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
  • 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 cefm compound having an excellent antibacterial activity, a method for producing the same, and a pharmaceutical composition.
• Cefm antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, for example, in the treatment of diseases caused by bacteria that are resistant to epsilon antibiotics and in the treatment of patients susceptible to penicillin. Particularly useful. In this case, it is desirable to use a cefm antibiotic that is active against both gram-positive and gram-negative bacteria.For this reason, research on cefm antibiotics having a broad antibacterial spectrum has been actively conducted. Done I have been. As a result of long-term studies, introduction of 2 -((2-aminothiazol-1-4-yl-12-alkoxy, cyminoacetate amide) at the 7- position of the cefm ring activates both gram-positive and gram-negative bacteria.
• cephalosporin-based compounds which led to the development of the so-called third-generation cephalosporin-based compounds, and several types of third-generation cephalosporin-based compounds are currently on the market.
• Another feature of the generational cephalosporin antibiotics is that they have demonstrated activity against the same ft-acting bacteria as those experienced with penicillin, the so-called cephalosporin-resistant bacteria.
• cefm compound having a quaternary ammonium methyl group at the position and the aminothiazolyloxyminoacetamides at the 7 position has a more excellent antibacterial activity and a unique antibacterial spectrum.
• the present invention has the general formula
• CI (Wherein, represents an amino group which may be protected, R 2 represents a hydrogen atom or a halogen atom, R 3 represents a hydrogen atom or a hydrocarbon residue which may be substituted, and R 4 represents a hydrogen atom.
• A represents an atom or a methoxy group, A represents an optionally substituted imidazolyl-1-1 monoyl group forming a condensed ring at the 2,3-position or 3,4-position, and n represents 0 or 1 Or a physiologically acceptable salt or ester thereof, a process for producing the same, and a pharmaceutical composition.
• Cefem compounds in this specification are related to “cepham” according to “The Journal” of the American Chemical “Chemical” Society, Vol. 84, page 340 (1962). And refers to a compound having a double bond at the 3,4-position among cephem compounds.
• a cephalic compound having a quaternary ammonium methyl group at the 3rd position and an aminothiazolyloxyminoacetamide at the 7th position is more effective than third-generation cephalosporin compounds. It has been gradually found to have even better antibacterial activity and a unique antibacterial spectrum.
• the substituent Eh represents an amino group which may be protected, that is, an amino group or a protected amino group.
• the protecting groups for amino groups have been thoroughly studied and the protection methods have already been established. In the present invention, any known protecting groups for amino groups may be appropriately used. Can be adopted. Amino group protecting groups as, for example C 6 ⁇ 10 ⁇ Re Ichiru - ⁇ ⁇ le group, C i to 5 Al force Noiru group, C 3 ⁇ 5 Arukenoiru group, Cs ⁇ t. Aryl sulfonyl group,
• Trifluroyl roacetyl Trifluroyl roacetyl, monoiodoacetyl, acetoacetyl, 3-oxobutyryl, 4-chloro-3-oxoxobutyryl, fueracetyl, P—cloguchi fenyl acetyl, phenoxyacetyl, ⁇ -chlorofuenchil, etc. can give.
• Specific examples of the substituted alkenoyl group include cinnamoyl.
• substituted arylsulfonyl group examples include p-to-norenens-norefonyl, p-tert-butylbenzenesulfonol, p-methoxybenzenesulfoninole, and p-cyclobenzenesulfonyl, —Examples include double-ended benzenesulfol. C 1 ⁇ 1 0 alkylsulfonyl 3 ⁇ 4
• the substituted Okishi carbonyl group e.g. main butoxycarbonyl, Etoki carbonyl, I isopropoxy force carbonyl, tert- butoxycarbonyl, such as I Sobol sulfonyl Okishi carbonyl ( ⁇ 1-8 alkoxy one carbonyl ⁇ group, e.g. Fueno Kin force Lupo two Honoré, etc. c 7 ⁇ 1 2
• Ararukiruoki Ichiriki Ruponiru group such as C 6 ⁇ 1 0 Ariruokishi Ichiriki Ruboni Le group e.g.
• Benjiruoki carbonyl such as naphthyl O alkoxycarbonyl is exemplified.
• alkoxycarbonyl group examples include methoxymethyloxy / carbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trikyloxycarbonyl, Mouth roto xycarponyl, 2-cyanoethoxycarbonyl, etc .; C 6 through i 0 Ariruoki ⁇ - aromatic carbonyl group and the C 7 through i 0 ⁇ Rarukiruokishi one carbonyl group C i to 4 alkyl, C to 6 alkoxide ⁇ , halogen, optionally substituted with like two preparative ⁇ Is also good.
• substituted aryloxycarbonyl group examples include ⁇ -methylphenoxycarbonyl, ⁇ -methoxyphenoxycarbonyl, and ⁇ -chlorophenoxycarbonyl.
• substituted aralkyloxycarbonyl group examples include ⁇ -methylbenzyloxycarbonyl, ⁇ -methoxybenzyloxycarbonyl, ⁇ -k —Nitoguchi benzyloxycarbonyl and the like.
• the C 7 ⁇ 12 ⁇ Rarukiruokishi force Ruponiru alkyl group C 6 ⁇ 10 ⁇ reel, Bruno, may be substituted with such Rogge emissions, in particular, such as base Nzuhi drill Ruokishikaru Boniru the like.
• the carbamoyl group may be substituted.
• Specific examples of the substituted carbamoyl group include N-methylcarbamoyl, N-ethylcarbamoyl, N, ⁇ -dimethylcarbamoyl, ⁇ -phenylcarbamoyl, and ⁇ — ( ⁇ -methoxyphenyl) carbamoyl. And so on.
• Thiocarbamoyl groups may be similarly substituted.
• Specific examples of the substituted thiocarbamoyl group include ⁇ -methylthiocarbamoyl.
• C 6 ⁇ 10 ⁇ Li one Rumechiru base as specifically the base Njiru, naphthylmethyl, and these aromatic rings C t ⁇ 4 Al kill, C Iota ⁇ 6 alkoxy, halogen, such as a secondary Bok port It may be replaced.
• Specific examples of the substituted arylmethyl group include p-methylbenzyl , P-methoxybenzinole, p-chlorobenzil, ⁇ 12-benzil, etc.
• the methylation group Arirume methyl group may be substituted by another 1-2 C 6 ⁇ 10 Ariru group, specifically base Nzuhi drill, etc. Application Benefits chill and the like.
• Njiriden base is specifically as alkylene groups exemplified et these aromatic rings Ci-4 alkyl, ( ⁇ 1-6 alkoxy, halogen, optionally substituted by such as a secondary Bok port . the substitution has been ⁇ reel methylene groups specifically p- main Chirubenjiride down -., specific examples of an 0 6-10 ⁇ Li Ruchio group such as p- black port base Njiriden the like 0- two ⁇
• Rio .Rg, Rio 'each example methylation, Echiru shows a C 6 ⁇ 10 ⁇ aryl group such as Ci ⁇ 4 alkyl or e.g. phenyl, such as tert- butyl, may be the same or different.
• Z represents, for example, a Ci- 3 alkylene group such as methylene and ethylene.] Specifically, trimethylsilyl, tert-butyldimethylsilyl, and Si (CH 3 CH 2 CH 2 Si (CH 3 :> 2 —) and the like.
• Examples of the C 1-8 alkoxy group of the alkoxy-1-carboxy 1-methyl-1-ethenyl group include methoxy, ethoxy, tert-butoxy and the like.
• Substituents R 2 in the above cephem compound [I] 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
• O PI Represents an optionally substituted hydrocarbon residue.
• the carbide zk3 ⁇ 4 residues e.g. c 1 ⁇ 6 alkyl group.
• Specific examples of the Cis alkyl group include methyl and ethyl.
• alkylthio group 1 to 6 alkylthio group, C 3 ⁇ s black alkyl thio group, C 6 ⁇ 10 ⁇ Li one thio group, C 7 through i 2 Ararukiruchio group, Amino groups, mono ( ⁇ 4 Al Kiruamino group, di C i to 4 alkylene J Reami amino group, C 3 ⁇ 6 consequent opening Arukiruami amino group, c 6 ⁇ 10 Ariruamino group, c 7 ⁇ 12 Ararukiruamino group, cyclic ⁇ Mi amino group, azide de group, nitro port Group, halogen atom, cyano group, carboxy group,
• C 3 ⁇ 6 cycloalkyl radical is shea click port propyl, sik Robuchiru, consequent opening pentyl, cyclohexyl and the like, C t ⁇ .
• Bibaroi Ruokishi c 3 ⁇ 5 alkenyl noisy Ruo alkoxy group ⁇ click And substituted carbamoyl groups such as N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N "-phenylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, and morpholinyl.
• a substituted thiocarbamoyl group such as N-methylthiocarbamoyl group, a substituted rubamoyl group i / group is N-methylcarbamoyloxyN, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, etc.
• OMPI It may be substituted with a group, and specific examples include benzhydryloxy 'benzhydrylthio, benzhydrylamino. Benzhydrylcarbonyl, benzhydryloxycarbonyl, and the like. Specific examples of the substituted hydrocarbon residue include methoxymethyl, 1-methoxyethyl, 1-ethoxyquinethyl, 2-hydroxyhexyl, 2-aminoethyl, 2-fluoroethyl, 2-chloroethyl and 2-chloroethyl. Moethyl, carboxymethyl, 1-carboxy-1- 1-methylethyl, 1-carboxycyclopropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,
• the substituent A may be substituted in the cefm compound [I].
• the condensed ring means a form in which an imidazole ring and a 5- or 6-membered aromatic heterocycle are condensed, and this condensed ring is further condensed with another aromatic ring or an aromatic heterocycle. Is also good.
• the @ added to the substituent A indicates that the substituent A has a monovalent positive charge. 2 may be substituted, 3 - position or 3, 4 ones I to form a condensed ring Midazo - rule 1 Ichii Le group (A® J general formula CAJ or [A 2]
• B is a group forming a 5- or 6-membered aromatic heterocyclic ring which may be condensed with another aromatic ring or an aromatic heterocyclic ring
• i is a hydrogen atom or an imidazole ring
• Ri 2 represent a hydrogen atom or a substituent on the ring condensed with the imidazo ring.
• B consists of a carbon atom, a nitrogen atom s an oxygen atom and / or a sulfur atom, of which a carbon atom is bonded to one hydrogen atom or one substituent, or is a fused ring with an adjacent carbon atom
• a i group The following are specific examples of the A i group.
• OMPI Although fit the 3-position nitrogen atom of Les, - the above formula [A i], [A 2] and specifically exemplified with A i groups, Oite the A 2 groups are conveniently Imidazo the positive charge of the substituents In some cases, the quaternary nitrogen atom is assigned to the nitrogen atom at the first position. In some cases, the monovalent positive charge is delocalized on the imidazo monocyclic ring, and sometimes on the entire condensed ring. So even if
• hydroxyalkynole group is hydroxymethinole, 2-hydroxydecynole, etc.
• Ci to 6-anolekyl group is methynole, ethyl, propynole, isopropynole, butyl, isobutynole, sec-butynole, tert-butyl, pentyl.
• C 2 to 6 anolekenyl groups include bier, aryl, isoproleninole, methallyl, 1,1-dimethinorea linole, 1-butenyl, 2-butenyl, 3-butenyl, and the like.
• C 6 -ioaryl groups include phenyl, naphthyl, etc.
• C 2 -aralkyl groups include benzylinole, phenyl, etc.
• heterocycles are 2-pyridyl.
• OMPI examples of the killing group include methoxymethyl, ethoxymethyl, 2-methoxethyl and the like.
• C 3 to 6.Dichlorophenolic groups include cyclopropynoleoxy and cyclohexanoloxy, and C 6 to 10 arylesoxy groups include phenoxy, Naphthyloxy and the like;
• C 7 to 12 aralkyloxy groups such as benzyloxy '1-phenyl ethenyl / reoxy, 2 — phenyl / ethynoleoxy and the like;
• C i to 4 menolecaptoquinoleno groups are menolecaptomethyl; 2-mercaptoethyl, C-4 sulfoalkyl group f
• Ci to 6 anoalkylthio groups include methiothio, ethylthio, propylthio, isoprobi, / recio, butylthio, etc., and C1 to 6 alkyl groups.
• Ci to 4 acrylyl groups are methinolethiomethyl and 2-methylthioethynole. etc., C 3 ⁇ 6 consequent opening alkylthio group sik port propylthio, cyclohexylthio and the consequent opening, and C 6 to 1 0 ⁇ Li
• Norechio groups off e Ruchio, C 7 ⁇ 1 2 Araruki Lucio groups Such as N.
• C i -4 aminoalkyl groups include aminoamino, 2-aminoethyl, etc.
• Mono C -4 alkylamino groups include methylamino, ethylamino, propylamino, butinoreamino, etc.
• the 1-4 alkynoleamino groups include dimethylamino, getiamino, methylethylamino, dipropylamino, dibutylamino, etc., and the mono-Ci-4alkylamino C1-4alkyl groups are methylaminomethyl, ethinoreaaminomethyl, 2 - (N-Mechiruami Roh) Echinore, 3 - (N - Mechirua Mi Roh) Puropinore etc., di C i to 4 alkylamine plasminogen C i ⁇ 4 Anorekiru groups N, N-dimethylaminomethyl, N, N-Jechirua Minomechiru, 2 one (N »N-Jimechinoreamino) Echinore, 2- (N, N - Jechiruamino) Echiru, 3- (N, N-Jimechiruamino) Puropinore etc., C 3 ⁇ 6 cyclo Anore Kino Rea amino
• Amino C-4 phenolic alkyl groups include pyrrolidinomethyl, piperidinomethyl, piperazinomethyl, morpholinomethyl, 2- (morpholino) ethyl and the like, and cyclic amino C1-4 alkyl.
• Noreamino groups include pyrrolidinomethine / 'reamino, pyridinomethylamino, pyrazinomethylamino, morpholinomethylamino, and halogen atoms such as fluorine, chlorine, and bromine.
• Nohonorekinore group or monophnore group diphnole group, trichnole group, 1-phnole group, 2 Phenoleochinole, Monochloromethinole, Dichloromethinole, Trichloromethinole, 1-Chlorochinole, 2-Chloroethyl, Bromomethinole, Iodomethinole, etc., and Cyano C i-4 ethyl groups such as cyanoethyl and 2cyanomethyl Carboxy-Ci-4 alkyl group is carboxymethyl, 1-carboxyethyl, 2-carboxystyl and the like, C i-8 alkoxy-carbonyl group is methoxycarbonyl, ethoxycanolebonii //, propoxycanoleboniz Les, Isof.
• Rho 1 "xycarbonyl, carbonyl, butoxycarbonyl, tert-butoxycarbonyl, isobornyloxycarbonyl, etc., C i- 8 alkoxy-carbocarbonyl C 1-4 alkyl groups and methoxycarbonylmethy Toxylcarbonylmethyl, tert-butoxycarbonylmethyl, etc., C 6 to 1.
• Aryl xyl alcohol group is phenoxycarbonyl, etc., C 3 to 6 cycloalkyl alcohol xylboninole group ⁇ cyclopropyl alcohol X-carbonyl, cyclohexyloxycarbonyl, etc., C-I 2 aralkyloxy-carboxyl group is a benzyl group, 'leboninole, etc., C 6 -i 0-ary Le group base Nzoiru, phthaloyl, full We two / Reasechiru etc., C 1 ⁇ 5
• C 2 ⁇ 5 alkanoylthio Honoré group is ⁇ Se butoxy, propionitrile Two, 'Reokishi, blanking Chirinoreokishi, etc. Pibaroi / Reokishi, C. 2 to 5 ⁇ Honoré Kano I Ruo carboxymethyl one C ⁇ . ⁇ 4 alkyl group ⁇ Se Toximeti, 1-Acetokischinore, 21-Acetokischinore, etc., C3-5 alkenoyloxy group is acryloyloxy, etc., C1-4 anolexyl- group is C1-4 anorecyl-methyl, etc., Substituting power rubamoyl group is N-methylcarbamoyl, N, N-methyl tylcarno; moyl, N-ethylcarbamoyl, N, N-getyl, molybdenum, N-phenylcanolenomoyl, pyridinoyl olevon
• the -12-aralkyloxycarbonylamino group represents benzyloxycarbonylamino and the like.
• OMPI Al constituting the Rarukiruokishi group, c 7 ⁇ 1 2 Ararukiruchio group, c 7 ⁇ 1 2 Ararukirua amino group, c 7 ⁇ 12 Ararukiruokin one carbonyl group, and c 7 ⁇ 1 2 ⁇ la Rukiruokishi Ararukiru groups, such as single carbonyl ⁇ amino group kill group may be substituted with one more C 6 ⁇ 10 Ariru group, specifically ⁇ Both or Benzuhi drill, Benzuhi de Riruokishi, Benzuhi de Riruchio, Benzuhi drill Rua Mino, Benzuhi drill O butoxycarbonyl Benzhydrylcarbonylcarbonylamino and the like. A plurality of these substituents may be the same or different and may be substituted.
• the 5- and 6-positions of the imidazole ring may be condensed with an alicyclic, aromatic or heterocyclic ring. Examples of these
• n O or 1.
• a carboquinol substituent at the 4-position indicates that the carboxylic group is a propyloxydione, which is paired with a positive charge on the substituent A to form an inner salt.
• compound [I] is physiologically It may be an acceptable salt or ester.
• Physiologically acceptable salts include inorganic salts, ammonium salts, organic salts, inorganic acid addition salts, organic acid addition salts, and basic amino salts.
• An inorganic base capable of forming an inorganic salt is, for example, an alkali metal [eg, sodium or potassium such as J; an alkaline earth metal (eg, such as calcium ⁇ )]
• An organic base capable of forming an organic salt S3 ⁇ 4 is, for example, procaine.
• Inorganic acids that can form inorganic acid addition salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid nitrate.
• Organic acids that can form organic acid addition salts include, for example, P-toluenesulfonic acid, methanesulfonic acid, and the like. , Formic acid, trifluoroacetic acid, maleic acid, etc. For example, lysine, arginine, ordinine, histidine, etc. are opened.
• Compound! : I] means an ester that can be formed by esterifying a carboxyl group contained in a molecule, and is an ester usable as a synthetic intermediate and a metabolically unstable nontoxic ester.
• Esters usable as synthetic intermediates include C alkyl esters.
• alkenyl esters C 3 to 6 cycloalkyl esters, C 3 to 6 Shikuroa alkyl - ( ⁇ - alkyl esters' C 6 ⁇ 10 ⁇ reel esters, C 7 ⁇ 12 ⁇ La alkyl ester, substituted Siri, Reesuteru and Gerare, it may be further substituted.
• specific examples thereof include methyl as alkyl to form the C t ⁇ 4 alkyl esters, Echiru, propyl, butyl, tert- butyl and the like, the C. 2 to 4 alkenyl esters
• Specific examples of the alkenyl to be formed include vinyl, aryl and isopropyl, and C 3 to 6 cycloalkyl.
• OMPI Specifically, click port propyl as consequent opening alkyl which forms Kill ester, evening Robuchiru, ⁇ Kuropenchiru, and cyclohexyl, and alkyl to form a C 3 ⁇ 6 click port alkyl one C i to 4 alkyl esters cyclohexylmethyl and Te to consequent opening propyl methyl Sik port Specifically, C 6 ⁇ 10 ⁇ Li - the specifically ⁇ re Ichiru forming the glycol ester Hue - Le etc., C 7 ⁇ 1 2
• Specific examples of aralkyl for forming an aralkyl ester include benzyl and phenethyl, and specific examples of substituted silyl for forming a substituted silyl ester include trimethylsilyl and tert-butyldimethylmethyl.
• alkyl constituting the aralkyl ester may be substituted with one or two C 6 -lflaryl , and specific examples include a benzylhydryl ester and a trityl ester. .
• non-toxic esters that are metabolically unstable those already established in the fields of ⁇ niline and cephalosporin can be conveniently employed in the present invention.
• the compound [I] of the present invention has broad spectrum antibacterial activity and can be used for the prevention and treatment of various diseases caused by pathogenic bacteria in humans and animals, for example, respiratory tract infection and urinary tract infection. .
• the features of the antibacterial spectrum of compound [I] include the following.
• Gram-positive bacteria eg, Staphylococcus aureus, Corynepacterium diphtheria
• amino acids belonging to the genus Eudomonas amino acids such as amikacin and gentamicin have been used.
• Compound [I] only shows antibacterial activity comparable to these amino acids. It has significant advantages because it is much less toxic to humans and animals than aminoglycosides.
• a ' represents an imidazole which forms a condensed ring at the optionally substituted 2,3- or 3,4-position] or a salt thereof;
• Ri has the same meaning as defined above, and the compound [1] can be produced by reacting with a compound represented by the following formula or, if necessary, removing the protecting group.
• the production methods (1) to (4), the method for removing the protecting group, and the method for purifying the compound [1] will be sequentially described. .
• a 7-amino compound [—] is acylated with a carboxylic acid [II] or a reactive derivative thereof.
• the carboxylic acid [H] 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 [I]. That is, free acid [I] or free acid! : H], an inorganic salt, an organic salt, an acid halide, an acid azide, an acid anhydride, a mixed acid anhydride, an active amide, an active ester, an active thioester, and other reactive derivatives are subjected to the acylation reaction.
• Potassium metal salts eg, sodium salt, potassium salt, etc.
• alkaline earth metal salts eg, calcium salt, etc.
• organic salts such as trimethylammine salt, triethylaminium salt, etc.
• Acid salts tert-butyldimethylamine, dibenzylmethylamine, benzyldimethylamine, N, N-dimethylaniline, pyridine, quinoline salts, and the like.
• an acid Puromai de is mono C i to 4 alkyl carbonate mixed acid anhydride is a mixed acid anhydride (e.g.
• C 7 to 1 1 aromatic carboxylic acid mixed acid anhydride for example a free acid [ ⁇ ] benzoic acid, Mixed acid anhydrides with P-toluic acid, P-chlorobenzoic acid, etc., and organic sulfonic acid mixed acid anhydrides (for example, methanesnolefonic acid, ethanesnolefonic acid, benzenesnolefonic acid, p-tonolenesulphonic acid)
• the active amides include amides (eg, free acid [M] with virazole, imidazole, benzotriazole, etc.) as active amides. With acid amide, These nitrogen-containing heterocyclic compounds C.
• active esters used for this purpose in the field of 3-lactam and peptide synthesis can be used as active esters, for example, organic phosphoric esters (eg ethoxylinyl ester, diphenyloxylinyl ester).
• the 7-amino compound [I] is used as a salt or ester as it is.
• the salt of compound [H] include inorganic base salts, ammonium salts, organic base salts, inorganic salt addition salts, and organic salt addition salts.
• Inorganic base salts include alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salts), and organic base salts include, for example, trimethylamine salt and triethylamine salt. , Tert-butyldimethylamine, dibenzylmethylamine, benzyldimethylamine, N, N-dimethylaniline, pyridine, quinoline, and the like.
• inorganic acid addition salts include hydrochloride and odorant.
• Hydrocarbonates, sulfates, nitrates, phosphates, etc., and organic acid addition salts include formate, acetate, trifluorate, methane-sulfonate, p-toluenesulfonate, etc. can give.
• Compound ! The esters already mentioned as the ester derivative of compound [I] as the ester of : :) can also be used here as they are.
• C1-4 anolequinoleester C2-4 anolekeninoleestenole, Cg-6 cycloalkyl ester, C3-6 cycloalkyl—C1-4 alkyl Esters, C 6 to 1 0 ⁇ Li Ruesuteru, C 7 to 1 2 ⁇ Lal kill esters, C. 1 to 5 alkano Iruokishime Chiruesuteru, C.
• an appropriate condensing agent is used.
• the condensing agent include N, N-disubstituted carbodimids such as N, N-dicyclohexylcarbodiimide, for example, N, ⁇ '-force carbonylylimidazole, ⁇ , N'-thiocarbonyldiimidazole, and the like.
• Dehydrating agents such as diethoxycarbonyl-12-ethoxy-1,2, -dihydroxyquinoline, oxychlorine, alkoxyacetylene, etc., for example, 2 Odide and 2-fluoropyridinium salts such as 2-fluoropyridinium methyl iodide are used.
• these condensing agents are used, the reaction is thought to proceed via the reactive derivative of carboxylic acid [H].
• the reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
• a solvent examples include ethers such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropinole ether, ethyl glycol monomethyl ether, and esters such as ethyl formate, ethyl acetate, and butyl acetate.
• ethers such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropinole ether, ethyl glycol monomethyl ether, and esters such as ethyl formate, ethyl acetate, and butyl acetate.
• ethers such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropinole ether, ethyl glycol monomethyl ether, and esters such as
• WIPO ⁇ -Genated hydrocarbons such as methane, chloroform, carbon tetrachloride, trichlorene, 1,2-dichloroethane, and hydrocarbons such as n-hexane, benzene, and toluene.
• amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetate, ketones such as acetate, methylethylketone, methylisobutylketone, etc.
• Nitrites such as acetonitrile and propionitrile, cadmium thioresulfoxide, sulfolane, hexamethyl phosphoramide, water, etc. are used alone or as a mixed solvent.
• the amount of the acylating agent [I] to be used is generally 1 to 5 mol, preferably 12 mol, per 1 mol of compound [H].
• the reaction is carried out in a temperature range from 180 to 80 ° C, preferably from 140 to 50 ° C, most preferably from 130 to 30 ° C.
• the reaction time depends on the type of the compounds CH] and [HI], the type of solvent (and the mixing ratio if a mixed solvent is used), the reaction temperature, etc., and is usually 1 minute to 72 hours, preferably 15 minutes. ⁇ 3 hours.
• the reaction can be carried out in the presence of a deoxidizing agent for the purpose of removing released hydrogen hydride from the reaction system.
• Examples of such a deoxidizing agent include inorganic bases such as sodium carbonate, calcium carbonate, calcium carbonate, sodium hydrogencarbonate, etc., for example, triethylamine, tripropylamine, tributylamine, cyclobutylamine. Tertiary compounds such as hexyldimethylamine, pyridine, lutidine, r-colysine, N, N-dimethylaniline, N-methylpyridinine, N-methylbiphenyl, N-methylmorpholine And alkylene oxides such as propylene oxide and epichlorohydrin.
• inorganic bases such as sodium carbonate, calcium carbonate, calcium carbonate, sodium hydrogencarbonate, etc.
• triethylamine, tripropylamine, tributylamine, cyclobutylamine Tertiary compounds such as hexyldimethylamine, pyridine, lutidine, r-colysine, N, N-dimethylaniline,
• R 5 represents a hydroxyl group, an acyloxy group, a rubamoyloxy group, a substituent rubamoyloxy group or a halogen atom.
• Ashiruo alkoxy groups optionally substituted C 2 ⁇ 5 Arca noisy Ruo alkoxy group or,
• C 6-10 ary represents a monosulfoxy group, optionally substituted
• 2 to 5 alkanoyloxy groups include acetoxy, chloroacetoxy, propionyloxy, butyryloxy, pyrryloxy, 3-oxobutyryloxy, 4-chloro-3-oxobutyryloxy, 3-carboxypropionyloxy, 4 monocarboxybutyryloxy, 3 —ethoxycarbamoylpropionyloxy and the like may be optionally substituted C 6- ⁇ ry-l-acyloxy groups, specifically, o-carboxybenzo. Examples include inoleoxy, o- (ethoxycanoleboninole), benzoinoleoxy, and 0— (ethoxycarbonylsnorefamoinole) benzoyloxy.
• rubamoyloxy group examples include methylcarba'moyloxy and N, N-dimethylcarnomoyloxy.
• Halogen atoms include chlorine, bromine and iodine.
• Compound [IV] can be used as it is as a salt or ester.
• salts and esters of the compound [ ⁇ ] those given as the salts and esters of the compound [B] in the production method (1) can be applied here as they are.
• imidazole compound A represents imidazole which forms a condensed ring at the optionally substituted 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. This condensed ring may be further condensed with another aromatic ring or an aromatic heterocycle.
• Optionally substituted 2, 3-position, or 3, 4 ones i to form a condensed ring imidazole (A) has the general formula:! ⁇ ') or (A 2']
• N J [A 2 ']
• 'a is A4 group of said At group, compound [IV] Compound Alpha 2' objective compound capable synthesis when reacted with compound [ff] and compound [ ⁇ ] reacting
• the human groups of the target compound [I] which can be synthesized in this case are the above two groups, respectively.
• the symbol B in the formulas of the condensed imidazoles ⁇ 'and A2' is the same as that mentioned above for B in the At group and A 2 group.
• N J _ ⁇ 0
• N J.
• substituents' and Ri 2 'on the compound A' those already mentioned as the substituents Ri 1 and Ri 2 of the group A can be directly applied here, respectively.
• the 5,6-position of the imidazole ring may be fused with an alicyclic, aromatic or heterocyclic ring. Examples of these are ,
• substituents Ri i ', R i 2 f may be further substituted.
• Compound A! Is also used as a salt.
• Salts of compound A! include, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like, for example, formate, acetate, trifluoroacetate, methansulfone, and the like. Acid salts, p-toluenesulfonic acid salts and other organic acid addition salts.
• the general synthesis method of compound A ' is known and can be easily produced by a method described in a literature or a method analogous thereto.
• the present substitution reaction of compound [iy] with a compound is a reaction known per se, and is usually carried out in a solvent.
• Solvents used for this reaction include ethers, esters, hydrogen halides, hydrocarbons, amides, ketones, nitriles used in the production method (1). Although a solvent such as water is fit as it is, these Toebame Tano Lumpur was Besides, ethanol, Purobanoru, Sopurono ⁇ 0 Bruno Lumpur, E Ji glycol, 2 - also alcohols such as main butoxy ethanol Used 0
• a more preferred solvent is water or a mixed solvent of water and an organic solvent miscible with water, and among the organic solvents miscible with water, more preferred are acetone, methylethylketon, and acetonitrile. .
• the amount of the nucleophilic reagent A 'to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [].
• the reaction is carried out in a temperature range of 10 to 10 (C, preferably 30 to 8 (f C.)
• the reaction time depends on the type of compound [iy] and ⁇ ', and the type of solvent (or mixed solvent if mixed).
• the reaction time is usually 30 minutes to 5 days, preferably 1 to 5 hours, and the reaction is carried out at pH 2 to 8, preferably near neutral, ie, pH 5 to 8.
• the reaction is usually carried out
• O PI Proceeds more easily in the presence of 2-30 equivalents of iodide or thiocynate.
• salts include sodium iodide, potassium iodide, sodium thiocyanate, and potassium thiocyanate.
• quaternary hydroxides having surface active properties such as trimethylbenzylammonium bromide, triethylenolbenzilammonium bromide and trietinolevenzilammonium bromide are also available. In some cases, the reaction can be allowed to proceed smoothly by adding a graded ammonium salt.
• the reaction is carried out in the presence of an organic phosphorus compound according to a method described in Japanese Patent Laid-Open Publication No. 58-43979.
• organic phosphorus compound used herein include 0-phenylene phosphorochloride, 0-phenylene phosphorofluoride, methinole o-phenylene phosphate, and 0-phenylene phosphate and propynoleate.
• Phenylene phosphate Isopropyl 0—Phenylene phosphate, Butyl 0—Phenylene phosphate, Isobutynole 0—Phenylene phosphate, sec—Butinole 0—Phenylene phosphate, cyclohexynole 0—Phe Diene phosphate, phenylene 0-phenylene phosphate, p-cloth phenylene o-phenylene phosphate, p-acetinole phenylene 0-phenylene phosphate, 2—chloroethynole 0—phenylene Renphosphate, 2,2,2-trichloroethynole Dilen phosphate, ethoxy canolepo'-dinoleme chinole o-phenylene phosphate, canoleno ⁇ moylmethyl 0—phenylene phosphate, 2—cyano etizole 0—phenylene
• the solvent used in the reaction may be any solvent as long as it does not inhibit the reaction, and is preferably the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles and the like. Used alone or as a mixed solvent.
• favorable effects can be obtained by using, for example, dichloromethane, acetonitrile, formamide, a mixed solvent of formamide and acetonitrile, and a mixed solvent of dichloromethane and acetonitrile.
• the amounts of the nucleophile A 'and the organophosphorus compound used are 1 to 5 mol, 1 to 10 mol, more preferably 1 to 3 mol, and 1 to 1 mol, respectively, per 1 mol of the compound [IV]. 6 moles.
• the reaction is carried out at a temperature of 180 to 50 ° C, preferably 1 "to 40 to 40 ° C.
• the reaction time is usually 1 minute to 15 hours, preferably 5 minutes to 2 hours.
• An organic base may be added to the reaction system, such as triethylamine, tributylamine, dibutylamine, diisobutylamine, dicyclohexylamine, 2,6-lutidine. Amines such as etc.
• the amount of the base to be added is preferably 1 to 5 mol per 1 mol of the compound [W.
• Preferred solvents are the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water and the like.
• the amount of the nucleophile A 'to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [IV].
• 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 between 30 minutes and 15 minutes, preferably between 1 and 5 hours.
• the reaction can be carried out in the presence of a dehalogenating agent to promote the reaction.
• dehalogenating agents examples include the inorganic tertiary amines and alkylene oxides described in the section of the production method (1). Such deoxidizing agents are also mentioned here, but the nucleophile itself may act as a dehacogenating agent.
• the halogen atom represented by I is chlorine, bromine, iodine, etc., and is preferably iodine.
• the compound [] in which I is iodine can be produced, for example, by the method described in Japanese Patent Application Laid-Open No. 58-57390.
• This method is a method for synthesizing a compound [I] by reacting a compound represented by the general formula Rs'OH or a reactive derivative thereof with a hydroxyamino compound [V], and by a well-known etherification reaction. is there.
• 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 'OH is used as it is or as a reactive derivative thereof.
• the reactive derivative of R 3 'OH means a derivative of I' OH having a group leaving together with a hydrogen atom of the compound [V], that is, a compound represented by the general formula I'Y.
• the group Y released with a hydrogen atom represents a halogen atom, a sulfo group, a mono-substituted sulfonyl ⁇ , or the like.
• Halogen atoms include chlorine, bromine and iodine.
• Substituted sulfonino ⁇ is, for example, methanesulfonino ethanesulfoni.
• C1-4 diazoalkanes such as diazomethane and diazoethane, for example, dimethyl sulfate
• getyl DiCi-4 alkyl sulfuric acid such as sulfuric acid is also used.
• compound [V] is reacted with an appropriate dehydrating agent to synthesize compound [I:!.
• an appropriate dehydrating agent used for this purpose for example, examples thereof include phosphorus chloride, dialkyl thionyl chloride / dialkyl azodicarboxylate + phosphine, N,]> 1-zinc hexylcarbodiimide and the like, and preferably, acetyl diphenyl carboxylate + triphenylphosphine.
• Azojikarubon di Echiru + Application Benefits Fuweniruhosufu I. reactions using emissions are typically conducted in anhydrous solvents, the ethers, such as hydrocarbons are used.
• the reaction between R 3 ′′ Y and the compound [Y] is a usual etherification reaction, which is carried out in a solvent.
• the solvent include polyesters and esters mentioned in the section of the production method (1).
• mixed solvents such as halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water, etc., and preferably water-miscible solvents. (Eg, aqueous methanol, aqueous ethanol, aqueous acetate, aqueous dimethyl sulfoxide, etc.)
• bases include, for example, sodium carbonate and carbonate.
• OMPI Examples include alkali metal salts such as sodium hydrogen and potassium carbonate, and inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.
• this reaction PH 7.. 5 to 8. may be performed in a buffer solution of 5.
• the number of moles of the reagent R 3 ′ Y and the base used is 1 to 5, 1 to 10, preferably 1 to 3, and 1 to 5, respectively, per 1 mole of the raw material compound [V].
• the reaction temperature ranges from 130 to 100 ° C, preferably from 0 to 80 ° C.
• 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 diazoalgan compound is added.
• the reagent is used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound [V].
• the reaction is carried out at a relatively low temperature and is between 150 and 20 ° C, preferably between 130 and 0 ° C.
• the reaction time is 1 minute to 5 hours, 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 (a-2).
• This reaction is carried out, for example, in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.
• the reagent is a compound [ ⁇ ]
• the reaction temperature is between 2 and 100 ° C, preferably between 50 and 100 ° C.
• the reaction time is 10 minutes to 5 hours, preferably 30 minutes to 3 hours.
• the reaction is usually performed in a dish.
• the amount of the NH 2 is usually 1 to 5 moles relative to the compound 00, preferably 1 to 3 mol.
• Reaction is from 0 to: 100. C, preferably in the temperature range of 20 to 60 ° C.
• Reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours.
• the compound [I] is usually obtained as a mixture of syn [Z] mono and anti [E] mono isomers.
• a method known per se or a method analogous thereto is applied. Examples of such methods include a fractionation method utilizing differences in solubility and crystallinity, a separation method using chromatography, and a separation method utilizing a difference in the hydrolysis rate of an ester derivative.
• Protecting group removal method as described above—In the field of lactam and peptide synthesis, protecting groups for amino groups have been well studied and their protection methods have been established. In addition, the method for removing the amino-protecting group is similarly confirmed: Si, and in the present invention, the conventional technique can be used for removing the protecting group as it is. For example, a monohalogenoacetyl group (chloroacetyl, bromoacetyl, etc.) is treated with thiourea, an alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.) is treated with an acid, and an aralkyloxycarbonyl group (benzyloxy).
• a monohalogenoacetyl group chloroacetyl, bromoacetyl, etc.
• an alkoxycarbonyl group methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.
• Xyloxycarbonyl, p-methisolebenzyloxycarbonyl, ⁇ 12-nitrobenzyloxycarbonyl, etc. can be removed by catalytic reduction, and 2,2,2-trichloroethoxycarbonyl can be removed by zinc and acid. it can.
• the ester residue can be removed by a method known per se. For example, 2-methylsulfonylethyl ester is converted to alkali, and aralkyl esters (benzyl ester, p-methoxybenzylester, p-nitrobenzyl ester, etc.) are converted to acid or catalytic reduction.
• 2,2-Tricycloethyl ester can be removed with zinc and acid, and silinole ester (trimethylsilyl ester, tert-butyldimethylsilyl ester, etc.) can be removed with water only.
• Purification method of compound [1] The compound [1] produced in the reaction mixture by various production methods detailed in (1) to ( 4 ) and, if necessary, by following the above-mentioned protective group removal method. ] Can be isolated and purified by known processing means such as extraction, column chromatography, precipitation, and recrystallization. On the other hand, the isolated compound [1] can be converted into a desired physiologically acceptable salt or a metabolically unstable nontoxic ester by a known method.
• Oxidizing agents suitable for the oxidation of sulfur atoms in the septum ring include, for example, oxygen, peracids, hydroperoxides, 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, dichloromethane, chloroform, and benzene, and the like, for example, formic acid, acetic acid, and the like. And organic acids such as trifluoroacetic acid, and amides such as dimethylformamide and dimethylacetamide.
• the above-mentioned oxidation reaction for obtaining the sulfoxide may be carried out before the reactions (i) to (4) or after the reactions (1) to (4).
• the compound [1] of the present invention can be used with known dinulin and cephalosporins.
• OMPI Similarly, it can be administered parenterally or parenterally as injections, capsules, tablets, or granules.
• the dosage is 0.5 to 80 days per body weight, more preferably 1 to 20 days per body weight of humans and animals infected with pathogenic bacteria as described above, and more preferably 1 to 20 days divided into 3 to 4 times a day. It may be administered.
• the carrier when used as an injection, for example, distilled water or physiological saline is used.
• a known pharmaceutically acceptable excipient for example, starch, lactose, sucrose, calcium carbonate, phosphoric acid, calcium, etc.
• binders eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.
• lubricants eg, Stear! / It is used as a mixture with magnesium phosphate, talc, etc., and a disintegrant (eg, carboxymethyl calcium, talc, etc.).
• Kieselgel 60 230 to 400 mesh
• XAD- ⁇ resin is from Rohm & Haas Co.
• NMR spectra are tetramethylsilyl as internal or external reference.
• Image 0 Dimethinoresnorreoxide (dimethyl sulfoxide)
• CDCI 3 Deuter ochloroform
• IR spectacle! -1 1770, 1710, 1620, 1520.
• reaction mixture was stirred at 20 C for 24 hours, and then a mixed solution of ethyl ether and petroleum ether (1: 1) (200 W) was added. After removing the ether layer, 50 »of water was added to the residue, and then the mixture was adjusted to pH with 10 ⁇ hydrochloric acid. When set to 4.0, crystalline powder is precipitated. This was collected, washed with water, washed with methyl ether, and dried to give the title compound 139.
• the imidazo [1,2a] pyridine derivative and the imidazo [1,5-a] pyridine derivative can be prepared by known methods [for example, WW Paudler and H. L-Blewi 11 J. Org. Chem. 30, 4081 ( 1965), JP
• the solvent is distilled off under reduced pressure.
• Acetonitrile 100 is added to the residue to solidify, and the powder is collected.
• the powder was subjected to silica gel column chromatography, and acetonitrile and water
• the residue is extracted four times with 50 parts each of a mixture of tetrahydrofuran and ethyl acetate (1: 1), dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. You.
• the residue was subjected to silica gel column chromatography, and eluted with a mixture of acetonitrile and water (: 9: 1; 3 – [(imidazo [1,2–a J pyridinidum 1-yl).
• IR z c-i 1765, 1610, 1535, 1035.
• Example 8 7 ⁇ -2-(2-aminothiazole-1-4yl)-2 (Z)-methoxyiminoacetamide]-3-[(6-chloroimidazo [1,2-a] pyri Gen 1-Inore) Mechinore 1-3-Sefmu 4-Canolepo'xile
• IR spectrum ⁇ ⁇ -1 1770, 1670, 1615, 1525.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Cephalosporin Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 1984
  • 1984-04-23 WO PCT/JP1984/000212 patent/WO1985004879A1/ja unknown
• 1985
  • 1985-04-18 AT AT8585104687T patent/ATE79882T1/de active
  • 1985-04-22 HU HU851546A patent/HU195966B/hu not_active IP Right Cessation
  • 1985-04-22 DK DK179985A patent/DK179985A/da not_active Application Discontinuation
  • 1985-04-23 ZA ZA853017A patent/ZA853017B/xx unknown
• 1987
  • 1987-09-29 MY MYPI87002280A patent/MY102089A/en unknown

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