US20040063754A1 - Dehalogeno compounds - Google Patents

Dehalogeno compounds Download PDF

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Publication number
US20040063754A1
US20040063754A1 US10/432,043 US43204303A US2004063754A1 US 20040063754 A1 US20040063754 A1 US 20040063754A1 US 43204303 A US43204303 A US 43204303A US 2004063754 A1 US2004063754 A1 US 2004063754A1
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group
salts
hydrates
cyclopropyl
carbon atoms
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Hisashi Takahashi
Rie Miyauchi
Masao Itoh
Makoto Takemura
Isao Hayakawa
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Daiichi Pharmaceutical Co Ltd
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Daiichi Pharmaceutical Co Ltd
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Assigned to DAIICHI PHARMACEUTICAL CO., LTD. reassignment DAIICHI PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAYAKAWA, ISAO, ITOH, MASAO, MIYAUCHI, RIE, TAKAHASHI, HISASHI, TAKEMURA, MAKOTO
Publication of US20040063754A1 publication Critical patent/US20040063754A1/en
Priority to US11/644,901 priority Critical patent/US7902226B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

Definitions

  • This invention relates to a synthetic quinolone antibacterial agent which is useful as medicaments, veterinary drugs, drugs for fishery use, or antibacterial preservatives.
  • Quinolone derivatives having a pyrrolidinyl group having an aminomethyl group at the 3-position, as the substituent at the 7-position of the quinolone mother skeleton, are known to exhibit strong antibacterial activity against gram-negative and gram-positive bacteria.
  • there are 7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolone carboxylic acid derivatives [Journal of Medicinal Chemistry, vol. 29, p. 445 (1986)].
  • quinolone carboxylic acid derivatives having a substituent on the carbon atom of the aminomethyl group of the 3-(1-aminomethyl)pyrrolidin-1-yl group include 7-[3-(1-aminoethyl)pyrrolidin-1-yl]quinolone carboxylic acid derivatives [Journal of Medicinal Chemistry, vol. 36, p. 871 (1993)]; 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]quinolone carboxylic acid derivatives [Journal of Medicinal Chemistry, vol. 37, p.
  • PCT/JP96/00208 does not provide a specific description concerning quinolone carboxylic acids wherein hydrogen is substituted at the 6-position. Furthermore, this publication does not provide any specific disclosure as embodiments of 3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolone carboxylic acids, wherein the present invention is concerned.
  • R 2 is represented by formula B:
  • PCT/WO99/14214 indicates a 6-hydrogen-substituted-quinolone carboxylic acid derivative, in which a nitrogen-containing heterocyclic substituent, for example, the 3-(1-aminoethyl)pyrrolidin-1-yl group, is introduced via a carbon-nitrogen bond into the 7-position of the quinolone skeleton and which is relevant to this invention.
  • a nitrogen-containing heterocyclic substituent for example, the 3-(1-aminoethyl)pyrrolidin-1-yl group
  • This application describes compounds represented by the formulas C and D. However, this application does not contain any description whatsoever concerning a 3-(1-aminocycloalkyl)pyrrolidin-1-yl group, which is relevant to the present invention, as a substituent at the 7-position of the quinolone skeleton shown in formula C.
  • R1 represents a cyclic alkyl group having 3 to 6 carbon atoms, an alkyl group having 1 or 2 carbon atoms, a straight-chain alkenyl group having 2 to 3 carbon atoms, or a branched-chain alkyl group or alkenyl group having 3 to 4 carbon atoms, this alkyl group or cyclic alkyl group may be unsubstituted or the alkyl group or cyclic alkyl group may be substituted by 1 to 3 fluorine atoms or by a phenyl group which is unsubstituted or is substituted by 1 to 3 fluorine atoms or is substituted at the 4-position by a single hydroxyl group
  • R6 represents a hydrogen atom, a hydroxyl group, an aminocarbonyl group, a bromine atom, a cyano group, an alkyl group having 1 or 2 carbon atoms, or an alkenyl group or alkynyl group having
  • R7 represents an amino group, which is bonded to a carbon that is not adjacent the nitrogen atom of the pyrrolidine ring and may be unsubstituted or substituted by one or two alkyl groups with 1 to 3 carbon atoms, or an aminoalkyl group, which is bonded to a carbon on the pyrrolidine ring and may be unsubstituted or substituted by an alkyl group having 1 to 3 carbon atoms
  • R9 represents a group selected from among the group comprised of a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group and alkynyl group having 2 to 6 carbon atoms, and fused and spiroalkyl group having 3 to 6 carbon atoms, the alkyl group portions of these groups maybe unsubstituted or substituted by 1 to 3 fluorine atoms, and the abovementioned substituents R7 and R9 may be integrated to form a fused or S
  • the compounds of this invention are excellent both in terms of safety and pharmacokinetics and thus enable use in clinical situations, which could not be achieved with compounds prior to this invention which have substituents of the same structure at the 7-position of the quinolone mother skeleton.
  • the present invention has been achieved based on these findings.
  • the 6-hydrogen-substituted-quinolone derivatives which are the compounds of this invention, are compounds that, in comparison to the 6-fluorine-substituted-quinolone derivatives, are compounds of excellent safety that are reduced in acute toxicity and significantly reduced in micronuclus induction, and also exhibit good pharmacokinetics, such as improved urinary recovery, etc.
  • quinolone compound which has a 3-(1-aminocycloalkyl)pyrrolidin-1-yl group having a cyclic alkyl group as a substituent on the methyl group of the 3-(aminomethyl)pyrrolidin-1-yl group and which as has been mentioned above is known to be low in selective toxicity, will unexpectedly be a compound with excellent selective toxicity and be a compound of excellent pharmacokinetics as long as it is a quinolone compound with the structure of the present invention.
  • the present invention concerns compounds represented by the following general formula (I), its salts, and hydrates thereof:
  • R 1 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, a heteroaryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
  • R 2 represents an alkylthio group having 1 to 6 carbon atoms or a hydrogen atom
  • R 2 and the abovementioned R 1 may be integrated to form a ring structure by incorporating a part of the mother skeleton, the thus formed ring may contain a sulfur atom as a ring-constituent atom, and the ring may be substituted by an alkyl group having 1 to 6 carbon atoms, which may have a substituent;
  • R 3 represents a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl group, or a 3-acetoxy-2-oxobutyl group;
  • R 4 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogen atom, an amino group, a hydroxyl group, a thiol group, or a halogenomethyl group, and
  • the amino group may have one or more substituents selected from among the group consisting of an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and a formyl group;
  • A represents a nitrogen atom or a partial structure represented by formula (II):
  • X represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, or a halogenomethoxy group,
  • the amino group may have one ore more substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and a formyl group,
  • X 1 and the aforementioned R 1 may be integrated to form a ring structure by incorporating a part of the mother skeleton, the thus formed ring may contain an oxygen atom, a nitrogen atom, or a sulfur atom as a ring constituent atom, and this ring may be substituted by an alkyl group having 1 to 6 carbon atoms, which may have a substituent);
  • each of R 5 and R 6 independently represents an alkyl group having 1 to 6 carbon atoms, a hydrogen atom, or a substituted carboxyl group derived from an amino acid, dipeptide, or tripeptide,
  • alkyl group may have one ore more substituents selected from the group consisting of an alkylthio group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, and a halogen atom; and n represents an integer 1 or 2].
  • the present invention also relates to each of the following:
  • a medicament which comprises a compound of formula (I), its salts or hydrates thereof as an active ingredient;
  • an antibacterial agent which comprises a compound of formula (I), its salts or hydrates thereof as an active ingredient;
  • a therapeutic agent for an infectious disease which comprises a compound of the formula (I), its salts or hydrates thereof as an active ingredient;
  • a method for treating a disease which comprises administrating a compound of the formula (I), its salts or hydrates thereof as an active ingredient;
  • a method for treating an infectious disease which comprises administrating a compound of the formula (I), its salts or hydrates thereof as an active ingredient;
  • a method for producing a medicament which comprises formulating a compound of the formula (I), its salts or hydrates thereof as an active ingredient;
  • a method for producing an antibacterial agent which comprises formulating a compound of the formula (I), its salts or hydrates thereof as an active ingredient;
  • a method for producing an infectious disease treating agent which comprises formulating a compound of the formula (I), its salts or hydrates thereof as an active ingredient;
  • the substituent R 1 is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, a heteroaryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms.
  • an alkyl group having 1 to 6 carbon atoms may be a straight-chain or branched-chain alkyl group, preferably an alkyl group having 1 to 4 carbon atoms, more preferably an ethyl group.
  • an alkenyl group having 2 to 6 carbon atoms a vinyl group or a 1-isopropenyl group is preferable.
  • a halogenoalkyl group having 1 to 6 carbon atoms a 2-fluoroethyl group is preferable.
  • a cyclic alkyl group a cyclopropyl group is especially preferable.
  • the cyclic alkyl group may have a substituent, and a halogen atom is preferable as the substituent.
  • a halogenocyclopropyl group is preferable as the cyclic alkyl group, which may have a substituent, and a fluorine atom is especially preferable as the halogen atom in this group.
  • a halogenocyclopropyl group a monohalogenocyclopropyl group is preferable and a cis-substituted group is even more preferable.
  • Examples of an aryl group, which may have a substituent include a phenyl group, etc., which may have 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom such as fluorine atom, chlorine atom and bromine atom, a hydroxyl group, an amino group, a nitro group, etc. (in the case where the aryl group has a plurality of substituents, the substituents may be of a single type or may be of a plurality of types).
  • a phenyl group, a2-fluorophenyl group, a 4-fluorophenyl group, a 2,4-difluorophenyl group, a 2-fluoro-4-hydroxyphenyl group, a 3-amino-4,6-difluorophenyl group, and a 4,6-difluoro-3-methylaminophenyl group are preferable.
  • aryl group a group that is derived from an aromatic hydrocarbon compound is referred to.
  • the aryl group may also be a naphthyl group or a tricyclic aryl group having more rings.
  • a heteroaryl group is a group that is derived from a pentacyclic or hexacyclic aromatic heterocyclic compound that contains one or more hetero atoms selected from among the nitrogen atom, oxygen atom, and sulfur atom.
  • a pentacyclic or hexacyclic nitrogen-containing heterocyclic substituent that contains 1 or 2 nitrogen atoms is especially preferable.
  • a pyridyl group, pyrimidyl group, etc are cired.
  • An alkyl group, a halogen atom, etc. are preferable as substituents on these rings.
  • a 6-amino-3,5-difluoro-2-pyridyl group is especially preferable.
  • an alkoxy group having 1 to 6 carbon atoms an alkoxy group that is derived from an abovementioned alkyl group is preferable and among these, the methoxy group is preferable.
  • the alkyl portion may be an abovementioned alkyl group.
  • a methylamino group is preferable as the alkylamino group.
  • a cyclic alkyl group or a halogenocycloalkyl group is preferable.
  • a cyclopropyl group or a 2-halogenocyclopropyl group is preferable.
  • a halogen atom in the 2-halogenocyclopropyl group a fluorine atom is preferable.
  • the substituent R 2 represents an alkylthio group having 1 to 6 carbon atoms or a hydrogen atom
  • R 1 and R 2 may be integrated to form a ring structure comprised of a polymethylene chain by incorporating a part of the mother skeleton (that is, so as to contain the nitrogen atom to which R 1 is bonded and the carbon atom to which R 2 is bonded).
  • the thus formed ring may contain a sulfur atom as a ring constituent atom, and this ring may also have an alkyl group or halogenoalkyl group having 1 to 6 carbon atoms as a substituent.
  • the formed ring may be tetracyclic to hexacyclic in size and this ring may be also saturated or unsaturated.
  • a methyl group or a fluoromethyl group is preferable as the substituent on the formed ring. Examples of the fused ring structure formed in this manner include the following:
  • R 7 represents an alkyl group having 1 to 6 carbon atoms, such as a methyl group, a halogenoalkyl group having 1 to 6 carbon atoms, such as a fluoromethyl group, or a hydrogen atom
  • R 8 represents a halogen atom, such as a fluorine atom, or a hydrogen atom.
  • a hydrogen atom is preferable as the substituent R 2 of the compound of formula (I).
  • the substituent R 3 is a phenylalkyl group (aralkyl group) composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, or an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl group, or a 3-acetoxy-2-oxobutyl group.
  • aralkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, or an alkyl group having 1 to 6 carbon atoms, an alk
  • R 4 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogen atom, an amino group, a hydroxyl group, a thiol group, or an halogenomethyl group, and among the above, the amino group may have one ore more substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and a formyl group. In the case where there are a plurality of substituent groups, the substituents may all be of the same type or may be of a plurality of different types.
  • alkyl group which may either be a straight-chain or branched-chain group having 1 to 6 carbon atoms, a methyl group, an ethyl group, a normal propyl group, or an isopropyl group is preferable.
  • alkenyl group which may either be a straight-chain or branched-chain group having 2 to 6 carbon atoms
  • a vinyl group is preferable.
  • alkynyl group which may be a straight-chain or branched-chain group having 2 to 6 carbon atoms
  • an ethynyl group is preferable.
  • the halogen of a halogenomethyl group a fluorine atom is especially preferable and the number thereof may be 1 to 3.
  • alkoxy group which may have 1 to 6 carbon atoms, a methoxy group is preferable.
  • the substituent R 4 is preferably a hydrogen atom, an alkyl group, or an amino group, and among these, a hydrogen atom, a methyl group, or unsubstituted amino group (—NH 2 ) is especially preferable.
  • R 4 is an amino group, a hydroxyl group, or a thiol group, it may be protected by a protective group that is normally used in the relevant fields.
  • Examples of such protective groups include (substituted) alkoxycarbonyl groups, such as tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, etc.; (substituted) aralkyloxycarbonyl groups, such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, etc.; (substituted) acyl groups, such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, etc.; (substituted) alkyl groups or (substituted) aralkyl groups, such as tert-butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group, etc.; (substituted)
  • A represents a nitrogen atom or a partial structure expressed by formula (II):
  • X 1 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, or a halogenomethoxy group, and among the above, the amino group may have one ore more substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and a formyl group.
  • a halogen atom a fluorine atom, a chlorine atom, and a bromine atom are preferable and the fluorine atom and chlorine atom are especially preferable.
  • an alkyl group which may be a straight-chain or branched-chain group having 1 to 6 carbon atoms, a methyl group, an ethyl group, a normal propyl group, or an isopropyl group is preferable.
  • an alkenyl group which may either be a straight-chain or branched-chain group having 2 to 6 carbon atoms, a vinyl group is preferable.
  • an alkynyl group which may be a straight-chain or branched-chain group having 2 to 6 carbon atoms
  • an ethynyl group is preferable.
  • a fluorine atom is especially preferable and the number thereof may be 1 to 3.
  • an alkoxy group which may have 1 to 6 carbon atoms
  • a methoxy group is preferable.
  • a fluorine atom is especially preferable and the number thereof may be 1 to 3.
  • an alkyl group or an alkoxy group is preferable.
  • a methyl group, an ethyl group, a methoxy group, or a difluoromethoxy group is especially preferable.
  • this X 1 and the abovementioned R 1 may be integrated to form a ring structure comprised of a polymethylene ring by incorporating a part of the mother skeleton (so as to contain the carbon atom to which X 1 is bonded and the nitrogen atom to which R 1 is bonded).
  • the thus formed ring may contain an oxygen atom, a nitrogen atom, or a sulfur atom as a ring constituent atom, and this ring may also have as a substituent an alkyl group having 1 to 6 carbon atoms, which may have a substituent in turn.
  • the formed ring may be pentacyclic to heptacyclic in size and the ring constituent atoms are not limited to a carbon atom and may include an oxygen atom, a nitrogen atom, or a sulfur atom. Further, this ring may be saturated or unsaturated.
  • the thus formed ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. This alkyl group may be considered to be the same as the above-described alkyl group and is preferably a methyl group. This alkyl group may be substituted by a halogen atom, an alkoxy group, etc.
  • R 4 and X 1 are those in which R 4 is an alkyl group having 1 to 6 carbon atoms, an amino group, a hydrogen atom, or a hydroxyl group and X 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxy group 1 to 6 carbon atoms, a halogenomethoxy group, or a hydrogen atom.
  • R 4 is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group and X 1 is a methyl group, a methoxy group, a difluoromethoxy group, or a hydrogen atom.
  • R 4 is a hydrogen atom, a hydroxyl group, or a methyl group and X 1 is a methyl group or a methoxy group.
  • Each of substituent R 5 and R 6 independently represents an alkyl group having 1 to 6 carbon atoms, a hydrogen atom, or a substituted carboxyl group derived from an amino acid, a dipeptide, or a tripeptide.
  • This alkyl group may have one ore more substituents selected from the group consisting of an alkylthio group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, and a halogen atom.
  • alkyl group which may either be a straight-chain or branched-chain group having 1 to 6 carbon atoms, a methyl group, an ethyl group, a normal propyl group, or an isopropyl group is preferable.
  • the alkyl group may be a straight-chain or branched-chain group having 1 to 6 carbon atoms, and the hydroxyl group is more preferably substituted on the terminal carbon atom of the alkyl group.
  • the alkyl group having a hydroxyl group those with up to 3 carbon atoms is preferable and a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, etc. are preferable.
  • the alkyl group may be a straight-chain or branched-chain group having 1 to 6 carbon atoms, and the halogen atom is preferably a fluorine atom.
  • the number of fluorine atoms may correspond to a mono-substituted condition to a perfluoro-substituted condition. Examples thereof include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, etc.
  • the alkyl group may be a straight-chain or branched-chain group having 1 to 6 carbon atoms, and thealkylthio group may also be a straight-chain or branched-chain group having 1 to 6 carbon atoms.
  • an alkyl group having an alkylthio group an alkylthiomethyl group, an alkylthioethyl group, or an alkylthiopropyl group is preferable and it is more preferable for the alkylthio group to be a group having 1 to 3 carbon atoms as well. More preferable examples thereof include a methylthiomethyl group, an ethylthioethyl group, and a methylthioethyl group.
  • the alkyl group may be a straight-chain or branched-chain group having 1 to 6 carbon atoms, and the alkoxy group may also be straight-chain or branched-chain group having 1 to 6 carbon atoms.
  • an alkyl group having an alkoxy group an alkoxymethyl group, an alkoxyethyl group, or an alkoxypropyl group is preferable and it is more preferable for the alkoxy group to be a group having up to 3 carbon atoms as well. More preferable examples thereof include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group.
  • R 5 and R 6 are those in which one is a hydrogen atom and the other is a hydrogen atom, an alkyl group, or a substituted carboxyl group derived from an amino acid, a dipeptide, or a tripeptide.
  • a combination in which one of either R 5 or R 6 is a hydrogen atom and the other is a hydrogen atom or an alkyl group is more preferable.
  • an alkyl group a methyl group or an ethyl group is preferable and a methyl group is especially preferable.
  • R 5 and R 6 are hydrogen atoms or a combination in which one of either R 5 or R 6 is a hydrogen atom and the other is a methyl group is especially preferable.
  • a compound of this combination can especially express favorable physiological activity as an antibacterial agent.
  • a quinolone derivative wherein one of either substituent R 5 or R 6 is a hydrogen atom and the other is a substituted carboxyl group derived from an amino acid, a dipeptide, or a tripeptide is especially useful as a prodrug. Specific examples regarding this shall be described below.
  • the substituent halogen atom is preferably a fluorine atom or a chlorine atom and a fluorine atom is especially preferable.
  • the halogen atom and the quinolone carboxylic acid moiety have cis-configuration on the cyclopropane ring.
  • the cis-configuration substituent in this case may take the form of a 2-(S)-halogeno-1-(R)-cyclopropyl group or a 2-(R)-halogeno-1-(S)-cyclopropyl group, the former is preferable.
  • a compound of this invention exhibits excellent characteristics when there is a substituent of the structure represented by the following formula E at the 7-position of a quinolone mother skeleton, in particular, a 1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid skeleton having a 2-(S)-halogeno-1-(R)-cyclopropyl group.
  • 3-(1-aminocycloalkyl)pyrrolidinyl substituted-6-hydrogen-substituted-quinolone carboxylic acids, represented by formula (I), its salts, and hydrates thereof exhibit potent antibacterial activity against a wide range of gram-negative bacteria and gram-positive bacteria, and in particular, a characteristic of these compounds of this invention is that they exhibit potent antibacterial activity against resistant bacteria as represented by gram-positive cocci, including MRSA, PRSP, and VRE.
  • the characteristics of the compounds of this invention are that they exhibit excellent safety and good pharmacokinetics that enable the compounds to be used inclinical situations, which could not be achieved with compounds prior to this invention even if they had substituents of the same structures.
  • Such excellent properties of the compounds of this invention are exhibited by compounds in which the n in the above-described substituent is an integer of 1 or 2, and the excellent effects are seen especially with compounds for which n is an integer 1. That is, compounds wherein the cyclic part is a tricyclic ring are preferable compounds.
  • a compound comprised of a single diastereomer is preferably administered when the compound of this invention is administered to human or animals.
  • the term, “comprised of a single diastereomer” as used herein means not only a case in which it is completely free from the other diastereomer but also a case in which it is in a chemically pure degree. That is, it may be interpreted that the other diastereomer may be contained as long as there are no influences on the physical constants and physiological activities of the compound.
  • stereochemically pure means that, in the case where a compound or the like exists in a plurality of isomer forms due to the bpresence of asymmetric carbon atoms, the compound is comprised of only one of them.
  • pure in this case can also be considered in the same manner as described above.
  • the quinolone carboxylic acid derivative of this invention may be used either in its free form or as an acid addition salt or a salt of its carboxyl group.
  • the acid addition salt include inorganic acid salts, such as hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates, etc.; and organic acid salts, such as methanesulfonates, benzenesulfonates, toluenesulfonates (and other sulfonates), acetates, citrates, maleates, fumarates, lactates (and other carboxylates), etc.
  • salts of the carboxyl group include alkali metal salts, such as lithium salts, sodium salts, potassium salts, etc.; alkaline earth metal salts, such as magnesium salts, calcium salts, etc.; ammonium salts, triethylamine salts, N-methylglucamine salts, tris-(hydroxymethyl)aminomethane salts; etc., and these could either be inorganic salts or organic salts.
  • a carboxylic acid compound wherein the substituent R 3 is a hydrogen atom is preferably used
  • a quinolone derivative whose carboxylic acid moiety is an ester is useful as a synthesis intermediate or a prodrug.
  • alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters are useful as synthesis intermediates.
  • the ester to be used as a prodrug is an ester which is easily hydrolyzed in the living body and form free form of carboxylic acid
  • its examples include oxoalkyl esters, such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl esters, and 3-acetoxy-2-oxobutyl ester.
  • oxoalkyl esters such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxole
  • a quinolone derivative wherein one of either of the substituents R 5 and R 6 is a hydrogen atom and the other is a substituted carboxyl group derived from an amino acid, a dipeptide, or a tripeptide, is useful as a prodrug.
  • An amino acid, a dipeptide, or a tripeptide to be used for obtaining such a prodrug is one wherein the peptide bond, which is formed by the carboxyl group derived from the amino acid, dipeptide, or tripeptide and the amino group that exists on the substituent at the 7-position of the quinolone carboxylic acid derivative, can be easily hydrolyzed in the living body and form free form of amine, and its examples include those derived from glycine, alanine, aspartic acid, and other amino acids, glycine-glycine, glycine-alanine, alanine-alanine, and other dipeptides, and glycine-glycine-alanine, glycine-alanine-alanine, and other tripeptides.
  • the compound of this invention represented by the formula (I) can be produced by various methods, and in a preferred example, such a compound can be produced for example by reacting a compound represented by formula (III):
  • X 2 represents a substituent which functions as a leaving group, such as a substituted or unsubstituted phenylsulfonyl group, a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms, a fluorine atom, a chlorine atom or a bromine atom;
  • R 31 is the R 3 defined in the formula (I) or a boron-containing group represented by formula (IV):
  • Y 32 and Y 33 may be the same or different from each other with each being a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms);
  • R 1 , R 2 , R 4 , R 5 , R 6 , and A are as defined in the formula (I)] with a compound of the following formula (V) or an addtion salt thereof:
  • each of R 51 and R 61 independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a protective group for an amino group, or one of either R 51 or R 61 represents a hydrogen atom and the other represents a substituted carboxyl group derived from an amino acid, a dipeptide, or a tripeptide with an amino group that is unsubstituted or is protected by a protective group for an amino group, and
  • this alkyl group may have a substituent selected from the group consisting of an alkylthio group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, and a halogen atom, and
  • n is the same as defined in the formula (I)]
  • reaction in the case where an addition salt is used, the reaction is carried out under the presence of reagents that cause the addition salt to become a free form).
  • Examples of the acid addition salts include inorganic acid salts, such as hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates, etc.; and organic acid salts, such as methanesulfonates, benzenesulfonates, toluenesulfonates (and other sulfonates), acetates, citrates, maleates, fumarates, lactates (and other carboxylates); etc.
  • inorganic acid salts such as hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates, etc.
  • organic acid salts such as methanesulfonates, benzenesulfonates, toluenesulfonates (and other sulfonates), acetates, citrates, maleates, fumarates, lactates (and other carboxylates); etc.
  • the reaction may be carried out using a solvent or without using a solvent.
  • a solvent to be used in the reaction may be any solvent which have no an adverse effect on the reaction, and its examples include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, 3-methoxybutanol, or a mixture of thereof.
  • the reaction is preferably carried out under the presence of an acid receptor, such as an inorganic base or an organic base, for example, an inorganic basic compound, such as a carbonate or bicarbonate of an alkaline metal or an alkaline earth metal, or an organic basic compound, such as triethylamine, pyridine, 1,8-diazobicycloundecene, N-methyl piperidene, N,N-diisopropylethylamine, etc.
  • an acid receptor such as an inorganic base or an organic base
  • an inorganic basic compound such as a carbonate or bicarbonate of an alkaline metal or an alkaline earth metal
  • organic basic compound such as triethylamine, pyridine, 1,8-diazobicycloundecene, N-methyl piperidene, N,N-diisopropylethylamine, etc.
  • the reaction temperature should normally be in the temperature range of room temperature to 200° C. and preferably in the range of 25 to 150° C.
  • the reaction time should be in the range of 30 minutes to 48 hours, and the reaction is normally completed in approximately 30 minutes to 8 hours.
  • the protective group of an amino group may be any protective group that is generally used in the relevant field, and its examples include alkoxycarbonyl groups, which may have a substituent, such as tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, etc.; aralkyloxycarbonyl groups, which may have a substituent, such as benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, etc.; acyl groups, which may have a substituent, such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, etc.; alkyl groups, which may have a substituent, and aralkyl groups, which may have a substituent, such as tert-butyl group, benzyl group, para-nitro
  • each of R 3 and R 31 is an alkyl group having from 1 to 6 carbon atoms, an alkoxymethyl group having from 2 to 7 carbon atoms or a phenylalkyl group (aralkyl group) composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, it can be converted into a corresponding carboxylic acid by treatment under acidic or basic conditions which are generally used for the hydrolysis of carboxylic acid esters.
  • R 31 has a structure of the formula (IV), it can be converted into a corresponding carboxylic acid by subjecting it to hydrolysis under acidic or basic conditions after allowing the compound (V) to react with the compound (III).
  • the compound of interest represented by the formula (I) can be obtained by removing the protective group under appropriate conditions suitable for the protective group.
  • a compound of the formula (V) may be produced by various methods, and though a method shown in PCT/JP96/00208 maybe given as an example, the method of production is not limited to thereto.
  • a compound of the formula (V) can be produced by removing Q from a compound represented by the following formula (VI):
  • R 512 is the same as the R 5 defined in the formula (I) or represents a protective group of an amino group
  • R 6 and n are the same as defined in the formula (I)
  • Q is a protective group of an amino group
  • the protective group of an amino group may be selected from the group consisting of a (substituted) alkoxycarbonyl group, a (substituted) aralkyloxycarbonyl group, a (substituted) acyl group, a (substituted) alkyl group, a (substituted) aralkyl group and a substituted silyl group.
  • An above-described compound may be present in the form of a salt thereof, a hydrate thereof, or a hydrate of the salt.
  • the acid addition salt include inorganic acid salts and organic acid salts. Specific examples thereof include inorganic acid salts, such as hydrochlorides, sulfates, hydrobromides, hydroiodides, phosphates, etc.; and organic acid salts, such as methanesulfonates, benzenesulfonates, toluenesulfonates (sulfonic acid salts); acetates, citrates, maleates, fumarates, lactates (carboxylic acid salts); etc.
  • R 512 and Q are protective groups of an amino group, they may be the same or different from each other. However, it is more favorable for the production of compound (I) that each is cut off under different reaction conditions.
  • R 512 and Q which are protective groups of amino groups, include the following. That is, examples thereof include a (substituted) alkoxycarbonyl group, a (substituted) aralkyloxycarbonyl group, a (substituted) acyl group, a (substituted) alkyl group, a (substituted) aralkyl group, and a (substituted) silyl group.
  • alkoxycarbonyl groups such as tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, etc.
  • aralkyloxycarbonyl groups such as benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, etc.
  • acyl groups such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, etc.
  • alkyl groups or (substituted) aralkyl groups such as tert-butyl group, benzyl group, para-nitrobenzyl group, para-methoxybenzyl group, triphenylmethyl group, etc.
  • substituted alkoxycarbonyl groups such as tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group,
  • a compound of the formula (VI) can be produced by various methods, and though a method described in PCT/JP96/00208 may be given as an example, the production method is not limited thereto.
  • Cis-2-fluorocyclopropylamine comprised of a single isomer which is desirable for the synthesis of a compound of the formula (I) comprised of a single isomer, may synthesized for example by the method described in JP-A-2-231475 (the term “JP-A” as used herein means an unexamined published Japanese patent appliction”). Synthesis of the compound of formula (I) comprised of a single isomer using an optically active cis-2-fluorocyclopropylamine derivative obtained in the manner described above as a raw material, may be carried out for example in accordance with the method described for example in JP-A-2-231475.
  • the compound of this invention has potent antibacterial actions, it can be used as medicaments for use in human bodies, animals, and fishes or as preservatives of agricultural chemicals and food.
  • the compound of this invention is used as a medicament for human bodies, its dose is within the range of from 50 mg to 1 g, preferably from 100 mg to 500 mg, per day per adult.
  • the dose varies depending on the purpose of its administration (treatment or prevention), kind and size of each animal to be treated, kind and degree of each infected pathogenic bacterium, but is within the range of generally from 1 mg to 200 mg, preferably from 5 mg to 100 mg, per 1 kg body weight of each animal as a daily dose.
  • the daily dose is administered once a day or by dividing it into two to four doses per day. As occasion demands, the daily dose may exceed the abovementioned amounts.
  • the compounds of this invention are active against a broad range of microorganisms which cause various infectious diseases, it can treat, prevent or alleviate diseases caused by such pathogens.
  • bacteria and bacterioid microorganisms on which the compounds of this invention are effective include the genus Staphylococcus, Streptococcus pyogenes, hemolytic streptococcus, enterococcus, pneumococcus, the genus Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli , the genera Citrobacter, the genus Shigella, Klebsiella pneumoniae , the genera Enterobacter, the genus Serratia, the genus Proteus, Pseudomonas aeruginosa, Haemophilus influenzae , the genus Acinetobacter, the genus Campylobacter, Chlamydia trachomatis , and the like.
  • Examples of the diseases caused by the above pathogens include folliculitis, furuncle, carbuncle, erysipelas, phlegmon, lymphangitis (lymphadenitis), panaritium, subcutaneous abscess, hidrosadenitis, aggregated acne, infectious atheroma, anal abscess, mastitis, superficial secondary infections of traumatic wounds, burn wounds, operative wounds, etc., pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infections of chronic respiratory diseases, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, non-gonococcal urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, inflammation of the uterine appendages
  • examples of acid-fast bacteria on which the compounds of this invention are effective include tubercle bacilli [Mycobacterium (abbreviated as “M.” hereinafter) tuberculosis, M. bovis, M. africanum] , a typical acid-fast bacteria [ M. kansasii, M. marinum, M. scrofulaceum, M. avium, M. intracellulare, M. xenopi, M. fortuitum, M. chelonae] , etc.
  • tubercle bacilli infections may be seen in the thoracic cavity, trachea/bronchus, lymph nodes, in a generally disseminated manner, in the bones and joints, meninges/brain, digestive organs (intestines, liver), skin, mammary glands, eyes, middle ear/throat, urinary tract, male genitals, female genitals, etc.
  • the lungs are the main affected parts of a typical acid-fast bacteria infections (non-tubercle acid-fast bacteria infections), and other examples of a typical acid-fast bacteria infections include local lymphadenitis, soft skin tissue infections, articular infections, general dissemination type infections, etc.
  • the compounds of this invention are also effective against various microorganisms that cause infections in animals.
  • microorganisms include Escherichia, Salmonella, Pasturella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma, etc.
  • fowl diseases include escherichiosis, pullorum disease, fowl paratyphoid fever, fowl cholera, infectious coryza, staphylococcal infection, Mycoplasma infection, etc.
  • specific examples of pig diseases include escherichiosis, salmonellosis, pasturellosis, Haemophilis infection, atrophic rhinitis, exudative epidermitis, Mycoplasma infection, etc.
  • cattle diseases include escherichiosis, salmonellosis, hemorrhagic septicemia, Mycoplasma infection, contagious bovine pleuropneumonia, mastitis, etc.
  • specific examples of dog diseases include coliemia, Salmonella infection, hemorrhagic septicemia, pyometra, cystitis, etc.
  • specific examples of cat diseases include exudative pleurisy, cystitis, chronic rhinitis, Haemophilus
  • An antibacterial preparation which comprises the compound of this invention can be prepared by selecting an appropriate pharmaceutical preparation in accordance to the method of administration and using any of the generally used methods of preparing various pharmaceutical preparations.
  • dosage forms of antibacterial preparations having the compound of this invention as its principle agent tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, etc. can be given as examples of forms of oral pharmaceutical preparations.
  • a stabilizing agent, an antiseptic agent, a solubilizing agent, etc. may be used in the preparation, or a solution which may contain these auxiliary agents may be contained in a container and thereafter made into a solid preparation by freeze-drying or the like means to be re-dissloved when used.
  • a single dose may be contained in a single container or multiple doses may be contained in the same container.
  • Examples of forms of external-use preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays, etc.
  • a solid preparation may contain pharmaceutically acceptable additives together with the active compound.
  • pharmaceutically acceptable additives for example, fillers, extenders, binders, disintegrators, solubilization enhancing agents, moistening agents, lubricating agents, etc. may be selected and mixed as necessary to form a preparation.
  • Examples of forms of liquid preparations include solutions, suspensions, emulsions, and these may contain suspending agents, emulsifying agents, etc. as additives.
  • Examples of methods of administering the compound of this invention to an animal include a method of direct oral administration or oral administration by mixing it with feed, a method of preparing a solution and then performing oral administration of the solution directly or upon addition of the solution to drinking water or feed, a method of injection administration, etc.
  • a pharmaceutical preparation for administering the compound of this invention to an animal can be prepared optionally as powders, fine granules, soluble powders, syrups, solutions, or injections by the techniques generally used in the relevant field.
  • Formulation examples of pharmaceutical preparations are shown below.
  • Formulation Example 1 Capsule: Compound of Example 1 100.0 mg Corn starch 23.0 mg CMC calcium 22.5 mg Hydroxymethyl cellulose 3.0 mg Magnesium stearate 1.5 mg Total 150.0 mg
  • Formulation Example 2 (Solution): Compound of Example 1 1 to 10 g Acetic acid or sodium hydroxide 0.5 to 2 g Ethyl para-hydroxybenzoate 0.1 g Purified water 88.9 to 98.4 g Total 100 g
  • Formulation Example 3 (Powder to be mixed in feed) Compound of Example 1 1 to 10 g Corn starch 98.5 to 89.5 g Light silicic anhydride 0.5 g Total 100 g
  • IR (KBr, disk): 3055, 2985, 2933, 2875, 2814, 1942, 1693, 1630, 1593, 1477, 1431, 1379, 1277, 1255, 1221 cm ⁇ 1 .
  • IR (KBr, disk): 3438, 3097, 2983, 2939, 2902, 1907, 1720, 1630, 1593, 1566, 1460, 1429, 1387, 1367, 1311, 1250 cm ⁇ 1 .
  • IR (KBr, disk): 3097, 3014, 2956, 2642, 1957, 1728, 1618, 1566, 1508, 1469, 1435, 1389, 1321, 1254, 1200 cm ⁇ 1 .
  • IR (KBr, disk): 3375, 3062, 3006, 2925, 2864, 1728, 1610, 1508, 1475, 1431, 1394, 1348, 1315, 1257 cm ⁇ 1 .
  • the yellow extract obtained was then dissolved in toluene (800 ml), the para-toluenesulfonic acid salt of (1R, 2S)-2-fluorocyclopropylamine (60.1 g, 246 mmol) was added, and while stirring at ⁇ 15° C., a solution, in which triethylamine (40.8 ml, 293 mmol) was dissolved in toluene (200 ml), was added dropwise thereto. After stirring the reaction solution for 4 hours at room temperature, water (500 ml) was added, and the organic layer was separated. After washing the organic layer with saturated saline solution (500 ml ⁇ 2), it was dried over anhydrous sodium sulfate.
  • IR (KBr, disk): 3373, 3315, 3091, 3003, 2976, 2935, 2856, 1903, 1714, 1618, 1518, 1439, 1371, 1313, 1261, 1219 cm ⁇ 1 .
  • Ethyl 2-(2,6-dichloronicotinoyl)acetate (7.03 g, 26.8 mmol) was dissolved in acetic anhydride (30 ml), and after adding triethyl orthoformate (60 ml) thereto, it was stirred in an oil bath of 140° C. for 2 hours. After letting the reaction solution cool, it was concentrated under a reduced pressure, and after adding toluene (50 ml) to the residue obtained, a concentration operation under a reduced pressure was performed. This operation was repeated 3 times, and the residue obtained was dried under a reduced pressure. 8.42 g of ethyl 2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate was thereby obtained in the form of a yellow oily substance.
  • the residue was dissolved in a mixed solvent of ethyl acetate (100 ml) and dichloromethane (50 ml), and after washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 ml) in that order, the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (15 ml) to the residue while cooling with ice, it was stirred at the same temperature for 30 minutes.
  • n-hexane (10 ml) was then added, and after performing heated refluxing for 30 minutes, the reaction solution was allowed to stand under room temperature. The precipitated crystals were then filtered out, washed with a 1:1 mixed solution of n-hexane:ethyl acetate and dried under a reduced pressure at 60° C. for 16 hours. 869 mg (38%) of the title compound was thereby obtained as a yellow powder.
  • the precipitated crystals were filtered out, washed with excess water, a small amount of cold ethanol and excess diethyl ether in that order, and then dried under a reduced pressure at 80° C. for 17 hours. 552 mg (82%) of the title compound was thereby obtained in the form of yellow crystals.
  • Ethyl 3-dimethylamino-2-(2,3,4-trifluorobenzoyl)acrylate (15.0 g, 49.8 mmol) was dissolved in ethanol (30 ml), and to this solution, an ethanol (10 ml) solution of (S)-2-amino-1-propanol (4.50 g, 59.8 mmol) was added dropwise while stirring and cooling with ice. After completion of dripping, the reaction solution was stirred for 1 hour at room temperature and then concentrated under a reduced pressure. The residue obtained was dissolved in dimethyl sulfoxide (50 ml), and after adding spray-dried calcium fluoride (16 g) thereto, it was stirred at 120° C. for 26 hours.
  • IR (KBr, disk) v 3440, 3329, 3082, 3005, 2964, 2937, 2877, 1716, 1620, 1549, 1506, 1437, 1404 cm ⁇ 1 .
  • Ethyl 1-acetylcyclopropanecarboxylate 200 g, 1.28 mol was dissolved in ethanol (1000 ml), and bromine (72.7 ml, 1.41 mol) was added dropwise while stirring and cooling with ice. After completion of dripping, the temperature of the reaction solution was raised to 30° C. and stirring was performed for 2 hours. After adding water (1000 ml) to the reaction solution while cooling with ice, it was concentrated under a reduced pressure was performed.
  • the concentrate was subjected to extraction with diisopropyl ether (75 ml ⁇ 2) and then washed with water (75 ml). After extracting the organic layer into 1 mol/l hydrochloric acid (100 ml ⁇ 2), the acidic aqueous solution was washed with ethyl acetate (100 ml). After adding a 1 mol/l aqueous sodium hydroxide solution (100 ml) to this acidic aqueous solution and then further adding saturated sodium bicarbonate water (100 ml), extraction with ethyl acetate (100 ml) was performed.
  • the concentrate was dissolved in anhydrous tetrahydrofuran (300 ml) and after adding dropwise an anhydrous tetrahydrofuran (300 ml) solution of ethyl 1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (45.7 g, 166 mmol) and triethylamine (25.1 ml, 183 mmol) while stirring and cooling with ice, it was stirred while cooling with ice for 1.5 hours and then stirred at room temperature for 2 hours.
  • the instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.
  • the instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.
  • the aqueous layer was then made acidic by concentrated hydrochloric acid while cooling with ice and then subjected to extraction with chloroform (70 ml ⁇ 3).
  • the organic layer was then dried over anhydrous sodium sulfate, and after filtering, the filtrate was concentrated under a reduced pressure. 9.40 g (99%) of the title compound was thereby obtained as white solids.
  • a toluene (15 ml) solution of triethylamine (9.6 ml, 69 mmol) and diphenylphosphoric acid azide (DPPA; 10.4 g, 37.9 mmol) was added to a toluene (80 ml) suspension of 1-[1-[1-(S)-phenylethyl]-2-one-4-(S)-pyrrolidin-4-yl]-1-cyclopropanecarboxylic acid (9.4 g, 34.4 mmol), and after stirring at room temperature for 1 hour under a nitrogen atmosphere, it was heated under reflux for 1.5 hours.
  • DPPA diphenylphosphoric acid azide
  • the aqueous layer obtained was gradually made acidic with concentrated hydrochloric acid while cooling with ice and the resulting crystals were filtered out. After washing the filtered-out crystals with water, the water was removed by azeotropic distillation with toluene. 22.33 g (91%) of the title compound was thereby obtained as a pale yellow powder.
  • reaction solution After stirring at room temperature for 3 hours, the reaction solution was cooled with ice and the above-described solution A was dripped into this reaction solution over a period of 10 minutes. After then washing solution A into the reaction solution using tetrahydrofuran (10 ml), it was stirred at room temperature for 14 hours, and then the reaction solution was poured into a 10% aqueous citric acid solution (200 ml). This was then extracted with ethyl acetate (200 ml), washed with saturated saline solution (200 ml), and then dried over anhydrous sodium sulfate.
  • the combined organic layer was then dried over anhydrous sodium sulfate, and after removing the drying agent bt the filtration, the solvent was evaporated under a reduced pressure.
  • the residue was partitioned in chloroform (50 ml) and 10% aqueous citric acid solution (30 ml), and after separating the organic layer, the organic layer was washed with saturated saline solution (30 ml). The organic layer obtained was then dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure.
  • reaction solution was stirred at ⁇ 78° C. for 1 hour and then dried carbon dioxide was bubbled into this reaction solution for 30 minutes. Thereafter, the reaction solution was stirred at ⁇ 78° C. for 1 hour, then raised gradually in temperature, and then stirred at room temperature for 12 hours. 100 ml of 1 mol/l Hydrochloric acid was then added to the reaction solution while cooling with ice and extraction into diethyl ether (500 ml ⁇ 2) was performed. The combined organic layer was washed with saturated saline solution (500 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under a reduced pressure, thereby obtaining 29.7 g (90%) of the yellow, amorphous compound of the title. This product was used in the subsequent reaction without further purification.
  • Antibacterial activities of the compounds of this invention were measured in accordance to the standard method designated by the Japan Society of Chemotherapy, with the results shown as MIC values (microgram/ml) units in the following table.
  • Example Example Example 1 2 3 10 11 E. coli , ⁇ 0.003 ⁇ 0.003 ⁇ 0.003 ⁇ 0.003 0.006 NIHJ S. flexneri , 0.006 0.012 ⁇ 0.003 0.006 0.012 2A 5503 Pr. vulgalis , ⁇ 0.003 0.012 ⁇ 0.003 0.006 0.012 08601 K. 0.025 0.05 0.012 0.025 0.1 pneumoniae , Type 1 Ser. 0.025 0.1 0.025 0.05 0.2 marcescens , 10100 Ps. 0.05 0.2 0.05 0.1 0.2 aeruginosa , 32104 Ps.
  • Example Reference 14 15 drug 1 LVFX CPFX E. coli , ⁇ 0.003 ⁇ 0.003 ⁇ 0.003 0.012 ⁇ 0.003 NIHJ S. flexneri , 0.006 0.006 ⁇ 0.003 0.025 0.006 2A 5503 Pr. vulgalis , 0.012 0.012 ⁇ 0.003 0.012 ⁇ 0.003 08601 K. 0.05 0.025 0.006 0.1 0.025 pneumoniae , Type 1 Ser. 0.1 0.1 0.012 0.1 0.025 marcescens , 10100 Ps. 0.1 0.1 0.025 0.2 0.005 aeruginosa , 32104 Ps.
  • Example 1 of this invention the micronucleus test in bone marrow of mice was performed by the following method.
  • mice each consisting of five, six-week-old, Slc:ddY male mice, were used.
  • the 0.1 mol/l NaOH/saline solvent was used as a control, and as a positive Reference drug, a drug solution, prepared by dissolving and diluting cyclophosphamide (CP) in saline solution, was used. All drug solutions were disinfected by filtration through Mylex GS 0.22 ⁇ m filters. With each drug solution, a single intravenous dose of 10 ml/kg was administered at an administration rate of 0.2 ml/min. 24 hours after administration, myeloma cells were collected from the femur bone, the smear preparations were prepared, and these were dyed with acrylic orange.
  • CP cyclophosphamide
  • Example 1 For the compound of this invention described as Example 1, the blood concentration and organ concentration after oral administration were determined by the following methods. Measurements were also made by the same methods for Reference drug 1.
  • An administration solution was prepared by dissolving a tested compound to a concentration of 2 mg/ml (as free compound) in distilled water, and using a 2.5 ml disposable syringe or a metal oral probe, the solution was orally administered at a dose of 20 mg/kg to fasting rats (Crj: CD IGS; male; 7-week-old; Charles River Japan, Inc.).
  • the absorption test groups (4 rats per group; total of 6 groups) were killed by exsanguination while under ether anesthetization 0.25, 0.5, 1, 2, 4, or 6 hours after drug administration, and the blood, liver, kidneys, and lungs were sampled. With the blood, serum was sampled by centrifugation (3000 rpm ⁇ 15 minutes, 4° C.) after coagulation. Tissues were homogenized after adding 3 to 5 ml of 0.1M phosphate buffer solution (pH 7.0) and the centrifugation supernatants (3000 rmpm ⁇ 15 minutes, 4° C.) were collected.
  • the excretion test groups (4 rats per group) were put in a metabolic cage after drug administration, and collected urine samples for 0 to 4 hours and 4 to 24 hours were sampled while cooling with ice, and at the time of sampling, the interior of the cage was washed with approximately 15 ml of 0.1 mol/l phosphate buffer solution (pH 7.0) to recover the urine attached to the interior of the cage. Also in order to examine glucuronide and other conjugated compounds, a part of the sample was separated, hydrolyzed with an equivalent amount of 1 mol/l aqueous sodium hydroxide solution, and thereafter neutralized with 0.5 mol/l hydrochloric acid, and concentration measurements were made on samples prepared in this manner.
  • test medium was prepared by inoculating a suspension containing 5 ⁇ 10 7 CFU/ml of spores of the test bacteria at a proportion of 1% into an nutrient agar (Eiken Kagaku) that was sterilized at 121° C. for 15 minutes and then cooled to approximately 50° C. After placing 10 ml each of this medium in a sterilized Petri dish and solidifying horizontally, four holes of 8 mm diameter were made to prepare a test plate medium.
  • the Bioassay System TDA-1 (Dainippon Seiki) was used for preparation of the test plate media.
  • the test samples diluted with serum or phosphate buffer solution as necessary
  • serial dilutions of the drug solutions for calibration two-fold serial dilutions prepared so that the inhibition ring diameter will be approximately 10 to 30 mm
  • a reference drug solution a drug solution of given concentration for correction of the error among plates; normally, a concentration of forming an inhibition ring of approximately 20 mm is used
  • 50 ⁇ L of the test sample (or the drug solution for calibration) were placed in each of two of the four holes of each plate and 50 ⁇ L of the reference solution was placed in each of the other two holes.
  • the plate medium was set still for 1 hour at 4° C. to perform preliminary dispersion and then culturing at 37° C. was performed for approximately 18 hours, and the inhibition ring diameters were measured using CA-400 (Dainippon Seiki).
  • the concentrations of the test samples were measured using a calibration curve determined by second-order regression from the logarithmic values of the drug concentration of the calibration curve serial dilutions and the inhibition ring diameters.
  • the concentration ( ⁇ g/ml) in the homogenate supernatant was determined from the tissue weight (g) and the added phosphate buffer amount (ml) and using the following equation:
  • the urinary excretion rate (%) was determined from the amount ( ⁇ g) of drug administered, amount (ml) of urine (or washing solution), and concentration ( ⁇ g/ml) in urine (or washing solution):
  • Compounds of this invention exhibit excellent antibacterial action upon a broad range of both gram-negative and gram-positive bacteria and, in particular, exhibit potent antibacterial activity even against resistant gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), vancomycin-resistant Enterococcus (VRE), etc., and quinolone-resistant bacteria, and yet are excellent in safety characteristics, such as being negative in micronucleus tests, and excellent in pharmacokinetics, such as being improved in urinary recovery rates and being excellent in oral absorption and tissue penetration, etc.
  • MRSA methicillin-resistant Staphylococcus aureus
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • VRE vancomycin-resistant Enterococcus
  • quinolone-resistant bacteria and yet are excellent in safety characteristics, such as being negative in micronucleus tests, and excellent in pharmacokinetics, such as being improved in urinary

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US20060122396A1 (en) * 2003-06-19 2006-06-08 Daiichi Pharmaceutical Co., Ltd. Method of selectively introducing amino substituent
US20060135775A1 (en) * 2003-06-06 2006-06-22 Daiichi Pharmaceutical Co., Ltd. Intermediates and process for the production of optically active quinolonecarboxylic acid derivatives
US20080255190A1 (en) * 2003-09-29 2008-10-16 Daiichi Pharmaceutical Co., Ltd. 8-Cyanoquinolonecarboxylic Acid Derivative
CN100441580C (zh) * 2006-07-14 2008-12-10 中山大学 喹啉二酮衍生物及其在制备抗菌药物中的应用
US20090117205A1 (en) * 2004-07-02 2009-05-07 Daiichi Pharmaceutical Co., Ltd Quinolone-containing medicinal composition

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CA2429440C (en) 2000-11-20 2009-12-29 Daiichi Pharmaceutical Co., Ltd. Dehalogeno-compounds
JP4629973B2 (ja) * 2003-09-22 2011-02-09 第一三共株式会社 光学活性シクロプロピルアミン誘導体およびその製造方法
ES2537976T3 (es) 2003-12-12 2015-06-16 Daiichi Sankyo Company, Limited Compuestos intermedios para la producción de derivados de ciclopropilamina ópticamente activos y procedimiento para la producción de los compuestos intermedios
TW200744598A (en) * 2005-09-28 2007-12-16 Daiichi Seiyaku Co Process for the production of freeze-dried preparations containing quinolones
KR101502453B1 (ko) * 2006-08-11 2015-03-24 노던 안티바이오틱스 리미티드 폴리믹신 유도체들 및 이들의 용도
JP5174365B2 (ja) * 2007-03-23 2013-04-03 第一三共株式会社 キノロン含有凍結乾燥製剤の製造方法

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US5476950A (en) * 1985-06-26 1995-12-19 Daiichi Seiyaku Co., Ltd. Intermediates for pyridonecarboxylic acid derivatives
US5849757A (en) * 1995-02-02 1998-12-15 Daiichi Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives substituted by a bicyclic amino group as antibacterials
US6121285A (en) * 1995-11-22 2000-09-19 Daiichi Pharmaceutical Co., Ltd. Substituted aminocycloalkylpyrrolidine derivatives and cis-substituted aminocycloalkylpyrrolidine derivatives
US6184388B1 (en) * 1995-11-22 2001-02-06 Daiichi Pharmaceutical Co., Ltd. Substituted aminocycloalkylpyrrolidine derivatives and cis-substituted aminocycloalkylpyrrolidine derivatives
US6448266B1 (en) * 1997-05-30 2002-09-10 Daiichi Pharmaceutical Co., Ltd. Substituted cyclobutylamine derivatives

Cited By (9)

* Cited by examiner, † Cited by third party
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US20060135775A1 (en) * 2003-06-06 2006-06-22 Daiichi Pharmaceutical Co., Ltd. Intermediates and process for the production of optically active quinolonecarboxylic acid derivatives
US7915418B2 (en) 2003-06-06 2011-03-29 Daiichi Pharmaceutical Co., Ltd. Intermediates and process for the production of optically active quinolonecarboxylic acid derivatives
US20060122396A1 (en) * 2003-06-19 2006-06-08 Daiichi Pharmaceutical Co., Ltd. Method of selectively introducing amino substituent
US7626029B2 (en) 2003-06-19 2009-12-01 Daiichi Pharmaceutical Co., Ltd. Method of selectively introducing amino substituent
US20100069435A1 (en) * 2003-06-19 2010-03-18 Daiichi Pharmaceutical Co., Ltd. Method of selectively introducing amino substituent
US20080255190A1 (en) * 2003-09-29 2008-10-16 Daiichi Pharmaceutical Co., Ltd. 8-Cyanoquinolonecarboxylic Acid Derivative
US7723524B2 (en) 2003-09-29 2010-05-25 Daiichi Pharmaceutical Co., Ltd. 8-cyanoquinolonecarboxylic acid derivative
US20090117205A1 (en) * 2004-07-02 2009-05-07 Daiichi Pharmaceutical Co., Ltd Quinolone-containing medicinal composition
CN100441580C (zh) * 2006-07-14 2008-12-10 中山大学 喹啉二酮衍生物及其在制备抗菌药物中的应用

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TWI315308B (en) 2009-10-01
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EP1336611A4 (en) 2004-07-21
BR0115326A (pt) 2004-02-25
US7902226B2 (en) 2011-03-08
MXPA03004437A (es) 2004-05-04
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HK1056729A1 (en) 2004-02-27
AR035599A1 (es) 2004-06-16
US20070123560A1 (en) 2007-05-31
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WO2002040478A1 (fr) 2002-05-23
ATE372338T1 (de) 2007-09-15
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CA2429440C (en) 2009-12-29

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