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WO1993006102A1 - Derive de 2-(pyrrolidinylthio substitue) carbapenem - Google Patents

Derive de 2-(pyrrolidinylthio substitue) carbapenem Download PDF

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Publication number
WO1993006102A1
WO1993006102A1 PCT/JP1991/001286 JP9101286W WO9306102A1 WO 1993006102 A1 WO1993006102 A1 WO 1993006102A1 JP 9101286 W JP9101286 W JP 9101286W WO 9306102 A1 WO9306102 A1 WO 9306102A1
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Prior art keywords
group
lower alkyl
hydrogen atom
pyrrolidine
alkyl group
Prior art date
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PCT/JP1991/001286
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English (en)
Japanese (ja)
Inventor
Susumu Nakagawa
Norikazu Ohtake
Fumio Nakano
Koji Yamada
Ryosuke Ushijima
Satoshi Murase
Hiroshi Fukatsu
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MSD KK
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Banyu Phamaceutical Co Ltd
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Priority to PCT/JP1991/001286 priority Critical patent/WO1993006102A1/fr
Publication of WO1993006102A1 publication Critical patent/WO1993006102A1/fr
Anticipated expiration legal-status Critical
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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 venom (7-oxo-1-azabicyclo [3. 2. 0] hept-2-en-2-carboxylic acid) compound, an antibacterial agent containing the compound as an active ingredient And the brightness of the process for producing the compound.
  • Imidenem maintains antibacterial activity at least as high as that of cenamycin against various bacterial species and -lactamase resistance, and its antibacterial activity against Pseudomonas aeruginosa is 2 to 4 times higher. Are better. In addition, the stability of imidenem as an aqueous solution and solid was remarkably 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 renal toxicity due to degradation products. Therefore, imidenem cannot be administered alone and must be used in combination with a DHP-I inhibitor such as cilastatin
  • JP-B-63-55514 in particular, meconipenem
  • meconipenem have greatly improved stability against DHP-I.
  • the antibacterial activity against the highly resistant methicillin-resistant Staphylococcus aureus is not sufficient, and there is a need for a potent venom compound having better antibacterial activity.
  • the present inventors have conducted intensive studies with the aim of providing a novel potent Lubabenem compound having excellent antibacterial activity and resistance to DHP-1. As a result, the general formula is
  • R 2 and R 3 are the same or different, and represent a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a formimidoyl group, an acetate tomidoyl group, one COOR 1 , —CON (R 5 ) R 6 , — N (R 5 ) R 6 , — CH 2 COOR ⁇ — CH 2 N (R 5 ) R 6 or one CH 2 CON (R 5 ) R 6 (where R 4 is a hydrogen atom or lower alkyl
  • the groups R 5 and R 6 are the same or different and are each selected from a hydrogen atom, a lower alkyl group or a nitrogen atom in which the lower alkyl group is bonded to each other and an adjacent nitrogen atom to form an azide, J-dinyl group, azetidinyl group, pyrrolidinyl group and piperidyl group;
  • the present invention has the general formula
  • R is a hydrogen atom or a methyl group
  • R is a hydrogen atom or a negative charge
  • R 2 and R 3 are the same or different, and are a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, Midinole group, acetomidyl group, one COOR 4 , — CON (R 5 ) R one N (R 5 ) R S , — CH 2 COOR ⁇ — CH 2 N (R 3 ) R 6 or one CH 2 CON (R 5 ) R s
  • R 4 is a hydrogen atom or a lower alkyl group
  • R 5 and R s are the same or different
  • the compound of the present invention has a basic structure One one
  • the present invention encompasses optical isomers and stereoisomers based on asymmetric carbon atoms at positions 1, 5, 6, and 8 of the carbane skeleton, and preferred compounds among these isomers are: A compound with a 5R, 6S configuration (5,6-trans) having a configuration similar to that of mycin and a carbon atom at the 8-position in the R configuration (5R, 6S, 8R) configuration, or a 1-position When the compound has a methyl group, a compound having the (1R, 5S, 6S, 8R) configuration can be mentioned.
  • the present invention also relates to a 2- (alicyclic heterocyclic-substituted or alicyclic heterocyclic lower alkyl) pyrrolidine-4_ylthio group on the 2-position side chain, the 2-, 4- and 2-position side chain of the pyrrolidine nucleus.
  • Preferred compounds among these isomers are those having (2'S, 4'S) configuration and (2'R, 4'R) configuration when p is 0. And when p is an integer of 1 to 3, compounds having the (2′R, 4 ′S) configuration and the (2 ′S, 4′R) configuration can be mentioned.
  • the alicyclic heterocyclic group at the 2-position of the pyrrolidine nucleus also has isomers based on asymmetric carbon, but the present invention includes both isomers.
  • a lower alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group and an ieri-butyl group.
  • Group, pentyl group, hexyl group and the like, A methyl group, an ethyl group, an rt-butyl group and the like are preferred.
  • the hydroxy lower alkyl group refers to a hydroxyalkynole group in which the above lower alkyl group is substituted with a hydroxy group, such as a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, and the like. Hydroxyethyl groups and the like are preferred.
  • the lower alkyl moynole group refers to a molybamoyl group substituted by the lower alkyl group, for example, an N-methyl canolebamoyl group, an N-ethyl canolebamoyl group, or an N-propyl canolebamoyl group. And an N-methylcarbamoyl group.
  • the di-lower alkyl group rubamoyl group refers to a canolebamoyl group in which the lower alkyl group is di-substituted, for example, N, N-dimethylcarbamoinole group, N, N-methyl carbamoinole group, N-ethyl-N -Methylcarbamoinole group and the like, and N, -dimethylcanolebamoinole group and the like are preferable.
  • carboxyl-protecting group examples include lower phenols such as methyl, ethyl, propyl, isopropyl, iert-butyl, and the like; -Halo-substituted lower alkyl groups such as -trifluoroethylinole group: lower alkanoinoleoxy such as acetoxymethyl group, propionyloxymethyl group, bivaloyloxymethyl group, triacetoxetinole group, 1-propionyloxetyl group; Alkyl group; lower alkoxycarbonyldioxyalkyl group such as tri (methoxycarboxy) ethyl group, tert- (ethoxycarbonyldioxy) ethyl group, 1- (isopropoxycarbonyloxyethyl) ethyl group; for example, 2-propenyl group , 2-chloro-2-propenyl, 3-methoxycarbonyl-2-propenyl, 2-methyl
  • Examples of the protecting group for the hydroxy group include: lower alkylsilyl groups such as trimethylsilinole group and iert-butyldimethylsilyl group; lower alkoxymethynole groups such as methoxymethyl group and 2-methoxyshethoxymethinole group; Vilaninole group; for example, benzyl group, _p-methoxybenzinole group, 2,4-dimethoxybenzyl group, 0-nitrobenzinole group, P-nitrobenzinole group, aralkyl group such as trityl group; for example, formyl Lower alkoxycarbonyl groups such as ri-butoxycarbonyl group, 2-odoethoxycarbonyl group, and 2,2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxy group Carbonyl group, 2-chloro-2-propoxycarbonyl group, 3-methoxycarbonyl-2-propenyl group Alkenyloxycarbon
  • amino- or imino-protecting group examples include benzylidene, benzylidene, -nitrobenzylidene, salicylidene, -naphthylidene, and aralkylidene groups such as / 5-naphthylidene; Aralkyl such as methoxybenzyl group, 3,4-dimethoxypentinole group, 0-nitrobenzinole group, -2 trobenzinole group, benzhydryl group, bis ( ⁇ -methoxypheninole) methyl group and trityl group A lower alkanol group such as a formyl group, an acetyl group, a propionyl group, a ptyryl group, an oxalyl group, a succinyl group, a vivaloyl group; for example, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl
  • Halo-substituted lower alkoxycarbinole groups such as 2-chloroethoxycarbonylcarbonyl group and 2,2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2 -Propenyloxycarbonyl, 3-methoxycarbonyl-2-propenyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl, 2-butenyloxycarbonyl, cinnamyloxycarbonyl Alkenyloxycarbonyl groups such as benzyloxycarbonyl group, 0-nitrobenzyloxycarbonyl group, dibenzyloxycarbonyl group, phenethyloxycarbonyl group Cyloxycarbonyl groups; for example, lower alkylsilyl groups such as trimethylsilinole group and ieri-butyldimethylsilyl group; Preference is given to a noroxycarbinole group, a ri-butoxycarbinole
  • the alicyclic heterocyclic group on the pyrrolidine-4-ylthio group which is the 2-position side chain of the pyranidine skeleton, is substituted at the 2-position of the pyrrolidine nucleus;
  • R 2 and R 3 are the same or different and each represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a formimidoyl group, an acetateimidoyl group, one COOR —CON (R 5 ) R 6 , — N (R 5 ) R 6 , — CH 2 COOR ⁇ — CH 2 (R 5 ) R 6 or one CH 2 C ⁇ N (R 5 ) R 5 (where R 4 is a hydrogen atom or a lower alkyl group, and R s is the same or different and is selected from the group consisting of a hydrogen atom, a lower alkyl group or an adjacent nitrogen atom in which the lower alkyl group is bonded to each other, together with an azide, a J-dinyl group, a azetidinyl group, a pyrrolidinyl group and a piperidyl group.
  • R 7 and R 8 are the same or different, a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, Horumui Mi Doyl group, Acetimidyl group, One C00R 4 , —CON (R 5 ) R s , — N (R 5 ) R s , one CH 2 C ⁇ 0R ”, — CH 2 N (R 5 ) R B or one CH 2 CON (R 5 ) R 6 (where RR 3 and R 6 have the same meanings as above), p is an integer of 0 to 3, q and r are the same, and 0 to 5 One _
  • R 2 and R 3 may be the same or different, and can be substituted at any substitutable position on the carbon forming the alicyclic complex ring.
  • R 2 and R 3 are a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, one CON (R 5 ) R 6 , one N (R 5 ) R 6 [where R 5 and R 6 are as defined above; Having a taste] and the like, and among them, a hydrogen atom and the like are preferable.
  • A represents a partial structure of the alicyclic heterocyclic group.
  • the A, R 7 or R 8 is a hydrogen atom or a lower alkyl group are preferred, especially R 7 or R 8 is a hydrogen atom, preferably when such as a methyl group.
  • p represents an integer of 0 to 3, preferably 0 or 1, particularly preferably 0.
  • R ′ represents a hydrogen atom or a negative charge.
  • R 1 shows a negative charge and forms a pair with the ammonium ion, whereby the compound of the general formula [I] is Forms internal salts.
  • the salt of the general formula [I] means a pharmaceutically acceptable and conventional salt, and is a carboxylic acid group at the 3-position of the carnoxenem skeleton or a pyridine base at the 2-position side chain. Salts in the base of the alicyclic heterocyclic group can be exemplified.
  • Examples of the basic addition salt at the carboxyl group include: alkaline metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt: ammonium salt; trimethylamine Salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine salts, ethanolamine salts, benzene salts, triethanolamine salts, and proforce salts; for example, N, ⁇ '-dibenzylethylenediamine Aralkylamine salts such as amines; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; for example, tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts Salt, benzyltriethylammonium salt, benzyltributylammonium Salts, quaternary ammonium salts such
  • Acid addition salts of pyrrolidine bases or bases of alicyclic heterocyclic groups include, for example, inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, perchlorate; Organic salts such as acid, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate: methanesulfonate, isethionate, Sulfonates such as benzenesulfonate and p-toluenesulfonate; and acidic amino acids such as aspartate and glutamate.
  • inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, perchlorate
  • Organic salts such as acid, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate: methanesulfonate, isethionate, S
  • the non-toxic ester of the general formula [I] means a conventional pharmaceutically acceptable carboxyl group at the 3-position of the carbane skeleton.
  • an ester with an alkanoyloxymethinole group such as an acetooxymethyl group and a bivaloyloxymethinole group
  • an ester with an alkoxycarbonyloxynoleyl group such as a 1- (ethoxycarboninoleoxy) ethyl group.
  • Preferred examples of the compound of the general formula [I] include the following compounds (in the table, Me represents a methyl group).
  • particularly preferred compounds include, for example, hi), (, (10), (11). (12), (13), (21), (22), (23), (24), (25), (26), (27), (35), (36). (37), (38), (46), (47), (48), (95), (96), (98 ), (101), (103), (104). (105), (106), (107), (109), (114), (115), (116), (117), (118), (119). (120), (121), (123), (126), (128), (129), (130), (131), (132), (134), (139), (140), (141) ) Or (142).
  • Methyl-l-potassyl-2-em-3-carboxylic acid and the like are more preferred, especially (96) (1R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -1.
  • -Methyl_2-[(2S, 4S) -2- (N-methylbiperidine-4-inole) pyrrolidine-4-ylthio]-]] -Irvalpen-2--2-em-3-carboxylic acid is preferred.
  • R represents a hydrogen atom or Mechinore group
  • R 9 is coercive Mamorumoto hydrogen atom or a hydroxy group
  • R 1 () denotes a hydrogen atom or a protecting group of a carboxyl group] in compounds represented by, not Reaction of an activating reagent in an active organic solvent in the presence of a base yields a compound of the general formula
  • R, R 9 and R ′ Q have the above-mentioned meaning, and Y represents a leaving group].
  • inert organic solvent used in the above reaction examples include getyl ether, tetrahydrofuran, dioxane, benzene, toluene, chloroform, benzene, chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, acetone, and ethyl acetate.
  • Examples of the base used in the reaction include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1, 8-jiazabi Tertiary aliphatic amines such as cyclo [5.4.0] pandan-7-ene (DBU) and 1,5-diazabicyclo [4.3.0] non-5-ene (DBN); for example, pyridine, 4- Examples thereof include aromatic amines such as dimethylaminopyridine, picoline, lutidine, quinoline, and isoquinoline, and N, N-diisopropylpropylethylamine and triethylamine are particularly preferable.
  • Examples of the activating reagent used in the reaction include hydrates such as trifluoroacetic anhydride, methanesulfone anhydride, trifluoromethanesulfonic anhydride, and toluenesulfone hydrate; methanesulfonyl chloride, -Acid chlorides such as toluene sulphonyl chloride and diphenyl chlorophosphate; and diphenyl chlorophosphate is particularly preferred.
  • the group ⁇ in the general formula [ ⁇ '] represents a leaving group, for example, trifluoroacetoxy, methanesulfoninoleoxy, trifluoromethanesulfonyloxy, toluenesulfonyloxy, diphenoxyphosphoryl And a diphenyloxyphosphoryloxy group.
  • the reaction is carried out in a temperature range of ⁇ 40 to 50 ° C., preferably ⁇ 20 to 20 ° C., and is usually completed quantitatively in 0.5 to 3 hours.
  • reaction is carried out according to a conventional method to quantitatively obtain the reactive derivative [ ⁇ '] of the general formula [II].
  • R " is a protecting group for a hydrogen atom or an imino group
  • R 2 ° and R 3 ° are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally protected hydroxy lower alkyl group, formimi Doyle or acetimidyl, ⁇ COOR ' Q , -CON (R 50 ) R 6 ,-N (R 30 ) R 6. , CH 2 COOR 4 °, -CH 2 N (R 5 ° ) R 60
  • R 2 ° and R 3 ° are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally protected hydroxy lower alkyl group, formimi Doyle or acetimidyl, ⁇ COOR ' Q , -CON (R 50 ) R 6 ,-N (R 30 ) R 6. , CH 2 COOR 4 °, -CH 2 N (R
  • R 10 is a hydrogen atom, a lower alkyl group or a carboxyl protecting group
  • R 5 ° and R 6 ° are the same or different, a hydrogen atom, a lower atom
  • R 7D N (R 7 °) R 8 ° (where R 7 ° and R 8 are the same or different and are a hydrogen atom, a lower alkynole group, a protected A hydroquinyl lower alkyl group, a formimidinole group or an acetateimidinole group, a protecting group for an imino group, COOR 4 . ⁇ —CON (R 5 ) R 6 .
  • R, R s, R 10 , R u, R 2 °, R 3 °, B, p, q and r are as defined above] and a compound represented by.
  • the reaction 1 to 2 mol of a base, preferably 1 to 5 mol of L, and 1 to 1.2 mol of a compound of the general formula [III] are used per 1 mol of the reactive derivative [ ⁇ ]. Preferably, it is performed in the temperature range of -20 to 20 ° C, and usually completes 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 [II]. That is, the compound of the general formula [IV] is reacted in the same reaction system without isolating the reactive derivative [ ⁇ ] derived from the compound of the general formula [II] to efficiently convert the compound of the general formula [IV]. Can be manufactured well. When performing in one stage ⁇ —
  • the base is used in an amount of 2 to 4 mol, preferably 2.5 to 3.5 mol, per 1 mol of the compound of the general formula [ ⁇ ].
  • the compound of the general formula [IV] can be removed from the compound of the general formula [IV] thus obtained, if necessary, by appropriately combining the reaction of removing a protecting group for a hydroxy group, an imino group and a carboxyl group. ] Can be produced.
  • the removal of the protecting group is carried out according to a conventional method which differs depending on the kind, for example, by solvolysis, ionic reduction or hydrogenation.
  • the protecting group for the hydroxy group and the Z or amino group or the imino group is, for example, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a nitrobenzyloxycarbonyl group.
  • the carboxyl group-protecting group is an aralkyl group such as a benzyl group, a -nitrobenzyl group or a benzhydryl group, for example, a platinum catalyst such as platinum oxide, a platinum wire or platinum black;
  • the protecting group can be removed by catalytic hydrogenation using a palladium catalyst such as palladium oxide, palladium-carbon, or palladium hydroxide-carbon.
  • Examples of the solvent used in the catalytic hydrogenation reaction include methanol, ethanol, tetrahydrofuran, dioxane, acetic acid and the like, or a mixed solvent of these organic solvents and a buffer such as water or phosphate.
  • the reaction is carried out in a temperature range of 0 to 50 ° C. under a hydrogen gas flow of 1 to 4 atm for 0.5 to 4 hours.
  • Examples of the solvent used for the reaction include water, acetone, getyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, methylene chloride, chloroform and the like, or a mixed solvent thereof.
  • Suitable palladium compound complexes used in this reaction include, for example, palladium monocarbon, palladium hydroxide-carbon, palladium chloride (11), palladium acetate (11), tetrakis (triphenylphosphine) palladium (0), Tetrakis (triphenyloxyphosphine) radium (0), tetrakis (triethoxyphosphine) palladium (0), bis [ethylenebis (diphenylphosphine)] palladium (0), tetrakis [tri (2- Furinole) phosphine] palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (triphenylphosphine) palladium (II) acetate, and the like.
  • scavengers for the aryl group include dimedone, formic acid, acetic acid, ammonium formate, sodium formate, sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, pyrrolidine, piperidine, and hydrogen. And tributyltin halide.
  • the reaction is carried out in a temperature range of ⁇ 10 to 50 ° C., preferably 0 to 0.1 ° C., using 1 to 6 mol of the catalyst and 1 to 6 mol of the nucleophile per 1 mol of the compound of the formula [IV]. It is performed in the temperature range of ⁇ 30 ° C, and usually completes in 0.5 to 3 hours.
  • the protecting group for the hydroxy group and Z or the amino group or the 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 (J. Org. Chem.), Vol. 39, pp. 192-196 (1974). Year)).
  • the compound of the general formula [I] is subjected to a usual treatment method, for example, column chromatography using silica gel or an adsorption resin, or lyophilization or crystallization.
  • the compound can be isolated.
  • the protecting group for the carboxyl group at the 3-position of the compound of the general formula [IV] is, for example, Lower alkanoyloxyalkyl groups such as ethoxymethyl group and bivaloyloxymethinole group; for example, methoxymethinole group, indanyl group and phthalidyl group; As it is degraded, it can be administered directly to humans or animals without removing protecting groups.
  • the compound of the general formula [I] can be converted into a pharmaceutically acceptable salt or ester by a conventional method.
  • the starting material represented by the general formula [ ⁇ ] can be prepared by the method of Salzmann et al. [J. Am. Chem. So], J. Am. 102, 6161-6163 (981)]; when R is a methyl group, see the method of Shih et al. [Heterocycles. Vol. 21, pp. 29-40, 984). ] Or a method analogous thereto.
  • the starting material represented by the general formula [III] can be synthesized, for example, by the following method.
  • R ' 2 is a hydrogen or hydroxy protecting group
  • X is a chlorine atom, a bromine atom, an iodine atom, a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group.
  • - leaving group selected from the group consisting of toluene sulfonyl O alkoxy group, Ac represents an Asechiru group, R '', R 2. , R 3 °, B, p, q and r have the meaning given above]
  • the compounds of the present invention exhibit strong antibacterial activity against various Gram-positive and Gram-negative bacteria.
  • the MIC of the test compound is calculated by the blocking radial force produced by the disc containing the test conjugate, the formula reported by Humphrey and Lightbown [The Journal of General Micronockey]. Calculated using the methodology (J. Gen. Microbiol.), Vol. 7, 129 (1952)]. The geometric mean of the MIC was determined for each strain, and the activity ratio to chenamycin was calculated.
  • the compound of the present invention has excellent antibacterial activity against various gram-positive bacteria and gram-negative bacteria, and is an antibacterial agent for treating and preventing bacterial infections in humans using these pathogenic bacteria as causative bacteria. Is a useful compound.
  • Representative pathogens susceptible to the antimicrobial agents of the present invention include, for example, Staphylococcus
  • the compounds of the present invention show superior blood concentration shifts and biological half-life in rodents such as mice, and primates such as Lisa monkeys, compared to imidenem and melanin. Was.
  • the compounds of the present invention are extremely stable against different forces DHP-1 depending on each compound, and have excellent force, physicochemical stability and solubility in water. You.
  • the compound of the present invention can be mixed with a solid or liquid excipient carrier known in the art and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration and external administration.
  • the main ones are topical or parenteral (intravenous or intramuscular) administration by injection.
  • the pharmaceutical preparations 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 contain commonly used additives such as bases, auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters, and surfactants, if necessary.
  • the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.
  • the dosage varies depending on the patient's condition, body weight, age, sex, dosage form, number of administrations, etc.In general, the preferred daily dose for adults is about 5 to 50 mgZ kg, and the preferred daily dose for children is about 5 to 50 mgZkg. It is preferably in the range of 2525 mgZkg, and it is preferable to administer once or several times a day.
  • the compound of the present invention may optionally contain cilastatin [(Z) -7- (reamino-2-force lipoxicetylthio) -2- (2,2-dimethylcyclopropanecarboxamide) -2-sodium heptenoate] DHP-poisoning agents [JP-A-56-81518, European Patent Application No. 28,778, Journal of Medicinal Chemistry (J. Med. Chem-), Vol. 30, p. 1074 (1987)] ] Can also be administered in combination.
  • TMS tetramethylsilane
  • DSS silapentane-5-sulfonate
  • Boc tert-butoxycarbonyl group
  • Tr Trityl group one
  • the filtrate obtained was concentrated to 20 ml, subjected to reverse phase column chromatography (YMC'GEL TM ODS-AQ 120-S50, 20% aqueous methanol solution), and the target fraction was concentrated and lyophilized to give the title.
  • the compound (556 mg, yield: 87.5%) was obtained.
  • the obtained filtrate was concentrated to about 3 ml.
  • the residue was subjected to reverse phase column chromatography (LC-SORB TM SP-B-ODS, 10% aqueous methanol solution), and the target fraction was concentrated and lyophilized to give the title compound (14.4 mg, yield: 38.8%). ).
  • Triethylamine (7.54 ml, 54.2 mmol) was added to an aqueous solution (40 ml) of L-hydroxyproline methyl ester hydrochloride (8.2 & 45.2 mmol) at room temperature, and then 2- (rt-butoxycarbonylthio) -4
  • a solution of 1,6-dimethylpyrimidine (10.8 g, 45 mmol) in dioxane (80 ml) was added. After stirring the reaction solution at room temperature for 1.5 hours, dioxane was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (250 ml).
  • Boc Lithium chloride (4.49 g, 106 mmol) and then sodium borohydride (4.0 g, 106 mmol) were added to a tetrahydrofuran solution (180 ml) of the compound (19.0 & 52.9 mmol) obtained in the above reaction in a nitrogen stream. added.
  • Ethanol (180 ml) was added dropwise to this mixture, and the reaction solution was stirred at room temperature overnight.
  • a saturated aqueous solution of ammonium chloride (100 ml) was added to the reaction mixture to decompose excess reducing agent, and then the mixture was concentrated under reduced pressure.
  • Methanesulfonyl chloride (0.21 ml, 2.6 mmol) was added dropwise to a solution of (0.37 ml, 2.6 mmol) in tetrahydrofuran (15 ml) under ice-cooling and stirring. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. To a solution of the residue in methylene chloride (10 ml) was added trifluoroacetic acid (3.5 ml) under ice cooling and stirring, and the mixture was stirred at the same temperature for 1 hour.
  • Triethylamine (3 ml) was added to a solution of the residue obtained by evaporating the solvent and trifluoroacetic acid under reduced pressure, and the mixture was stirred at room temperature for one hour.
  • di-ieri-butyl dicarbonate (599 mg, 2.7 mmol) was added at room temperature under stirring. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Methanesulfonyl chloride (0.14 ml, 1.8 mmol) was added dropwise to a solution of the residue and triethylamine (0.25 ml, 1.78 mmol) in tetrahydrofuran (10 ml) under ice cooling and stirring. After stirring at the same temperature for 1 hour, ethyl acetate (10 ml) and water (aOml) were added. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • N-dimethylformamide 50 ml was added ice-cooled and stirred 60% sodium hydride (559 mg, Hmmol), and the mixture was stirred at the same temperature for 20 minutes. Stirred.
  • the compound (225.7 g, 0.523 mol) obtained in the above reaction was dissolved in tetrahydrofuran (3.3 L), and a borane-dimethylsulfide complex (128.9 ml, 1.36 mol) was added dropwise under a nitrogen stream and ice cooling. After stirring at room temperature for 2 hours, water (200 ml) and aqueous sodium hydrogencarbonate solution (100 ml) were added, extracted with ethyl acetate, and washed with brine. The organic layer was dried and concentrated under reduced pressure.
  • reaction mixture was filtered, the filtrate and the washings were combined, concentrated under reduced pressure, ethyl acetate (1 L) was added to the residue, dilute hydrochloric acid (200 ml), saturated aqueous sodium hydrogen carbonate solution (200 ml ⁇ 2), saturated saline ( 200ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and crude (2S, 4R) -N-ieri-butoxycarboninole-4-ri-butyldimethylsiloxy-2- (1,5-dimethyl Sulfonyloxypent-3-yl) pyrrolidine (302 g, yield: 86%) was obtained.
  • a suspension of 60% sodium hydride (10 g, 250 mmol) in tetrahydrofuran (700 ml) was stirred in a nitrogen stream under ice-cooling and stirring under stirring with ethyl cyanoacetate (26.6 ml, 250 mmol) and tetra-n-butylammonium bromide. (8.06 g, 25 mmol) and stirred for 30 minutes.
  • N, N-dimethylmethyleneammonium chloride (1.65 17.6 mmol) and triethylamine (2.8 ml, 20 mmol) were added at room temperature, and the reaction solution was stirred at room temperature overnight. After addition of chloroform (100 ml), the organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the compound (283 mg, 0.53 mmol) obtained in the above reaction was dissolved in a 0.65 N hydrogen chloride-methanol solution (5 ml) and stirred at room temperature overnight.
  • the reaction solution was concentrated under reduced pressure, and dioxane (5 ml) and water (2.5 ml) were added to the residue.
  • the solution was adjusted to pH 9 with sodium hydroxide IN, 4,6-dimethyl-2-(-nitrobenzyloxycarbonyldithio) pyrimidine (170 mg, 0.53 mmol) was added, and the mixture was stirred at room temperature overnight.
  • the reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 ml).
  • the compound of the present invention is a novel compound that has not been described in the literature, and has a strong antibacterial activity against susceptible 'resistant gram-positive bacteria and gram-negative bacteria, and excellent stability against ⁇ -octamidase and DHP-I. Useful as an antibacterial agent.

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Abstract

Composé répondant à la formule générale (I), ses sel et ester pharmaceutiquement acceptables, sa production, et son utilisation en tant qu'agent antibactérien. Dans ladite formule (I), R représente hydrogène ou méthyle; R1 représente hydrogène ou une charge négative; R2 et R3 sont identiques ou différents et chacun représente hydrogène, alkyle inférieur, alkyle inférieur hydroxylé, formimidoyle, acétimidoyle, COOR?4, CONR5R6, NR5R6, CH¿2COOR4, CH2NR5R6 ou CH¿2?CONR?5R6¿; A représente =NR?7 ou =NR7R8, où R7 et R8¿ sont identiques ou différents et chacun représente hydrogène, alkyle inférieur, alkyle inférieur hydroxylé, formimidoyle, acétimidoyle, COOR?4, CONR5R6, NR5R6, CH¿2COOR4, CH2NR5R6 ou CH¿2?CONR?5R6¿; p est un nombre entier compris entre 0 et 3; et q et r sont identiques et représentent un nombre entier compris entre 0 et 5.
PCT/JP1991/001286 1991-09-27 1991-09-27 Derive de 2-(pyrrolidinylthio substitue) carbapenem Ceased WO1993006102A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60104088A (ja) * 1983-11-11 1985-06-08 Sumitomo Chem Co Ltd 新規なβ−ラクタム化合物およびその製造法
JPS62155279A (ja) * 1984-11-08 1987-07-10 Sumitomo Pharmaceut Co Ltd 新規なβ−ラクタム化合物
JPS63170379A (ja) * 1986-11-24 1988-07-14 Fujisawa Pharmaceut Co Ltd ３−ピロリジニルチオ−１−アザビシクロ〔３．２．０〕ヘプト−２−エン−２−カルボン酸化合物
JPH021491A (ja) * 1988-03-18 1990-01-05 Fujisawa Pharmaceut Co Ltd ３―ピロリジニルチオ―１―アザビシクロ［３．２．０］ヘプト―２―エン―２―カルボン酸化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60104088A (ja) * 1983-11-11 1985-06-08 Sumitomo Chem Co Ltd 新規なβ−ラクタム化合物およびその製造法
JPS62155279A (ja) * 1984-11-08 1987-07-10 Sumitomo Pharmaceut Co Ltd 新規なβ−ラクタム化合物
JPS63170379A (ja) * 1986-11-24 1988-07-14 Fujisawa Pharmaceut Co Ltd ３−ピロリジニルチオ−１−アザビシクロ〔３．２．０〕ヘプト−２−エン−２−カルボン酸化合物
JPH021491A (ja) * 1988-03-18 1990-01-05 Fujisawa Pharmaceut Co Ltd ３―ピロリジニルチオ―１―アザビシクロ［３．２．０］ヘプト―２―エン―２―カルボン酸化合物

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