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WO1985005620A1 - Composes cephem - Google Patents

Composes cephem Download PDF

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Publication number
WO1985005620A1
WO1985005620A1 PCT/JP1984/000270 JP8400270W WO8505620A1 WO 1985005620 A1 WO1985005620 A1 WO 1985005620A1 JP 8400270 W JP8400270 W JP 8400270W WO 8505620 A1 WO8505620 A1 WO 8505620A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
acid
ester
salt
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/JP1984/000270
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English (en)
Japanese (ja)
Inventor
Akio Miyake
Masahiro Kondo
Masahiko Fujino
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/JP1984/000270 priority Critical patent/WO1985005620A1/fr
Priority to NO851538A priority patent/NO165842C/no
Priority to AT8585104687T priority patent/ATE79882T1/de
Priority to EP85104687A priority patent/EP0160252B1/fr
Priority to PH32153A priority patent/PH23134A/en
Priority to DE8585104687T priority patent/DE3586547T2/de
Priority to DE8585104687A priority patent/DE3586547D1/de
Priority to NZ211858A priority patent/NZ211858A/xx
Priority to GR850965A priority patent/GR850965B/el
Priority to FI851592A priority patent/FI851592A7/fi
Priority to JP60086746A priority patent/JPH07103130B2/ja
Priority to PT80328A priority patent/PT80328B/pt
Priority to DK179985A priority patent/DK179985A/da
Priority to ES542447A priority patent/ES8606362A1/es
Priority to US06/726,438 priority patent/US4788185A/en
Priority to CA000479769A priority patent/CA1283096C/fr
Priority to AU41700/85A priority patent/AU580995B2/en
Priority to KR1019850002737A priority patent/KR920008945B1/ko
Priority to ES549180A priority patent/ES8707245A1/es
Priority to NO85854730A priority patent/NO167293C/no
Publication of WO1985005620A1 publication Critical patent/WO1985005620A1/fr
Priority to ES553666A priority patent/ES8706692A1/es
Priority to ES557129A priority patent/ES8800950A1/es
Anticipated expiration legal-status Critical
Priority to MYPI87002280A priority patent/MY102089A/en
Priority to KR1019910020376A priority patent/KR920008953B1/ko
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hetero atoms directly attached in position 7
    • C07D463/16—Nitrogen atoms
    • C07D463/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D463/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D463/22—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen further substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to a novel cef compound having an excellent antibacterial activity, a method for producing the same, and a pharmaceutical composition.
  • Background Technology-Conventionally a quaternary ammonium methizole group is in the third position, and 2- (2-aminothiazole) is in the seventh position.
  • Various sepham compounds or derivatives thereof having a hydroxy (or substituted hydroxy) iminoacetamide group have been synthesized and patented [for example, see Japanese Patent Application Laid-Open No. 53-34779 5.
  • CFM antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, such as in the treatment of diseases caused by bacteria resistant to benicillin antibiotics and in the treatment of bencilin-sensitive breaths. It is especially useful for the treatment of the elderly. In this case, it is desirable to use a cefm antibiotic that is active against both gram-positive bacteria and gram-negative bacteria. For this reason, research on cefe antibiotics having a broad antibacterial spectrum has been pursued. Actively performed
  • the present invention has the general formula
  • R i is an amino group which may be protected
  • R 2 is a hydrogen atom or a halogen atom
  • R 3 is a hydrogen atom or a hydrocarbon residue which may be substituted
  • R 4 is A represents a hydrogen atom or a methoxy group
  • A represents an optionally substituted imidazole-11-yl group which forms a condensed ring at the 2,3-position or the 3,4-position
  • Or 1 or a physiologically acceptable salt or esthetic thereof, a process for producing the same, and a pharmaceutical composition.
  • the chemical compound in the present specification is based on “The 'Jana' Saiji Buji professionalismn.Chemical.Society”, vol. 84, p. 3400 (1962). Named in connection with “cepham”, it refers to a compound having a double bond at the 3,4-position among cepham compounds.
  • a cephalic compound having a quaternary ammonium methyl group at the 3rd position and an aminothiazolyl xyminoacetamide at the 7th position has a more excellent antibacterial effect and a unique antimicrobial effect.
  • an antibacterial agent Numerous compounds in which the quaternary ammonium group at the 3-position is derived from a nitrogen-containing aromatic heterocycle have already been synthesized and patent applications have been filed, but those heterocycles are monocyclic pyridinium groups or on their rings.
  • the substituent Ri represents an amino group which may be protected, that is, an amino group or a protected amino group.
  • the protecting group of amino group has been thoroughly studied and its protection method has already been established.
  • those known as the protecting group of amino group are also used. It can be adopted as appropriate.
  • Amino protecting groups as, for example C 6 ⁇ 10 ⁇ Li of - / Leer Shinore group, Ci ⁇ 5 ⁇ / Leka noisy Honoré group, C 3 ⁇ 5 Anorekeno I, Les group, Cg i. ⁇ ⁇ ⁇ ⁇ ⁇ ( ⁇ ⁇ ⁇
  • aryl / leacinole group examples include benzoinole, naphthoinole, and phthalonyle, and these aromatic rings are substituted with ( ⁇ to 4 arequinole, ( ⁇ 6 anorecoxy, halogen, nitro, etc.).
  • substituted aryl / leacene group examples include p-tonoleinole, -tert-butynolebenzo'inole, p-methoxybensoinole, p-tert-. Butoxybenzoinole, ⁇ -crobenzoenore, p-2-nitrobenzonole, etc.
  • Kunoreta Rinore are mentioned, these a Kanoinore groups further ( ⁇ 1-6 a Job shea, halogen, C 6 ⁇ 10 ⁇ Re one / Les, C 6 ⁇ 10 ⁇ Li Noreokishi, C 6 ⁇ 10 ⁇ rie Norechio etc. In may be substituted.
  • a le in concrete is black WINCH Bruno I Honoré and maleoyl can be mentioned, Arukenoiru group of these are further substituted with such C 6 ⁇ 10 Ariru You may.
  • Specific examples of the substituted alkenyl group include cinnamoyl.
  • C 6 ⁇ 1 0 ⁇ Li Rusuruhoniru specifically, base Nze Nsuruhoniru as groups, such as naphthalene sulfonyl and the like, these aromatic rings C i to 4 alkyl, C 'i ⁇ 6 alkoxy, halogen, Two Bok port It may be replaced by, for example.
  • substituted arylsulfonyl group examples include p-northene sulfoninole, p-tert-butynolebenzenes zolephoninole, p-methkinbenzenebenzenesulfonyl, p-chlorobenzenesulfonyl, ⁇ —Power such as benzenesulfonyl; C 1 ⁇ ln alkylsulfonyl ⁇ and specifically is methanesulfonyl, ethanesulfonyl, etc. mosquitoes Nfasuruho sulfonyl and the like,. These alkylsulfonyl ® or C 6 ⁇ 1 0 Ariru, C
  • aryloquin ' may be substituted by halogen or the like.
  • substituted oxycarbonyl group include ( ⁇ to 8- alkoxycarbonyl groups such as methoxycarbonyl, ethoxyquincarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and isovonolenylcarbonyl, such as phenoxycarbonyl and naphthyl).
  • benzyl O Kin c 7 ⁇ such as carbonyl 1 2 Ararukiruoki Ichiriki Lupo 'sulfonyl group etc. are exemplified et. are. C alkoxy one The carbonyl group is additionally C
  • alkoxy-carbonyl group examples include methoxymethyloxycarbonyl, acetinolemethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methansulfonylethoxycarbonyl, 2,2,2-trichlorocarbonyl. Loro Toki i carbonyl, 2-ano Toki carbonyl and the like.
  • substituted canolebamoyl group examples include N— Methyl / Reca / Rebamoyl, N-Ditylcarbamoyl, N, "-Dimethylcarbamoyl, N-Phenylcarbamoyl, N-(— Meth-Xyphenyl) Lubamoyl, and the like. ..
  • N- main Chiruchio force Rubamoi Le C 6 ⁇ 10 Ariru - base is specifically a methyl group Njiru, Nafuchirume
  • These aromatic rings may be substituted with ( ⁇ to 4 alkyl, C i to 6 alkoxy, halogen, nitro, etc.)
  • Reel methyl group is specifically P-methyl pen , P-methoxybenzinole, p-cloth venzinole, ⁇ 12-t venzinole, and the like.
  • the methyl group of Arirumechiru group may be substituted by another 1-2 amino C 6 ⁇ 10 Ariru group, specifically base Nzuhi drill, etc.
  • C 6 ⁇ 10 ⁇ Li Ichiru -
  • the methylol alkylene group specifically including benzylidene, and these aromatic rings C. 1 to 4 alkyl, C 1 ⁇ 6 alkoxy, halogen, substituted with such as a secondary Bok port May be.
  • Specific examples of the substituted arylmethylene group include P-methylbenzylidene and p-chlorobenzylidene.
  • the C 6 ⁇ 10 ⁇ Li one Lucio groups specifically such 0- two Bok ⁇ -phenylene thioether can be mentioned.
  • the substituted silino group is represented by the general formula R 6 R 7 R 8 S i NH,
  • R 10 H 9 ', R 10 ' are each for example methyl
  • Echiru shows a C 6 ⁇ 10 Ariru group such as C ⁇ 4 alkyl or e.g. phenyl, such as tert- butyl, it may be the same or different.
  • main styrene it means a silyl group such as represented by showing the C. 1 to 3 alkylene group such as Edjiren], specifically Bok Li main Chirushi Li Le, tert- Puchirujime Chirushi Lil, - Si (CH 3 2 CH 2 CH 2 Si (eg, ⁇ 3 2 — and the like.
  • Examples of the C alkoxy group of 2—C ⁇ salkoxy-carboxyl 1—methyl-1-ethenyl group include methoxy, ethoxyquin, tert-butoxy.
  • Substituents Ii 2 in the above cephem compound [ ⁇ ] represents a hydrogen atom or a halogen atom.
  • the halogen atom include fluorine, chlorine, and bromine, and chlorine is preferable.
  • the substituent R 3 is a hydrogen atom or a substituted
  • CMPI Represents an optionally substituted hydrocarbon residue.
  • hydrocarbon residues include
  • n-propynole, isopropynole, n-butynole, isof * chinole, sec — ' ⁇ -!, tert—butene / let, n-one; , Ethinole and ⁇ -propi / re are preferred.
  • cycloanole keninole groups include, specifically, 2-cyclohexylbenzene, 3-cyclohexylbenzene, 2-cyclohexynole, 3-cyclohexynole, and the like.
  • Fueniruchi O, C 7 ⁇ 12 ara ⁇ quinthio group is benzyl retinyl, mono-C i- 4 alkylamino, methinoleamino, ethylamino, n-propylamino, n-butylamino, di ( ⁇ 4alkylamino is dimethylamino, getinoleamino Bruno, Mechinoreechirua Mi Bruno, di (n -. off Robinore) ⁇ Mi Bruno, and di (n- butyl amino, Ji 6 black alkylamidyl Groups Kurofu necked Piruamino, etc.
  • Hue Niruasechiru ( ⁇ 5 alk Noiru group Hor Mitsure, Asechiru, full opening Pioniru, butyryl, valeryl, Pibaroiru the like, c 3 ⁇ 5 Arukenoi Le group ⁇ click Li Roy Honoré, black Tonoiru, maleoyl the like, C 6 ⁇ 10 Arirua Ruo ⁇ The sheet group and Benzoiru old Kin, C 2 ⁇ 5 Arukanoiru old alkoxy group ⁇ Seto key sheet, off. Mouth Pioniru old carboxy, butyl re / Reokishi, etc.
  • Substituted rubamoyl groups include N-methylthioamine and N-methylcarbamoyloxy, N, N-dimethylcarnoyl, N-ethyl / recarnomoy / reoxy, etc.
  • the heterocyclic group of the heterocyclic group, the heterocyclic oxy group, the heterocyclic thio group and the heterocyclic amino group represents a heterocyclic group specifically described later as the heterocyclic group forming the substituents R n and R 12. .
  • the above-mentioned aralkyl group, aralkyl group, aralkylthio group and aralkylamino group are the aralkyloxycarbonyl group and the alkyl group constituting the aralkyl group of the aralkyl group. Another one.
  • 0 may be substituted with an aryl group, and specific examples thereof include Benzhydryl, Bens “Hydrolux”, Bens “Hydroluci, Bens” Hidrilamino, Bens 'Hydroxy / reoxycarboni / re, Bence' include hydryl xycanolevonylamino. Two or more of these substituents may be the same or different May be present.
  • substituted hydrocarbon residues more preferred are a hydroxyl group, a cycloanolekyl group, an ⁇ / recoxy group, an alkylthio group, an amino group, a nodroken atom, a force phenol group, an alkoxycarbonyl group, a carnomoyl group, a cyano group.
  • the most preferable ones are linear C i- 3 alkyl groups such as meth / yl, ethynole, and n-propyl; and 2-fluoroethyl, 2-chloroethyl, Reboxoxymethyl, tert-butoxycarbo-2-methynorole, 1-carboxy-1.1-methy / reethy / re, 1-tert-butoxycarbonyl-1-1-methylethyl, etc., substituted with norogen, carboxy, alkoxyl / reponyl Linear Ci ⁇ s alkyl group
  • All of the compounds [I] of the present invention having these as R 3 groups have strong antibacterial activity, and particularly have an excellent bactericidal action against resistant bacteria. Further, in this specification, all three OR groups are in a syn-coordination (Z-coordination).
  • the substituent R 4 represents a hydrogen atom or a methoxy group.
  • the substituent A represents an imidazolyl-1-yl group which may be substituted to form a condensed ring at the 2,3-position or the 3,4-position.
  • the condensed ring means a condensed form of an imidazole ring and a 5- or 6-membered aromatic heterocycle, and this condensed ring may be condensed with another aromatic ring or an aromatic heterocycle.
  • the symbol attached to the substituent A indicates that the substituent A has a monovalent positive charge.
  • Optionally substituted 2, 3-position, or 3, 4 ones I imidazole one to form a condensed ring 1 - I le group (A®) is the general formula or [A 2]
  • B is a group forming a 5- or 6-membered aromatic complex which may be fused with another aromatic ring or an aromatic heterocycle, and 1 ⁇ is a hydrogen atom or A substituent on the midazole ring;
  • R l 2 represents a hydrogen atom or a substituent on the ring condensed with the imidazole ring;
  • c B is a carbon atom, a nitrogen atom, an oxygen atom, and a hydrogen or sulfur atom; Forms a condensed ring with one hydrogen atom or one substituent, or with adjacent carbon atoms.
  • the compound with a group is generally superior, although it depends on the combination with the R 3 group.
  • the positive charge of the substituent was conveniently applied to the nitrogen atom at the 3-position of imidazo- /
  • the quaternary nitrogen atom may be applied to the nitrogen atom at the first position in some cases.
  • the monovalent positive charge is delocalized on the imidazole ring. Further, it may be delocalized on the entire condensed ring. So, for example, in the case of
  • This positive charge changes fluidly depending on the state of compound [I] (in a solid resting solution), the type of solvent and liquidity, the temperature, the type of substituent, and the like. It includes both the case where the field charge is localized on the nitrogen atom and the case where the field charge is delocalized on the entire imidazole ring or the complex ring. Hatato example, if a hydroxyl group as a substituent Ri i and R 12 on the condensed ring, C. 1 to 4 arsenide Dorokishia Rekinore groups, C i to 6 Anorekiru groups, C 2-6 alkenyl group - C. 2 to 6 ⁇ / gravel two '.
  • Riruchio group C 7 through i 2 Ararukiru Chisaimoto, A Mi amino group, C i to 4 A Mi-alkyl group, mono C. 1 to 4 alkyl amino group, di C. 1 to 4 alkylamine amino group, mono C i to 4 alkylamine Mi node on C i to 4 alkyl group, di C. 1 to 4 alkylamine Mi node on C. 1 to 4 ⁇ , gravel Le group, C 3 ⁇ 6 consequent Roarukirua Mi amino group, C 6 ⁇ 1.
  • Cyclic amino group cyclic amino C i to 4 alkyl group, cyclic amino C to 4 alkynoleamino group, Azide group, nitro group, halogen atom.
  • Halogenoalkyl group Shiano group, ⁇ Roh one Ci ⁇ 4 alkyl group, a carboxy group, a carboxyl i ( ⁇ -4 alkyl group. ( ⁇ 1-8 alkoxy one carbonyl group, ( ⁇ 1-8 alkoxy one carbonylation Lou Ci ⁇ 4 alkyl group, C 6 ⁇ 10 Ariruokishi Ichiriki carbonyl group, C 3, ⁇ .
  • ⁇ 4 Hydroxyalkyl group is hydroxymethyl, 2-hydroxyxetizole, etc., C ⁇ 6 alk. / Group is methyl, ethyl, n-propynole, isopropy, n-butyl, isobutynole, sec-f ' Chinole, tert-butynole, n-pentyl, n-hexyl, etc., C 2-6 phenol “nyl group is vinyl”, arylene, isoflurinole, metalyl, 1, 1 - dimethyl ⁇ Chinorea Li Honoré, 1 one Buteni Honoré, 2-butene, second, 'Les, 3 - butenyl, etc., C 2 ⁇ 6 alkynylene,' Les group E Ji two Honoré, 1 one Zaro Bininore, 2 - Purohininore, Buropaginore etc., 1 C.
  • C7- ⁇ 2 aralkyl groups are benzyl, phenetinole, etc.
  • Heterocyclic groups are 2-pyridinole, 3-pyridinole, 4-pyridyl, N-oxide.
  • Amino, di-n-phthyl) amino, etc. are converted to mono C 1 -anolequinolemino C i -4 -anolequinole group or methinorea minometinole, echinorea minometinole, 2-(N- N-N-N-dimethylaminomethyl, N, N-ethylamino, such as chinolemino) ethylenole, 3- (N-methylamino) propyl, etc.
  • Mouth viramino, cyclohexinoleamino, etc., C 6- ⁇ 0 arylamino group is anilino, N-methylanilino, etc .; 7-; L2 aralkylamino group is benzylamino, 111-amino. ⁇ , 'Letinoreamino' 2 — ⁇ 2, 'reethylamino, etc., and cyclic amino groups are pyrrolidino, pyridino, virazino, mo / reholino, 1-pyrrolyl Etc.
  • - ⁇ Amino C 1-4 alkynole groups are pyrrolidinomethyl, bilidinomethyl, biradinomethinole, mo./refolinomethyl, and 2 — (mo / reholino) etinole, but are referred to as' cyclic amino C 1 ⁇ 4 alkynoleamino groups are pyrrolidinomethylamino, Peri-dinomethylamino, pyra-dinomethine / rare-mino, monorefolino-methyl / 'reamino, halogen atom such as fluorine, chlorine, bromine, etc.' Ci to 4- norogenoalkynole group Chinore, Zihu / Leorome Chinore, Tri-Funore Chileno Chinole, 1—Funoret Chileno Chile, 2—Funore Chile Lochinore, Monochloromethinole, Dichloromethinolle, T
  • C 6 ⁇ 1 0 ⁇ Li Lumpur one ⁇ Silyl groups include benzoyl, phthaloyl, phenylacetyl, etc., and Ci to 5 alkanoyl groups [forminole, acetyl. Propyl, butylinole, norrelyl, and vivaloyl.
  • Neunole—C i-4 alkyl groups include acetylmethyl, 1-acetylethyl, 2-acetylethyl, etc., and C 3-5 anoreckenyl groups (macroylol, crotonoynole, male cinnole, etc .; ⁇ 10 aryl / reoxy groups are benzoyloxy and the like; Chiriruokishi, etc. Bibaroi old alkoxy, C.
  • N- Echirukarunoku moil N, N- Jechiru force Rubamoi Le, N- Hue carbamoylmethyl, piperazinyl Li Gino Kanoreboniru, bi Perajino carbonyl, etc.
  • Ruanrua Mi de group base Nzua Mi de, C ⁇ alkoxy i - - ⁇ 1 0 ⁇ Li force Ruboniruami amino group is main butoxy carbonitrile Nino les amino, ethoxy Kin carbonyl ⁇ Mino, and tert- butoxycarbonyl ⁇ Mi Bruno, C 6 ⁇ 10 ⁇ ! ; Ruo key and one force Ruboniruamino group Fueno alkoxycarbonyl ⁇ amino, C 7
  • a plurality of these substituents may be the same or different and may be substituted.
  • the 5, 6-position of the imidazole ring may be fused with an alicyclic, aromatic or heterocyclic ring. Examples of these are
  • ⁇ represents ⁇ or 1.
  • the carboxyl substituent at the 4-position indicates that the carboxyl group is a sulfoxylate anion, and forms a salt with the positive charge on the S-substituent to form an inner salt.
  • compound [I] may be a physiologically acceptable salt or ester, which may be an inorganic base salt, an ammonium salt, an organic base salt, an inorganic acid addition salt, or a salt thereof.
  • inorganic bases that can form inorganic base salts include alkali metals (eg, sodium and potassium, and alkaline earth metals (eg, Examples of organic bases that can form organic base salts such as potassium include proforce, 2-phenylene Rubenzizoleamine, dibenzylethylenediamine, ethanolanolamine, diethanolane, trishydroxymethylaminomethane, polyhydric quinalkylamine, N-methyldarcosamine, etc .; inorganic Inorganic acids capable of forming an acid addition salt include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids capable of forming an organic acid addition salt include, for example, P-toluenesulfonic acid and methanesulfonic acid.
  • alkali metals eg, sodium and potassium
  • organic bases that can form organic base salts such as potassium include proforce, 2-phenylene Rubenzizoleamine, dibenzylethylenediamine,
  • ester derivative of the compound [I :!] means an ester that can be formed by esterifying a carboxyl group contained in the molecule, and an ester that can be used as a synthetic intermediate and a nontoxic non-toxic metabolically unstable compound. Is an ester.
  • Esters usable as synthesis intermediates include C i- 4 alkyl esters, C
  • C 2 ⁇ 4 for concrete is alkenyl to form the alkenyl ester Bulle, Ariru, and I Sopuro Bae alkenyl, C 3 ⁇ 6 £ / Kuroaru kill ester specifically as click port alkyl to form a the Nkuro propyl, click Roff 'chill, click Ropenchiru, and click Roeki Le, C 3
  • alkyl forming the C1-4 alkyl ester include cyclo ⁇ -propylmethyl and chlorohexylmethyl.
  • nontoxic ester which is metabolically unstable
  • those already established in the field of penin phosphorus and cephalosporin can be conveniently employed in the present invention.
  • Examples include loyloxy methyl ester, methoxymethyl ester, ethoxyquin methyl ester, isopropoxy methyl ester, 1-methoxyl ethyl ester, 1-ethoxyethyl ester, methylthiomethyl ester, and ethylthiomethyl ester.
  • the present invention includes, in addition to the above ester derivatives, physiologically acceptable compounds which are converted into the compound [I] in vivo.
  • the compound [I] of the present invention has a broad spectrum antibacterial activity and is used for prevention and treatment of various diseases caused by pathogenic bacteria in humans and animals, for example, respiratory tract infection and urinary tract infection. Can be done. Characteristics of the antibacterial spectrum of the compound [I] are as follows.
  • Gram-positive bacteria for example, Staphylococcus. It has high activity against J, such as Nebacterium 'dibuteriae.
  • Aminoglycoside antibiotics such as amicane and gentamicin have been used for microorganisms of the genus Pseudomonas in particular.
  • [CI] has not only an antibacterial activity comparable to these aminoglycosides, but also has a great advantage because its toxicity to humans and animals is much lower than that of aminoglycosides.
  • R 5 is a hydroxyl group, an acyloxy group, a carbamoyloxy group 'substituted rubamoyloxy group or a halogen: an atom, and the other symbols have the same meanings as described above]
  • a '[A! Represents imidazole which forms a condensed ring at the optionally substituted 2,3-position or the 3,4-position.
  • the compound [I] can be produced by reacting with a compound represented by NH 2 [wherein R i has the same meaning as described above], and then, if necessary, removing the protecting group.
  • the production method will be described in order) to (4), the method for removing the protecting group, and the method for purifying Compound II. Manufacturing method (1)
  • a 7-amino compound [—] is acylated with a carboxylic acid [II] or a reactive derivative thereof.
  • the carboxylic acid [M] is free or its salt or a reactive derivative is used as an acylating agent for the 7-amino group of the 7-amino compound [III].
  • Reactive derivatives such as inorganic salts, organic salts, acid halides, acid azides, acid anhydrides, mixed acid anhydrides, active amides, active esters, active thioesters and the like of the free acid r I or the free acid [M] Is subjected to an acylation reaction.
  • Inorganic salts include alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, etc.).
  • Organic salts include, for example, trimethylamine. Salt, triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt,,
  • an acid Buromai de is mono C 1 ⁇ 4 alkyl as a mixed acid anhydride
  • Carbonic acid mixed acid anhydrides eg free acid [: 111] Mixed acid anhydrides of acetic acid with monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisobutyl carbonate, monotert-butyl carbonate, monobenzyl carbonate, mono (P-nitrobenzyl) carbonate, monoaryl carbonate, etc.
  • ( ⁇ 6 Aliphatic carboxylic acid mixed anhydrides (eg free acid [11] and acetic acid trichloroacetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, Shun Yoshikusa, Isokoshikusa) Mixed acid anhydrides with pi
  • Active thioesters include esters of aromatic heterocyclic thiols (eg, 2-pyridylthio). Esters, 2-benzothiazolyl thiol esters, etc. These heterocycles are represented by Ct-4 alkyl'Cie alkoxy, halogen atom'C
  • the 7-amino compound [I] is used as a salt or ester as it is.
  • Compounds [II ⁇ include inorganic base salts, ammonium salts, organic base salts, inorganic ⁇ ! "Salts and organic acid addition salts.
  • inorganic base salts are alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, etc.).
  • organic base salts for example, trimethylamine salts, triethylamine salts, tert-butyldimethylamine salts, dibenzylmethylamine salts, benzyldimethylmethylamine salts, N, N-dimethylaminophenyl salts
  • inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, — nitrate and phosphate, and organic acid addition salts as inorganic acid addition salts. Formate, acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, etc.
  • the compound II] is an ester derivative of the compound [ ⁇ ] Ester mentioned already can be given as here.
  • Raw material [! 1] Salts and esters, raw material [mJ and its reactive conductors can be obtained by any known method or a method similar thereto. And easy to manufacture.
  • the reactive derivative of the compound [n] can be reacted with the compound [II] as a substance isolated from the reaction mixture, or a reaction mixture containing the reactive derivative of the compound [II] before isolation.
  • an appropriate condensing agent is used.
  • condensing agent examples include ⁇ , ⁇ ′-dicyclohexylcarbodiimide and other ⁇ , ⁇ ′-disubstituted rubodiimides, such as ⁇ , N′-force rubonyldiimidazole, ⁇ , N′-thiocarbo ⁇
  • Dehydrating agents such as azirazides, such as ruzimidazole, for example, diethoxycarbonyl-2-ethoxy-1,2,2-dihydroxyquinoline, oxychlorine, and alkoxyacetylene, for example, 2-cyclopentyl 2-Halogenopyridinium salts such as diphenylmethyiodide and 2-fluoropyridinidimethyi iodide are used.
  • the reaction is thought to proceed via the reactive derivative of carboxylic acid [m].
  • the reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction can be appropriately selected.
  • solvents include ethers such as dioxane, tetrahydrofuran 'ethethyl ether, tert-butyl methyl ether ether, diisopropyl ether ether, ethylene glycol-dimethyl ether, such as ethyl formate, and the like.
  • Esters such as ethyl acetate and n-butyl acetate, for example, halogenated hydrocarbons such as dichloromethan, chloroform, carbon tetrachloride, trichlorene, 1,2-dichloroethane, etc.
  • hydrocarbons such as n-hexane, benzene, and toluene.
  • amides such as formamide, N, N-dimethylformamide, and N, N-dimethylacetamide, for example, 'acetate , Methylethyl ketone, methylinolesobutyl ketone and other ketones such as acetonitril
  • You two door Lil two door Lil class of any intensification, such as, dimethyl Chirusunorehokishi de, - Suruhora down, to Kisame Chiruhosuhoru Amides and water are used alone or as a mixed solvent.
  • the use of the acylating agent [19: 1] is usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound :: II).
  • the reaction is carried out in a temperature range from -80 to 80 ° C, preferably from 140 to 50 ° C, most preferably from -30 to 30 ° C.
  • the reaction time depends on the type of compounds II] and [II:], the type of solvent (and the mixing ratio if a mixture is used), the reaction temperature, etc., and is usually 1 minute to 72 hours, preferably 15 minutes. ⁇ 3 hours.
  • an acid halide is used as the acylating agent
  • the reaction can be carried out in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system.
  • Such deoxidizing agents include, for example, inorganic salts such as sodium carbonate, calcium carbonate, calcium carbonate, and sodium hydrogencarbonate, such as triethylamine, tri (n-propynole) amine, and tri (n- (Butyl) amine, cyclohexinoresimetylamine, pyridine, norethidine, r- collidine, N, N-dimethylphenylaniline, N-methylpyridinine, N-methylpyridine mouth, N —Tertiary amines such as methyl morpholine, and alkylene oxides such as propylene oxide and epichlorohydrin.
  • inorganic salts such as sodium carbonate, calcium carbonate, calcium carbonate, and sodium hydrogencarbonate
  • triethylamine tri (n-propynole) amine
  • tri (n- (Butyl) amine tri (n- (Butyl) amine
  • cyclohexinoresimetylamine pyridine,
  • This method is a method in which an imidazole compound A 'is reacted with a septum compound [:], and a compound [1] is synthesized by a nucleophilic substitution reaction.
  • R 5 represents a hydroxyl group, an acyloxy group, a rubamoyloxy group, a substituent rubamoyloxy group or a halogen atom.
  • 3 - Okisobuchiri Ruokishi 4-click throat one 3 - Okisobuchiri Ruokishi, 3 - Power Rubokishipuro Pioniruokishi, 4 - force Rubokishibuchiri Ruokishi, 3 - E Tokishikarubamoi Rupuro Pioniruokishi like, optionally substituted C 6 to 1 0 Ryori —
  • Specific examples of the rusiloxy group are 0 — Carboxybenzoyloxy, o — (Ethoxycarbinolecarpa'moinole) Benzo'inoleoxy, o — (Ethoxycarboninole) ) Benzo'loxy.
  • substituting rubamoyloxy group examples include methylcarno'moinoleoxy, N, N-dimethylmethylnoreoxy and the like.
  • (Halogen) Izumi includes chlorine, bromine and iodine.
  • the compound [IV1 is used as it is as a salt or ester of the compound as it is free.
  • W and the ester of the compound [W] those given as the salts and esters of the compound [H] in the production method (1) can be applied as they are.
  • Compound [IV] salts and esters thereof can be easily produced by a method known per se or a method analogous thereto.
  • the fused ring here is an imidazole ring and 5- to
  • A condensed ring imidazole
  • substituents Ri 1 and R 12 of A apply here as well, respectively.
  • the 5,6-position of the imidazole ring may be condensed with an alicyclic, aromatic or heterocyclic ring. Examples of these are l2 'etc., where ⁇ ; Ri2' is the same as described above.
  • the substituents R 11 ′ and Ri 2 ′ described above may be further substituted.
  • Compound A! Is also used as a salt.
  • inorganic acid addition salts such as hydrochloride, hydrobromic acid, sulfate, nitrate, phosphate, and the like, for example, formate, vinegar salt, trifluoroacetate
  • Organic acid addition salts such as sulfonic acid salts and p-toluene sulfonic acid salts.
  • the general method for synthesizing compound A ' is known, and can be performed by methods described in the literature or by methods analogous thereto.
  • R "with Compound A 1 is a per se well-known reaction usually carried out in a solvent.
  • Solvents such as ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, and water that are used can be applied as they are.
  • Alcohols such as methanol, ethanol, n-prononol, isopronodiol 0 , ethylene glycol, and 2-methoxyethanol are also used.
  • R 5 is an acyloxy group, a carbamoyloxy group or a substituted carbamoyloxy group
  • More preferable solvent is water or a mixed solvent of water and an organic solvent miscible with water, and an organic solvent miscible with water. Of these, more preferred are acetone, methylethylketone, and acetonitrile.
  • the amount of the nucleophilic reagent Ar to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound CIV].
  • the reaction is carried out in the temperature range of 10 to: I 0 (C, preferably 30 to 8 (f C.)
  • the reaction time depends on the type of compound '1 ⁇ ' and A 'and the type of solvent (mixed solvent).
  • the reaction time is usually 30 minutes to 5 days, preferably 1 to 5 hours.
  • the reaction is carried out at pH 2 to 8, preferably near neutral, that is, PH 5 to 8
  • the reaction is usually more easily carried out in the presence of a thiocyanate or a thiocyanate of 2 to 30 ′ i: F.
  • a salt includes sodium iodide.
  • reaction can proceed smoothly by adding a salt.
  • organic phosphorus compound used herein include 0-phenylene phosphorochloride and 0-phenylene phosphorochloride.
  • Phenylenphosphate 3-methylen-2-yl 0-phenylene phosphate, 2—Chenylmethyl 0—phenylenphos fate, 2—furenole quinole o-phenylenphos , Bis — 0 — phenylene pyrophosphate, 2 — phenyl 1, 3, 2 — benzodioxaphosphorin 1 — 2-oxide, 2 — (p-phenyl) 1, 3'2—benzodi Kisahosuho Lumpur - 2-year old sulfoxide - 2 - butyl 0 — 1,3,2 —Benzodioxaphosphoryl 1 2 —Oxide, 2 —Annilino and 3,2 —Benzoxoxaphosphol 1 2 —Aged oxide, 2 —Fenrthio-1 , 3,2-benzodioxaphosphol-l- 2-oxide, 2-methoxy-l-5-methinole-l
  • 2-dioxaphosphor 2,2-dihydro-1,2,2,2-trimethoxy-1,4,5-dimethyl-1,1,3,2-dioxaphosphoryl, 2,2-dihydroxy Doro-2,2,2—triphenoxy-1,5-dimethyl-2,3,2
  • the solvent used in the reaction may be any solvent that does not hinder the reaction, and is preferably the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles and the like. Is used alone or as a mixed solvent.
  • dichloromethane, acetonitrile, honolemuamide, honolemuamid and acetonitrile Use of a mixed solvent, such as a mixed solvent of dichlorometh- ane and acetonitrile, provides good effects.
  • the amount of the nucleophile A 'and the organophosphorus compound used is 1 to 5 mol, 1 to 10 mol, more preferably 1 to 3 mol, 1 to 6 mol, respectively, per 1 mol of the compound fIV]. It is.
  • the reaction is carried out in a temperature range of -80 to 50 ° C, preferably 140 to 40 "C.
  • the reaction time is usually 1 minute to 15 hours, preferably 5 minutes to 2 hours.
  • Organic bases may be added to the system, such as triethylamine, tri (n-butyl) amine, di (n-butyl) amine, disobutylamine, dicyclohexylamine, and the like. , 2, 6-Lutidine, etc. Addition of a base-1 to 5 mol per 1 mol of compound [IV].
  • Preferred solvents are the above-mentioned r-ters, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water and the like.
  • the use of the nucleophile A ' is usually 1 to 5 moles, preferably 1 to 3 moles per mole of the compound !: 1 ⁇ ;
  • the reaction is carried out in a temperature range from 0 to 80 ° C, preferably from 20 to 60 ° C.
  • the reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours.
  • the reaction can be carried out in the presence of a dehalogenating agent to promote the reaction.
  • dehalogenating agents examples include the deacidifying agents such as the inorganic bases, tertiary amines, and alkylene oxides described in the section of the production method (1). It may work as a dehalogenating agent. In this case, A 'is used in an amount of 2 mol or more per 1 mol of the compound [IV].
  • the halogen atom represented by R 5 is a force s ′ such as chlorine, bromine, iodine, etc., preferably iodine.
  • Compound [IV] wherein R 5 is iodine [IV] can be easily produced, for example, by the method described in Japanese Patent Application Laid-Open No. 58-57390 or a method analogous thereto. Manufacturing method (3)
  • This method is a way to synthesize human Dorokishii amino compound [formula R 3 with respect to V ⁇ 'to a compound or compounds by reacting a reactive derivative thereof represented by OH i'], well-known ether Reaction.
  • R 3 ' represents an optionally substituted hydrocarbon residue, and as such a hydrocarbon residue, those already mentioned as the optionally substituted hydrocarbon residue in R 3 can be directly applied here.
  • R 3 ′ 0H is used as it is or as a reactive derivative thereof. Is the reactive derivative of Rs'0H a hydrogen source of compound [V]? A derivative of R 3 ′ 0H which represents a group that leaves with the compound, that is, a compound represented by the general formula I′Y. Where is the hydrogen field?
  • the group Y leaving with is a halogen atom, a sulfonyl group, a sulfonyloxy group.
  • Halogen atoms include chlorine, bromine and iodine.
  • Examples of the mono-substituted sulfonyloxy group include ( ⁇ -alkylsulfonyloxy group, Cg ⁇ iO aryl, Sulfoninoleoxy ⁇ j; etc.
  • anti-tS derivatives especially when producing the (: t- 4 alkyl ether compound) of the compound [V], for example, diazomethane, diazozeta C! -4 diazoline, such as dimethyl sulfate, getyl sulfate, etc., are also used.
  • the reaction between R 3 ′ Y and the compound [V: 1 is a normal etherification reaction and is carried out in a solvent.
  • the solvent include ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water, etc. mentioned in the section of the production method (1).
  • the solvent and the mixed solvent include water, and preferably a mixed solvent of water and a water-miscible solvent (eg, hydrated methanol, hydrated ethanol, hydrated acetone, hydrated dimethyl sulfoxide, etc.). ). This reaction can be allowed to proceed smoothly in the presence of a suitable base.
  • Examples of such a base include alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, and potassium carbonate, and alkali metal water such as sodium hydroxide and potassium hydroxide.
  • Examples include inorganic bases such as oxides.
  • This reaction may be performed in a buffer solution of pH 7.5 to 8.5.
  • the number of moles of the reagent R 3 ′ ⁇ and the base used is 1 to 5,:! To 10, preferably 1 to 3, and 1 to 5, respectively, per mole of the starting compound [y.
  • the reaction temperature is between ⁇ 30 and ⁇ 100 ° C., preferably between 0 and 80 ° C. Range.
  • the reaction time is 10 minutes to 15 hours, preferably 30 minutes to 5 hours.
  • the reaction is usually performed in a solvent.
  • the solvent the above-mentioned ethers, hydrocarbons and the like are used.
  • the reaction proceeds when a solution of the diazoal compound is added.
  • the reagent is used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound.
  • the reaction is carried out at a relatively low temperature and is between 150 and 20 ° C, preferably between ⁇ 30 and 0 ° C.
  • the reaction time is 1 minute to time, preferably 10 minutes to 1 hour.
  • the reaction is usually carried out in water or a mixed solvent of water and a water-miscible solvent.
  • the mixed solvent include the water-containing solvents mentioned in the section (3-2).
  • This reaction is carried out, for example, in the presence of an alkali metal hydroxide of sodium hydroxide or potassium hydroxide.
  • the reagent is used in an amount of 0.5 to 10 mol, preferably 1 to 2 mol, per 1 mol of the compound [Y].
  • the reaction temperature ranges from 20 to 100 ° C, preferably from 50 to 100 ° C.
  • the reaction time is 10 minutes to 5 hours, preferably 30 minutes to 3 hours. Manufacturing method (4)
  • Compound [M] is used as a salt or ester as it is.
  • X in the compound [VI] represents a halogen atom such as chlorine, bromine and iodine.
  • the salt of [VI] the salt of the compound [B] (inorganic base salt, ammonium salt, organic base salt, inorganic acid addition salt, organic acid addition salt, etc.) mentioned in the production method (1) may be used. But that's true.
  • the starting compound [VI] has the general formula XCH 2 COC-COOH
  • the conductor can be easily manufactured by a method known per se or a method analogous thereto.
  • the solvent for example di-old hexane, Te preparative Rahi mud furans, ethers such as Jechi ethers, for example methanol over Alcohols such as mouth / ethanol, amides such as dimethylformamide, dimethylacetamide, etc. are used. or normal 1-5 moles' to a derivative conductor) the amount of Nyuita 2 compound [VI 3; Preferably it is 1-3 mol.
  • the reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours.
  • Protecting method ⁇ ⁇ removal method: As mentioned above, in the field of ⁇ -lactam and peptide synthesis, protecting groups for amino groups have been thoroughly studied, and the protection method has already been established. In addition, a method for removing amino protection ⁇ has been established in the same manner, and in the present invention, the conventional technique can be used as it is for removing ⁇ . For example, 'monohalogenoacetyl' (chloroacetyl, bromoacetyl, etc.) can be converted to an acid (eg, salt completed) by alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxydicarbonyl).
  • alkoxycarbonyl eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxydicarbonyl.
  • aralkyloxycarbonyl such as benzyloxy carbonyl
  • p-methinolebenzinoleoxy canolepo p-nitrobenzinoleoxycarbonyl
  • 2,2 .- 2 Trichloroethoxycarbonyl can be removed with ⁇ lead and acid (such as acetic acid).
  • acid such as acetic acid
  • 2,2,2-Tricycloethyl ester can be converted to sulfuric acid (for example, with trifluoroacetic acid) or acid (for example, acetic acid) by catalytic reduction.
  • Tert-phenyl thioresin dimethyl styrene ester can be removed only with water.
  • Oxidizing agents suitable for the oxidation of sulfur atoms in the cefum ring include, for example, oxygen, peracid, hydroperoxide, and hydrogen peroxide. Can also be manufactured. The reaction is usually performed in a solvent. Solvents used in this reaction include, for example, ethers such as dioxane and tetrahydrofuran; for example, halogenated carbons such as dichloromethane, chloroform-form and cyclo-benzene. Danihydrogens, for example, organic acids such as formic acid, acetic acid, and trifluoroacetic acid. Examples include amides such as dimethylformamide and dimethylacetamide.
  • the reaction is carried out at a temperature in the range of 120 to 80 ° C., but preferably at a temperature as low as possible, preferably at ⁇ 20 to 20 ° C.
  • R- and S-sulphoxides differ in their different solubilities and in the chromatographic separation Separated by moving speed.
  • the above oxidation reaction for obtaining the sulfoxide may be performed before the above-mentioned reactions (1) to (4), or may be performed after the reactions (1) to (4).
  • the compound [I] of the present invention can be parenterally or orally administered as injections, capsules, tablets, or granules in the same manner as known penicillins and cephalosporins.
  • the dosage is 0-5 to 80 W per day, more preferably 1 to 20 z days per body weight of humans and animals infected with the pathogenic bacteria, and more preferably 1 to 20 z days divided into 3 to 4 times a day. Administration.
  • the carrier is, for example, distilled water or physiological saline, and when used as a capsule, powder, granule, or tablet, a known pharmaceutically acceptable excipient is used.
  • NMR spectrum was measured inside or using te Toramechirushi run-as external reference XL- lOOA (lOOMHz), EM 390 (9 ⁇ ⁇ ) or T60 (6 ⁇ ) Katasupeku Torome over data mono-, total ⁇ 5 values are given in ppm.
  • the numerical values shown in parentheses are volume mixing ratios of the respective solvents.
  • the solution represents the number 9 in the solution 100.
  • IR Spectral OB-1 1790, 1730. 1710, 1660,
  • the title compound is obtained by operating in the same manner as in Reference Example 3 using 3) -sefumu 4-carboxylic acid.
  • IR spectrometer ⁇ cm -1 1770, 1720, 1640, 1550.
  • IR spectrum ⁇ 1 1770, 1705, 1660, 1630,

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Abstract

Nouveaux composés céphem de formule générale (I), où R1 représente un groupe amino éventuellement protégé, R2 représente un atome d'hydrogène ou un atome d'halogène, R3 représente un atome d'hydrogène ou un résidu d'hydrocarbure éventuellement substitué, R4 représente un atome d'hydrogène ou un groupe méthoxy, A représente un groupe imidazol-1-yle éventuellement substitué formant un anneau fusionné en positions 2 et 3 ou 3 et 4, et n représente 0 ou 1. Ces composés présentent une excellente activité antibactérienne.
PCT/JP1984/000270 1984-04-23 1984-05-25 Composes cephem Ceased WO1985005620A1 (fr)

Priority Applications (24)

Application Number Priority Date Filing Date Title
PCT/JP1984/000270 WO1985005620A1 (fr) 1984-05-25 1984-05-25 Composes cephem
NO851538A NO165842C (no) 1984-04-23 1985-04-17 Analogifremgangsmaate for fremstilling av terapeutisk aktive cefem-forbindelser.
AT8585104687T ATE79882T1 (de) 1984-04-23 1985-04-18 Antibakterielle verbindungen.
EP85104687A EP0160252B1 (fr) 1984-04-23 1985-04-18 Composés antibactériens
PH32153A PH23134A (en) 1984-04-23 1985-04-18 3-condensed imidazolium cephem compounds
DE8585104687T DE3586547T2 (de) 1984-04-23 1985-04-18 Antibakterielle verbindungen.
DE8585104687A DE3586547D1 (de) 1984-04-23 1985-04-18 Antibakterielle verbindungen.
ES542447A ES8606362A1 (es) 1984-04-23 1985-04-22 "un procedimiento para preparar un derivado de cefem".
GR850965A GR850965B (fr) 1984-04-23 1985-04-22
FI851592A FI851592A7 (fi) 1984-04-23 1985-04-22 Antibakteeriset yhdisteet.
JP60086746A JPH07103130B2 (ja) 1984-04-23 1985-04-22 抗菌性化合物
PT80328A PT80328B (en) 1984-04-23 1985-04-22 Process for the preparation of cephem bactericides
DK179985A DK179985A (da) 1984-04-23 1985-04-22 Cephemforbindelser samt deres fremstilling og anvendelse
NZ211858A NZ211858A (en) 1984-04-23 1985-04-22 Heterocyclic-substituted cephalosporins and analogues thereof and pharmaceutical compositions
AU41700/85A AU580995B2 (en) 1984-04-23 1985-04-23 3-fused imidazol-l-yl-methyl cephalosporins
CA000479769A CA1283096C (fr) 1984-04-23 1985-04-23 Composes antibacteriens
US06/726,438 US4788185A (en) 1984-04-23 1985-04-23 Cephalosporin compounds
KR1019850002737A KR920008945B1 (ko) 1984-04-23 1985-04-23 항균 화합물의 제조방법
ES549180A ES8707245A1 (es) 1984-04-23 1985-11-22 Un metodo para preparar nuevos derivados de cefem
NO85854730A NO167293C (no) 1984-04-23 1985-11-26 Mellomprodukter.
ES553666A ES8706692A1 (es) 1984-04-23 1986-04-03 Un metodo para preparar nuevos derivados de cefem
ES557129A ES8800950A1 (es) 1984-04-23 1986-10-03 Un metodo para preparar nuevos derivados de cefem
MYPI87002280A MY102089A (en) 1984-04-23 1987-09-29 Antibacterial compounds.
KR1019910020376A KR920008953B1 (ko) 1984-04-23 1991-11-16 항균 화합물의 제조방법

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1984/000270 WO1985005620A1 (fr) 1984-05-25 1984-05-25 Composes cephem

Publications (1)

Publication Number Publication Date
WO1985005620A1 true WO1985005620A1 (fr) 1985-12-19

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1984/000270 Ceased WO1985005620A1 (fr) 1984-04-23 1984-05-25 Composes cephem

Country Status (1)

Country Link
WO (1) WO1985005620A1 (fr)

Non-Patent Citations (1)

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

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