has two asymmetric carbons in the basic skeleton, there are theoretically four kinds of stereoisomers, and each of these isomers and a mixture thereof are also included in the present invention.
  • the groups represented by R 1 and R 2 have an asymmetric carbon, stereoisomers are similarly produced, and the respective isomers and mixtures thereof are also included in the present invention. In the above reaction, these isomers are mixed
  • the respective isomers can be isolated by a conventional method such as various chromatography and recrystallization, if necessary.
  • the compound (I) of the present invention may act with a base to form a salt.
  • a base include inorganic bases such as sodium, potassium, lithium, calcium, magnesium, and ammonia, and organic bases such as pyridine, colizine, triethylamine, and triethanolamine.
  • the compound (I) of the present invention When the compound (I) of the present invention is obtained in a free form, it may be formed into a salt using a conventional method, and the compound obtained as a salt may be converted into a free form using a conventional method. .
  • Compound (I) may form an inner salt, which is also included in the present invention.
  • stereoisomers of compound (I) can be used as a medicament alone or in a mixture.
  • the compound (I) thus obtained is useful as a medicine, and has an antibacterial activity against, for example, certain gram-positive bacteria and gram-negative bacteria.
  • Table 1 shows the antibacterial spectrum of representative compounds of compound (III) against various microorganisms.
  • Inoculum volume 1 0 8 CFU / ml
  • the compound (I) or a salt thereof of the present invention has an antibacterial activity against certain gram-positive bacteria and gram-negative bacteria, and has low toxicity, so that mammals infected with bacteria are caused.
  • Bacterial infections in animals eg, mice, rats, dogs, cows, pigs, humans
  • respiratory infections urinary tract infections, purulent diseases, biliary tract infections, enteric infections, obstetrics and gynecology Infections and surgical infections
  • the daily dose of compound (I) is about 2 to 10 OmgZKg, more preferably about 5 to 4 Otng / Kg as compound (I).
  • compound (I) or a pharmaceutically acceptable salt thereof is mixed with an appropriate pharmaceutically acceptable carrier, excipient, or diluent by a conventional means,
  • an appropriate pharmaceutically acceptable carrier, excipient, or diluent for example, it can be administered orally in the form of tablets, granules, capsules, drops, etc., or it can be formed into injections by conventional means, for example, and compounded into sterile carriers manufactured by conventional means. It can be administered parenterally.
  • binders eg, hydroxypropylcellulose, hydroxy-methylpropyl cellulose, macrogol, etc.
  • disintegrants eg, starch, carboxymethylcellulose calcium
  • a glidant eg, lactose, starch, etc.
  • a lubricant eg, magnesium stearate, talc, etc.
  • parenteral preparations such as isotonic agents (eg, glucose, D-solzitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, Butanol, methyl para-oxybenzoate, propyl para-oxybenzoate, etc.), buffers (eg, phosphate buffer, sodium formate buffer, etc.) can be appropriately compounded.
  • isotonic agents eg, glucose, D-solzitol, D-mannitol, sodium chloride, etc.
  • preservatives eg, benzyl alcohol, Butanol, methyl para-oxybenzoate, propyl para-oxybenzoate, etc.
  • buffers eg, phosphate buffer, sodium formate buffer, etc.
  • the antibiotic TAN-588 which is a raw material compound used in the method of the present invention, is obtained by culturing an antibiotic TAN-588-producing bacterium belonging to the genus Endobactor or Rhizobacta in a medium, and culturing the culture. It can be produced by producing and accumulating the antibiotic TAN-588, and collecting it.
  • the production bacteria include Empedobacter lactamgenus YK-258 strain and Lysobacter ⁇ Albus (Lysobacter albus) sp. Nov. YK-422 strain.
  • the microorganism is a foundation law
  • a para-nitrobenzyl group or a benzhydryl group is introduced into TAN-588 or a salt thereof to give a para-nitrobenzyl ester or benzhydryl ester, and the -ester is deacetylated to deacetyl of TAN-588.
  • a paracetyl benzyl ester or a benzhydryl derivative of the compound, and the ester group is eliminated to produce a deacetyl derivative of TAN-588.
  • CHP-20 Diaion CHP-20 (Mitsubishi Chemical Industries, Japan)
  • HP-20 Diaion HP-20 (Mitsubishi Chemicals, Japan)
  • X AD—2 Amber Light X AD—2 (Roam & Haas, USA)
  • the entire volume of the culture was inoculated into the above medium in a tank of 50 J2 containing a medium 300 containing 0.05% of an antifoaming agent Actcol (manufactured by Takeda Pharmaceutical Company Limited, Japan). . Under the conditions of 50 5 / min and 200 rpm / min at V
  • the main culture was repeated twice, and the culture solution (230 J2) was adjusted to ⁇ 8, followed by filtration using 9 Kg of Hyph-mouth, super-one-cell (Jyons Manville, USA). After adjusting the filtrate (200 J2) to pH 6, Amberlite IRA—402 (C J2 type, 10 ⁇ , manufactured by Rohm and Haas, USA). The antibiotic was eluted with 2% saline, adjusted to an eluate (53 Jg) ⁇ pH 6, and then subjected to activated carbon chromatography (5, manufactured by Takeda Pharmaceutical Co., Ltd., Japan). The antibiotic was eluted with 8% isobutanol, and the eluate (141 :) was concentrated under reduced pressure to 5 J2.
  • the concentrated solution was adjusted to pH 6 and extracted with a 2% tree ⁇ -octylmethylammonium chloride / dichloromethane solution (2.59 ⁇ 2).
  • the extract was treated with 1.6% aqueous sodium iodide (2.5 J2) to transfer the antibiotic to the aqueous layer.
  • the aqueous layer was concentrated, the concentrate was subjected to activated carbon chromatography (50 Oml), and eluted with 8% isobutanol.
  • the eluate was concentrated and lyophilized to obtain 1.4 ig of a crude powder. Dissolve the coarse powder (1.48) in water (100 ml), and dissolve the solution in QAE—Sephade, Sox A—
  • the molecular ion peaks by the S I MS method are as follows.
  • the main absorption (wave number) of the absorption spectrum by the bromide-repellent tablet is as follows.
  • a negative Coton effect is shown at 2 3 ⁇ 3 nm.
  • Stability Stable at pH 5 in aqueous solution, slightly unstable at pH 3 and 7, unstable at pH 9.
  • HP LC High Performance Liquid Chromatography (HP LC) (Carrier: YMCA-312, manufactured by Yamamura Chemical Laboratory, Japan, mobile phase: 4%, methanol / 0.01 M phosphate buffer (PH6.3) , 2ml / niin):
  • TAN-588 obtained above may be referred to as compound (R-1).
  • Benzophenone hydrazone 58.8 g, 1,1,3,3-tetramethylguanidine 42 ml and eodo 150 mg were dissolved in dichloromethane 500 ml. After cooling the mixture to 0 ° C. to 15 ° C., 74 g of m-chloroperbenzoic acid (70% purity) was added, and the mixture was stirred at 0 ° C. for 40 minutes. After washing the reaction solution with water, it was dried over sodium sulfate, and the solvent was distilled off to obtain diphenyldiazomethane.
  • TAN-5883 lg was suspended in tetrahydrofuran, and the total amount of diphenyldiazomethane obtained above was dissolved in 150 ml of tetrahydrofuran and added. After cooling the mixture to 0 ° C., 1.6 mL of 2N HCl was added dropwise, and the mixture was stirred at room temperature for 1 hour. 2 NHC (10 ml) was added, and the mixture was further stirred for 1 hour. The obtained solution was washed with water, concentrated, and ether was added to the residue to obtain 28 g of a white crystalline powder of TAN-588 benzhydryl ester (a mixture of type A and type B).
  • B-type compound (400 mg) and a mixture of A-type and B-type (476 mg) were obtained as colorless crystals.
  • the TAN-588 benzhydryl ester obtained above may be referred to as a compound (R-2).
  • TAN-588 benzhydryl ester (mixture of Form A and Form B) (26 g, 59IMO1) was suspended in dichloromethane and suspended in 2J2, and cooled to 120 ° C. To the mixture were added 49 ml of pyridine and 37.6 g of phosphorus pentachloride, and the mixture was stirred at 110 ° C. to 115 ° C. for 50 minutes. After the temperature was lowered to 130 ° C., 180 ml of methanol was added, and the mixture was stirred at 150 ° C. for 30 minutes, and further stirred at room temperature for 1 hour.
  • the benzhydryl ester of the decetyl form of TAN-588 obtained above may be referred to as a compound (R-3).
  • 3400 3050, 2970, 1800, 1780, 1740, 1600, 1500, 1460, 1305, 1270, 1190, 1110, 1060, 980, 920, 880, 850, 750, 710, 650, 620, 605 cm one 1
  • Benzhydryl ester of a deacetyl group of TAN-588 (mixture of Form A and Form B) (396 mg) was suspended in 1 Oml of dichloromethane, and the suspension was cooled to 120. Cooled to C. Anisol 43 4 zl, trifluoroacetic acid 924; 1 plus 20. The mixture was stirred at ⁇ 10 ° C. for 40 minutes. The reaction solution Axis every mouth methane 2 8 0 ml was added, 0. 1 MH 3 P 0 4 - extracted with Na 2 HP 0 + solution (pH 7. 3) (4 2 Oml).
  • the extract was adjusted to pH 5.5, concentrated, passed through a column filled with Dia HP-20 (50-100 Omesh 100 ml), washed with water and eluted with 40% methanol water Fractionated. Fractions showing antibacterial activity were collected, concentrated, and lyophilized to obtain 143 mg of a white powder of a detanyl form of TAN-588 (mixture of type A and type B).
  • the main absorptions are as follows.
  • a negative Coton effect is shown at 233 ⁇ 3 nm.
  • HP L C Equipment, carrier, flow rate are the above-mentioned deacetyl-benzhydryl
  • the main absorption is as follows.
  • a negative Coton effect is shown at 238 ⁇ 3 nm.
  • TAN-588 benzhydryl ester (form B) 6557 mg was subjected to the same reaction and treatment as in Reference Example 3 to obtain a decetyl form of benzhydryl ester of TAN-588 (form B) 200 mg was obtained. 180 mg of the compound was dissolved in 18 ml of tetrahydrofuran (1: 1), 90 mg of 10% palladium on carbon was added, and the mixture was stirred in a hydrogen stream. After the catalyst was removed by filtration, the filtrate was concentrated, and the aqueous layer was washed with getyl ether. The aqueous layer was concentrated and freeze-dried to obtain 77 mg of a powder of a deacetyl compound (B type) of TAN-588. .
  • the main absorption is as follows
  • a negative Coton effect is shown at 224 ⁇ 2 nm.
  • TAN-588 sodium salt 400 mg was dissolved in DMF (4 ml), and triethylamine (1001) and paranitrobenzil bromide (800 mg) were added. Stirred for hours. To the reaction solution was added 0.01 M phosphate buffer (pH & 0.3, ⁇ Oml), and the mixture was extracted twice with ethyl ethyl sylate (50 ml). After the extract was washed with water, the resulting oil was concentrated to a powder (507 mg) with ethyl acetate-petroleum benzine, and the TAN-588 paranite benzyl ester (type A) and TAN-1.5 A mixture of 88 paranit mouth benzyl esters (form B) was obtained.
  • TAN-588 paranitrobenzyl ester type A
  • TAN-588 paranitol benzyl ester type B
  • silica gel (Merck, West Germany)
  • silica gel (Merck, West Germany)
  • T L C T AN — 5 8 8 Same conditions as for paranitral benzyl ester (Type A)
  • compound (13a) which is the diphenyl methyl ester of title compound (13b) was obtained in the same manner as in Example 2 (a) (by chromatography using silylation gel, The stereoisomers for position 2, A and B, were isolated.). Then, the title compound (13b) was obtained in the same manner as in Example 2 (b) using a mixture of both isomers A and B of the compound (13a).
  • Example 14 Using the compound a4a) obtained in Example 14, the compound was reacted with 4-pyridylmercaptan.
  • a compound (15a) which is a diphenylmethyl ester of the title compound (15b) was obtained.
  • the title compound (15b) was obtained in the same manner as in the above.
  • the reaction conditions, yields, and physicochemical properties of the resulting compounds in Examples li to 15 are described below.
  • the crystals (mixture of forms A and B, lg) were subjected to chromatography on silica gel (50 g) and eluted and fractionated with a solvent system of ⁇ ⁇ form: methanol (30: 1).
  • the fraction eluted earlier was concentrated and crystallized to obtain the title compound (Type 16 of 16), and the title compound (Type 16 of Type 16) was obtained as a crystalline powder from the fraction eluted later.
  • the compound (R-3) was dissolved in dichloromethane, pyridine and a mixed solution of acetic anhydride and formic acid were added, and the mixture was stirred. After washing the reaction solution with hydrochloric acid and a 2% aqueous sodium hydrogen carbonate solution, the organic layer was dehydrated and concentrated, and ether was added to the residue to obtain a powder of compound (21a).
  • Example 22 (b) The compound (23a) was reacted in the same manner as in Example 22 (b), and the reaction solution was treated in the same manner as in Example 21 (b) to obtain a powder of the title compound (23b).
  • N-benzyloxycarbonylglycine (Z-glycine) and triethylamine are added to THF, and a liquid obtained by suspending compound (R-3) in THF is added to the solution, followed by stirring. did.
  • the reaction solution was treated in the same manner as in Example 2ia to obtain a compound (24a) crystal.
  • the compound (24a) was reacted in the same manner as in Example 22 (b) and post-treated to obtain a powder of the title compound (24b).
  • the compound (R-3) was dissolved in dichloromethane, and DMA and benzoyl chloride were added, followed by stirring.
  • the reaction solution was treated in the same manner as in Example 21 (a) to obtain a compound (25a) crystal.
  • the compound (25a) was reacted in the same manner as in Example 22). After work-up, the product was subjected to column chromatography on Diaion HP-20, and the effective fraction was eluted with 40% aqueous methanol to give the title compound. A powder of (25 b) was obtained.
  • the compound (R-3) was dissolved in dichloromethane, and DMA and nicotinic acid chloride were added, followed by stirring.
  • the reaction solution was treated in the same manner as in Example 21 (a) to obtain a compound (27a) crystal.
  • Mouth lid (0.28ml) 1780,1675, 2.4-3.4 (4H, m), 4.1-5.5 (3H, DMA (0.8ml) 1190,1055
  • the compound (R-3) was dissolved in acetonitrile, and formaldehyde, sodium cyanoborohydride and acetic acid were added, followed by stirring. Water was added to the reaction solution, acetonitrile was distilled off, and the aqueous layer was extracted with ethyl acetate. The extract was washed with 2% sodium bicarbonate and concentrated. THF was added to the concentrated solution, 2N hydrochloric acid was added, and the mixture was stirred overnight at room temperature. The organic layer was concentrated, water was added to adjust the pH to 10 with dilute sodium hydroxide water, the aqueous layer was extracted with ethyl acetate, and the extract was concentrated to obtain a powder of compound (32a). .
  • the compound (32a) was reacted in the same manner as in Example 25 (5) and post-treated to obtain a powder of the title compound (32b).
  • Example 5 The compound (5a) obtained in Example 5 was dissolved in THF, and while cooling with a dry ice / aceton bath, a methanol solution of t-butylhippolide and a methanol solution of lithium methoxide were added, followed by stirring for 5 minutes. Then, one drop of acetic acid was added, and the mixture was diluted with ethyl acetate. The organic layer was washed successively with an aqueous sodium thiosulfate solution and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel to obtain a compound (34a) which was a diphenylmethyl ester of the title compound (34b).
  • the compound (34a) was dissolved in THF, pH 7.0 buffer, palladium black and palladium oxide were added, and the mixture was stirred in a hydrogen stream.
  • the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the aqueous layer was washed with ether. After concentration, the concentrate was subjected to column chromatography using XAD-2 and eluted with 10% ethanol. The eluate was concentrated under reduced pressure and freeze-dried to obtain the title compound (34b) as a white powder.
  • the compound (R-3) is suspended in dichloromethane and stirred under ice-cooling, butylene oxide and 2-chloroacetado 4-thiazolyl 2- (4-2-trobenzoyloxycarbonylmethyloxyimino) An acid chloride was added and reacted for 1 hour. Ethyl acetate was added, and the organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate.
  • Tablets are prepared by conventional means using the following ingredients.
  • Compound (I) or a salt thereof has excellent antibacterial activity and is used as an antibacterial agent or a therapeutic agent for bacterial infection.

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Abstract

Des composés représentés par la formule générale (I) (où R1 représente un aminé ou un résidu organique fixé par l'intermédiaire d'un atome d'azote, R2 représente un carboxy ou un groupe dérivé, et X représente de l'hydrogène, du méthoxy ou du formylamino, à condition que R2 ne représente pas du p-nitrobenzyloxycarbonyle ni benzhydryloxycarbonyle lorsque R1 est acétylamino ou amino et X est de l'hydrogène) et leurs sels ont une excellente action antibactérienne et sont utilisés comme agents antibactériens.
PCT/JP1984/000602 1984-12-18 1984-12-18 Nouveaux derives antibiotiques, leur procede de preparation et leur utilisation Ceased WO1986003752A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PCT/JP1984/000602 WO1986003752A1 (fr) 1984-12-18 1984-12-18 Nouveaux derives antibiotiques, leur procede de preparation et leur utilisation
PCT/JP1985/000358 WO1987000178A1 (fr) 1984-12-18 1985-06-25 Derives antibiotiques nouveaux, leur procede de preparation et d'utilisation
DK558885A DK558885A (da) 1984-12-18 1985-12-03 Oxoisoxazolidinderivater og laegemiddelpraeparat indeholdende dem
JP60280139A JPH0674275B2 (ja) 1984-12-18 1985-12-12 抗生物質ｔａｎ―５８８誘導体
IE319885A IE59102B1 (en) 1984-12-18 1985-12-17 Antibiotic isoxazole derivatives, their production and use
CN85109633A CN1024668C (zh) 1984-12-18 1985-12-17 2-(2-异噁唑烷基)-2-四氢呋喃羧酸衍生物的制备方法
DE8585309197T DE3586591T2 (de) 1984-12-18 1985-12-17 Antibiotisch wirkende isoxazolderivate, ihre herstellung und verwendung.
KR1019850009508A KR930001405B1 (ko) 1984-12-18 1985-12-17 2-(4-치환아미노-3-옥소-이속사졸리디닐)-5-옥소-2-테트라히드로푸란카르복실산 유도체의 제조방법
AT85309197T ATE80162T1 (de) 1984-12-18 1985-12-17 Antibiotisch wirkende isoxazolderivate, ihre herstellung und verwendung.
ES550040A ES8705431A1 (es) 1984-12-18 1985-12-17 Un metodo para producir derivados de acido 2-(4-amino susti-tuido-3-oxo-2-isoxazolidinil)-5-oxo-2-tetrahidrofuran-carbo-xilico
EP85309197A EP0191989B1 (fr) 1984-12-18 1985-12-17 Dérivés de l'isoxazole à activité antibiotique, leur préparation et leur application
US07/058,265 US4897489A (en) 1984-12-18 1987-05-21 Antibiotic derivatives, their production and use

Applications Claiming Priority (1)

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PCT/JP1984/000602 WO1986003752A1 (fr) 1984-12-18 1984-12-18 Nouveaux derives antibiotiques, leur procede de preparation et leur utilisation

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4897489A (en) * 1984-12-18 1990-01-30 Takeda Chemical Industries, Ltd. Antibiotic derivatives, their production and use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
No relevant documents have been disclosed. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4897489A (en) * 1984-12-18 1990-01-30 Takeda Chemical Industries, Ltd. Antibiotic derivatives, their production and use

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