WO1986006380A1 - Composes antibacteriens, utilisation et preparation - Google Patents

Composes antibacteriens, utilisation et preparation Download PDF

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Publication number
WO1986006380A1
WO1986006380A1 PCT/JP1985/000247 JP8500247W WO8606380A1 WO 1986006380 A1 WO1986006380 A1 WO 1986006380A1 JP 8500247 W JP8500247 W JP 8500247W WO 8606380 A1 WO8606380 A1 WO 8606380A1
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Prior art keywords
compound
group
reaction
acid
formula
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PCT/JP1985/000247
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English (en)
Japanese (ja)
Inventor
Hideaki Natsugari
Yasuhiko Kawano
Akira Morimoto
Kouichi Yoshioka
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Takeda Chemical Industries, Ltd.
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Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1985/000247 priority Critical patent/WO1986006380A1/fr
Priority to EP86302819A priority patent/EP0219923B1/fr
Priority to AT86302819T priority patent/ATE80163T1/de
Priority to DE8686302819T priority patent/DE3686632T2/de
Priority to ES554495A priority patent/ES8802317A1/es
Priority to DK195986A priority patent/DK195986A/da
Priority to HU861788A priority patent/HU197742B/hu
Priority to CA000507875A priority patent/CA1285950C/fr
Priority to KR1019860003319A priority patent/KR930005174B1/ko
Priority to US06/857,834 priority patent/US4851422A/en
Priority to CN198686102923A priority patent/CN86102923A/zh
Publication of WO1986006380A1 publication Critical patent/WO1986006380A1/fr
Priority to ES557661A priority patent/ES8801650A1/es

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    • 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

Definitions

  • Antimicrobial compounds their uses and their production
  • the present invention relates to a novel 2- (4-substituted amino-3-oxo-2-isoxazolidinyl) -15-oxo-12-tetrahydrofurancarboxylic acid derivative having excellent antibacterial activity and a method for producing the same. Seki).
  • TAN-588 which has antibacterial activity against Gram-positive and Gram-negative bacteria
  • TAN-588 which has antibacterial activity against Gram-positive and Gram-negative bacteria
  • the antibiotic TAN-588 has a completely unknown skeleton in which a 5-oxo-12-tetrahydrofurancarboxylic acid is bonded to a nitrogen atom of a 3-oxoisoxazolidine ring. ing. Thus, when a derivative of TAN-588 was synthesized, it was found that the derivative had excellent antibacterial activity and could be used as an antibacterial agent.
  • the present inventors may further add a checkup time, and may have a g-substituent at the 5-position of the 3-oxoisoxazolidin ring, the 3-position or the 4-position of the 5-oxotetrahydrofuran ring, or the like.
  • a method for chemically producing 2- (4-monosubstituted amino-3-oxo-2-isoxazolidinyl) -5-oxo-1-tetrahydrofurancarboxylic acid derivatives has been found. Further, they have found that the compound obtained by this method has an excellent antibacterial action, and as a result of further intensive studies, the present invention has been completed.
  • the present invention provides (1) a general formula
  • R 1 represents an amino group or an organic residue via nitrogen.
  • R 2 represents a carboxyl group or a group derivable therefrom.
  • R 3 , R 4 , R 5 , R S , R 7 and R 8 are the same or different and represent hydrogen or an organic residue, and R 5 or Re and R 7 or R 8 form a chemical bond. Including the case.
  • X represents hydrogen, methoxy or formylamino.
  • R 8 , R 7 and R 8 are not simultaneously hydrogen. Or a salt thereof,
  • R represents an organic residue via nitrogen.
  • R 3 , R 4 and X have the same meaning as described above.
  • R 2 ′, R 5 , R 8, R 7 and R 8 have the same meanings as described above. However.
  • the above formula ( ⁇ ) includes the case where R 3 and R 4 are simultaneously hydrogen.
  • the above formulas ( ⁇ ), (IT) and (R, the case where R 5 , R 8 , R 7 and R 8 are simultaneously hydrogen is included.
  • examples of the organic residue via nitrogen represented by R 1 or R 1 ′ include, for example, acylamino, carbon-substituted amino, alkenylamino, thioamino, silylamino, phosphoric acid And amino, a group represented by the formula C0—C0—NH— and the like.
  • acyl in the above-mentioned amino group examples include the 6-position of a conventionally-known penicin derivative; an acyl group substituted for an amino group, and an acyl group substituted for the 7-amino group of a Cef V-rosporin derivative. And the like.
  • acylamino group examples include, for example,
  • R 13 is hydrogen, alkyl ⁇ ′ (in the description of each group in the present specification, the group with ⁇ indicates that the group may have a substituent.), Alkenyl ⁇ . , Cycloalkyl *, aryl 85 , heterocycle *, alkoxy 58 , aryloxy ⁇ , R 14 represents hydrogen, alkyl ⁇ •, acyl ⁇ ′, and R 13 forms a ring with R ′′
  • R ie is an alkyl 5 ⁇ , Ariru, cycloalkenyl or heterocyclic ", refers respectively.
  • R 18 is the formula R 2Q — C— ⁇ where R 2 . Is alkyl ' ⁇ ⁇ , heterocycle * or
  • R 21 is hydrogen, alkyl 58 , alkenyl ⁇ ', aryl carbonyl *, cycloalkyl *, heterocycle 55 or a formula —R 22 —R 23 (
  • R 22 represents alkylene, cycloalkylene or alkenylene
  • R 23 represents aryl ′, carboxy * or an ester thereof or mono- or dialkylamide, respectively. Represents a group represented by
  • R 13 represents a chemical bond or a group represented by the formula: CO—NH—CH— (wherein, R 24 represents an alkyl, aryl, or heterocyclic ring X in the formula—R 24 ). , Respectively.
  • R 25 represents aryl 35 , heterocycle ⁇ or cycloalkenyl
  • R 2S represents hydroxy, carboxy ⁇ ', sulfamoyl, sulfo, sulfoxy, aryloxycarbonyl or acyloxy'.
  • R 28 is a chemical bond or a
  • R 29 and R 3 ° are the same or different and represent hydrogen, alkyl ⁇ ⁇ , aryl ⁇ , heterocyclic ⁇ ′, cycloalkyl, and ⁇ represents 0 or S, respectively.
  • the group represented by each is mentioned.
  • R 2 ° —C— in R 18 is a synth represented by the formula R 2 ° —C—
  • aminos substituted through carbon as examples of organic residues via nitrogen represented by R 1 or R above include, for example, the formula
  • R 31 represents alkyl 35 , aryl, alkenyl or heterocyclic ring.
  • R 32 and R 33 are the same or different and each represents alkyl *, aryl, alkenyl ⁇ ], and includes the case where R 32 and R 33 form a co-heterocycle with an adjacent nitrogen atom.
  • R 3 R 35 and R 36 are the same or different and represent alkyl 5 , aryl ⁇ , alkenyl ⁇ , and R 34 and R 35 or R 36, and a complex with an adjacent nitrogen atom. This includes the case where a ring is formed. ] And the groups represented by
  • alkenylamino as an example of an organic residue via nitrogen represented by R 1 or R 1 ′ above include, for example, a compound represented by the formula
  • R 37 and R 38 are the same or different and represent hydrogen, alkyl, aryl *, cycloalkyl, amino or heterocycle 56 , and R 37 and R 38 are cycloalkyl together with adjacent carbon atoms. Includes the case where « ⁇ or heterocycle ⁇ ⁇ is formed. ] The group represented by] is mentioned.
  • Examples of thioamino as an example of an organic residue via nitrogen represented by R 1 or R 1 ′ above include, for example, the formula
  • R 39 -S On- ⁇ - [wherein, R 33 represents alkyl ⁇ 'or aryl ⁇ , and n represents an integer of 0 to 2, respectively. ]
  • the group represented by] is mentioned.
  • silylamino as an example of an organic residue via nitrogen represented by R 1 or R 1 ′ above include, for example, a compound represented by the formula
  • amino phosphinates as examples of nitrogen-mediated organic residues represented by R 1 or R above include, for example, the formula
  • R "and R” are the same or different and represent alkyl, ⁇ , aryl, alkoxy ⁇ or aryloxy ⁇ , and R "and R '* 5 form a heterocycle ⁇
  • the group represented by] is mentioned.
  • Examples of the group represented by the formula — C 0 — C 0 — ⁇ — as an example of an organic residue via nitrogen represented by R 1 or R above include, for example, the formula:
  • the organic residue via nitrogen represented by R 1 or R 1 ′ preferably has, for example, a molecular weight of up to 500.
  • examples of the group which can be derived from the carboxyl group represented by R 2 or are, for example,
  • R 47 is alkyl, alkenyl ⁇ , aryl *, cycloalkyl, Represents a heterocyclic ring 'or a silyl ⁇ '. Group represented by]
  • R 4 8 and R 49 are the same or different and are hydrogen, alkyl 35, ⁇ reel 55, cycloalkyl ",, 7 alkenyl-chi-or indicates a heterocyclic ring-chi, R 48 and R 43 is Including the case where a heterocyclic ring is formed with an adjacent nitrogen atom. ], Respectively.
  • R 2 or a group from the carboxyl group may be derived represented by R 2 ', is, for example molecular weight is preferably up to 5 0 0.
  • alkyl in the group in the above formula for example, those having 1 to 6 carbon atoms are preferable, and examples thereof include, for example, methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-methyl Butyl, 1,1-dimethylpropyl, ⁇ -pentyl, isopentyl, ⁇ -hexyl, isohexyl and the like. '
  • substituents which the alkyl group may have include, for example, halogen, nitro, amino (which may have alkyl, alkenyl, cycloalkyl, aryl) as a substituent, sulfo, cyano, and hydroquine.
  • Replacement It may have amino, amino, halogen, rubamoyl. Hydroxy, cyano, carboxy or sulfo as a substituent. ), Acyl, acyloxy, alkoxycarbonyl, alkoxycarbonyloxy, acyloxyethoxy, aralkyl (alkyl, alkoxynoperogen, amino, hydroxy, nitro, cyano, carbamoyl, sulfamoyl). :), and aralkyloxy (oxy, alkyl, alkoxynoprogen, amino, hydroxy, nitro, cyano, carbazyl, sulfamoyl) as substituents.
  • Arylthio, heterocyclic group-thio (Siano, hydroxy, It may have mino, alkylamino, alkylnoperogen and oxo as substituents :)), iminomethylamino, iminoethylamino, silyl (may have alkyl and aryl as substituents), Alkyloxycarbonyl, arylcarbonyl (may have a substituent such as acyloxyperogen, amino, hydroxy, alkoxy, and sulfamoyl. :), phthalimid, succinimide, dialkylamino, dialkyla Minocarbonyl, arylcarbonylamino, formula
  • ⁇ 52> ⁇ wherein, R 5 1, R 5 2 may be the same or different and indicate a hydroxyl group. Amino groups. And the like.
  • the cyclic alkyl or the cyclic alkyl forming the ring in the groups in the above formula is preferably those having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexyl. Mouth heptyl, shiku mouth-to-mouth chill, and the like.
  • Examples of the substituent which the cycloalkyl group may have include, for example, Examples include logen, nitro, amino, hydroxy, sulfo, cyano, carboxy, and oxo.
  • Examples of the cycloalkylene in the group in the above formula include those in which the cycloalkyl further has another bond.
  • aryl in the above-mentioned formula examples include phenyl, naphthyl, biphenyl, anthryl, indenyl and the like.
  • substituents which the aryl group may have include, for example, halogen, nitro, cyano, amino (which may have an alkyl, alkenyl, cycloalkyl, aryl) as a substituent, sulfo, hydroxy, Sulfoxy, sulfamoyl, alkyl (which may have an amino, halogen, hydroxy, cyano as a substituent-group), alcohol, aralkyloxy, alkylsulfonamide, methylenedioxy, alkylsulfonyl, alkylsulfonylamino and the like.
  • a condensed ring eg, tetrahydronaphthyl, indanyl, acenaphthyl, etc.
  • a condensed ring eg, tetrahydronaphthyl, indanyl, acenaphthyl, etc.
  • alkoxy in the group in the above formula those having 1 to 6 carbon atoms are preferable, and examples thereof include methoxy, ethoxy, ⁇ -propoquine, i-propoxy, ⁇ -butoxy, i-butoxy, t —Butoxy, n-pentyloxy, n-hexyloxy and the like.
  • substituents which the alkoxy group may have include, for example, halogen, nitro, amino, hydroxy; sulfo, cyano, carboxy, aryl, silyl (which may have alkyl, aryl, aralkyl as a substituent). Yes).
  • alkylthio in the groups in the above formula those having 1 to 6 carbon atoms
  • ⁇ lyse Preferred examples thereof include methylthio, ethylthio. N-propylthio, i-propylthio, n-butylthio, i-butylthio, n-pentylthio, and ⁇ -hexylthio.
  • substituent which may have an alkylthio group include the same substituents as those described above for the alkoxy.
  • the alkenyl or alkenylene in the groups in the above formula is preferably, for example, one having 1 to 4 carbon atoms, and examples thereof include, for example, methylene, vinyl, allyl, isopropyl, and 1-propenyl. , 2-butenyl, 1,3-butadenyl, ethylidene, isopropylidene, propylenylene, vinylene. 3-methyl-3-butenyl.
  • Examples of the substituent which the alkenyl group may have include, for example, halogen, nitro, amino, sulfo, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, aryl (ary 1), acyl and the like.
  • heterocyclic ring in the above formula or the heterocyclic ring formed by these groups examples include a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, and 2 to 4 nitrogen atoms.
  • heterocyclic groups include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, birazinyl, pyridazinyl, piperazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, Pyrido [2,3-d] pyrimidyl, benzoviranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl , Mushroom replacement , Thieno [2,3-b] pyridyl, tetrazolyl, thiadiazolyl, oxadizazolyl, triazinyl,
  • heterocyclic group may have include, for example, amino (which may have a substituent such as acylno, logen-substituted alkylacyl, phenyl, or alkyl), halogen, nitro, sulfo, cyano, Hydroxy, alkoxy, oxo, thioxo, Ci-ioalkyl (optionally having arylnoperogen, amino, hydroxy, alkylsulfonyl, dialkylaminoalkyl as a substituent), cycloalkyl , Alkoxy (which may have a halogen or a hydroxy as a substituent), an acyl having 1 to 4 carbon atoms, aryl (having a carboxylic acid, nitro, aralkyl, alkoxy, amino, sulfo, Hydroquinine and cyano may be substituted.), Oxo, thioxo, amino acid residue-thio (examples of
  • Heterocyclic alkyl, Arukokishino ⁇ androgenic, two preparative port. Shiano, carboxy, formyl, alkylsulfonyl which may have a substituent.
  • R 5 3 - CH N- [wherein, R 5 3 is heterocyclic (alkyl, Arukokishino ⁇ androgenic, nitro, Shiano, human Dorokishi, carboxy, formyl, alkylsulfonyl which may have a substituent.) Is shown. ] And the like.
  • examples of the acyl represented by R 1 + include, for example, phthaloyl, succinyl, maleoyl, citraconoyl, glutaryl, aziboyl and the like which are cyclic with R 13 .
  • substituent which the acyl group may have include, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, and hydroxy.
  • the Ashiru in 1 is preferably a carbon number of 1-4, formyl example and examples thereof, Asechiru, propionyl, Puchiriru, etc. I Sopuchiriru.
  • substituent such as alkyl ( ⁇ Minono, androgenic , Cyano, alkoxy, carboquine, and hydroxy may be substituted.).
  • amino acid residue represented by R 15 for example, glycyl, aranyl noril, leucyl, isoleucyl, seryl, threonyl, cystinyl, cistyl, methionyl, — or / 3-asparagyl, ⁇ — or y Glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptophanyl, prolyl and the like.
  • Examples of the substituent which the amino acid residue may have include halogen, hydroxy, sulfo, carboxy, cyano, alkylamino, aralkyloxycarbonyl, aralkyloxy and guanidino.
  • the protecting group for the amino group represented by R 15 for example, those used for this purpose in the field of synthesis of ⁇ -lactams and peptides are expediently searched for.
  • aromatic acyl groups such as phthaloyl, 412-trobenzoyl, 4-tert-butylbenzoyl, 4-tert-butylbenzenesulfonyl, benzenesulfonyl, and toluenesulfonyl, for example, formyl, acetyl, propionyl, monochloroacetyl, Aliphatic acyl groups such as dicycloacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl, succinyl, etc., for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, isopropoxyl force , 2-cyanoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, 412-hydroxybenzyloxycarbonyl, 4-
  • Protecting groups for amino groups other than the acyl group such as phenylthio, benzylidene, 412 trobenzylidene, di- or trialkylsilyl, benzyl and 412 trobenzyl.
  • the choice of the protecting group is not particularly limited in the present invention, but monochloroacetyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl are particularly preferred.
  • alkyl, logen, cyano, and hydroquine may be substituted.
  • Aryl alkyl, alkoxy. Halogen, hydroxy, acyloxy, sulfo, cyano, sulfazyl may be substituted as a substituent. :
  • silyl alkyl, aryl, aralkyl has a substituent. :
  • heterocyclic ring amino, alkylamino, sulfamoyl, sulfamoyl, halogen, cyano, nitro
  • amino (alkyl, aryl, And may have a cycloalkyl, a sulfo or an aralkyl as a substituent, and may form a 5- to 6-membered heterocycle together with the nitrogen in the amino group.).
  • Substitution of optionally substituted amino in the groups in the above formula Examples of the group include amidine, iminomethyl, imino (aryl-substituted) methyl, guanidylcarbonyl, heterocycle ⁇ (may have the same substituent as the above-mentioned heterocycle. :), imino ( (Heterocyclic substitution) methyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, alkyl and the like.
  • Examples of the substituent in the silyl which may have a substituent in the above formula include alkyl, aryl, aralkyl and the like.
  • R * ° and R 4 may form a cyclic group with R + 3, and examples thereof include 2,5-disilylazaci-clopentyl and the like, such as alkyl and aryl. May have a substituent.
  • substituents include chlorine, bromine, fluorine and iodine.
  • Alkyl in the description of the above substituents preferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, ⁇ -propyl, i-propyl, Examples include ⁇ -butyl, i-butyl, t-butyl, sec-butyl, ⁇ -pentyl, isopentyl, ⁇ -hexyl, isohexyl, heptyl, octyl, nonyl, and decyl.
  • cycloalkyl those having 3 to 6 carbon atoms are preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • alkoxy those having 1 to 4 carbon atoms are preferable, and examples thereof include methoxy, ethoxy, n-propoxy, and i-substitution. Oral oxy, n-butoxy, i-butoxy, t-butoxy and the like.
  • aryl examples include phenyl and naphthyl.
  • heterocyclic ring as the substituent examples include those similar to the above-described heterocyclic ring.
  • acyl as a substituent, those having 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms are preferable, and examples thereof include formyl, acetyl, propionyl, butyryl, isoptyryl phenol, isovaleryl, viva mouthyl, and hexanol. I can do it.
  • aralkyl examples include benzyl, phenyl, phenyl loop-opened pill and the like.
  • alkenyl or alkenylene as the substituent examples include those similar to the aforementioned alkenyl.
  • amino acid residue as the substituent those similar to the amino acid residue represented by R 1 5 can be mentioned.
  • Examples of the 5- or 6-membered complex ring formed together with the nitrogen in the amino group as the above substituent include pipericidin, pyrrolidine, imidazolidine, mololin, piperazine and the like.
  • the substituent in each of the above groups is preferably 1 to 3.
  • the leaving group represented by Y may be any as long as it can be substituted for the hydrogen at the 2-position of the compound (gourd).
  • examples thereof include sulfonyloxy having a halogen (eg, bromo, chloro), a substituent (eg, alkyl, aryl) (the alkyl and aryl include the same as the above-mentioned substituents).
  • substituents eg, alkyl, aryl
  • substituents eg, alkyl, aryl
  • substituents eg, alkyl, aryl
  • Specific examples include, for example, p-toluenesulfonyloxy, ⁇ -nitrophenylsulfonyloxy, methanesulfonyloxy).
  • Disubstituted phosphoryloxy eg, diphenylphosphoryloxy,
  • amino group examples include, for example, 3- (2,6-dichlorophenyl) -1-methylisoxazole-4-ylcarbonylamino, 41-ethyl1-2,3-dioxo-1-piperazine 2-carbonyl-2-aminocarbonyl, 3-phenyl-1-5-methylisoxazo-l 4-yl-propanolamino, 3- (2-chlorophenyl) -1-methyl-oxoxazole-4-ylcarbonylamino, 3- (2 —Chloro-6-fluorophenyl) -1-5-methyl isoxa 0
  • Examples thereof include bonylamino, 2,2-dimethyl-5-oxo-1-41-imidazolysine, and 4- (l-rubamoylcarboxymethylene) -1,1,3-dithiethane-2-ylcarbonylamino.
  • R 1 6 body examples, for example, D- Araniruami Bruno, benzyl New - Karubobe
  • acylamino group represented by the formula R 18 —R 13 —C 0—NH— include, for example, N— [2- (2-amino-4,3-thiazolyl) -12-methkinyl Minoacetyl] —D—Aranylamino, N— [2— (2—amino-4 monothiazolyl) -12—methoxyethoxyminoacetyl] —D—Phenyldalicylamino, 2— (2—amino 4-Thiazolyl) 1-2-[2-(2-amino 4-thiazolyl)-1-2-methoxyaminoacetamide] acetylamino, 2-(2-chloroacetamido-4-thiazolyl)-1-2-meth Toxiiamino acetylamino, 2- (2-amino-4-thiazolyl) -12-methoxymininoacetylamino, 2— (2-amino-4-thiazolyl) -12
  • 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, carbonylcarbonylamino, carbonylcarbonylaminoamino, carbonylcarbonylaminoamino , 412-nitrophenylamino, 4-bromophenylaminocarbonyl, thio-rubamoylamino, methylaminothiocarbonyl, ethylaminothiocarbonyl, phenylaminothiocarbonylamino, Dimethylaminocarbonylamino, 3-fluorophenylaminocarbonylamino, and the like.
  • R 31 —NH— examples include, for example, methylamino, ethylamino, arylamino, cyclohexylamino, cyclohexylmethylamino, benzylamino, 4-cyclobenzylbenzyl, Phenylamino, 2-imidazolylamino, 1-methyl-2-imidazolylamino, 2- (2-amino-4,1-thiazolyl) -1,2-methoxyminothioacetylamino, 1-benzyl-4,1-pyri Gindinamino, 2-acetyl-methylvinylamino and the like.
  • alkylamino group represented by the formula ⁇ 3 3 2 3 > N— include:
  • dimethylamino getylamino, dipropylamino, dibenzylamino, dicyclohexamino, dibenzylamino, dibenzylamino, diarylamino, diphenylamino, methyldiamino, pyrrolidinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl And perforinyl.
  • Examples include trimethylammonium, triethylammonium, tribenzylammonium, benzyldimethylammonium, methylpyrrolidinium, methylpyridinium, and the like.
  • R 3 9 Examples of Chioami amino group represented by SO n-New .eta., e.g. downy emissions Zen sulfonyl ⁇ Mi Bruno, 4 Mechiru base emissions Zen sulfonyl ⁇ Mi Bruno, 4-main butoxy benzenesulfonyl two Ruami Bruno, 2,4,6-Trimethylbenzenesulfonylamino, benzylsulfonylamino, 4-methylbenzylsulfonylamino, trifluoromethylsulfonylamino, phenacylsulfonylamino, methylsulfonylamino, ethylsulfonylam Mino, 4-fluorobenzenesulfonylamino, benzenesulfinylamino, 2-nitrobenzenesulfinylamino, 2,4-dimethylbenzenesulfinylamino, 4-monobenzenebenzenes
  • trimethylsilylamino triethylsilylamino, t-butyldimethylsilylamino, t-butyldiphenylsilylamino, isopropyl pyrdimethylsilylamino, triphenylsilylamino, and triphenylsilylamino.
  • examples thereof include mino, triisopropylsilylamino, tribenzylsilylamino, (triphenylmethyl) dimethylnonlylamino, 2,2,5,5,5-tetramethyl-2,5-disilylazazacyclopentane.
  • Examples thereof include dimethylaminophosphate, aminoethylethylamine, aminovinyldiphenylate, aminobenzenedibenzylate, aminoamine di-4-chlorophenyloxyphosphate, and the like.
  • R s —C 0— C 0—NH— examples include, for example, methoxoxalylamino, ethoxyoxalylamino, phenoxyoxalylamino, and benzyloxalylyl.
  • Mino Methyloxalylamino, Etyloxalylamino, Oxamoylamino, Benzylaminoxalylamino, Chenyluxalylamino, 2-Amino1-41-thiazolyloxalylamino, Ethylaminominoxalylamino And the like.
  • N-Propyl ester isopropyl ester, t-butyl ester, t-amyl ester, benzyl ester, 4-bromobenzyl ester, 4-to-2 benzyl ester, 2-to-2 benzyl ester, 3,5-dinit Benzyl ester, 4-methoxybenzyl ester, benzhydryl ester, phenacyl ester, 4-promophenacyl ester, phenyl ester, 412 trophenyl ester, methoxymethyl ester, methoxetoxymethyl ester, ethoxymethyl ester, Benzyloxymethyl ester, acetooxymethyl ester, pivaloyloxymethyl ester, 2-methylsulfonylethyl ester, 2-trimethylsilylethyl ester, methylthiomethyl ester, Tyl ester, 2,2,2-trichloroethyl ester, 2-e
  • Specific examples of the group represented by the formula 1—CO—N—, 3 include, for example, dimethylamide, getylamide, dipropylamide, dibenzylamide, dicyclohexylamide, benzyl-methylamide, and diarylamide. And phenyl-methyl-amide, pyrrolidine amide, piperidinamide, piperazine amide, morpholinamide, carboxymethylamide, and 1-lupoxicetilamide.
  • examples of the organic residue represented by R 3 and R 4 include an organic residue bonded at a carbon atom. .
  • organic residue bonded at the carbon atom examples include, for example, alkyl *, cycloalkyl, alkenyl *, aryl «,, acyl, cyano or carboxyl which may be esterified or amidated. Is preferred.
  • the organic residue represented by R 5 , R e , R 7 and R 8 includes: an organic residue bonded at a carbon atom; an organic residue bonded via an oxygen atom, a nitrogen atom or a sulfur atom; Or halogen.
  • Examples of the organic residue which is bonded through the carbon atom include alkylcycloalkyl, alkenyl, aryl *, acyl, cyano, carbamoyl, heterocyclic ring, and esterification or amidation.
  • R 3 represents hydrogen, alkyl, aryl, acyl, or rubamoyl. Or an oxo group.
  • Examples of the organic residue bonded through the nitrogen atom include, for example, a compound represented by the formula
  • R 11 are the same or different and represent hydrogen, alkyl, aryl, or acyl. ] Is preferable.
  • Examples of the organic residue bonded through the above sulfur atom include the following: S ( ⁇ ) ⁇ -R 12 [wherein R 12 is hydrogen, alkyl *, aryl *, heterocycle *, or And * represents 0, 1 or 2. ] Is preferable.
  • alkyl group represented by R 3 As a group which may be substituted on the alkyl group represented by R 3 one 8 was Toebahi Dorokishi, Ashiruokishi, Scarpa ⁇ Iruokishi, ⁇ Mi, dialkyl Ruamino, Ashiruamino, alkylthio, heterocycle Chio, carboxy, alkoxycarbonyl Kishikaru - Examples include bonyl, calvamoyl, cyano, azide, aryl, and halogen.
  • Examples of the group which may be substituted on the aryl group in R 3 -8 include, for example, halogen, alkoxy, alkyl and the like.
  • esterified or unprotected carboxyl in the R 3 one 8, such as carboxy, etc.
  • a ⁇ Kiruokishi force carbonyl is exemplified et be.
  • alkyl including the case of alkyl in the group
  • those having 1 to 6 carbon atoms are preferable.
  • cycloalkyl those having 3 to 6 carbon atoms are preferable.
  • the alkenyl is preferably one having 1 to 4 carbon atoms.
  • acyl including the case of the acyl in the group
  • those having 1 to 6 carbon atoms and arylcarbonyl are preferable.
  • the above alkoxy (including the case of alkoxy in the group) is preferably one having 1 to 6 carbon atoms.
  • Alkyl having 1 to 6 carbon atoms Cyclic alkyl having 3 to 6 carbon atoms, alkenyl having 1 to 4 carbon atoms, acyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aryl, heterocycle (Except when formed together with an adjacent nitrogen atom.)
  • Examples of the halogen and the halogen include those similar to those represented by R 1 and the like described above.
  • the heterocyclic ring formed together with the adjacent nitrogen atom is preferably, for example, a 5- to 6-membered ring, and specific examples thereof include, for example, pyrrolyl, piperidinyl, piperidinyl, piperazinyl and the like.
  • Preferred examples of the group represented by R 3 and R + include, for example, methyl, ethyl, isopropyl, vinyl, aryl (ally 1), cyclopropyl,
  • Preferred examples of the groups represented by R 5 , R S , R 7 and R 8 include, for example, methyl, ethyl, cyclopropyl, cyclopentyl, cyclohexyl, vinyl, aryl, phenyl, parachlorof Zinyl, paramethoxyphenyl, acetyl, propionyl, benzoyl, cyano, carbamoyl, methoxycalponyl, ethoxycarbonyl, dimethylaminocarbonyl, acetomethyl, methylthiomethyl, acetamidomethyl, hydroxyquin, methoxy, ethoxy.
  • the target compound (1 ′) of the present invention can be produced by reacting the compound (III) with the compound (E) or a reactive derivative thereof.
  • the reaction is By reacting compound ( ⁇ ) with compound (no) in a solvent in the presence of a condensing agent or a Lewis acid, or by reacting a reactive derivative of compound ( ⁇ ) with compound (IE) in a solvent Done.
  • condensing agent used herein examples include ⁇ , ⁇ ′-dicyclohexylcarpoimide (DCC), and C-hydroxysuccinimide or 1-hydroxybenzotriazole added to DCC; ⁇ -Ethyru N '— [3- (Dimethylamino) propyl] carbodimid; carbodizymidazole; ⁇ -Ethyru 5 —Isoxazolidum 3' —Sulfonate; 2 —Ethyru 7 —Hydroxyquinedisoxazolidium Trifluoroboron salt; 1-ethoxycarbonyl 2—Ethkin-1
  • Lewis acid used in this reaction examples include boron trifluoride etherate, zinc chloride, tin tetrachloride, aluminum chloride, titanium tetrachloride, and boron trichloride.
  • the reactive derivative of the compound (II) As the reactive derivative of the compound (II), a reactive derivative used in the C-terminal activation method at the time of peptide synthesis can be applied. Used here replacement The reactive derivative can be prepared in a solvent without isolation, and used as it is for the condensation reaction. Specific examples of the reactive derivative of the carboxylic acid used here include acid halides such as acid chloride and acid bromide; acid azides; mixed acid anhydrides with monoalkyl carbonates such as acetic acid and pivalic acid.
  • a mixed acid anhydride composed of an acid, valeric acid, isovaleric acid, an aliphatic carboxylic acid such as trichloroacetic acid, etc. for example, a mixed acid anhydride composed of an acid such as dicarboxylic acid and acetic acid, and a sulfuric acid.
  • Acid anhydrides for example, mixed anhydrides of benzoic acid and the like, symmetrical acid anhydrides; for example, pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, thiazolidin — Amide compounds in which an acyl group is bonded to the ring nitrogen such as thione; for example, 4-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl , Pentafluorophenyl, cyanomethyl, ⁇ -hydroxysuccinimide ', ⁇ -hydroxydiphthalimide, etc .; for example, complex esters such as 2-pyridylthiol and 2-benzthiazolylthiol Active thioesters with ring thiols and the like can be mentioned.
  • This reaction is carried out by reacting an equivalent or a small excess of the compound (I) with an equivalent or excess of a condensing agent or a catalytic amount of a Lewis acid, or an equivalent or a small excess of the compound (H) with respect to the compound (I).
  • the reaction is carried out by reacting the derivative with a derivative in a solvent.
  • Any solvent can be used as long as it does not affect the reaction. Examples of such solvents include dichloromethane, chloroform, tetrahydrofuran, dioxane, getyl ether, ethyl ethyl ester, benzene, toluene, ⁇ -hexane, and the like. Normal solvents such as acetonitrile and dimethylformamide are used.
  • reaction may be carried out in the presence of a base (for example, 2-chloro-1-methylpyridinium iodide, 2,2'-dipyridyldisulfide-trifluorophosphine, carbon tetrachloride as a condensing agent)
  • a base for example, 2-chloro-1-methylpyridinium iodide, 2,2'-dipyridyldisulfide-trifluorophosphine, carbon tetrachloride as a condensing agent
  • reaction may be carried out in the presence of, for example, silver chloride, silver tetrafluoride, silver perchlorate, or the like (for example, 2,2′-dipyridyl disulfide-tolylphenylphosphine is used).
  • silver chloride for example, silver tetrafluoride, silver perchlorate, or the like
  • silver perchlorate for example, 2,2′-dipyridyl disulfide-tolylphenylphosphine is used.
  • condensing agent When used as a condensing agent).
  • the reaction temperature is not particularly limited as long as the reaction proceeds, but it is usually carried out at about 150 ° C. to 150 ° (preferably, about 10 ° C. to 100.
  • the time varies depending on the starting materials, reagents, type of solvent, reaction temperature, etc., but is usually about 5 minutes to 30 hours.
  • a dehydrating agent such as bush may coexist.
  • Compound (1 ′) can also be produced by reacting compound ( ⁇ ) with compound (E.
  • compound ( ⁇ ) and compound (RO) are reacted with a base in a solvent.
  • the base for example, triethylamine, tripropylamine, tri- ⁇ -butylamino, diisopropylethylamine.
  • Triethylenediamine (DABC 0), 1, 8—Diazabicyclo [5.4.0] —— 7—Pendecene (DBU), N-methylphorforin, N-methylbiperidine, N-methylpyrrolidin, 3,4-Dihidro 2H—Pyrido [1,2—a ] Pyrimidine 1-one, 4-dimethylaminoaminopyridines such as pyridine, pyridine, lutidine and alcohol, such as lithium, sodium, calcium and cesium.
  • Arca Metals such as alkaline earth metals such as magnesium and calcium or their hydrides, hydroxides, carbonates and alcohols
  • Usable solvents include, for example, ordinary solvents such as dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylacetamide and dimethylformamide.
  • a liquid base can be used also as a solvent.
  • the compound (RO and base are usually used in about equivalent amounts with respect to compound (I), but may be used in excess as long as the reaction is not hindered.
  • the reaction temperature is usually about ⁇ 20 ° C. to 10 ° C.
  • the reaction is carried out at 0 ° C, and the reaction time is usually about 5 minutes to 30 hours.
  • the compound thus obtained (if one has a protecting group, the protecting group can be removed as necessary.
  • the method of removing the protecting group depends on the type of the protecting group. Conventional methods such as a method using an acid, a method using a base, a method using hydrazine, a method using reduction, etc. can be selected as appropriate.
  • different acids include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid; and acidic ion exchange resins.
  • the base varies depending on the kind of the protecting group and other conditions.
  • the base may be an alkali metal such as sodium or potassium, or an alkali such as calcium or magnesium.
  • Inorganic bases such as earth metal hydroxides and carbonates, organic bases such as metal alkoxides, organic amines, and quaternary ammonium salts, as well as basic ion exchange resins are used.
  • a solvent is used in the method using a base, a hydrophilic organic solvent, water, or a mixed solvent is often used.
  • platinum catalysts platinum sponge, platinum black, and oxidized catalysts can be used in the catalytic reduction method.
  • Platinum catalysts such as platinum and colloidal platinum; palladium sponge, palladium black, palladium oxide palladium oxide, palladium oxide barium carbonate, palladium carbon, palladium catalysts such as palladium silica gel, colloid palladium, reduced nickel, nickel oxide , Raney Nickel, Urushibara 2 ': / Kel and the like.
  • a metal such as iron and chromium and an inorganic acid such as hydrochloric acid or an organic acid such as formic acid, acetic acid and propionic acid are used.
  • the reduction method is usually carried out in a solvent.
  • a solvent for example, in the catalytic reduction method, alcohols such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, and ethyl acetate are frequently used.
  • alcohols such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, and ethyl acetate 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 (2,5-dihydro 5-) Oxo-2-furancarboxylic acid derivative) can be hydrogenated if necessary.
  • the hydrogenation for example, a method similar to the above-described reduction method used for elimination of the protecting group can be employed. By performing the reduction reaction, hydrogenation of the double bond and elimination of the protecting group can be performed simultaneously.
  • the compound (1 ′ in which R 1 is an amino group in the compound (1) can be produced by subjecting the compound (I) to a reaction similar to the deprotection reaction described above.
  • a compound (a compound in which R 1 is an amino group in one compound (I ′ is, for example, acylation, periation (thiolation), alkylation, alkenylation, thiolation, silylation, phosphorylation)
  • R 1 can be converted into a compound (I) in which R 1 is an organic residue via nitrogen other than an amino group.
  • Ashiru of Amino groups in a solvent can be carried out with the raw material compound, Ashiru agent comprising an Ashiru group in group R 1, for example, by reacting a reactive derivative of a carboxylic acid.
  • a reactive derivative of a carboxylic acid for example, an acid halide, an acid anhydride, an amide compound, an active ester, an active thioester, and the like are used.
  • Such a reactive derivative is specifically described as follows.
  • 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, aliphatic carboxylic acids (for example, acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroperic acid, etc.), and aromatic anhydrides.
  • Mixed acid anhydrides, symmetrical acid anhydrides, etc., composed of carboxylic acids (for example, benzoic acid) 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.
  • esters such as ter, methoxymethyl ester, propargyl ester, 412 trophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, etc.
  • Esters with hydroxy-1H-2-pyridone, N-hydroxyquin succinimid, ⁇ -hydroxyphthalimid and the like are used.
  • active thioester for example, 2-pyridylthiol
  • a thioester with a heterocyclic thiol such as 2-benzothiazolyl thiol is used.
  • the various reactive derivatives as described above are appropriately selected depending on the type of the carboxylic acid.
  • This reaction may be carried out in the presence of a base.
  • the base used include aliphatic tertiary amines (eg, trimethylamine, triethylamine, tripropylamine, tri- ⁇ -butylamine).
  • Tertiary amines such as, ⁇ -methylbiperidine, ⁇ -methylpyrrolidine, cyclohexyldimethylamine, and ⁇ -methylmorpholine, such as di- ⁇ -butylamine, diisobutylamine, and dihexylamine.
  • Hydroxides such as dialkylamines, for example, aromatic amines such as pyridine, lutidine, and acoridine; alkali metals, for example, lithium, sodium, potassium, etc., and alkaline earth metals, for example, lithium and magnesium; Carbonates and the like are used.
  • a reactive derivative of a carboxylic acid is generally used in an amount equivalent to the compound (I ⁇ ) (the compound of R 1 -amino in the compound (I ′)), but it is used in excess as long as the reaction is not hindered Can also.
  • the amount of the base used depends on the starting compound (I ⁇ ) used and the reactivity of the carboxylic acid.
  • the compound (generally about an equivalent to 30 equivalents, preferably about an equivalent to 10 equivalents to each compound.
  • This reaction is usually carried out in a solvent.
  • ethers such as dioxane, tetrahydrofuran, getyl ether, diisopropyl ether, propylenoxide, and butylene oxide; esters such as ethyl ethyl formate and ethyl ethyl formate; Halogenated hydrocarbons such as 1,2-dichloroethane and 1,1,1-trichloroethane; hydrocarbons such as benzene, toluene, and n-hexane; N, N-dimethylformamide Amides such as N, N, N-dimethylacetamide, for example, nitriles such as acetonitrile Common organic solvents such as are used alone or in combination.
  • 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, preferably about 130 ° C. to 80.
  • the reaction is usually completed in tens of minutes to tens of hours depending on the family, base, reaction temperature and solvent used, but sometimes takes several tens of days. ⁇ Raid (Cho-Raid)
  • R 23 , R 3 Q and Z have the same meaning as described above.
  • the reaction is carried out by reacting a substituted isocyanate or a substituted isothiocyanate containing a group represented by).
  • the substituted isocyanate include methyl isocyanate, ethyl isocyanate, phenyl isocyanate, p-bromophenyl isocyanate and the like.
  • the substituted isocyanate include methyl isothiocyanate and Phenyl isothiosinate Which is used.
  • the substituted isocyanate or the substituted isothiocyanate is usually used in about the equivalent amount of the compound (1), but may be used in excess as long as the reaction is not hindered.
  • reaction temperature is about 1
  • the reaction time is usually from about 10 minutes to about 5 hours at a temperature of about 20 to 50 ° C.
  • the alkylation of the compound (1 ′) can be produced by reacting the compound (1 ′) with an alkylating agent containing a group that binds to the nitrogen of the group R 1 via carbon.
  • alkylating agent containing a group that binds to the nitrogen of the group R 1 via carbon.
  • alkylating agent containing a group that binds to the nitrogen of the group R 1 via carbon.
  • alkylating agent containing a group that binds to the nitrogen of the group R 1 via carbon.
  • alkylating agent containing a group that binds to the nitrogen of the group R 1 via carbon examples thereof include halogenated alkyl compounds such as propyl chloride, butyl chloride, benzyl chloride, butyl bromide, benzyl bromide, aryl bromide, methyl iodide, chloroiodide, and propyl iodide; Dialkyl sulfate compounds, for example, substituted s
  • 1,4-dichlorobutane This reaction is usually performed in a solvent, and the solvent used is usually used.
  • the medium include water, methanol, ethanol, benzyl alcohol, benzene, N, -dimethylformamide, tetrahydrofuran, acetonitrile, etc.
  • the reaction temperature is about 20 ° C to 200 ° C.
  • the reaction time is about 30 minutes to 50 hours This reaction is carried out under the reaction conditions, for example, by changing the molar ratio of the compound (1 ′ to the alkylating agent, the second amine compound, the third amine compound). Selective production of amine compounds or quaternary amine compounds can do. It is also possible to introduce a different substituent to nitrogen by carrying out the reaction stepwise.
  • the reaction for introducing a group bonded via carbon other than alkyl can be carried out in the same manner as described above.
  • the alkylation can also be carried out by combining the compound (I 'and a carbonyl compound in the presence of a reducing agent.
  • the reducing agent used in this reaction is lithium aluminum hydride, Examples include cyanoborodium, sodium borohydride, sodium, sodium amalgam, a combination of zinc and an acid, etc. It is also carried out by catalytic reduction using palladium, platinum, rhodium, etc. as a catalyst.
  • 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, N, N-dimethylformamide, chloroform, acetone, acetonitrile, or water.
  • a solvent such as dioxane, tetrahydrofuran, N, N-dimethylformamide, chloroform, acetone, acetonitrile, or water.
  • it is carried out by reacting with imidoesuls.
  • Suitable imidoesters are, for example, methylformimide, ethylformimidate, benzylformimidate, methylacetimidate, ethylacetimidate, methylphenylimidate, methylphenylimidate, methyl N-methylformimidate, methyl N-ethylformimidate, methyl N-isopropylformimidate, etc. are used.
  • the reaction temperature is from 0 ° C to around 25, and the reaction time is usually from 1 hour to 6 hours.
  • the conversion reaction of the amino group to the guanidino group is carried out in a solvent such as water, N, N-dimethylformamide, hexamethylene phosphoroamide, for example, 0-alkyl or 0-arylpseuidourea, or Reaction with S-alkyl or S-arylpsoydothioureas
  • a solvent such as water, N, N-dimethylformamide, hexamethylene phosphoroamide, for example, 0-alkyl or 0-arylpseuidourea, or Reaction with S-alkyl or S-arylpsoydothioureas
  • Examples of the above pseudoureas include 0-methylpseudourea, S-methylpseudourea, 0-2,4-dichloromouth phenylpseudourea, 0-N, N-trimethylpseudourea, and the like.
  • As the dothioureas S-p-nitrotropydosidourea and the like are used.
  • the reaction temperature is about 0 ° C to about 40 ° C, and the reaction time is usually about 1 hour to 24 hours.
  • the alkenylation (imination) of the compound (I) can be carried out by dehydration condensation with the compound (at least with a carbonyl compound. This reaction proceeds without solvent, but can also be carried out in a solvent. Acid or base Alternatively, the compound (I ′ and a carbonyl compound can be produced by ripening and refluxing in the presence of a dehydrating agent or using a dehydrating device such as Dean Stark ′.
  • the solvent used is, for example, benzene, toluene, dichloromethane, ethanol or the like, the reaction temperature is about 0 ° C to 200 ° C, and the reaction time is about 1 to 20 hours.
  • Examples of the acid used as a catalyst include benzenesulfonic acid, methanesulfonic acid, sulfuric acid, boron trifluoride, zinc chloride, and the like.
  • Examples of the dehydrating agent used in this reaction include molecular sieves, silica gel, anhydrous magnesium sulfate, and anhydrous sodium sulfate.
  • Examples of the solvent used in this reaction include water, Examples include acetone, dioxane, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide, benzene, tetrahydrofuran, dichloromethane, or a mixed solvent thereof.
  • Examples of the base include organic bases such as pyridine, picoline, triethylamine, diisopropyl pyrethylamine, and methyl morpholine, and inorganic bases such as sodium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, and sodium carbonate. Is used. This reaction generally uses about 1 equivalent of a halogenated thio compound and about 1 to 10 equivalents of a base to the compound (d), and the reaction temperature is about
  • the difference is 20 ° C to 80 ° C, and the reaction time is 15 minutes to 10 hours.
  • This reaction can also be performed using a thioic anhydride (eg, toluenesulfonic anhydride, trifluorosulfonic methanesulfonic anhydride, etc.) instead of a halogenated thio compound.
  • a fluorinating reagent such as N-sulfonyl N-methylpyrrolidinium, N-sulfonylimidazolide or N-sulfonyl 1H-1,2,4-triazolide. You can also do this.
  • the silylation reaction of the compound (') is usually
  • the reaction can be carried out by reacting with a silyl halide compound containing a group represented by the following formula (eg, silyl chloride compound, silyl promide compound) in the presence of a base.
  • a silyl halide compound containing a group represented by the following formula eg, silyl chloride compound, silyl promide compound
  • examples of the base include organic bases such as pyridine, picolin, triethylamine, diisopropylethylamine, and N-methylmorpholine.
  • the reaction is preferably carried out in a solvent, for example, acetone, dioxane, - ⁇ , ⁇ -dimethylform.
  • PL Examples include amide, benzene, tetrahydrofuran, and dichloromethane.
  • the reaction temperature is from about 120 ° C to the boiling point of the solvent, or from about 120 ° C to 80, and the reaction time is from about 15 minutes to 20 hours.
  • Phosphorylation of compound (1 ") is usually carried out in an amount equivalent to that of compound (1").
  • Formulas> P— (wherein, R 4 + . R + 5 have the same meanings as described above) (for example, dimethyl chloride, acetyl chloride, etc.). , Diphenylphosphoric acid chloride, dibenzylphosphoric acid chloride, etc.) in a solvent with about an equivalent or excess of a base.
  • 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, N, N-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 15 minutes to 15 hours.
  • a compound (compound ( ⁇ ′) in which R 1 ′ is an amino group in ⁇ ) may, for example, be prepared by acylation, elimination (thioperidation), alkylation, alkenylation, thiolation, silylation, phosphorylation, etc.
  • R By subjecting the compound to a reaction, R can be converted to a compound ( ⁇ ) in which R is an organic residue via a nitrogen other than an amino group.
  • These reactions can be carried out using the above compound (I compound (I ′)).
  • the reaction can be performed in the same manner as in the reaction.
  • meth-oxylation a 6- or 7-position meth- oxylation method performed in the fields of penicillin and cephalosporin can be applied.
  • EM Gordon, RB Sykes, et al. Chemistry, et al. Chemistry and Biology of 3-—Lactam Antibiotics vol. . 199 (1982), Academic Press (1) diazo intermediate, (2) acylimin intermediate, (3) ketenimin and related imine intermediates, It describes methods via (4) quinoidimine intermediates, (5) sulfenimine intermediates, (6) enimine intermediates, and the like.
  • the target compound can be produced by any of these methods, a method via an acylimine intermediate will be described in detail as a typical example of methoxylation.
  • the methoxylation reaction is carried out by reacting a starting compound with an alkali metal salt of methanol and a halogenating agent in the presence of methanol.
  • a metal salt of methanol lithium methoxide, sodium methoxide, potassium methoxide, and the like are used.
  • the halogenating agent include, for example, t-butylpipoctide, N-chlorsuccinimide, N-promosuccinimide, N-chloroacetamide, N-promoacetamide, N-chlorobenzenesulfonamide , Chlorine, bromine, etc. are used.
  • This reaction is carried out in a solvent, for example, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, methanol, N, N-dimethylformamide and the like.
  • a solvent for example, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, methanol, N, N-dimethylformamide and the like.
  • methanol is added thereto.
  • 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, trichloroacetic acid and the like.
  • the excess halogenating agent is removed by treating it with a reducing agent such as sodium thiosulfate or a trialkyl ester of phosphorous acid.
  • Compound (I, (The compound in which X is formylamino in (II) can also be produced by subjecting a compound (I, (M) in which X is hydrogen to a formylamino reaction.
  • Formyl amination is used as a starting compound.
  • R pro is a protecting group.
  • I Mi that you express in The protecting group represented by R pro is the same as the above-mentioned protecting group for an amino group.
  • the nucleophilic derivative include N-silyl, N-stannyl and N-phosphorylformamide derivatives, and particularly preferred are ⁇ , ⁇ -bis (trimethylsilyl) formamide.
  • the formylamidation reaction is usually performed in a solvent under an inert atmosphere such as nitrogen or argon, and the reaction temperature is changed. It is about 100 ° C. to 120 ° C., preferably about 180 ° C. (: To 150.
  • the reaction time is about 10 minutes to 8 hours, preferably about 15 minutes to 2 hours.
  • the solvent used is preferably a non-proton solvent.
  • a non-proton solvent for example, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, hexamethylphosphoramide, or dioxane, followed by hydrolysis with an acid or base, or mercury, silver, talium or a herd.
  • a formyl amide group can be produced by treating with a metal ion.
  • the production of an imine compound as a raw material compound is similar to the method described in the above-mentioned M. Gordon et al. The method can be used.
  • Esterification of a carboxylic acid is carried out, for example, by the following method.
  • the starting compound is a mixture of a diazoalkane, for example, diazomethane, phenyldiazomethane, diphenyldiazomethane, etc., and a solvent, for example, tetrahydrofuran, furan, dioxane, ethyl acetate, acetonitrile, etc., at about 0 ° C to a reflux temperature. For about 2 minutes to 2 hours.
  • a diazoalkane for example, diazomethane, phenyldiazomethane, diphenyldiazomethane, etc.
  • a solvent for example, tetrahydrofuran, furan, dioxane, ethyl acetate, acetonitrile, etc.
  • Activate the alkali metal salt of the starting compound with an activated alkyl halide such as methyl iodide, benzyl bromide, p-nitro-benzylbenzyl bromide, m-phenoxybenzyl bromide, ⁇ -t-butylbenzyl bromide And vivaloyloxymethyl chloride.
  • Suitable reaction conditions are from about 0 ° C. to 60 using a solvent such as ⁇ , ⁇ -dimethylformamide, ⁇ ⁇ ⁇ ⁇ dimethylacetamide or hexamethylphosphoramide.
  • the acid anhydride of the raw material compound obtained by reacting the raw material compound with an acid chloride for example, ethyl ethyl carbonate, benzyl chlorocarbonate, etc.
  • an acid chloride for example, ethyl ethyl carbonate, benzyl chlorocarbonate, etc.
  • the reaction is carried out under the reaction conditions described in 3).
  • This anhydride can be used as a raw material compound in an acid chloride and a solvent such as tetrahydrofuran, dichloromethane, and the like. It is obtained by reacting at C to reflux temperature for about 15 minutes to 10 hours.
  • the starting compound is converted into a silylating agent such as trimethylsilyl chloride, t-butyl-dimethylsilyl chloride with triethylamine, etc. in a solvent such as dichloromethane, chloroform, tetrahydrofuran or the like at about 0 ° C to reflux. Incubate at the temperature for about 5 minutes to 16 hours. Amidation of carboxylic acids
  • Carboxylic acid amidation is carried out by converting the starting compound to an acid chloride, for example, ethyl ethyl carbonate, benzyl carbonate, or an acid anhydride, for example, anhydrous anhydride, trifluoroacetic anhydride, or the like. It is carried out by synthesizing and reacting with an ammonia or a selected amine, for example, the above-mentioned alkyl-1, dialkyl-1, aralkyl or heterocyclic amine.
  • an acid chloride for example, ethyl ethyl carbonate, benzyl carbonate, or an acid anhydride, for example, anhydrous anhydride, trifluoroacetic anhydride, or the like. It is carried out by synthesizing and reacting with an ammonia or a selected amine, for example, the above-mentioned alkyl-1, dialkyl-1, aralkyl or heterocyclic amine.
  • the target compound (1 ') thus obtained can be isolated by a method known per se, for example, concentration, liquid conversion, lysing, solvent extraction, lyophilization, crystallization, recrystallization, fractionation, chromatography, etc. It can be purified.
  • each isomer can be isolated by various conventional methods such as chromatography, recrystallization, etc., if necessary. It may form salts with bases, for example, inorganic bases such as sodium, potassium, lithium, calcium, magnesium, ammonia, etc., for example pyridine, colizine, triethylamido. And organic bases such as triethanolamine.
  • bases for example, inorganic bases such as sodium, potassium, lithium, calcium, magnesium, ammonia, etc., for example pyridine, colizine, triethylamido.
  • organic bases such as triethanolamine.
  • the compound of the present invention (I is obtained in a free form), it may be used to form a salt using conventional means, and the compound obtained as a salt may be used in a free form using conventional means.
  • the compound (I may form an inner salt may be included in the present invention.
  • Each of the stereoisomers of the compound (I ′) can be used as a medicine either alone or as a mixture.
  • Compounds ( ⁇ ), ( ⁇ and () are useful as raw material compounds for producing compound (ji).
  • This step is for converting the compound ( ⁇ ) into the compound (iy).
  • This reaction is usually carried out by reacting with an activator in a solvent or without a solvent.
  • the activator used herein include thionyl chloride, thionyl bromide, sulfuryl chloride, oxychloride, oxalyl chloride, chlorine, bromine, or a mixture of carbon tetrachloride and triphenylphosphine.
  • Halogenating agents such as P-toluenesulfonic acid anhydride, p-nitrobenzenesulfonic acid anhydride, 2,4,6—triisopropylphenylsulfonic acid, methanesulfonic anhydride, ⁇ -toluenesulfonyl ester And sulfonylating agents such as benzene, sulfonyl chloride and the like, and phosphorylating agents such as difluorophosphoric acid chloride, cymethylphosphoric acid chloride and getyl phosphoric acid chloride. This reaction is carried out by reacting compound (D) with an approximately equivalent to excess amount of the above-mentioned activator in a solvent or without solvent.
  • a base such as triethylamine, diisopropylethylamine, pyridine, or 4-dimethylaminopyridine may be used.
  • Solvents include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ⁇ , ⁇ -dimethyl
  • This step is based on the formula
  • the compound represented by the formula (1) is reacted with a halogenating agent to form a compound () (Here, a general formula (RO, where R s and R 8 form a chemical bond, and Y represents halogen)
  • a halogenating agent to form a compound ()
  • This reaction can be carried out by reacting compound (1) with an equivalent or a small excess of a halogenating agent in a solvent.
  • Preferred are chlorine, bromine, etc.
  • Solvents include chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloromethane.
  • the reaction temperature is about 0 to 80 ° C, and the reaction time is about 10 minutes to 10 hours.
  • Compound (II) used as a starting compound in the method of the present invention can be produced, for example, by the following method.
  • R 2 ', R 5 one 8 in the formula has the same meaning as defined above.
  • This reaction is carried out by reacting compound (V) with about an equivalent to a small excess of an esterifying agent in a solvent in the presence of an equivalent of a base.
  • esterifying agent used herein examples include: 'methyl iodide, benzylbutyromid, ⁇ -nitrobenzyl bromide, 01-pentoxybenzyl bromide, ⁇ -t-butylbenzylbromide-, Examples include halides such as diphenylmethyl bromide and bivaloyloxymethyl chloride, and dialkyl sulfates such as dimethyl sulfate and getyl sulfate.
  • Examples of the base include diisopropylamine, dicyclohexylamine, cyclohexylisopropylamine, triethylamine, tripropylamine, tri-n-butylamine, diisopropylethylamine, DABCO, DBU.
  • N-Methylmorpholine N-methylpyrrolidine, N-methylpyrrolidine, 3,4—Dihydro-1 2H-pyrido [1,2, a] pyrimidin 1-2-one, 4—Dimethylamine
  • Organic amines such as pyridine, pyridine, lutidine, and y-collidine; hydrides, hydroxides, and carbonates with alkali metals such as lithium, sodium, potassium, and zinc. Salt or the like is used.
  • Solvents include ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, and dichloromethane.
  • the reaction temperature is usually about -20 to 100 ° C, and the reaction time is about 5 minutes to 30 hours.
  • This reaction is carried out by using about an equivalent to a small excess of benzyl carbamate with respect to compound (V), and usually performing dehydration condensation by heating without solvent under reduced pressure.
  • the pressure drop is about Q.li Hg to 5 OiMHg.
  • the reaction temperature is usually about 50 ° C to about 120 ° C, and the reaction time is about 30 minutes to about 20 hours.
  • Compound (1) is then subjected to an esterification reaction to convert to compound (1 ′).
  • the esterification reaction is carried out by applying the same conditions as in the esterification of compound (V) ⁇ compound (H). More
  • esterification may be carried out with diazoalkanes such as diazomethane and the like, or with methanol, ethanol and benzyl alcohol, for example, in the presence of a carbodiimide condensing agent such as DCC.
  • the method of esterification is appropriately selected depending on the desired ester, but the ester used here is selected from those which are stable to a comparative acid since an acid is used in the next reaction.
  • Compound (VT) is converted to compound (II) by acid treatment.
  • hydrochloric acid for example, hydrochloric acid, sulfuric acid, hydrobromic acid, perchloric acid, periodic acid, formic acid, acetic acid, trifluoroacetic acid, ⁇ -toluenesulfonic acid and the like are used alone or in combination. Among them, a combination of hydrobromic acid and acetic acid is preferable.
  • the reaction temperature is about 0 to 50 ° C, and the reaction time is about 15 minutes to 5 hours.
  • Compound (V) ⁇ Compound (VM) Compound ( ⁇ ):>-In this step, compound (V) is reacted with a halogenocarbonate to form
  • the compound (D) is produced by introducing the compound (vi) represented by the formula (1) and then decarboxylation.
  • compound (V) is reacted with a halogenocarbonate in a solvent in the presence of a base.
  • the compound (I) is produced by decarboxylation.
  • the halogenocarbonate include, for example, methyl methyl carbonate, ethyl methyl carbonate, benzyl carbonate, and 1,2-, 2-trichloromethyl ethyl carbonate.
  • the base and the solvent used herein include those described in the production method in the step of compound (RO ⁇ compound (J)).
  • the reaction temperature is usually about 30 ° C. to 60 ° C., and the reaction time is about 1 minute to 2 hours.Compound (VI) is particularly required to be isolated.
  • the decarboxylation reaction continues to proceed under the above reaction conditions, and the compound (H) can be obtained at once.
  • the dehydrating agent used in this reaction include oxychloride and thionyl chloride. , Chlorosulfonic acid, etc., halogen compounds such as acetic anhydride, trifluoroacetic anhydride, etc., acid anhydrides of lower fatty acids, eg, acetyl chloride, etc., acid halides, eg,
  • Imidazole derivatives such as —, ⁇ '-carbonildimidazole, ⁇ -trifluoroacetylimidazole, and DCC.
  • an organic base such as pyridine and triethylamine may be used in combination. This reaction is carried out in an amount
  • a solvent for example, dichloromethane, benzene, toluene, acetonitrile and the like are used.
  • the reaction temperature is usually about 0 ° C to 100 ° C, and the reaction time is about 15 minutes to 30 hours.
  • a compound (EG) is reacted with an approximately equivalent or excess amount of alcohol to obtain a compound (II).
  • Specific examples of alcohols include, for example, methyl alcohol, ethyl alcohol, benzyl alcohol, and p-nitrobenzene.
  • reaction for example, sulfuric acid, ⁇ -toluenesulfonic acid, zinc chloride, sodium acetate, pyridine, 4-dimethylamino pyridine, and 4-pyrrolidino are used.
  • a catalyst such as pyridine, triethylamine, calcium carbide, etc. may be used.
  • the reaction temperature is about 0 ° C to 100 ° C, and the reaction time is about 10 minutes to 4 days.
  • R 5 Q in the above formulas ( ⁇ ), ( ⁇ , ( ⁇ ⁇ ⁇ ⁇ ) include aralkyl groups such as methyl and ethyl, and aralkyl groups such as benzyl, p-bromobenzyl and p-nitrobenzyl. .
  • the esterification agent and the base are each added in an amount of about 2 equivalents to compound (V) in the method described in the production method of compound (V) ⁇ compound (I).
  • excess amount c compound is carried out by using (X) ⁇ compound hydrolysis of (XI) is usually, for example, lithium, diisocyanato Riumu, Kariumu, hydroxides of Al force Li metal such as cesium, carbonate, Al
  • the reaction is performed in a solvent with a base such as a collate.
  • a base such as a collate.
  • the solvent water, methanol, ethanol, tetrahydrofuran, dimethylsulfoxide and the like can be used alone or as a mixed solvent.
  • This hydrolysis reaction is carried out using about an equivalent of a base relative to the compound (X).
  • the reaction temperature is usually about 0 to 80 ° C, and the reaction time is about 10 minutes to 20 hours.
  • the esterification reaction of the compound (xo ⁇ compound ⁇ ) can be carried out according to the method described in the production method of compound (V) “compound (H). Further, compound (XI) is present in the presence of an acid catalyst.
  • a half ester compound [compound ()] is obtained.
  • a reduction method for example, a method by catalytic reduction using a metal catalyst such as palladium carbon, palladium black, palladium carbonate, platinum oxide, platinum black, Raneynitz gel, etc., for example, a metal such as zinc, iron, chlor, etc.
  • a reduction method using an acid such as acetic acid, formic acid or acetic acid is applied.
  • the reduction method is usually carried out in a solvent, for example, water, methanol, ethanol, ethyl acetate, acetone, or the above-mentioned acids.
  • the reaction temperature is generally about 0 ° C to 60 ° C, and the reaction time is about 10 minutes to 20 hours.
  • This step is based on the formula
  • the compound (II) may be added with an argen such as isobutene and a catalyst such as sulfuric acid and boron trifluoride to produce a t-alkyl ester, and this reaction is usually carried out in a solvent.
  • a solvent dichloromethane, chloroform, dioxane, getyl ether, tetrahydrofuran, benzene, etc. are used. After introducing an excessive amount of isobutene, the mixture is sealed, and is sealed at about 0 ° C to 50 ° C. It is carried out by reacting for about 5 hours to several days.
  • oxidizing agent examples include permanganate potassium manganese dioxide, dimethylsulfoxide (DMSO) -DCC, DMS O-Oxyl anhydride, DMS 0-oxalyl chloride, DMS 0-linoleum pentoxide, etc.
  • Solvents include dichloromethane, chromatoform, acetonitrile, ethyl acetate, benzene, toluene, DMS 0, N, N-dimethylformamide, acetone, ether, etc. This reaction usually uses about an equivalent or excess amount of oxidizing agent to compound (XVI). 0 ° C to 60 ° C, reaction time is about 10 minutes Stone 3 0 hours.
  • Compound (V) which is a starting compound used in this study, can be produced by various methods already reported.
  • the compounds themselves are known from the following documents, or the compound (V) can be obtained according to the methods described in these documents.
  • Compound (V) can be produced, for example, according to the following reaction scheme.
  • R 2 ', R 5 one 8 have the same meaning as defined above.
  • the conversion of compound (XVI) -compound (XIX) is a reaction well known as so-called Claisen condensation, and is a step of condensing compound (X) and compound (XVI) in a solvent in the presence of a base.
  • the base used in this reaction is, for example, an alkali metal such as lithium, sodium and potassium, for example, an alkaline earth metal such as magnesium and calcium, or a hydride, an alcoholate or an amine thereof.
  • quaternary ammonium salts eg, tetra-n-butylammonium hydroxide).
  • alcohols such as methanol and ethanol (when alcoholate is used, the same alcohol as the alkoxyl group of the ester), ether, tetrahydrofuran, dioxane, N, N-dimethylformamide , 1,2-Dimethoxyethane, dichloromethane, benzene, toluene, etc. are used.
  • the reaction temperature is usually about 0 ° C to 80 ° C, and the reaction time is about 10 minutes to 10 hours.
  • Compound (XO ⁇ Compound (V) can be converted by acid, alkaline or reductive treatment
  • Compound (m), which is one of the starting compounds used in the present invention can be produced by various known methods.
  • the compounds themselves are known from the literatures listed below, or the compound (no can be obtained according to the method described therein).
  • Esterification of compound (XX) ⁇ compound (XI) can be achieved by various commonly used known esterifications. For example, it can be produced according to the above-mentioned esterification production method. Among them, a method of treating with thionyl chloride in alcohol is preferably used. At this time, the amino group may form a salt as a hydrochloride, but does not hinder the reaction.
  • Compound (XXI) -Compound (XXD is a step of converting a hydroxyl group to a leaving group Y.
  • a method for converting a hydroxyl group to a leaving group Y is, for example, the above-mentioned compound (II) -compound (R Compound (XXII) ⁇ Compound (II) ⁇ Compound (XXR is a reaction of compound (XXI) with hydroxylamine in the presence of a base to give compound
  • the compound (XX ⁇ ) can also be isolated at once. It is possible to convert to the compound (xxjy) at once without isolation.
  • This reaction is usually carried out using water as a solvent, and is carried out by reacting about an equivalent or a small excess of hydroxylamine with respect to compound (XXI) in the presence of an about equivalent or excess base.
  • the base include hydroxides and carbonates of alkali metals such as lithium, sodium, potassium and cesium, and alkaline earth metals such as magnesium and calcium.
  • the reaction temperature is usually about ⁇ 20 ° C. to 60 ° C., and the reaction time is about 10 minutes to 10 hours.
  • Compound (xxiy) can be used in the next reaction step without isolation and purification.
  • Compound (xxiy) ⁇ Compound (m) is a step of producing compound (XX) by converting the amino group of compound (XXB) to an organic residue via nitrogen. This reaction is carried out in the above-mentioned compound (I). It can be carried out in the same manner as in the method of converting one amino group into an organic residue via nitrogen.
  • Each of the intermediate compounds thus obtained can be 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.
  • the compound obtained as described above (I is useful as a medicine, for example, has antibacterial activity against certain Gram-positive bacteria and Gram-negative orchids.
  • Compound (I) The antibacterial spectrum against various microorganisms is shown in Table 1 below.
  • Compound (25) refers to compound (25) produced in Example 25 described later.
  • the toxicity of the compound (I is low.
  • the compound of the present invention (I or a salt thereof) has an antibacterial activity against certain gram-positive bacteria and gram-negative bacteria, so that it can be infected by bacteria.
  • Bacterial infections in mammals eg, mice, rats, dogs, pigs, cows, humans, etc.
  • respiratory infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections can be used as a therapeutic agent for bacterial infections or as an antibacterial agent for the treatment of infections, gynecological infections, surgical infections, etc.
  • the daily dose of the compound (ji) is about 2 to 10 Omg / Kg, more preferably about 5 to 4 Omg / Kg as the compound (ji).
  • the compound (I or a pharmaceutically acceptable salt thereof) is mixed with an appropriate pharmaceutically acceptable carrier, excipient, or diluent by a conventional means. It can be administered orally in the form of tablets, granules, capsules, drops, or the like, or it can be formulated by conventional means, for example, into injections, and compounded into sterile carriers manufactured by conventional means. It can be administered orally.
  • binders eg, t-doxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.
  • disintegrants eg, starch, carboxymethylcellulose calcium, etc.
  • ⁇ excipients eg, lactose, starch, etc.
  • lubricants eg, magnesium stearate, talc, etc.
  • isotonic agents eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.
  • preservatives eg, benzyl alcohol, chlorobutanol, paraoxyl
  • buffers eg, phosphate buffer, sodium acetate buffer, etc.
  • HF-20 Diaion HP-20 (Mitsubishi Kasei Kogyo Co., Ltd., Japan)
  • XAD-2 Amplitude XAD-2 (Machine & And Haas, USA)
  • IR 1 3325, 1700, 1550, 1310, 1280
  • (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone was replaced by (4 S) - 4-amino-3-Isokisazori with Gino emissions, benzyl O alkoxycarbonyl chloride to Nichinichi colorless ⁇ the title compound subjected to reaction with a 4 twelve Torobe Nji Ruo alkoxycarbonyl chloride Li de instead of Li de to 0
  • Example 2 185 mg of the compound (2) obtained in Example 2 was dissolved in a mixed solution of ethyl acetate 5 ⁇ ⁇ a and water3 ⁇ 453 ⁇ 4, 5% palladium-carbon 20 Omg was added, and the mixture was stirred at room temperature in a hydrogen stream for 50 minutes. After removing the catalyst by filtration and washing with water, the filtrate and washing solution were combined, the aqueous layer was collected, and 53 ⁇ 4 £ of tetrahydrofuran was added, and under ice-cooling and stirring, 67 ⁇ of 2-chloryl chloride and an aqueous solution of sodium hydrogen carbonate were added. The reaction was maintained for about 30 minutes while being kept at around 0.0.
  • IR ⁇ ⁇ cm -1 3430, 1750, 1735, 1710, 1275, 1255, 1225, 1080
  • Example 8 22 Omg of the compound (8) obtained in Example 8 was dissolved in a mixture of ethyl acetate 5 ⁇ and PH7.Q phosphate buffer solution, and 10% palladium-carbon 22 Omg was added thereto. The mixture was stirred for 90 minutes. After removing the catalyst by filtration and washing with water, the filtrate and the washing solution were combined, and the aqueous layer was separated. Add tetrahydrofuran to the aqueous layer, cool with ice and stir with sodium hydrogen carbonate 11 Omg and (Z) -2-chloroacetamido 4-thiazolyl 2-methoxyiminoacetic acid chloride hydrochloride
  • Example 9 125 mg of the compound (9) obtained in Example 9 was dissolved in a mixed solution of ethyl acetate 6 ⁇ and PH7.0 phosphate buffer, and 125 mg of 10% palladium-carbon was added. The mixture was stirred for 1 hour under ice cooling. After removing the catalyst by filtration and washing with water, the filtrate and the washing solution were combined, and the aqueous layer was separated. To the aqueous layer was added tetrahydrofuran 4-2, and with ice cooling and stirring, 63 mg of sodium hydrogen carbonate and 102 mg of (Z) -2-chloroacetamido 4-thiazolyl 2-methoxyiminoacetic chloride hydrochloride were added.
  • Example 23 25 mg of the compound (23) obtained in Example 23 was dissolved in 5% of ethyl sulphate and 7.5% of pH 7.0 phosphate buffer, and 25 mg of 10% palladium-carbon was added thereto. The mixture was stirred in an air stream for 75 minutes under ice cooling. After removing the catalyst by filtration and washing with water, the filtrate and the washing solution were combined, and the aqueous layer was separated. To the aqueous layer was added 5% of tetrahydrofuran, and the mixture was cooled on ice and stirred with 110 mg of sodium hydrogen carbonate and (Z) -2-chloroacetamido 4-thiazolyl 2-methoxyiminoacetic acid chloride hydrochloride 18 Omg Was added.
  • IRV m ilajx at cm -1 1810, 1760, 1440, 1270, 1210, 1100, 880
  • 2-furancarboxylic acid (10.lg) was dissolved in a mixture of acetic acid (5) and acetic anhydride (10), and the internal temperature was kept at 7 ° C, and 4.55 g of chlorine gas was passed under stirring. After standing at room temperature for 40 hours, the solvent was distilled off, and the fraction distilled at a bath temperature of 17 O ° C and 0.05 mmHg was removed. The residue was subjected to column chromatography using silica gel and eluted with hexane-monoethyl acetate (6: 1) to obtain 2.6 g of benzyl 5-acetoxodi-2-furancarboxylate as a colorless oil.
  • IR i, tv at cnT ⁇ l O 1700, 1520, 1480, 1300, 1205, 1140, 1020
  • a _1 3350, 1810, 1770-1710, 1530, 1260, 1080, 1040,
  • R 1 3300, 1800, 1750, 1660, 1530, 1260, 1080, 1040,
  • RV miia®x at cm _1 3300, 1800, 1750, 1660, 1530, 1270, 1190, 1050
  • IR III! ⁇ 111 "" 1 ⁇ 300 '1800, 1760, 1660, 1530, 1260, 1080, 1035, 900
  • Example 32 68 mg of the compound (32) obtained in Example 32 was dissolved in a mixture of 5 mL of ethyl acetate and 5 phosphate buffer, pH 7.0, and 10% palladium-carbon 7 Omg was added thereto. The mixture was stirred under cooling for 2 hours. After removing the catalyst by filtration and washing with water, the filtrate and the washing liquid were combined, and the aqueous layer was separated. The aqueous layer was concentrated, and the concentrate was purified using an HP-20 column. The fraction eluted with 5% ethanol was freeze-dried to obtain 41 mg of the title compound (33) as a white powder.
  • Ethanethiol was added to a suspension of 1.00 g of dichloromethane containing 20 g of dichloromethane and 1.00 g of dichloromethane under ice-cooling and stirring, and then 1.83 g of triethylamine was added. After stirring the reaction solution at room temperature for 3 hours, the solvent was distilled off, and the residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried (Na 2 SC), and the solvent was distilled off to obtain 0.82 g of 3-ethylthio-2-oxodaltaric acid as a pale yellow oil.
  • IRV ⁇ at cm -1 1730, 1370, 1295, 1260, 1200, 1160, 1080
  • Example 4 Tablets are prepared by conventional means using the following ingredients.
  • 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.

Abstract

Composés représentés par la formule générale (I) où R1 représente un groupe amino ou un résidu organique par l'intermédiaire d'un atome d'azote, R2 représente un groupe carboxyle ou un groupe dérivé de ce dernier, R3, R4, R5, R6, R7 et R8 peuvent être identiques ou différents, chacun représentant de l'hydrogène ou un résidu organique, y compris le cas où R5 ou R6 et R7 ou R8 forment un liant chimique, à condition que R3, R4, R5, R6, R7 et R8 ne soient pas de l'hydrogène en même temps. Lesdits composés présentent une excellente activité antibactérienne et peuvent être utilisés comme agents antibactériens.
PCT/JP1985/000247 1985-04-30 1985-04-30 Composes antibacteriens, utilisation et preparation WO1986006380A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PCT/JP1985/000247 WO1986006380A1 (fr) 1985-04-30 1985-04-30 Composes antibacteriens, utilisation et preparation
EP86302819A EP0219923B1 (fr) 1985-04-30 1986-04-16 Dérivés antibiotiques, leur préparation et leur application
AT86302819T ATE80163T1 (de) 1985-04-30 1986-04-16 Antibiotische derivate, ihre herstellung und verwendung.
DE8686302819T DE3686632T2 (de) 1985-04-30 1986-04-16 Antibiotische derivate, ihre herstellung und verwendung.
DK195986A DK195986A (da) 1985-04-30 1986-04-29 2-(4-substituerede amino-3-oxo-2-isoxazolidinyl)-5-oxo-2-tetrahydrofurankarboxylsyrederivater og fremgangsmaade og anvendelse deraf
ES554495A ES8802317A1 (es) 1985-04-30 1986-04-29 Un procedimiento para preparar derivados de acido (2-aminosustituido-3-oxo-2-isoxazolidinil)-5-oxo-2-tetrahidrofuran-carboxilico
HU861788A HU197742B (hu) 1985-04-30 1986-04-29 Eljárás izoxazolidinil-tetrahidrofurán-kárbonsav antibiotikum-származékok, és hatóanyagként e vegyületeket tartalmazó gyógyszerkészítmények előállítására
CA000507875A CA1285950C (fr) 1985-04-30 1986-04-29 Derives de l'acide 2-(amino-3-oxo-2-isoxazolidinyl substitue en 4)-5-oxo-2-tetrahydrofuranecarboxylique, leur production et leur utilisation
KR1019860003319A KR930005174B1 (ko) 1985-04-30 1986-04-29 항생물질 유도체의 제조방법
US06/857,834 US4851422A (en) 1985-04-30 1986-04-30 Antibiotic 2-(3-oxo-2-isoxazolidinyl)-5-oxo-2-tetrahydrofuran-carboxylates
CN198686102923A CN86102923A (zh) 1985-04-30 1986-04-30 制备抗菌素衍生物的方法
ES557661A ES8801650A1 (es) 1985-04-30 1987-08-13 Un metodo para preparar derivados de acido (2-amino sustutuido-3-oxo-2-isoxazolidinil)-5-oxo-2-tetrahidrofuran-carboxilico.

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9108999B2 (en) 2011-12-20 2015-08-18 Riboscience Llc 2′, 4′-difluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9249176B2 (en) 2013-05-16 2016-02-02 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9708357B2 (en) 2011-12-20 2017-07-18 Riboscience, LLC 4′-azido, 3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9895442B2 (en) 2013-05-16 2018-02-20 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US10682369B2 (en) 2017-09-21 2020-06-16 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US10953030B2 (en) 2013-05-16 2021-03-23 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication

Non-Patent Citations (1)

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

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9108999B2 (en) 2011-12-20 2015-08-18 Riboscience Llc 2′, 4′-difluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9708357B2 (en) 2011-12-20 2017-07-18 Riboscience, LLC 4′-azido, 3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9249176B2 (en) 2013-05-16 2016-02-02 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9694028B2 (en) 2013-05-16 2017-07-04 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9895442B2 (en) 2013-05-16 2018-02-20 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US10953030B2 (en) 2013-05-16 2021-03-23 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US10682369B2 (en) 2017-09-21 2020-06-16 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US11351186B2 (en) 2017-09-21 2022-06-07 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication

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