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WO1991009860A1 - Nouveau derive de carbapenem - Google Patents

Nouveau derive de carbapenem Download PDF

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Publication number
WO1991009860A1
WO1991009860A1 PCT/JP1990/001720 JP9001720W WO9109860A1 WO 1991009860 A1 WO1991009860 A1 WO 1991009860A1 JP 9001720 W JP9001720 W JP 9001720W WO 9109860 A1 WO9109860 A1 WO 9109860A1
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Prior art keywords
group
hydrogen atom
coch
lower alkyl
compound
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English (en)
Japanese (ja)
Inventor
Susumu Nakagawa
Norikazu Otake
Koji Yamada
Ryosuke Ushijima
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MSD KK
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Banyu Phamaceutical Co Ltd
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Publication of WO1991009860A1 publication Critical patent/WO1991009860A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms

Definitions

  • the present invention relates to a novel compound (7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid) compound, a method for producing the compound and an active ingredient comprising the compound.
  • a novel compound (7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid) compound, a method for producing the compound and an active ingredient comprising the compound.
  • an antimicrobial agent As an antimicrobial agent.
  • Imidenem has antibacterial activity against various bacterial species at least as high as that of cenamycin. It retains sex and S-lactamase resistance, and its antibacterial activity is 2-4 times better, especially against Pseudomonas aeruginosa. In addition, the stability of imidenem as an aqueous solution and solid was significantly improved as compared to that of cenamycin.
  • imidenem like chenamycin, is degraded by DHP-I in the human kidney and cannot be used for urinary tract infections, but also exhibits nephrotoxicity due to degradation products. Therefore, imidenem cannot be administered alone and must be used in combination with DHP_IP and harmful agents such as cilastatin [Antimicrob. Agents Chemoter.]. 12 (Suppl D), 1 page (1983)]. In recent years, imidenem has been frequently used in the treatment and prevention of infectious diseases. . Imidenem has not shown a sufficient therapeutic effect on these resistant bacteria.
  • the compound of the present invention having an isooxazolidinylthio group or a birazolidinylthio group at the 2-position of the compound, which is a feature of the present invention is a novel compound not described in the literature, And in patent specifications, etc., are not disclosed at all and are not even suggested.
  • ⁇ -Lactam antibiotics have selective toxicity to bacteria only and have no effect on animal cells, so they are widely used as antibiotics with few side effects for the treatment of bacterial infectious diseases and have high utility. It is.
  • the present inventors have developed a novel drug Lubabe which has excellent antibacterial activity and is resistant to DHP-I. With the aim of providing nem compounds, intensive research was conducted. As a result, a new compound having a isoxazolidinylthio group or a birazolidinylthio group at the 2-position of the kerbaenem skeleton contains gram-positive bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. The present inventors have found that they have strong antibacterial activity against Gram-negative bacteria and also show excellent stability against DHP-I, and thus completed the present invention.
  • the present invention has the general formula
  • R is a hydrogen atom or a methyl group
  • R 1 is a hydrogen atom, a lower alkyl group, a lower alkanoinole group, a forminole group, a formimidoyl group, an acetimidoyl group, a imidino group, a prolyl group, or a compound represented by the following formula:
  • R 4 and R 5 represent a hydrogen atom or a lower alkyl group, or R 4 and R 5 together with an adjacent nitrogen atom form an aziridinyl group, an azetidinyl group, a pyrrolidinole group or a piperazinyl group
  • R 6 may be substituted by a hydroxyl group, a lower alkyl group or an aryl group
  • R 7 is a carboquinol group, a lower alkoxycarbonyl group, an aminocarbonyl group, an amino group, a lower alkylthio group or a guanidino group
  • R 8 Is a carboxyl group, lower alkoxycarbonyl group or aminocarboninole group
  • m is an integer of 0 to 3
  • n is an integer of 1 to 3
  • R 2 is a hydrogen atom, a hydroxy lower alkyl group Or the following formula
  • R 9 and R 1 represent a hydrogen atom or a lower alkyl group, or R 9 and R w together with an adjacent nitrogen atom form an aziridinyl, azetidinyl, pyrrolidinyl or piperidyl group, and n A has a methylene group or a carbonyl group
  • B is an oxygen atom or a formula> NR 3 (where R 3 is a hydrogen atom, a lower alkyl group, a lower alkanol group, a formizole group) , Holm imino Doyle group, Asetoimi Doyle group, amidino group, prolyl group or the following formula i) - CO (CH 2) m N / R4 z R s
  • R 4 , R 5 , R 6 , RR m and n have the same meanings as described above
  • R, R 2 and R 3 are both hydrogen Or a pharmaceutically acceptable salt or ester thereof, a method for producing them, and an antibacterial agent containing them as an active ingredient.
  • R 100 is a hydrogen atom, a lower alkyl group, a formimidoyl group, an acetate dinole group, an amidino group, a prolinole group, or the following formula:
  • R 4 ° and R 5 ° represent a hydrogen atom or a lower alkyl group
  • R 6 , R and n has the above-mentioned meaning
  • R and R 2 have the above-mentioned meanings].
  • R, II 1 , R 3 and A have the above-mentioned meanings (excluding the case where R 1 and R 3 are both hydrogen atoms)].
  • the compound of the present invention has a basic structure
  • the present invention encompasses optical isomers and stereoisomers based on the asymmetric carbon atoms at positions 1, 5, 6, and 8 of the carbane skeleton, and preferred compounds among these isomers include: (5i?, 6S) configuration (5,6- (5R.6S.8R), or a compound with a methyl group at position 1 (1R, 5S, 6S, 8R) Compounds can be mentioned.
  • the compounds of the present invention have stereoisomers based on the asymmetric carbon atom of the isoxazolidinylthio group or the vilazolidinylthio group, which is the 2-position side chain of the carbane skeleton. Included within the scope of the invention.
  • the lower alkyl group means an anoalkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a ri-butyl group, and a methyl group, an ethyl group, and a propyl group are preferable. is there.
  • the lower alkanosole group means an acetyl group, a propionyl group, an acryloniole group, a propioloyl group, and the like.
  • the aryl group means a phenyl group, a naphthyl group or the like.
  • the lower alkoxycarbonyl group refers to an oxycarbonyl group substituted by the above-mentioned lower alkyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, ieri_butoxycarbonyl group. And a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group.
  • the lower anoalkylthio group refers to a thio group substituted by the above lower alkyl group, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a teri-butylthio group, and the like, and particularly, a methylthio group, an ethylthio group, Butylthio groups are preferred.
  • the hydroxy lower alkyl group refers to the above-mentioned lower alkyl group substituted by a hydroxy group, such as a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, an I-hydroquinpropyl group, and a 3-hydroxy group. And a propyl group.
  • a hydroxymethyl group and a 2-hydroxyethyl group are preferred.
  • R represents a hydrogen atom or a methyl group.
  • R 1 and R 3 is a hydrogen atom, a lower alkyl group, a lower Arukanoiru group, a formyl group, Horumuimi Doyle group, Asetoimi Doyle group, amidino group, the following formula was or prolyl group Roh R 6
  • R 4 and R 5 is a hydrogen atom or a lower alkyl group
  • R 4 and R 5 together with the adjacent nitrogen atom, form an aziridinyl group, Azechijiniru group, pyrrolidin Le group or piperazinyl group
  • R 6 is but it may also be substituted by hydroxyl, a lower alkyl group or Ariru group
  • R 7 is a carboxyl group, a lower an alkoxy carbonyl group, ⁇ amino carbonyl group, an amino group, a lower alkylthio group or Guanijino group
  • R 8 is carboxyl A lower alkoxycarbonyl group or an aminocarbonyl group
  • m represents an integer of 0 to 3
  • n represents an integer of 1 to 3].
  • R 1 and R 3 may be the same or different.
  • R 1 or R 3 include a hydrogen atom, a lower alkyl group, a lower alkyl group,
  • R 4 and R 5 represent a hydrogen atom or a lower alkyl group, or R 4 and R 5 together with an adjacent nitrogen atom represent an aziridinyl group, an azetidinyl group, and a piperidinyl group.
  • a m or a piperazinyl group, and m represents an integer of 0 to 3).
  • R 100 include a hydrogen atom or one CO (CH 2 ) n N (wherein
  • R 40 and R 5Q each represent a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 3.).
  • R 1 , R 3 or R 100 include a hydrogen atom, a methyl group, an ethyl group, an rt-butynole group, an aminocarbonyl group, an N-methylaminocarbonyl group, an N, N-dimethylaminocarbonyl group , 1-aziridinylcarbonyl group, 1-azetidinylcarbonyl group, 1-pyrrolidinylcarbonyl group, piperazinylcarboninole group, formimidoyl group, acetimidinole group, amidino group, prolyl group, glycyl group, 3 -Aranyl group, 4-aminobutyrinole group, sarkosyl group, N-dimethyldaricyl group, N, N-dimethyl-3-aralanyl group, N-methyl- -aralanyl group, 4- (aminomethyl) butyrinole group, aranyl group, 2 -Amin
  • a substituent derived from a natural amino acid is particularly preferable, and a glycyl group, a ⁇ -aralanyl group, a sarcosyl group, an N, N-dimethylglycyl group, an alanyl group, a seryl group, (3,4-dihydroxyphenyl)
  • a glycinole group, a -aspartinole group, a 4-methoxyaspaltoyl group, a methionyl group, an arginyl group and the like are preferable.
  • R 2 is a hydrogen atom, a hydroxy lower alkyl group or the following formula
  • R 9 and R 1Q represent a hydrogen atom or a lower alkyl group, or R 9 and together with an adjacent nitrogen atom form an aziridinyl, azetidinyl, pyrrolidinyl or piperidyl group, and n is 1 to Represents an integer of 3] Means a group.
  • R 2 include a hydrogen atom or one of CON ′, 3 ⁇ 4 ⁇ [wherein R g and
  • R 1Q has the above-mentioned meaning.
  • R 2 include a hydrogen atom, a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, an aminocarbonyl group, an N-methylaminocarboninole group, an N-dimethylaminocarbonyl group, and a 1-azine Lysinylcarbonyl group,
  • 2-aminoaminocarbonyloxyethyl 2- (N-methylaminocarbonyl) ethyl, 2- (NN-dimethylaminopropyl) ethyl, 2- (1-aziridinylcarbonyloxy) ethyl Group, 2- (1-azetidinylcarbonyldioxy) ethyl group, 2- (topyrrolidinylcarbonyloxy) ethyl group, 2-piperidinocarbonyloxyshethyl group, 3-amino Carbonyloxypropyl group, 3-
  • (N-methylaminocarbonyloxy) propyl group, 3- (N, N-dimethylaminopropylonyloxy) propyl group and the like are preferable, and preferable ones are a hydrogen atom, a hydroxymethyl group, an aminocarbonyl group, an I- ⁇ Diridinylcarbonyl group, 1-azetidininolecarbonyl group, 1-pyrrolidinylcarbonyl group, piperidinocarbonyl group, aminocarbonylmethyl group, N-methylaminocarbonylmethyl group, N, N- Dimethylaminocarbonylmethyl group, 1-aziridinylcarbonylmethyl group, 1-azetidinylcarbonylmethyl group, 1-pyrrolidinylcarbonylmethyl Group, piperidinocarbonylmethyl group, 2-aminocarbonylethylesole group, 2- (N-methylaminocarbonyl) ethyl group, 2- (N, N-dimethylaminocarbodizole)
  • R 11 represents a hydrogen atom or a protecting group for a carboxy group.
  • the protecting group for the carboxyl group include lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and ri-butyl group; for example, 2,2,2-trichloroethyl group, 2,2, Halo-substituted lower alkyl groups such as 2-trifluoroethyl group; lower groups such as acetoxmethyl group, propioninoleoxymethyl group, pivaloneoleoxymethyl group, 1-acetoxethyl group and 1-propionyloxethyl group; Alkyloxyalkyl groups: lower alkoxycarbonyl groups such as 1- (methoxycarbonyloxy) ethyl group, tri (ethoxycarbonyloxy) ethyl group, 1- (isopropoxycarbonyloxy) ethyl group and the like.
  • Xyalkyl group for example, 2-propenyl group, 2-chloro-2-propenyl group, 3-methoxycarbonyl-2-propininole group, 2-methyl-2-pro- Lower alkenyl groups such as ⁇ ninole group, 2-butenyl group and cinnamyl group; for example, benzyl group, P-methoxybenzyl group, 3,4-dimethoxybenzinole group, 0-nitrobenzinole group, -nitrobenzinole group
  • An aralkyl group such as a benzhydrinole group or a bis (/)-methoxyphenyl) methyl group; for example, a (5-) group such as a (5-methylino-2-oxo-1,3-dioxo-1-yl) methyl group; Substituted-2-oxo-1,3-dioxo-1-yl) methinole group; lower alkylsilyl group such as trimethyl
  • R 12 represents a hydrogen atom or a protecting group for a hydroxyl group.
  • the protecting group for the hydroxyl group include lower alkyl groups such as trimethylsilyl group and ieri-butyldimethylsilyl group.
  • a lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydroviranyl group; a benzyl group, a ⁇ -methoxybenzyl group, a 2,4-dimethoxybenzyl group;
  • An aralkyl group such as a -nitrobenzyl group, a p-nitrobenzyl group or a trityl group; an acyl group such as a formyl group or an acetyl group; an ri-butoxycarbonyl group or a 2--3-ethyloxycarbonyl group;
  • Lower alkoxycarbinole groups such as 2,2,2-trichloroethy
  • R 13 , R 21 , R 31 , R 41 , R 51 , R 71 , R 81, and R ′′ ° are the aforementioned R ′, R 2 , R 3 , RVR 5 , Included in the definitions of R 7 and R 8 respectively are the amino, imino and hydroxyl groups and isoxazozo in R 13 , R 21 , R 31 , R 41 , R 5i , R 71 , R 81 and R 110.
  • the nitrogen atom on the lysine ring must be protected by reaction conditions and the like.
  • Examples of the protecting group for the amino or imino group include benzylidene, /)-chlorobenzylidene, -nitrobenzylidene, salicylidene, na-naphthylidene, and 3-naphthylidene;
  • benzyl group -methoxybenzyl group, 3,4-dimethoxybenzyl group, 0-nitrobenzyl group, nitrobenzyl group, benzhydrisole group, bis ( ⁇ -methoxyphenolene) methinole group, etc.
  • An aralkyl group for example, a lower alkanoinole group such as a forminole group, an acetyl group, a propionyl group, a butyrinole group, an oxalyl group, a succinyl group, a bivaloyl group; Halo-substituted lower alkanoyl groups such as o-acetyl group; for example, phenylacetinole group, phenol ⁇ Li one Ruarukanoinore groups such Asechinore group; e.g.
  • main preparative alkoxycarbonyl group E butoxycarbonyl group, a propoxycarbonyl group, Ieri - lower alkoxycarbonyl group such as a blanking butoxycarbonyl group; for example 2- Yodoechi Halo-substituted lower alkoxycarbinole groups such as oxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propeninoleoxy Carbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group, 2-butenyloxycarbinole group, cinnamyloxycarbonyl group, etc.
  • Alkenyloxycarbonyl group for example, benzyloxycarbonyl group, 0-nitrobenzyloxycarbonyl group, -nitrobenzyloxycarbonyl group, phenylalkyloxycarbonyl group such as phenyloxycarbonyl group; for example, trimethylsilyl And lower alkylsilyl groups such as tert-butyldimethylsilyl group, and particularly, 2-propenyloxycarbonyl.
  • Specific compounds having the general formula [I] include, for example, the following compounds.
  • the compound of the general formula [I] can be converted into a pharmaceutically acceptable non-toxic salt or ester by a conventional method.
  • the non-toxic salt of the compound of the general formula [I] means a conventional pharmaceutically acceptable salt, and means a carboxyl group at the 3-position of the carbenem skeleton or an isoxoxazolidine ring or virazolidine at the 2-position side chain. salts can be mentioned at the carboxyl group or Amino group substituted on salifiable nitrogen atom or R ⁇ R 2 or R 3 on the ring.
  • Examples of the basic addition salt at the carboxyl group include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as potassium salt and magnesium salt; ammonium salt; trimethylamine salt Aliphatic amine salts such as triethylamine salt, dicyclohexylamine salt, ethanolamine salt, genoleamine salt, triethanolamine salt and procaine salt; for example, NV * -dibenzylethylenediamine and the like.
  • Aralkylamine salts for example, aromatic heterocyclic amide salts such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt; for example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium ⁇ salt, benzyltributylammonium salt Methyl trioctyl ammonium Niu arm salts, quaternary Anmoniumu salts such as tetramethylammonium Petit Ruan monitor ⁇ unsalted; e.g. arginine salt, basic amino acid salts such as lysine salts.
  • aromatic heterocyclic amide salts such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt
  • tetramethylammonium salt tetraethylammonium salt
  • benzyltrimethylammonium salt benzyltriethyl
  • Examples of the acid addition salt at the nitrogen atom capable of forming a salt on the isoxazolidine ring or villazolidine ring or at the amino group substituted with R 2 or R 3 include, for example, hydrochloride, sulfate, nitrate, phosphate, Inorganic acid salts such as carbonates, bicarbonates and perchlorates; for example, acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbic acid Organic salts such as salts; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; acidic amino acids such as aspartate and glutamate And the like.
  • the non-toxic ester of the general formula CI] includes a carboxyl group at the 3-position of the carbane skeleton or a drug at the carboxyl group substituted for RR 2 or R 3 on the isoxazolidine ring or villazolidine ring at the 2-position. Means the conventional ones permitted above.
  • an ester with an alkanoyloxymethyl group such as an acetooxymethyl group or a bivaloyloxymethyl group, 1- (ethoxycarbonyloxy) C) an ester with an alkoxycarbonyloxyalkyl group such as an ethyl group, an ester with a phthalidyl group, or a .5- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group; -Substituted-2-oxo-1,3-dioxomono-4-ynole) Ester with methyl group.
  • an alkanoyloxymethyl group such as an acetooxymethyl group or a bivaloyloxymethyl group, 1- (ethoxycarbonyloxy) C) an ester with an alkoxycarbonyloxyalkyl group such as an ethyl group, an ester with a phthalidyl group, or a .5- (5-methyl-2-o
  • the compound of the general formula [I] of the present invention has the general formula
  • R represents a hydrogen atom or a methyl group
  • R 11 represents a hydrogen atom or a carboxyl group protecting group
  • R 12 represents a hydrogen atom or a hydroxyl group protecting group
  • R 21 is a hydrogen atom, an optionally protected hydroxy lower alkyl group, or a compound represented by the following formula 9:
  • R 9 and R 1 represent a hydrogen atom or a lower alkyl group, or R 9 and R ′ ° together with an adjacent nitrogen atom form an aziridinyl group, azetidinyl group, pyrrolidinyl group, or pyridyl group.
  • ⁇ represents an integer of 1 to 3
  • R "° represents a hydrogen atom, a protecting group for an imino group, a lower alkyl group, a lower alkanoyl group, a formyl group, or a formyl group which may be protected.
  • R 13 is a hydrogen atom or a protecting group for an amino or imino group
  • R 41 and R 51 are a hydrogen atom, a lower alkyl group or a protecting group for an amino group or an imino group, or R 41 and R 51 are Together with an adjacent nitrogen atom, forms an aziridinyl, azetidinyl, pyrrolidinyl or optionally protected piperazinyl group
  • R 61 is a lower alkyl group optionally substituted by an optionally protected hydroxyl group
  • R 71 is a carboxyl group which may be protected, a lower alkoxycarbonyl group, an aminocarbonyl group, an amino group which may be protected, a lower alkylthio group or a guanidino group which may be protected
  • R 81 is a protected or unprotected carboxyl group, a lower Arukokishikarupo Nirumotoma other aminocarbonyl group
  • m is 0
  • R 11D and R 31 are each a hydrogen atom or a protecting group for an imino group, and R 21 is a hydrogen atom, and A is a methylene group.
  • R, n . R 12 , R 21 , R u A and B have the above-mentioned meanings]. If necessary, the protecting group of the compound of the general formula [IV] is removed. It can be manufactured in some cases.
  • R, R 11 and R 12 have the above-mentioned meanings, and Y represents a leaving group].
  • Examples of the inert organic solvent used in the reaction include getyl ether, tetrahydrofuran, dioxane, benzene, tonoleene, chlorobenzene, dimethylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, and acetone.
  • Examples of the base used in the reaction include trimethylamine, triethylamine, -diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, ⁇ , ⁇ -dimethylazine, 1,8 Tertiary aliphatic amines such as -diazavicik mouth [5.4.0] pendant-7-ene (DBU), 1,5-diazabicyclo [43.0] non-5-ene (DBN); for example, pyridine, 4- Examples thereof include aromatic amines such as dimethylaminopyridine, purine, lutidine, quinoline, and isoquinoline, and N-diisopropinoleethylamine and triethylamine are particularly preferable.
  • Examples of the activating reagent used in the reaction include trifluoroacetic anhydride, methanesulfonic anhydride, trifluorosulfonic methanesulfonic anhydride, and P-toluene.
  • Acid anhydrides such as sulfonic anhydride
  • acid chlorides such as methanesulfonyl chloride, P-toluenesulfonyl chloride, diphenyl chloride and the like, and diphenylchlorophosphate is particularly preferred.
  • the group ⁇ in the general formula [ ⁇ '] represents a leaving group, for example, trifluoroacetoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, diphenyl And a nonoxyphosphoryloxy group.
  • a diphenyloxyphosphoryloxy group is particularly preferable.
  • 1 to 3 bases preferably 1 to: 0.5 mol of the base and 1 to 1.2 mol of the activating reagent are used per 1 mol of the compound of the general formula [[].
  • the reaction is carried out at a temperature of 40 to 50 ° C, preferably at a temperature of 120 to 2 (TC
  • reaction is carried out according to a conventional method to quantitatively obtain the reactive derivative [ ⁇ ′] of the general formula [I].
  • the compound of the general formula [ ⁇ ′] can be isolated or reacted without isolation with the compound of the general formula [m].
  • the reaction is carried out using the above-mentioned inert organic solvent and a base, and 1 to 2 mol of a base, preferably 1 to 1.5 mol, and 1 to 1.5 mol of a compound represented by the general formula [m 1 to 1.2 mol is used in a temperature range of -40 to 50 ° C, preferably -20 to 20 ° C, and is usually quantitatively completed in 0.5 to 3 hours.
  • the compound of the general formula [IV] can also be produced in one step from the compound of the general formula [H]. That is, without isolating the reactive derivative of the general formula [ ⁇ '] derived from the compound of the general formula [H], the compound of the general formula [m] is reacted in the same reaction system to obtain the compound of the general formula [IV] ] Can be efficiently produced.
  • 2 to 4 moles, preferably 2.5 to 3.5 moles of a base are used per 1 mole of the conjugate of the general formula [ ⁇ ].
  • the crude product represented by the general formula [IV] can be subjected to deprotection reaction without purification by performing a usual treatment, but the crude product [IV] is crystallized or purified. Purification by column chromatography using silica gel or the like is preferred.
  • the compound of the general formula [IV] thus obtained can be subjected to a removal reaction of a protecting group for a hydroxyl group, an amino group, an imino group and a carboxyl group, if necessary, by appropriately combining the removal reaction.
  • the compound of the formula [I] can be obtained.
  • the removal of the protecting group varies depending on the type thereof, but is carried out in accordance with a conventional method, for example, by solvolysis, ionic reduction or hydrogenation.
  • the protecting group for the hydroxyl group and the Z or amino or imino group is, for example, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a nitrobenzyloxycarbonyl group;
  • the protecting group for the nore group is, for example, an aralkyl group such as a benzene group, a nitrobenzyl group or a benzhydryl group, a platinum catalyst such as platinum oxide, a platinum wire or platinum black;
  • the protective group can be removed by catalytic hydrogenation using a palladium catalyst such as palladium, norudium monocarbon, and palladium hydroxide monocarbon.
  • Examples of the solvent used for the catalytic hydrogenation reaction include methanol, ethanol, tetrahydrofuran, dioxane, acetic acid and the like, or a mixed solvent of these organic solvents with a water or phosphate buffer and the like.
  • the reaction is completed in 0.5 to 4 hours in a temperature range of 0 to 50 ° C under a hydrogen gas stream of 1 to 4 atm.
  • the protecting group for the hydroxyl group and Z or the amino or imino group is, for example, an arinoleoxycarbonyl group and the protecting group for the carboxyl group is, for example, an aryl group
  • the protective group can be removed by reacting an organic soluble palladium complex catalyst in an inert organic solvent containing a scavenger [McCombie et al., The Journal of Organic Chemistry (J. Org. Chem.), 47, 587-590 (1982)].
  • Examples of the solvent used for the reaction include acetone, getyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, methylene chloride, chloroform and the like, or a mixed solvent thereof.
  • Examples of the soluble palladium complex include tetrakis (triphenylphosphine) palladium.
  • Examples of the scavenger for an aryl group include sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, pyrrolidine, piperidine, and tributyltin hydride.
  • the reaction is performed using a catalyst of 0.01 to 0.5 mol and a nucleophile of 1 to 6 mol with respect to 1 mol of the compound of the general formula [IV], in a temperature range of 1 to 50 ° C, preferably 0 to 30 ° C. Temperature It takes about 0.5 to 3 hours.
  • the protecting group for the hydroxyl group or the amino or imino group is 0-nitrobenzyloxycarbonyl group
  • the protecting group for the carboxyl group is 0-nitrobenzyl group.
  • the protecting group can be removed by a photoreaction [Amit et al., The Journal of Organic Chemistry, Vol. 39, pp. 192-196 (1974). ) See].
  • the compound of the general formula [I] is subjected to an ordinary treatment method, for example, column chromatography using a silica gel or an adsorption resin, and freeze-drying or crystallizing.
  • an ordinary treatment method for example, column chromatography using a silica gel or an adsorption resin, and freeze-drying or crystallizing.
  • the compound can be isolated.
  • the protective group for the carboxyl group at the 3-position of the compound of the general formula [IV] may be, for example, a lower alkenyloxy group such as an acetomethyl group or a bivaloyloxymethyl group; for example, a methoxymethyl group, indanyl group, In the case of a group or the like, such an ester is physiologically hydrolyzed in vivo, and thus can be directly administered to a human or animal without removing the protecting group.
  • the compounds of the present invention exhibit strong antibacterial activity against various Gram-positive and Gram-negative bacteria.
  • the antibacterial activity of the compound of the present invention exemplified in the examples as a representative example thereof was determined by the method of Bauer et al. [The American Journal of Clinical Immunol. The measurement was carried out by a disk diffusion test according to Sorodi (Amer. J. Clin. Pathol.), Vol. 45, p. 493 (1966)]. Chenamycin or imidenem was used as an internal standard.
  • the MIC of the test compound was calculated using the formula reported by Humphrey and Lightbown from the block diameter produced by the disc containing the test compound [The Journal of General Microbiology (J Gan. Microbiol.), Volume 7, 129 (1952)]. Calculate geometrical average of MIC for each bacterial species and calculate activity ratio with chenamycin did.
  • the compound of the present invention has excellent antibacterial activity against various gram-positive bacteria and gram-negative bacteria, and is useful as an antibacterial agent in the treatment and prevention of human bacterial infections caused by these pathogenic bacteria.
  • Representative pathogens susceptible to the antibacterial agents of the present invention include, for example, Staphylococcus spp., Enterococcus spp., Escherichia spp., Enterobacter spp. Bacteria such as the genus Tia (Sia tia), the genus Proteus, and the genus Pseudomonas can be mentioned. Particularly, methicillin-resistant phycococcus varus (Methicillin resistant) is mentioned. Staphylococcus aureus) and cheenamycin resistant Pseudomonas aeruginosa.
  • the compound of the present invention which differs depending on each compound, is extremely stable to DHP-1, and has excellent physical stability and solubility in water.
  • the compound of the present invention is mixed with a solid or liquid excipient carrier known in the art, It can be used in the form of pharmaceutical preparations suitable for parenteral, oral and external administration.
  • the main ones are topical or parenteral (intravenous or intramuscular) administration by injection.
  • the pharmaceutical preparation include liquid preparations such as injections, syrups and emulsions; solid preparations such as tablets, capsules and granules; and external preparations such as ointments and suppositories.
  • These preparations may optionally contain commonly used additives such as bases, auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants and the like.
  • the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn hard powder, magnesium stearate, talc and the like.
  • the dosage depends on the patient's condition, body weight, age, sex, dosage form, number of administrations, etc., but usually the preferred daily dose for adults is about 5 to 50 mg Zkg of the active ingredient, and the preferred daily dose for children The dose ranges from about 5 to 25 mg / kg and is preferably administered once or several times a day.
  • the compound of the present invention can be optionally treated with cilastatin [(Z) -7- (L-amino-2-carboxhetylthio) -2- (2,2-dimethylcyclopropanecarboxamide) -2-heptoenoate ] And other DHP-IP [Japanese Patent Application Laid-Open No. 56-81518, European Patent Application No. 28,778, Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 30, p. 1074 (1987 )].
  • the NMR spectrum is determined using tetramethylsilane (TMS) as an internal standard when measuring with heavy dimethyl sulfoxide or heavy chloroform solution, and 2,2-dimethyl-2-silapentane when measuring with heavy aqueous solution.
  • TMS tetramethylsilane
  • DSS 5-sulfonate
  • XL-200 200 MHz; Varian
  • R-40 90 MHz; daily
  • Aryl--trihydroxyethyl] -2-oxo-tribasic ruvapenam -3-carboxylate 360 mg, 1.42 mmo ⁇
  • acetonitrile 15 ⁇ ⁇
  • immediately-di- Sopropylethylamine 0.43m, 4.27mmoi
  • diphenylchlorophosphite 0.25m, 1.57mmoi
  • IR KBr 1770, 1720, 1450, 1380, 1320, 1210
  • reaction solution was stirred for 30 minutes under ice-cooling, and further for 30 minutes at room temperature. Under ice-cooling, a 0.5 M 2-ethylhexanoic acid-ethyl acetate solution (2.35 mi L175 mmo) was added dropwise to the reaction mixture. After the reaction solution was stirred for 20 minutes under ice cooling, the precipitate was collected by filtration. Water (1 ⁇ ) was added to the precipitate, and the insolubles were removed by filtration. The filtrate was subjected to reverse phase column chromatography (LC-SORB® SP-B-ODS), and eluted with water to give the title compound (176 mg, yield: 48.8%).
  • LC-SORB® SP-B-ODS reverse phase column chromatography
  • Aryl (li?, 5S, 6S) -6-[(i?)-: I-hydroxyethyl] -trimethyl-2-oxo-1-canolebabenam-3-carboxylate 300 mg, 1.12 mmo
  • the same reaction as in Example 1) was performed using N- (N-peryloxycarbonylglycyl) -4-mercaptoisoxazolidine (300 mg, 1.22 mmo; the compound of Reference Example 8).
  • the compound (67 mg, O.lOmmoi) obtained in the above reaction was added to a mixture of tetrahydrofuran (6.7 mO, 0.1 M 3- (monorefolino) propanesulfonic acid buffer (pH 6.5, 6.7 ml) and ethanol (0.67 mi).
  • the catalyst was catalytically reduced for 2 hours at room temperature using 10% palladium on carbon catalyst (70 mg) After filtering off the catalyst, the filtrate was washed with ethyl acetate and then concentrated under reduced pressure to about 3 ⁇ ⁇ . After subjecting to reverse phase silica gel chromatography (LC-SOLB® SP-B-ODS, 5% methanol), the target fraction was concentrated and lyophilized to give the title compound (33 mg , yield: 87%) I got
  • N-perinoleoxycarbinole-4-methanesulfonyloxyi-soxazolidin 700 mg, 2.79 mmoi
  • sodium iodide 400 mg, 2.6 mmo
  • potassium thioacetate 480 mg, 4.2 mmc ⁇
  • ethyl acetate ethyl acetate (lOOmi) was added to the reaction solution, and the organic layer was washed with water (3 times) and saturated saline.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was subjected to silica gel column chromatography (Wakogel® C-300) and eluted with 10% ethyl acetate-hexane to give the title compound (333 mg, yield:
  • N- (N-aryloxycarbonylglycyl) -4-hydroxyisoxazolidin In a stream of nitrogen, carbonyldiimidazole (2.35 g, 14.4 mmol of N, N-dimethylformamide (25m>) was added to a solution of N-yl-linoleoxycarbonylglycine (2.0 g, 12.6 mmol) in tetrahydrofuran (25 mi). The solution was added dropwise at room temperature, and the solution was stirred at the same temperature for 1 hour.To the reaction solution was added triditylamine (1.74 mi, 12.5 mmo and 4-hydroxyisoxazolidine hydrochloride (l.Og, 7.97 mmo)).
  • the reaction solution was stirred at room temperature for 3 hours
  • the reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (200 mi)
  • the organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the residue was subjected to silica gel chromatography (Wakogel® C-300) and eluted with 3% methanol-chloroform to give the title compound (1.0 g, yield: 54.6 g). %).
  • Triethylamine (0.30m ⁇ , 2.16mmoi) was added to a solution of N- (N-aryloxycarbonylglycyl) -4-hydroxyisoxazolidinine (450mg, 1.96mmoi) in tetrahydrofuran (10mi) under ice cooling.
  • methanesulfonyl chloride (0.18m ⁇ , 2.32mmo) were added dropwise.
  • ethyl acetate 50mi was added to the reaction solution, and the organic layer was washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (560 mg, yield: 92.9%).
  • N_ (N-aryloxycarbonylglycyl) -4-methyl sulfonyloxyisoxazolidine 560 mg, 1.82 mmol of immediate-dimethylformamide (10 mi) solution in a nitrogen stream in a stream of nitrogen (136 mg, 0.91 mmoi) and potassium thioacetate (310 mg, 2.71 mmoi) were added, and this mixed solution was stirred for 5 hours at 60 ° C.
  • Methyl 3,4-0-isopropylidene-L-threonate [2.0 g, 10.5 strokes o; synthesized by The Journal Off, 'Organic Chem., 50, 3462 (1982)]
  • Trifle Enethylphosphine (3.31 g, 12.6 mmo ⁇ )
  • N-hydroxyphthalimid (2.05 g, 12.5 nuno)
  • tetrahydrofuran solution 40.0 mi
  • a tetrahydrofuran solution (10 mi) was added dropwise. The reaction was warmed to room temperature, stirred at room temperature for 1 hour, and then concentrated under reduced pressure.
  • the precipitated crystals were washed with ethyl acetate, separated by filtration, and the filtrate was again concentrated under reduced pressure.
  • the residue obtained is purified by silica gel column chromatography (Wakogel® C-300, ethyl ethyl hexane).
  • ONH-PNZ 1 A solution of methyl 3,4-Oisopropylidene-2-nitrobenzyloxycarbonylbonylamino) -L-erythreonate (9.6g, 24.9mmo) in metasodium solution (192mi) at room temperature with 6N sulfuric acid (8.3mi, 49.8mmoi), and the solution was added to 3.5 Stirred for hours.
  • the reaction solution was returned to room temperature, stirred for 1 hour, and pyridine was distilled off under reduced pressure.
  • the obtained residue was poured into saturated sodium bicarbonate water and extracted with ethyl acetate. and then drying the organic layer (MgS_ ⁇ 4), and enrichment residue by silica force gel strength column chromatography (Wakogel® C- 300, hexane 1 to acetic acid Echiru: 1). to give the target compound (9.5 g , Yield: 85%).
  • Triaryloxycarbonyl-3-birazolidinone (.62g, 9.53mmo) (DN 'N-dimethylformamide (17 ⁇ ⁇ ) solution in a nitrogen stream under anhydrous potassium carbonate (1.55 & 11.2mmo ⁇ ) and Methane (1.77m ⁇ 28.4mmoi) was added, and the mixture was stirred for 1.5 hours at 40 ° C. The reaction solution was concentrated under reduced pressure, and ethyl acetate (lOOrn ⁇ ) was added to the residue.
  • N-N-dimethylformamide of 1-arinolexy-propyl-4-methanesulfonyloquine-2-methyl-3-pyrazolidinone (580 mg, 2.08 mmoi) (10 m0 solution in a nitrogen stream at room temperature)
  • Potassium acetate 310 mg, 2.71 mmoi
  • the reaction solution was poured into ethyl acetate (50 mi)
  • the organic layer was washed with water (3 times) and saturated saline, and then dried over anhydrous sodium sulfate. And dried under reduced pressure And concentrated.
  • TBDMS-0 TBDMS-0.
  • reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with acetic acid Echiru. the organic layer was dried (MgSO 4), and concentrated under reduced pressure 4- (ri-butyldimethylcyclopropyl)-: I-methyl-2-nitrobenzyloxycarbonyl) villazolidine (555m) was obtained. Five)
  • reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate (20 mi), and extracted with methylene chloride (20 m ⁇ 2).
  • methylene chloride (20 m ⁇ 2).
  • the organic layer was dried (MgSO 4), and crude Bok Asechinore concentrated in vacuo - 2- (ieri- Butokishika carbonyl) -4- (ieri- butyldimethylsiloxy) was obtained Birazorijin (1.55 g).
  • N- ⁇ -Nitropentinoleoxycarbinole Oxalyl chloride (0.70mi, 8.1mmo and N-dimethylformamide (1 drop) in dimethyl chloride solution (13mi) of glycine (680mg, 2.7mmo) at room temperature The solvent was distilled off under reduced pressure, the residue was dissolved in benzene, and again distilled under reduced pressure (this operation was repeated three times).
  • reaction mixture was stirred under ice cooling for 30 minutes, and 4,6-dimethyl z-2- (4-ditrobenzinoleoxycarbonylthio) pyrimidine (0.97 g, 3.06 mmol) was added.
  • the reaction mixture was poured into 0.5N hydrochloric acid, extracted with methylene chloride, and the organic layer was dried (MgSOJ, concentrated under reduced pressure), and the obtained residue was subjected to silica gel gel chromatography (Wakogel).
  • the compound of the present invention is a novel compound not described in the literature, and has a gram of sensitivity and resistance.

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Abstract

Composé ayant la formule générale (I), ses sels et ses esters pharmaceutiquement acceptables, leur procédé de production et agents antibactériens qui contiennent ce composé comme ingrédient actif. Dans la formule (I), R représente hydrogène ou méthyle; R1 représente hydrogène, alkyle inférieur, alkanoyl inférieur, formyle, formimidoyl, acétimidoyl, diamidino, prolyle ou un des groupes (i), (ii), (iii) ou (iv); R2 représente hydrogène, hydroxy-(alkyle inférieur), ou un des groupes (v), (vi) ou (vii); A représente méthylène ou carbonyle; et B représente oxygène ou NR?3, où R3¿ représente hydrogène, alkyle inférieur, alkanoyl inférieur, formyle, formimidoyl, acétimidoyl, amidino, prolyle ou un des groupes (i), (ii), (iii) ou (iv), à condition que l'on exclue les cas où R?1, R2 et R3¿ représentent tous des atomes d'hydrogène et A représente méthylène.
PCT/JP1990/001720 1989-12-28 1990-12-27 Nouveau derive de carbapenem Ceased WO1991009860A1 (fr)

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JP34269489 1989-12-28
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JP10424990 1990-04-18
JP2/104249 1990-04-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0617036A3 (fr) * 1993-03-16 1998-01-14 American Cyanamid Company Composés de carbapénème substitués sur la position 2

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5533494A (en) * 1978-08-25 1980-03-08 Beecham Group Ltd Betaalactum antibacterial*its manufacture and composition
JPS5832879A (ja) * 1981-08-19 1983-02-25 Sankyo Co Ltd カルバペネム−３−カルボン酸誘導体およびその製法
JPS6019787A (ja) * 1983-07-12 1985-01-31 Sumitomo Chem Co Ltd 新規なβ−ラクタム化合物及びその製造法
JPS60202886A (ja) * 1984-03-27 1985-10-14 Sankyo Co Ltd １―置換カルバペネム―３―カルボン酸誘導体
JPS60233078A (ja) * 1984-04-23 1985-11-19 メルク　エンド　カムパニー　インコーポレーテッド ６‐〔１‐ヒドロキシエチル〕‐２‐ｓｒ↑８‐１‐メチル‐１‐カルバデチアペン‐２‐エム‐３‐カルボン酸
JPS6425779A (en) * 1987-04-11 1989-01-27 Lederle Japan Ltd (1r,5s,6s)-2-substituted-thio-6-((r)-1-hydroxyethyl)-1-methyl -carbapenem-3-carboxylic acid derivative

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5533494A (en) * 1978-08-25 1980-03-08 Beecham Group Ltd Betaalactum antibacterial*its manufacture and composition
JPS5832879A (ja) * 1981-08-19 1983-02-25 Sankyo Co Ltd カルバペネム−３−カルボン酸誘導体およびその製法
JPS6019787A (ja) * 1983-07-12 1985-01-31 Sumitomo Chem Co Ltd 新規なβ−ラクタム化合物及びその製造法
JPS60202886A (ja) * 1984-03-27 1985-10-14 Sankyo Co Ltd １―置換カルバペネム―３―カルボン酸誘導体
JPS60233078A (ja) * 1984-04-23 1985-11-19 メルク　エンド　カムパニー　インコーポレーテッド ６‐〔１‐ヒドロキシエチル〕‐２‐ｓｒ↑８‐１‐メチル‐１‐カルバデチアペン‐２‐エム‐３‐カルボン酸
JPS6425779A (en) * 1987-04-11 1989-01-27 Lederle Japan Ltd (1r,5s,6s)-2-substituted-thio-6-((r)-1-hydroxyethyl)-1-methyl -carbapenem-3-carboxylic acid derivative

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0617036A3 (fr) * 1993-03-16 1998-01-14 American Cyanamid Company Composés de carbapénème substitués sur la position 2

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