WO1998024781A1 - Derives d'aminomethylpyrrolidine substitue - Google Patents

Derives d'aminomethylpyrrolidine substitue Download PDF

Info

Publication number
WO1998024781A1
WO1998024781A1 PCT/JP1996/003552 JP9603552W WO9824781A1 WO 1998024781 A1 WO1998024781 A1 WO 1998024781A1 JP 9603552 W JP9603552 W JP 9603552W WO 9824781 A1 WO9824781 A1 WO 9824781A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
atom
alkyl
alkyl group
Prior art date
Application number
PCT/JP1996/003552
Other languages
English (en)
Japanese (ja)
Inventor
Makoto Takemura
Youichi Kimura
Katsuhiro Kawakami
Kazuyuki Sugita
Hitoshi Ohki
Original Assignee
Daiichi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Pharmaceutical Co., Ltd. filed Critical Daiichi Pharmaceutical Co., Ltd.
Priority to PCT/JP1996/003552 priority Critical patent/WO1998024781A1/fr
Priority to AU10405/97A priority patent/AU1040597A/en
Publication of WO1998024781A1 publication Critical patent/WO1998024781A1/fr

Links

Classifications

    • 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

Definitions

  • the present invention relates to an antibacterial compound useful as a medicament, an animal drug, a marine drug or an antibacterial preservative, and further relates to an antibacterial agent containing this compound.
  • the present inventors have conducted intensive studies to provide an excellent compound satisfying the above requirements, and as a result, a substituted aminomethylpyrrolidine derivative represented by the following general formula (I) and a salt thereof,
  • their hydrates have a wide range of antibacterial activity, exhibiting strong antibacterial activity, especially against gram-positive bacteria, especially quinolone-resistant bacteria including MRSA, and have good pharmacokinetics and safety
  • the inventors have found that the present invention also has the above-mentioned features and completed the present invention.
  • the present invention provides a compound represented by the following general formula (I) and a salt thereof, And for their hydrates:
  • R ′ and R 2 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 3 , R 4 and R 5 each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or 1 carbon atom; Represents from 6 to 6 alkylthio groups,
  • the alkyl group may have, as a substituent, at least one group selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms,
  • R 4 and R 5 are integrated to form a methylene chain having 3 to 6 carbon atoms (forming a pyrrolidine ring and a spiro ring system), a hydroxymino group, or a carbon atom having 1 to 6 carbon atoms. May be an alkyloxyamino group of
  • R 6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 7 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • the alkyl group may have, as a substituent, one or more groups selected from the group consisting of a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, and a halogen atom.
  • R 8 and R 9 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 1 D 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, and a carbon number which may have a substituent.
  • R ′ 1 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms.
  • R 11 and the above R 1 G are integrated so as to form a cyclic structure including a part of the mother nucleus.
  • This ring may contain a sulfur atom as a constituent atom of the ring, and further, the ring may have an alkyl group having 1 to 6 carbon atoms as a substituent .
  • X 1 represents a halogen atom or a hydrogen atom
  • R 12 is a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, 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, or carbon atom Represents an alkoxyl group of the formulas 1 to 6, wherein the amino group is selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms. It may have the above groups as substituents.
  • a 1 is a nitrogen atom or the formula (III)
  • X 2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, Or an alkenyl group having 6 to 6 carbon atoms, or an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms.
  • This amino group has, as a substituent, at least one group selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms. Is also good.
  • X 2 and the above R 1 Q may be integrated so as to form a cyclic structure including a part of the mother nucleus, and this ring may be an oxygen atom, a nitrogen atom, or a sulfur atom.
  • An atom may be included as a constituent atom of the ring, and the ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.
  • Y 1 is a hydrogen atom, a phenyl group, an acetomethyl group, a bivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, 5 — indanyl group, phthalidinyl group, 5 — Alkyl 2 -oxo 1, 3 -dioxo 4 -ylmethyl group, 3 -acetoxy-2 -oxobutyl group, alkyl group having 1 to 6 carbon atoms, alkoxymethyl group having 2 to 7 carbon atoms, Or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group. ]
  • R 13 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, or a carbon number which may have a substituent.
  • a cyclic alkyl group having 3 to 6 carbon atoms, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms Represents an alkylamino group, R represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, 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, or 1 represents an alkoxyl group having 6 carbon atoms, among which the amino group is a group of the group consisting of a formyl group, an alkyl group having 1 carbon atom, an alkyl group having 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms. It may have one or more selected groups as substituents
  • X 3 represents a halogen atom or a hydrogen atom
  • a 2 is a nitrogen atom or a formula (V)
  • X 4 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, Represents an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
  • the amino group has, as a substituent, at least one group selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms. May be.
  • X 4 and R 13 may be integrated so as to form a cyclic structure including a part of the mother nucleus, but this ring is composed of an oxygen atom, a nitrogen atom, or a sulfur atom. May be contained as a constituent atom of the ring, and the ring may further have an alkyl group having 1 to 6 carbon atoms as a substituent. )
  • Upsilon 2 is a hydrogen atom, Fuweniru group, ⁇ Se Tokishimechiru group, Viva Roy Ruo Kishime methyl group, Et butoxycarbonyl group, co re down group, Jimechirua Mi aminoethyl group, 5-b Ndaniru group, lid Li Jiniru group, 5 - Alkyl 2 -oxo 1, 3 -dioxo-1-ylmethyl, 3 -acetoxy-2 -oxobutyl, alkyl having 1 to 6 carbons, alkoxymethyl having 2 to 7 carbons, or Charcoal Represents a phenylalkyl group composed of an alkylene group having a prime number of 1 to 6 and a phenyl group. ]
  • the present invention provides the above compound having the structure represented by the formula (III) in the general formula (I), a salt thereof, and a hydrate thereof;
  • R ′ ° is a halogenocyclopropyl group, and hydrates thereof;
  • the above-mentioned compound wherein the halogenocyclopropyl group is a 1,2-cis-12-halogenocyclopropyl group, a salt thereof, and a hydrate thereof;
  • the above compound wherein the halogenocyclopropyl group is a (1R, 2S) 1-2-halogenocyclopropyl group, a salt thereof, and a hydrate thereof;
  • the above-mentioned compound in which the halogen atom of the hydrogenocyclopropyl group is a fluorine atom, a salt thereof, and a hydrate thereof;
  • a medicament comprising a compound of general formula (I) or a salt thereof or a hydrate thereof as an active ingredient
  • An antibacterial agent comprising a compound of the general formula (I) or a salt thereof or a hydrate thereof as an active ingredient;
  • the substituents R ′ and R 2 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkyl group having 1 carbon atom. Consisting of 6 alkoxyl groups It may have one or more groups selected from the group of the groups as a substituent.
  • the alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.
  • the alkyl group When a hydroxyl group is substituted on the alkyl group, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the hydroxyl group may be substituted on the terminal carbon atom of the alkyl group. Substitutions are more preferable.
  • the alkyl group having a hydroxyl group is preferably an alkyl group having up to 3 carbon atoms, and is preferably a hydroxymethyl group, a 2-hydroxyhexyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, or the like.
  • the alkyl group may be linear or branched having 1 to 6 carbon atoms, and a fluorine atom is preferable as the halogen atom.
  • the alkyl group When an alkylthio group is substituted on the alkyl group, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkylthio group may be linear or branched having 1 to 6 carbon atoms. Either may be used.
  • the alkyl group having an alkylthio group an alkylthiomethyl group, an alkylthioethyl group, and an alkylthiopropyl group are preferable, and an alkylthio group having up to 3 carbon atoms is also preferable. More preferred examples include a methylthiomethyl group, an ethylthiomethyl group, and a methylthioethyl group.
  • the alkyl group When an alkoxy group is substituted on the alkyl group, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkoxyl group may be linear or branched having 1 to 6 carbon atoms. It is good.
  • the alkyl group having an alkoxyl group an alkoxymethyl group, an alkoxyethyl group, and an alkoxypropyl group are preferable, and further, the alkoxyl group having up to 3 carbon atoms is preferable. More preferred examples include a methoxymethyl group, an ethoxyquinmethyl group and a methoxethyl group.
  • R 1 or R 2 is a hydrogen atom.
  • an alkyl group, and among the alkyl groups, a methyl group is preferred. That is, it is preferable that both R 1 and R 2 are methyl groups, or that one is a methyl group and the other is a hydrogen atom, and that both are hydrogen atoms.
  • the carbon atoms to which R 1 and R 2 are bonded are not the same, they become asymmetric carbons to give isomers, and the present invention includes both.
  • the substituents R 3 , R 4 and R 3 each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or Represents an alkylthio group of 1 to 6, wherein the alkyl group is at least one group selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms as a substituent. You may have it.
  • R 4 and R 5 combine to form a methylene chain having 3 to 6 carbon atoms (forming a pyrrolidine ring and a spiro ring system), a hydroxymino group, or an alkyloxy having 1 to 6 carbon atoms. It may be a amino group.
  • halogen atom a fluorine atom or a chlorine atom is preferable.
  • the alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group.
  • the alkoxyl group may be a linear or branched one having 1 to 6 carbon atoms, and is preferably a methoxy group or an ethoxy group.
  • the alkylthio group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methylthio group or an ethylthio group.
  • the alkyl group having 1 to 6 carbon atoms having a hydroxyl group may be linear or branched.
  • Preferred examples of the alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group include a hydroxymethyl group, a 2-hydroxylethyl group, and a 3-hydroxypropyl group.
  • halogen atom of the alkyl group having a halogen atom a fluorine atom and a chlorine atom are preferable, and a fluorine atom is particularly preferable.
  • Alkyl groups must be linear It may be any of branched or branched.
  • Any alkyl group portion of the alkyl group having 1 to 6 carbon atoms having an alkoxyl group may be straight-chain or branched, and is preferably an alkoxymethyl group or an alkoxyshethyl group. More preferably, mention may be made of a methoxymethyl group, an ethoxymethyl group and a 2-methoxethyl group.
  • a spirocyclic structure is formed by adding a new 3- to 6-membered ring to the pyrrolidine ring.
  • the size of the newly formed ring is preferably a cyclopropyl ring or a cyclobutyl ring having 2 or 3 carbon atoms.
  • R 4 and R 5 are integrated to form an alkyloxy amino group.
  • the alkyl group may be linear or branched.
  • Preferable alkyloxymino groups are methoxymino groups and ethoxymino groups.
  • R 3 , R or R 5 is preferably a lower alkyl group or a halogen atom, more preferably a methyl group, an ethyl group, a propyl group, a fluorine atom and a chlorine atom. Can be.
  • the substituent R 6 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • the alkyl group may be a straight or branched one having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group.
  • the substituent R 7 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is selected from a group consisting of a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, and a halogen atom.
  • the above groups may be present as substituents.
  • the alkyl group may be a straight or branched one having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group.
  • the alkyl group having 1 to 6 carbon atoms having a hydroxyl group may be straight-chain or branched, and the hydroxyl group is more preferably substituted at the terminal carbon atom of the alkyl group.
  • Preferable examples of the alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group include a hydroxymethyl group, a 2-hydroxyhexyl group and a 3-hydroxypropyl group.
  • a fluorine atom is preferable, and a number of 1 to 3 fluorine atoms is preferable.
  • the number of carbon atoms is preferably up to two.
  • the alkyl group having a halogen atom a 2-fluoroethyl group, a 2,2-difluoroethyl group, and a 2,2,2-trifluoroethyl group are particularly preferable.
  • the alkyl group When an alkoxy group is substituted on the alkyl group, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkoxyl group may be linear or branched having 1 to 6 carbon atoms. May be used.
  • the alkyl group having an alkoxyl group an alkoxymethyl group, an alkoxyethyl group, and an alkoxypropyl group are preferable, and further, the alkoxyl group having up to 3 carbon atoms is preferable. More preferred are a methoxymethyl group, an ethoxymethyl group, and a methoxyxethyl group.
  • the substituents R 6 and R 7 are preferably both hydrogen atoms, then one is preferably a hydrogen atom and the other is an alkyl group, and both are preferably an alkyl group.
  • the substituents R 8 and R 9 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • the alkyl group may be a linear or branched alkyl group having 1 carbon atom or 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group. Of these, the case where each is a hydrogen atom is preferred.
  • the substituent R 1 (1 and R 13 each may have 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, or a substituent Good C3-C6 cyclic alkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, C1-C6 alkoxyl Or an alkylamino group having 1 to 6 carbon atoms, wherein an ethyl group is particularly preferred as the alkyl group having 1 to 6 carbon atoms, and a vinyl is used as the alkenyl group having 2 to 6 carbon atoms.
  • a 1-isoprobenyl group is preferable, and a 2-fluoroethyl group is preferable as a halogenoalkyl group having 1 to 6 carbon atoms, and 3 to 5 carbon atoms which may have a substituent.
  • the cyclic alkyl group of 6 is a cyclic propyl group and 2 A chloropropyl group is preferred, and a fluorine atom is particularly preferred as the halogen atom of the 2-genocyclopropyl group.
  • aryl group which may have a substituent examples include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, a hydroxyl group, an amino group, a nitrogen atom, and a number of carbon atoms.
  • a phenyl group, and the like with preference given to a phenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group, a 2,4-difluorophenyl group, a 2-fluoro-4-hydroxyphenyl group, and the like.
  • a heteroaryl group is a substituent derived from an aromatic heterocyclic compound containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include a pyridyl group and a pyrimidyl group. As a substituent on these rings, an alkyl group, a halogen atom and the like are preferable. Further, it may be an alkoxyl group having 1 to 6 carbon atoms, and among them, a methoxy group is preferable. Furthermore, an alkylamino group having 1 to 6 carbon atoms may be used, and among them, a methylamino group is preferable.
  • R l fl and R 13 are substituents for substituent R l fl and R 13, arbitrarily favored cyclic alkyl group or a halogeno cycloalkyl group,. Of these, a cyclopropyl group or a 2-halogenocyclopropyl group is preferred. As the halogen atom, a fluorine atom is preferable.
  • the substituent R 11 is a hydrogen atom or a force representing an alkylthio group having 1 to 6 carbon atoms, or R 11 and R 1 D include a part of the mother nucleus (R 11 is bonded It may be integrated to form a ring structure (to include the carbon atom and the nitrogen atom to which R 1 Q is attached).
  • the ring thus formed may contain a sulfur atom as a constituent atom of the ring, and further, the ring has an alkyl group having 1 to 6 carbon atoms as a substituent. Is also good.
  • the ring formed here may have a size of 4 to 6 members, and this ring may be either saturated or unsaturated.
  • R 1 ′ a methylthio group is preferable.
  • R 11 and R l is fl and is a ring formed by one embodied, arbitrary preferable is 4 or 5 membered ring comprising a sulfur atom and methylene chain.
  • the position of the sulfur atom is preferably directly bonded to the mother nucleus.
  • the substituents X ′ and X 3 are a halogen atom or a hydrogen atom, and a halogen atom is preferably a fluorine atom. Of these, fluorine atoms and Is preferably a hydrogen atom as a substituent.
  • the substituents R 12 and R 14 are a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms, or a carbon atom.
  • the alkyl group may be a linear or branched one having 1 carbon atom or 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group.
  • the alkenyl group may be a straight-chain or branched chain having 2 to 6 carbon atoms, and is preferably a vinyl group.
  • the alkynyl group may be a linear or branched one having 2 to 6 carbon atoms, but is preferably an ethynyl group.
  • As the halogen of the halogenomethyl group a fluorine atom is particularly preferred, and the number may be from 1 to 3.
  • the alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxy group.
  • Substituents R 1 2 and R 1 4 and to the alkyl group or A Mi amino group is laid preferred, arbitrary preferable is a methyl group or an unsubstituted A Mi amino group is Of these,.
  • substituents R 12 and R 14 are an amino group, a hydroxyl group, or a thiol group, these may be protected by a commonly used protecting group.
  • protecting groups include, for example, tertiary butoxycarbonyl group, alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, and paramethoxybenzyl.
  • Aralkyloxycarbonyl groups such as oxycarbonyl group, paranitrobenzoyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, bivaloyl group, formyl group, benzoyl group, etc.
  • Alkyl groups such as acetyl group, tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group or aralkyl group, methoxymethyl group, tertiary butoxymethyl group, Tetrahydrobiranyl group, 2,2,2- Ethers such as chloroethoxymethyl group, silyl groups such as trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group, and tertiary butyldiphenylsilyl group Groups can be mentioned. Compounds having substituents protected by these substituents are particularly preferred as intermediates during production.
  • X 2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms.
  • the amino group is at least one group selected from the group consisting of a formyl group, a carbon atom, an alkyl group having 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms. It may have.
  • the alkyl group may be a linear or branched one having 1 to 6 carbon atoms, preferably a methyl group and an ethyl group.
  • the alkenyl group may be a linear or branched one having 2 to 6 carbon atoms, but is preferably a vinyl group.
  • the alkynyl group may be a linear or branched one having 2 to 6 carbon atoms, and is preferably an ethynyl group.
  • halogen of the halogenomethyl group a fluorine atom is particularly preferred, and the number thereof may be 1 to 3.
  • the alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxyl group.
  • halogen of the halogenomethoxyl group a fluorine atom is particularly preferred, and the number thereof may be 1 to 3.
  • an alkyl group, an alkoxyl group, or a halogenomethoxyl group is preferable. Even more preferred are the methyl, methoxyl, and difluoromethoxyl groups.
  • this X 2 and the above R 1 Q include a part of the mother nucleus (X 2 (Including carbon atoms and nitrogen atoms to which Rlfl is bonded) Cyclic structure (The size of the ring may be 4- to 7-membered and may be saturated or unsaturated.)
  • the ring may contain an oxygen atom, a nitrogen atom, or a sulfur atom as a member of the ring, and furthermore, the ring may have from 1 to 1 carbon atoms. It may have 6 alkyl groups as substituents.
  • the X 2 and is a ring R 1 and D are formed integrally, arbitrarily favored good pyrido benzo O hexa Gin skeleton have as a substituent a methyl group.
  • a 2 Power, Formula (V) X 4 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 2 to 4 carbon atoms.
  • the amino group is a substituent of at least one group selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.
  • the alkyl group which may have a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group and an ethyl group.
  • the alkenyl group may be a linear or branched one having 2 to 6 carbon atoms, but is preferably a vinyl group.
  • the alkynyl group may be a linear or branched one having 2 to 6 carbon atoms, and is preferably an ethynyl group.
  • halogen of the halogenomethyl group a fluorine atom is particularly preferred, and the number thereof may be 1 to 3.
  • the alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxyl group.
  • halogen of the halogenomethoxyl group a fluorine atom is particularly preferred, and the number thereof may be 1 to 3.
  • X 4 and R 13 include a part of the mother nucleus (the carbon atom to which X 4 binds).
  • ring size is from 4 to 7-membered ring and may be saturated or unsaturated), so as to include the carbon atom to which the bond and R 1 Q are bonded.
  • the ring may contain an oxygen atom, a nitrogen atom, or a sulfur atom as a ring constituent atom, and the ring may have 1 to 6 carbon atoms. May have an alkyl group as a substituent.
  • R 12 is an amino group, a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 6 carbon atoms
  • X 2 is An alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a halogenomethoxyl group, or a hydrogen atom.
  • R 12 is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group
  • X 2 is a methyl group, a methoxyl group, a fluorine atom, or a salt. This is the case for an elementary atom, a difluoromethoxyl group, or a hydrogen atom.
  • a preferable combination is a case where R 12 is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group, and X 2 is a methyl group or a methoxyl group.
  • X 1 is preferably a fluorine atom.
  • X 1 and X 2 are each a halogen atom
  • X 1 is particularly preferably a fluorine atom
  • X 2 is preferably a fluorine atom or a chlorine atom.
  • a 2 is the formula (V)
  • R 14 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 carbon atom and 6 carbon atoms
  • X is an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, and a halogen atom , A halogenomethoxyl group, or a hydrogen atom.
  • R M is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group
  • X 4 is a methyl group, a methoxyl group, a fluorine atom, or a chlorine atom. This is the case for an atom, difluoromethoxyl group, or hydrogen atom.
  • a preferable combination is a case where R 14 is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group, and X 4 is a methyl group or a methoxyl group.
  • substituents X 3 and X 4 are each a halogen atom
  • X 3 is particularly preferably a fluorine atom
  • X 4 is more preferably a fluorine atom or a chlorine atom.
  • halogen atom to be substituted examples include a fluorine atom and a chlorine atom, and a fluorine atom is particularly preferable.
  • the steric environment at this moiety is particularly preferably that the halogen atom and the pyridonecarboxylic acid moiety are in a cis configuration with respect to the cyclopropane ring.
  • the R '0 c is one 2 - eight Rogeno isomer only so-called antipode relationship cyclopropyl moiety is present, but high and strong antibacterial activity in any of these safety was observed.
  • the compound of the formula (I), which is the compound of the present invention has a structure in which diastereomers are present
  • a compound consisting of a single diastereomer may be administered. I like it.
  • the term "consisting of a single diastereomer” is understood to include not only the case where no other diastereomer is contained, but also the case where it is chemically pure. In other words, it is interpreted that other diastereomers may be included as long as they have no effect on physical constants and physiological activities.
  • stereochemically single means that if a compound or the like contains an asymmetric carbon atom and there are a plurality of species that are in an isomer relationship, one of them It means that it is composed only of In this case as well, this “unity” is considered in the same way as above.
  • the pyridonecarboxylic acid derivative of the present invention may be in a free form, but may be in the form of an acid addition salt or a salt of a carboxyl group.
  • acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate, or acetate, methanesulfone and the like.
  • Organic acid salts such as acid salt, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, and lactate.
  • Examples of the salt of the carboxyl group include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, and ammonium salt.
  • alkali metal salts such as lithium salt, sodium salt and potassium salt
  • alkaline earth metal salts such as magnesium salt and calcium salt
  • ammonium salt and ammonium salt.
  • quinolone derivatives in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs.
  • alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters are useful as synthetic intermediates.
  • the ester used as a prodrug is an ester which is easily cleaved in a living body to form a free form of a carboxylic acid.
  • Examples of the ester include acetomethyl ester and vivaloyl ester.
  • Xymethyl ester, ethoxy carbonyl ester, cholesteric ester, dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5—alkyl-1-oxo-1,3—dioxol-4-yl Methyl esters and oxoalkyl esters such as 3-acetoxy 2-oxobutyl ester may be mentioned.
  • the compound of the present invention represented by the formula (I) can be produced by various methods, One good example is that of the formula (VI)
  • X 5 is a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms Represents a substituent that functions as a leaving group such as
  • Upsilon 3 or is the same as Upsilon 1 as defined in formula (II), or Formula (VII)
  • Upsilon 31 and Upsilon 32 represents the full Tsu atom or an alkyl force Lupo two Ruokishi group having 2 to 4 carbon atoms.
  • R 15 , R 1G , R 17 , A 3 and X 15 are the same as R 10 , R 1 R 12 , A 1 and X 1 defined in formula (II). Or a compound represented by the formula (VIII):
  • X 7 is a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms.
  • a 4 , X 8 and Y 4 are the same as R 13 , R ′ ⁇ A 2 , X 3 and Y 2 defined by the general formula (VI)]
  • R 6 1 are the same as the R 6 as defined in formula (I), or represents a protecting group of ⁇ Mi amino group, R 1, R 2, R 3, R 4, R 5, R 7 , R 8 and R 9 are the same as defined in formula (I). ]
  • the reaction can be carried out with or without a solvent.
  • the solvent used in the reaction may be inert under the reaction conditions.
  • examples include dimethylsulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N —Methylpyrrolidone, tetrahydrofuran, water, 3—Methoxybutanol or mixtures thereof.
  • the reaction may be an acid acceptor such as an inorganic or organic base, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate, or triethylamine, pyridine or 1,8-diazabicycloundecene. It is preferable to perform in the presence of an acid acceptor such as an inorganic or organic base, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate, or triethylamine, pyridine or 1,8-diazabicycloundecene. It is preferable to perform in the presence of an acid acceptor such as an inorganic or organic base, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate, or triethylamine, pyridine or 1,8-diazabicycloundecene. It is preferable to perform in the presence of an acid acceptor such as an inorganic or organic base, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate
  • the reaction can be carried out usually at a temperature ranging from room temperature to 200, preferably from 25 to 150.
  • the reaction time may be 30 minutes to 48 hours, but is usually completed in 30 minutes to 2 hours.
  • the protecting group for the amino group may be any protecting group commonly used in this field, for example, a tertiary butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group.
  • Alkoxycarbonyl groups such as benzyloxycarbonyl Groups, aralkyloxycarbonyl groups such as paramethoxybenzyloxycarbonyl group, paranitrobenzoyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, vivaloyl group, holmi Alkyl groups such as tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl, etc., or aralkyl, methoxymethyl, etc.
  • Ethers such as butoxymethyl group, tetrahydrovinylyl group, 2,2,2-trichloroethoxymethyl group, trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, Silyl groups such as benzylsilyl group and tertiary butyldiphenylsilyl group It is possible to increase the group class.
  • Y 3 and Y 4 are an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group consisting of an alkylene group having 1 to 6 carbon atoms and a phenyl group
  • the compound can be converted to the corresponding carboxylic acid by treating under a general acidic or basic condition used for hydrolysis.
  • Y 3 'and Y 3 2 in the formula represents a fluorine atom or an alkyl force Lupo two Ruokishi group having 2 to 4 carbon atoms.
  • the target compound represented by the formula (I) can be obtained by removing the protecting group from the base requiring deprotection under appropriate conditions corresponding to the protecting group.
  • the compound of the present invention represented by the formula (I) can also be produced by the following method. That is, after introducing the pyrrolidine substituent part in advance, The method for constructing a ring is as follows:
  • R 21 is a nitrile group, a carboxyl group, a lower alkoxycarbonyl group. , Represents an acetyl group.
  • Is converted to the compound represented by The compound of the general formula (I) can be obtained by further using a commonly used conversion method based on a carboxylic acid compound obtained by applying a method usually used for this compound.
  • the compound of the present invention Since the compound of the present invention has a strong antibacterial action, it can be used as a medicament for humans, animals and fish, or as a preservative for agricultural chemicals and foods.
  • the dosage is one day for an adult. 5 O mg force, 1 g, preferably in the range of 10 O mg to 300 mg.
  • the dosage for animals will vary depending on the purpose of the treatment (treatment or prevention), the type and size of the animal to be treated, the type and extent of the infected pathogen, but is generally used as a daily dose. Range from lmg to 20 mg / kg animal body weight, preferably from 5 mg / mg to 100 mg / kg.
  • This daily dose can be administered once a day or in 2 to 4 divided doses.
  • the daily dose may exceed the above-mentioned amount if necessary.
  • the compounds of the present invention are active against a wide range of microorganisms that cause various infectious diseases and can treat, prevent or reduce the diseases caused by these pathogens.
  • Bacteria or bacterial-like microorganisms against which the compound of the present invention is effective include, but are not limited to, genus Budococcus, Streptococcus pyogenes, hemolytic streptococci, enterococci, pneumococci, Peptostreptococcus, gonococci, Escherichia coli, Examples of the genus Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter genus, Serratia, Proteus, Pseudomonas aeruginosa, Influenza orchid, Acinetobacter, Campylobacter genus, Trachomach lamella, etc. it can.
  • folliculitis folliculitis, cough, rash, erysipelas, cellulitis, lymphadenitis (glandular) inflammation, glanders, subcutaneous abscess, hidrosis, and acne condensate , Infectious nodules, perianal abscess, mastitis, superficial secondary infections such as trauma, burns, surgical wounds, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse Panbronchiolitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nongonococcal urethritis, cholecystitis, cholangitis, bacterial dysentery, Enteritis, uterine appendixitis, intrauterine infection, Bartholin's adenitis, blepha
  • various microorganisms that cause infectious diseases in animals such as Escherichia, Salmonella, Pasteurella, Hemofilus, Bordetella, and Staphylococcus It is effective against the genus Kas and Mycoplasma.
  • specific disease names include coliform illness, chicken dysentery, chicken paratyphoidosis, poultry cholera, infectious cholesterol, staphylococcal disease, mycoplasma infection, etc. in birds, and colicosis, salmonellosis, Pasteurellosis, Hemofilosis, Atrophic rhinitis, Exudative epidermitis, Mycoplasma infection, etc.In cattle, E.
  • the antibacterial preparation comprising the compound of the present invention can be prepared by selecting an appropriate preparation depending on the administration method and preparing various commonly used preparations.
  • Examples of the dosage form of the antibacterial preparation containing the compound of the present invention as a main component include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. It can be exemplified as a preparation.
  • Injectables may use stabilizers, preservatives, and solubilizing agents in the formulation.After storing a solution that may contain these adjuvants in a container, freeze-dry the solid formulation. As such, it may be a preparation prepared at the time of use. One dose may be stored in one container, or multiple doses may be stored in the same container.
  • examples of the external preparation include solutions, suspensions, emulsions, ointments, gels, creams, mouth lotions, sprays and the like.
  • Solid preparations contain the active compounds and pharmaceutically acceptable additives, e.g. fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents Liquids, lubricants, etc. can be selected and mixed as necessary to form a liquid formulation.
  • Liquid preparations include solutions, suspensions, emulsions, etc. May contain turbidity agents, emulsifiers, etc.
  • the method of administering the compound of the present invention to an animal is either directly or by orally administering it by mixing it with a feed, or once it has been made into a solution and then directly or by drinking water or feed. It can be shown how to orally administer it by adding it to the inside, or how to administer it by injection.
  • Formulations for administering the compound of the present invention to animals include powders, fine granules, soluble powders, syrups, solutions, and injections, as appropriate, using techniques commonly used in this field. can do.
  • test method for the antibacterial activity of the target compound was performed in accordance with the standard method specified by the Japanese Society of Chemotherapy, and the results were shown in MIC (/ g / m1).
  • the compound of the present invention has excellent antibacterial activity and safety, and is useful as a medicine.

Abstract

Cette invention concerne des médicaments antibactériens qui possèdent une excellente activité antibactérienne ainsi que d'excellentes qualités en matière de sécurité. Ces médicaments comprennent des dérivés de quinolone possédant divers substituants, y compris un aminométhylpyrrolidine substitué. Ces dérivés correspondent à la formule générale (I) ou Q représente (II) ou (IV). Cette invention concerne également des sels de ces dérivés, ainsi que des hydrates de ces dérivés et de leurs sels.
PCT/JP1996/003552 1996-12-04 1996-12-04 Derives d'aminomethylpyrrolidine substitue WO1998024781A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP1996/003552 WO1998024781A1 (fr) 1996-12-04 1996-12-04 Derives d'aminomethylpyrrolidine substitue
AU10405/97A AU1040597A (en) 1996-12-04 1996-12-04 Substituted aminomethylpyrrolidine derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1996/003552 WO1998024781A1 (fr) 1996-12-04 1996-12-04 Derives d'aminomethylpyrrolidine substitue

Publications (1)

Publication Number Publication Date
WO1998024781A1 true WO1998024781A1 (fr) 1998-06-11

Family

ID=14154180

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/003552 WO1998024781A1 (fr) 1996-12-04 1996-12-04 Derives d'aminomethylpyrrolidine substitue

Country Status (2)

Country Link
AU (1) AU1040597A (fr)
WO (1) WO1998024781A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2275141A1 (fr) 1999-03-17 2011-01-19 Daiichi Pharmaceutical Co., Ltd. Compositions pharmaceutiques au gout camoufle

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05163244A (ja) * 1991-05-28 1993-06-29 Dai Ichi Seiyaku Co Ltd ピリドンカルボン酸誘導体
JPH05262738A (ja) * 1991-07-19 1993-10-12 Bayer Ag ８−ビニル−および８−エチニル−キノロン−カルボン酸類
JPH07300416A (ja) * 1988-04-27 1995-11-14 Dai Ichi Seiyaku Co Ltd 抗菌性医薬
JPH08277284A (ja) * 1995-02-02 1996-10-22 Dai Ichi Seiyaku Co Ltd 複素環式化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07300416A (ja) * 1988-04-27 1995-11-14 Dai Ichi Seiyaku Co Ltd 抗菌性医薬
JPH05163244A (ja) * 1991-05-28 1993-06-29 Dai Ichi Seiyaku Co Ltd ピリドンカルボン酸誘導体
JPH05262738A (ja) * 1991-07-19 1993-10-12 Bayer Ag ８−ビニル−および８−エチニル−キノロン−カルボン酸類
JPH08277284A (ja) * 1995-02-02 1996-10-22 Dai Ichi Seiyaku Co Ltd 複素環式化合物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2275141A1 (fr) 1999-03-17 2011-01-19 Daiichi Pharmaceutical Co., Ltd. Compositions pharmaceutiques au gout camoufle

Also Published As

Publication number Publication date
AU1040597A (en) 1998-06-29

Similar Documents

Publication Publication Date Title
JP4040091B2 (ja) 置換アミノシクロアルキルピロリジン誘導体
EP0947513B1 (fr) Derives d'amine tricycliques
JP4094061B2 (ja) シス置換アミノシクロプロパン誘導体
JP3833738B2 (ja) 置換アミノメチルピロリジン誘導体
JP3760172B2 (ja) デハロゲノ化合物を有効成分とする医薬
RU2248970C2 (ru) Циклоалкилзамещенные производные аминометилпирролидина и антибактериальный агент на их основе
EP0995744B1 (fr) Derives cis-substitues de fluoromethylpyrrolidine
AU732175B2 (en) Substituted cyclobutylamine derivative
JPH10287669A (ja) 置換アミノメチルピロリジン誘導体
WO2000053594A1 (fr) Derives aminomethylpyrrolidine possedant des substituants aromatiques
KR100458146B1 (ko) 사이클로알킬아미노메틸피롤리딘유도체및이를유효성분으로하는항생제
WO1998024781A1 (fr) Derives d'aminomethylpyrrolidine substitue
WO1998013370A1 (fr) Derives de pyridobenzoxazine
JPH11199561A (ja) シス置換アミノシクロプロパン化合物
WO2006077984A1 (fr) Derive de fluoroalkylpyrrolidine
JPH1081682A (ja) シス置換アミノシクロプロパン誘導体
WO1996024593A1 (fr) Derives spiro heterocycliques
MXPA01005206A (en) Cycloalkyl-substituted aminomethylpyrrolidine derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BB BG BR CA CN CU CZ EE GE HU IL IS KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK TR TT UA US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase