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WO1993013101A1 - Compose de pyridonecarboxylate, son utilisation pharmaceutique et compose spiro - Google Patents

Compose de pyridonecarboxylate, son utilisation pharmaceutique et compose spiro Download PDF

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Publication number
WO1993013101A1
WO1993013101A1 PCT/JP1992/001739 JP9201739W WO9313101A1 WO 1993013101 A1 WO1993013101 A1 WO 1993013101A1 JP 9201739 W JP9201739 W JP 9201739W WO 9313101 A1 WO9313101 A1 WO 9313101A1
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Prior art keywords
dihydro
oxo
cyclopropyl
fluoro
oxa
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PCT/JP1992/001739
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English (en)
Japanese (ja)
Inventor
Kazuhiko Araki
Tsuyoshi Kuroda
Kazuhiro Tsutsumi
Hirotaka Isoshima
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Yoshitomi Pharmaceutical Industries, Ltd.
Japan Tobacco Inc.
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Publication of WO1993013101A1 publication Critical patent/WO1993013101A1/fr

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    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to a novel pyridonecarboxylic acid compound which is extremely excellent as an antibacterial agent, its pharmaceutical use, and a spiro compound useful as a synthetic intermediate for the pyridonecarboxylic acid compound.
  • quinoline carboxylic acid antibacterial compounds Compounds having various cyclic amino groups at the 7-position of the quinoline skeleton have been developed as quinoline carboxylic acid antibacterial compounds.
  • spiro compounds containing a nitrogen atom as a cyclic amino group are known.
  • JP-A-11-228683 and JP-A-2-289583 disclose a compound represented by the general formula of the 7-position cyclic amino compound having a quinolone skeleton.
  • a compound having a spiro substituent represented by is disclosed.
  • Japanese Patent Application Laid-Open No. 3-95176 discloses a general formula of a 7-position cyclic amino compound having a quinolone skeleton.
  • a compound having a spiro substituent represented by is disclosed.
  • the present invention is as follows.
  • R 1 is hydrogen, alkyl, substituted alkyl, cyano, COOR 3 (where R 3 represents hydrogen, alkyl or aralkyl)]
  • R 3 represents hydrogen, alkyl or aralkyl
  • R 4 and R 5 are the same or different and are hydrogen, alkyl, cycloalkyl, acyl, alkoxycarbonyl or aralkyl, or R 4 and R 5 are bonded to each other to form a heterocyclic ring with an adjacent nitrogen atom.
  • R 6 and R 7 are the same or different and are hydrogen, alkyl, cycloalkyl, R 6 and R 7 represent a group which forms a heterocyclic ring together with an adjacent nitrogen atom, R represents an oxygen atom or a sulfur atom, and q represents 0 or 1 to Indicates an integer of 3.
  • R 2 represents hydrogen or alkyl
  • X and Y are the same or different and each represent an oxygen atom, a sulfur atom or —NR 8 — (where R 8 represents a hydrogen, alkyl, aralkyl or amino protecting group, provided that X and Y are both NR 8 — Wherein R 8 may be the same or different.
  • n 0 or an integer of 1-2.
  • R 3 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, amino, or mono- or dialkylamino which may have a substituent
  • R 1 (1 is cryogen
  • R 11 is COOR 13 (where R 13 is hydrogen, alkyl, aralkyl or an ester residue which can be hydrolyzed in vivo),
  • R 12 is hydrogen, halogen, amino, mono or dialkylamino, alkyl, substituted alkyl, hydroxyl or alkoxy,
  • H a 1 is halogen
  • R s ′ is an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, amino, or mono- or dialkylamino of R s
  • a pharmacologically acceptable salt thereof is an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, amino, or mono- or dialkylamino of R s
  • R represents hydrogen, halogen
  • R s '' represents an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, an alkenyl, a substituted alkenyl, a phenyl, an amino, or a mono or dialkylamino which may have a substituent among R 9 ′.
  • R 14 ′ represents hydrogen, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy or cyano, and other symbols are as defined above.
  • R 14 ′ is the same as the above (1) or (2). Pyridone force Rubonic acid compounds and pharmacologically acceptable salts thereof.
  • R ′ represents hydrogen, alkyl, aralkyl or other amino protecting group
  • R 1 is hydrogen, alkyl, substituted alkyl, cyano, —CO ⁇ R 3 (where R 3 is hydrogen, alkyl or aralkyl Shown below:)
  • R 4 and R 5 are the same or different and are hydrogen, alkyl, cycloalkyl, acyl, alkoxycarbonyl or aralkyl, or R 4 and R 5 are bonded to each other to form a heterocyclic ring with an adjacent nitrogen atom.
  • p represents 0 or an integer of 1 to 3.
  • R 6 and R 7 are the same or different and are hydrogen, alkyl, cycloalkyl, acyl, alkoxycarbonyl or aralkyl, or R 6 and R 7 are bonded to each other to form a heterocyclic ring with an adjacent nitrogen atom.
  • Z represents an oxygen atom or a sulfur atom, and q represents 0 or an integer of 1 to 3.
  • R 2 represents hydrogen or alkyl
  • X is one NR 8 — (where R 8 is hydrogen, alkyl, aralkyl or amino Indicates a protecting group. ) Or an oxygen atom, Y represents an oxygen atom,
  • X represents one NR 8 —
  • Y represents an oxygen atom or —NR 8 —
  • n ′ represents an integer of 1 or 2
  • n ′′ represents 0 or an integer of 1-2
  • others Is the same as defined above, and spiro compounds and salts thereof.
  • a pharmaceutical composition comprising, as an active ingredient, the pyridonecarboxylic acid compound or the pharmacologically acceptable salt thereof according to (1) to (5).
  • Halogen refers to chlorine, bromine, fluorine and iodine.
  • Alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, etc., having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms. Linear or branched chain alkyl.
  • Substituted alkyl means halogen (fluorine, chlorine, bromine, iodine), hydroxyl group, alkoxy having 1 to 6 carbon atoms (methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy, etc.), Acyloxy (acetyloxy, propionyloxy, benzoyloxy, etc.), phenyl, substituted phenyl [substituents are halogen (fluorine, chlorine, bromine, iodine), alkoxy having 1 to 6 carbons, alkyl having 1 to 6 carbons, carbon Alkyl halides of numbers 1 to 6 (trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc.), alkyl of 1 to 6 carbons or 1 carbon Amino which may be substituted with 10 to 10 amino acids (amis
  • alkyl groups substituted with 1 to 3 of the above and specific examples thereof include trifluoromethyl, trifluoroethyl, difluoromethyl, fluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, and 2-hydroxy.
  • Droxethyl methoxymethyl, ethoxymethyl, 1-methoxethyl, 2-methoxyl, 2-ethoxy, 2,2-dimethoxyl, 2,2-jetoxyl, benzyl, 2-phenylethyl, benzhydryl, 3-hydryl
  • Examples include enylpropyl, 4-cyclobenzyl, 4-methoxybenzyl, 3-trifluoromethylbenzyl, 2-dimethylaminobenzyl, and 2- (4-fluorophenyl) ethyl.
  • Cycloalkyl refers to cycloalkyl having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • substituent of the substituted cycloalkyl include halogen, alkyl, and trifluoromethyl.
  • Alkenyl is alkenyl having 2 to 20 carbon atoms, preferably 2 to 6 carbon atoms, such as vinyl, 1-propenyl, aryl, isopropyl, 2-butenyl, 2-pentenyl, and 3-hexenyl. Show.
  • substituent of the substituted alkenyl include a halogen, a hydroxyl group, an alkoxy, a phenyl and a substituted phenyl.
  • Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy and the like, and preferably has 1 to 6 carbon atoms.
  • substituent of the substituted alkoxy include a halogen, a hydroxyl group, an alkoxy, a phenyl and a substituted phenyl.
  • the mono or dialkylamino includes methylamino, dimethylamino, ethylamino, acetylamino, propylamino, dipropylamino, butylamino, dibutylamino, methylethylamino, methylpropylamino, methylbutylamino, and the like.
  • Preferred is mono- or dialkylamino substituted with alkyl having 1 to 6 carbon atoms.
  • Alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, etc., and preferably has 1 to 6 carbon atoms in the alkoxy moiety.
  • Aryl includes phenyl, naphthyl and the like, and optionally substituted phenyl substituents include halogen, alkyl, alkoxy, amino, nitro, hydroxyl and the like.
  • Aralkyl is benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl which may have 1 to 3 substituents selected from halogen, aralkyl, alkoxy, trifluoromethyl, hydroxyl, nitro, and amino on the aromatic ring. And an alkyl moiety having 1 to 6 carbon atoms. Examples are 0-, m- or p-chlorobenzyl, 0-, m- or p-methylbenzyl, o-, m- or p-methoxybenzyl, 0-, m- or p-trifluoro.
  • acyl refers to an alkanol such as formyl, acetyl, propionyl, butyryl, valeryl, and pivaloyl, preferably an alkanol having 1 to 6 carbon atoms, or an aroyl such as benzoyl, toluoyl, and naphthoyl.
  • the amino protecting group is a protecting group commonly used in organic synthesis, and examples thereof include benzyl, 3,4-dimethoxybenzyl, diphenylmethyl, bis (4-methoxyphenyl) methyl, 2-nitrobenzyl, triphenyl and the like. Methyl, phenacyl, acetyl, trifluoroacetyl, benzyloxycarbonyl, tert-butoxycarbonyl and the like.
  • Ester residues of esters that can be hydrolyzed in vivo include alkanoyloxyalkyl esters such as acetomethyl, pizoloyloxymethyl, 1-acetoxityl, and 1-bivaloyloxycetyl, and ethoxycarbonyl.
  • Alkoxycarbonyloxyl esters such as methoxymethyl, 1-ethoxycarbonyloxetyl, esters such as fluoridyl and dimethoxyphthalidyl
  • Alkyl alkyl esters such as methyl, carbamoylethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, N, N-getylcarbamoylmethyl
  • alkoxyalkyl esters such as methoxymethyl, methoxethyl or 5-methyl-1 , 3—Dioxolen-1—2-On-4-ylmethyl ester
  • aminomethyl ester such as aminomethyl, aminoethyl, aminopropyl, etc., methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminomethyl, ethylaminoethyl, ethyl Alkylamino alcohols such as tylamin
  • a heterocyclic ring formed by R 4 , R 5 or R 6 , R 7 together with an adjacent nitrogen atom is a 5- to 7-membered heterocyclic ring containing at least one nitrogen atom, and Examples include peridine, morpholine, thiomorpholine, piperazine, and 4-alkyl-substituted piperazine (eg, 4-methylbiperazine).
  • Q containing a ring formed with R 11 has a nucleus of quinolone and naphthyridine known as a conventional quinolone skeleton and naphthyridine skeleton, and has, for example, the following general formula:
  • Z 1 represents an oxygen atom, a sulfur atom or 1 NR 8 — (where R s is as defined above), Z 2 represents an oxygen atom or a sulfur atom, and R 15 represents hydrogen or R 16 represents cyano, rubamoyl, mono- or dialkyl-substituted lubamoyl, alkoxycarbonyl, ru, nitro or trifluoromethyl.
  • quinolone and naphthyridine derivatives all of which are well-known as a core of a new quinoline antibacterial compound.
  • Salts of the compounds of the general formulas (I), (VI) and (VII) include acid addition salts, metal salts and heavy metal salts, and the acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Salts with inorganic acids such as nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, cunic acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.
  • salts with organic acids include metal salts such as alkali metal salts or alkaline earth metal salts (salts such as sodium, potassium, calcium, aluminum, and magnesium) and heavy metal salts (copper, sub forceps, iron, Salts of gold, silver, platinum, manganese, etc.), and salts with amino acids such as lysine, ordinine, arginine, and -alanine.
  • metal salts such as alkali metal salts or alkaline earth metal salts (salts such as sodium, potassium, calcium, aluminum, and magnesium) and heavy metal salts (copper, sub forceps, iron, Salts of gold, silver, platinum, manganese, etc.
  • salts with amino acids such as lysine, ordinine, arginine, and -alanine.
  • the present invention includes the optical isomers, diastereomers, enantiomers or racemates thereof derived therefrom. .
  • Honmei includes geometric isomers Both include hydrates.
  • the pyridonecarboxylic acid compound (I) of the present invention can be produced, for example, by the following synthesis method.
  • the compound (V) is used in an amount of 1 to 8 times the molar amount of the quinolone or naphthyridine derivative as described above,
  • the heating may be performed at a temperature of 2200 ° C., preferably 30 3150 ° C., for 1 to 48 hours.
  • Suitable solvents include water, alcohols such as methanol, ethanol, and propanol, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric amide, and 1-methyl-2-pyrrolidone. it can.
  • 1,8-diazabicyclo [5.4.0] pentacar 7-ene an organic base such as triethylamine or lithium carbonate, sodium carbonate, hydrogencarbonate, sodium hydrogencarbonate are used as deoxidizing agents.
  • an inorganic base such as calcium.
  • a compound represented by the formula (hereinafter sometimes referred to as compound ( ⁇ ')) is condensed with a spiro compound of compound (V),
  • compound (r) represented by the formula (I) and further treating with a base.
  • the compound (V) is used at 1 to 8 times the molar amount of the compound ([ ⁇ '), and at 0 to 150 ° C, preferably 30 to 100 ° C in the absence of a solvent or a suitable solvent. Perform i ⁇ 48 hours.
  • Suitable solvents include water, alcohols (methanol, ethanol, propanol, etc.), acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric amide, 1-methyl-2-pyrrolidone, and the like. Can be used.
  • an organic base such as triethylamine, 1,8-diazabicyclo [5.4.0] pendecar 7-ene or an inorganic base such as potassium carbonate, sodium carbonate, gallium hydrogencarbonate, sodium hydrogencarbonate, etc. May be used.
  • the base acting on the compound (II) may be an organic base such as triethylamine, 8-diazavinclo [5.4.0]
  • Inorganic bases such as lime, carbon dioxide, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide and the like can be mentioned.
  • Suitable solvents include water, alcohols (methanol, ethanol, propanol, etc.) or mixtures thereof.
  • the spiro compound of the general formula (V), which is a synthetic raw material for producing the compound (I), can be produced by the following production method.
  • Me stands for methyl
  • Et stands for ethyl
  • Bz stands for benzoyl
  • Bn stands for benzyl
  • Ac stands for acetyl
  • B0c stands for tertiary butoxycarbonyl
  • Ph stands for phenyl.
  • a spiro compound in which X is oxygen and Y is —NR 8 — and a spiro compound in which X is —NR 8 — and Y is oxygen are prepared by the following processes 1 to 4. Can be manufactured.
  • R represents hydrogen, alkyl, Ararukiru or other amino coercive Mamorumoto, R "is an alkyl or Ararukiru, R 8 'represents a group other than hydrogen R 8, R 8" Represents an alkyl, aralkyl, or phenyl optionally having 1 carbon atom (s) less than R 8 ′, and the other symbols are as defined above.
  • Step a is a step of obtaining compound (B) by reacting compound (A) with trimethyloxosulfonidimide in dimethyl sulfoxide in the presence of sodium hydride under ice cooling or at room temperature.
  • Step a ' is carried out by reacting compound (A) with trimethylsilyl nitrile in a solvent such as chloroform, methylene chloride, and toluene in the presence of a Lewis acid such as aluminum chloride or iodide powder.
  • a solvent such as chloroform, methylene chloride, and toluene
  • a Lewis acid such as aluminum chloride or iodide powder.
  • step b ′ the compound (C ′) is subjected to a reduction reaction with a compound such as lithium aluminum hydride, sodium bis (2-methoxhetoxy) aluminum, and the like in a solvent such as ether, tetrahydrofuran, and toluene, to thereby convert the compound (C ′).
  • a compound such as lithium aluminum hydride, sodium bis (2-methoxhetoxy) aluminum, and the like in a solvent such as ether, tetrahydrofuran, and toluene
  • Step b is an organic base such as pyridine or triethylamine, or sodium hydroxide, hydroxide hydroxide, sodium carbonate, carbonate carbonate, in toluene, chloroform, tetrahydrofuran, getyl ether, water or a mixture thereof.
  • compound (C ) is obtained by reacting compound (C ') with an acylating agent such as formic acid-acetic anhydride, acetyl chloride or anhydrous acetic acid in the presence of an inorganic base.
  • Step b “′” reduces compound (C) together with lithium aluminum hydride, sodium bis (2-methoxetoxy) aluminum, diborane, sodium borohydride-iodine in a solvent such as ether, tetrahydrofuran, or toluene
  • the compound (C) is obtained by subjecting the compound to a reaction.
  • Step b "" is a process in which, when R 'is other than hydrogen, hydrogenation is carried out in the presence of a palladium carbon catalyst in water, alcohol such as methanol, ethanol, or propanol, or hydrazine in the presence of a palladium carbon catalyst.
  • the compound (C “') is obtained by adding monohydrate and refluxing, and by hydrolysis with an acid or alkali. Compound (C “') can also be obtained.
  • Step b is performed in a solvent such as water, alcohols such as methanol, ethanol, and propanol, chlorinated hydrocarbons such as chloroform, toluene, dimethylformamide, dimethylacetamide, and dimethylsulfoxide, or in the absence of a solvent.
  • a solvent such as water, alcohols such as methanol, ethanol, and propanol, chlorinated hydrocarbons such as chloroform, toluene, dimethylformamide, dimethylacetamide, and dimethylsulfoxide, or in the absence of a solvent.
  • This is a step of obtaining a compound (C) by reacting (B) and an amide of R 8 ′ -NH 2 in an equimolar amount or more with respect to the compound (B) from room temperature to under heating.
  • the reaction is preferably performed at 50 ° C for 1.5 hours.
  • an inorganic base sodium hydroxide, potassium hydroxide, calcium hydroxide, or the like
  • water alcohol such as chloroform, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, methanol, ethanol, propanol, or a mixed solvent thereof.
  • compound (D) is obtained by reacting chloroacetic acid chloride under ice cooling or at room temperature.
  • Step d involves reacting compound (C) with chloroacetate in the presence of sodium hydride, potassium hydride, etc. in alcohols such as toluene, dimethylformamide, dimethylacetamide, methanol, ethanol, and propanol. This is a step of obtaining compound (E).
  • Step e is performed in alcohols such as dimethyl sulfoxide, toluene, dimethylformamide, dimethylacetamide, methanol, ethanol, and propanol, and in an inorganic base (sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium hydride). , Potassium hydride, etc., or a mixture of potassium hydroxide and neutral alumina), or ice in the presence of an organic base (triethylamine, dicyclohexylamine, N-methylmorpholine, pyridine, etc.)
  • the compound (F) is obtained by reacting the compound (D) under cooling or at room temperature.
  • step f compound (E) is heated to reflux in alcohols such as toluene, dimethyl sulfoxide, methanol, ethanol, and propanol. This is a step of obtaining a compound (F).
  • alcohols such as toluene, dimethyl sulfoxide, methanol, ethanol, and propanol.
  • Step g involves reducing compound (F) in a solvent such as ether, tetrahydrofuran, or toluene together with lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum aluminum, diborane, sodium iodide borohydride, and the like.
  • compound (G) is obtained by subjecting the compound to a reaction.
  • Steps g 'and g can be carried out in the same manner as in Step g.
  • the compound (F) is treated with hydrogen in the presence of a palladium carbon catalyst in an alcohol such as methanol, ethanol, or propanol.
  • the compound (F ′) is obtained by adding or hydrazine monohydrate in the presence of a palladium carbon catalyst and refluxing to obtain the compound (F ′), or by hydrolysis with an acid or alkali to obtain the compound (F ′). be able to.
  • steps ⁇ , ⁇ , and m ′ can be performed by the same operations as in step ⁇ .
  • nf " is an organic base such as pyridine or triethylamine, or a sodium hydroxide or sodium hydroxide, sodium carbonate, or carbonated lime in toluene, chloroform, tetrahydrofuran, ether, water, or a mixture thereof in an organic base such as pyridine or triethylamine.
  • Compound (F ') is reacted with an acylating agent such as formic acid-acetic anhydride, acetyl chloride, acetic anhydride, or an alkylating agent such as methyl iodide or benzyl chloride in the presence of an inorganic base such as This is a step of obtaining a compound (F ").
  • step f The reaction in step f can be carried out by the same operation as in step f ".
  • Step h includes reacting compound (A) in an alcohol such as ethanol, methanol, or propanol, or in a mixed solvent of these alcohols and water, in the presence of ammonium chloride or a mixture of ammonium chloride and aqueous ammonia.
  • An alkali metal cyanide such as sodium cyanide or potassium cyanide or an alkaline earth metal cyanide such as calcium cyanide or magnesium cyanide is added thereto, and the mixture is heated, preferably 30 to 70 ° C.
  • step of obtaining compound (H) by reacting at
  • step i compound (H) is dissolved in an organic solvent such as (Triethylamine, dicyclohexylamine, N-methylmorpholine, pyridin, etc.) and an inorganic base (sodium hydroxide, potassium hydroxide, etc.) in the presence of a halogenated benzoyl such as benzoyl chloride to react with the compound (I ).
  • organic solvent such as (Triethylamine, dicyclohexylamine, N-methylmorpholine, pyridin, etc.)
  • an inorganic base sodium hydroxide, potassium hydroxide, etc.
  • a halogenated benzoyl such as benzoyl chloride
  • step j the compound (I) is heated to reflux in alcohols such as ethanol, methanol, and propanol in the presence of an inorganic acid such as concentrated sulfuric acid or concentrated hydrochloric acid, and the alcohol is concentrated.
  • alcohols such as ethanol, methanol, and propanol
  • an inorganic acid such as concentrated sulfuric acid or concentrated hydrochloric acid
  • compound (J) is obtained by extraction with an organic solvent such as
  • Step h ' is carried out in an alcohol such as ethanol, methanol or propanol, or in a mixed solvent of such alcohols and water, in the presence of ammonium carbonate, in the presence of ammonium carbonate, or an alkali metal cyanide such as sodium cyanide or potassium cyanide, or
  • the compound (A) can be converted to the compound ( ⁇ ) by adding an alkaline earth metal salt such as calcium cyanide or magnesium cyanide and reacting the mixture under heating, preferably at 50 to 200 ° C. ').
  • an alkaline earth metal salt such as calcium cyanide or magnesium cyanide
  • step h " the compound ( ⁇ ') is suspended in an aqueous alkali solution such as sodium hydroxide or potassium hydroxide, refluxed, and then cooled with ice or heated, preferably under ice-cooling. After adding an acid such as acetic acid or the like to dryness under reduced pressure, further adding an alcohol such as methanol, ethanol, or propanol to the residue, and dropwise adding oxalyl chloride or thionyl chloride, preferably at room temperature.
  • This is a step of obtaining a compound (J) by reacting benzoyl chloride such as benzoyl chloride in the presence of potassium carbonate or sodium carbonate.
  • Step k is a reduction reaction of compound (J) with lithium aluminum hydride, bis (2-methoxyethoxy) sodium aluminum hydride, diborane, sodium iodine borohydride, etc. in a solvent such as tetrahydrofuran, ether or toluene.
  • a solvent such as tetrahydrofuran, ether or toluene.
  • Step ⁇ the compound (L) is reacted with a halogenated chloracetyl such as chloroacetyl chloride in a solvent such as chloroform, ether, toluene or the like, preferably in the presence of a base such as triethylamine.
  • Step m is a step of obtaining compound (M) by adding an alkali such as potassium hydroxide or sodium hydroxide or a mixture of alkali and neutral alumina in a solvent such as benzene, liquid form, ether, and toluene. is there.
  • Step n can be performed by the same operation as in step g.
  • Step 0 is a step for adding a substituent R 1 such as alkyl such as methyl or hydroxymethyl to the morpholine ring constituting the spiro ring, and converting the compound (M) to tetrahydrofuran, dioxane, ether, toluene or the like.
  • a step of obtaining compound (0) by reacting with an alkyl halide such as methyl iodide, an acid chloride or benzylchloromethyl ether in a solvent in the presence of a base such as lithium diisopropylamide, preferably while cooling. is there.
  • R 1 examples include alkyl, substituted alkyl, carbonyl, oxycarbonyl, sorbamoyl, nitrile and the like.
  • Step P is a step of obtaining compound (P) by reducing compound (0) by the same operation as in step g.
  • step q can be performed by the same operation as in step ⁇ ′.
  • step r and s the compound (C) obtained according to the method 1 or the compound (K) obtained according to the method 2 is reacted with 2-chloroacrylonitrile in toluene, dimethylformamide or dimethylacetamide. , Then sodium hydride, water In this step, compounds (Q) and (S) are obtained by the action of a base such as potassium iodide.
  • the reaction of the steps t, u, v or w can be carried out by the same operation as the reaction of each of the steps a, b, c and e or d and f of the production method 1.
  • Step x is dimethylformamidine de, under a solvent such as dimethyl ⁇ Seto Ami de, or without a solvent to the compound (W) and R 'Amin compound compound by reacting under heat and pressure represented by -NH 2 (X ).
  • Step y is a step of obtaining compound (Y) from compound (X) by the same operation as in the reaction of step g of production method 1.
  • R ′′ ′ represents halogen, hydroxy, or protected hydroxy, and other symbols are as defined above.
  • step (aa) compound (AA) is obtained by hydrolyzing compound (B) in the presence of an acid such as sulfuric acid or hydrochloric acid, or by hydrolyzing after reacting with a carboxylic acid such as acetic acid. About C.
  • Step (bb) is carried out in the presence of a base, with compound (AA) and a general formula
  • R 1 represents hydrogen, alkyl or aralkyl
  • R 1 represents hydrogen, alkyl or aralkyl
  • Step (cc) is carried out in the presence of a base, with compound (AA) and a compound of formula
  • Step (dd) is a step of obtaining a compound (CC) by reacting the compound (B) with the compound (B) in the presence of a base by reacting the compound (B) with a compound of the general formula
  • a compound (DD) is obtained by reacting with an alcohol compound represented by the following formula.
  • step (ee) when R ′′ ′ of the compound (DD) represents a halogen, the compound is closed in the presence of a base, or —OR ′′ ′′ (where R ′′ ′′ represents a protecting group for a hydroxy group).
  • this is a step of obtaining the compound (EE) by deprotection by a conventional method, followed by ring closure using an acid catalyst such as sulfuric acid, or by tosylation or mesylation and then ring closure in the presence of a base.
  • R le and R lb are the same or different and represent hydrogen, alkyl, aralkyl or amino protecting group. However, R le and R lb are not hydrogen at the same time. Is synonymous with.
  • the compound (H) is heated and heated, if necessary, in an alcohol such as ethanol, methanol, or propanol, in the presence of acetic acid or ammonia, using Raney nickel, palladium carbon, or the like as a catalyst.
  • This is a step of obtaining a compound (FF) by hydrogenation under reduced pressure or reduction with lithium aluminum hydride, sodium bis (2-methoxetoxy) aluminum in tetrahydrofuran, ether, or toluene.
  • 'Step (gg) is performed by converting compound (FF) in the presence of a base using a general formula
  • step (hh) compound (FF) is converted to a compound of the formula
  • step (ii) the compound (FF) is reacted at a temperature of 100 ° C. or higher, preferably 150 to 190 ° C., excluding the diester of oxalic acid and the generated alcohol, or in the presence of a base.
  • Step aj) of obtaining compound ( ⁇ ⁇ ) by reacting with an acid halide is a step of obtaining compound (GG) from compound ⁇ r) by the same reaction operation as step s.
  • the compound (GG) is reacted with a halogenated alkyl, dichloride, or acid anhydride in a solvent such as dimethylformamide, dichloromethane, tetrahydrofuran or the like in the presence of a base such as triethylamine.
  • a halogenated alkyl, dichloride, or acid anhydride in a solvent such as dimethylformamide, dichloromethane, tetrahydrofuran or the like in the presence of a base such as triethylamine.
  • a compound (KK) by a reaction or a reaction with a carboxylic acid in the presence of a condensing agent such as dicyclohexylcarpoimide.
  • R′R lb is a methyl group
  • compound (KK) can also be obtained by treating compound (GG) with formalin and formic acid.
  • step (kk) can be similarly carried out on the compound (V) (X or Y is one NH—) obtained by the above production methods 1 to 4.
  • a compound in which the substituent on the spiro ring is one COOR 3 Compounds in which the substituent on the spiro ring is an ester of one COOR 3 are compounds in which the substituent on the spiro II is one CN.
  • the compounds (Q) and (S) are substituted with an acid such as sulfuric acid or hydrochloric acid.
  • corresponding! ? 3 - can be prepared by heating under reflux with alcohol represented by 0H.
  • the compound in which the substituent on the spiro ring is —C0NH 2 is a compound such as hydrochloric acid or sulfuric acid, which is then hydrolyzed by reacting the compound in which the substituent on the spiro ring is 1 CN with the above. Can be manufactured.
  • water-containing compound substituent on the spiro ring is -C00R 3 Aruko Ichiru solvent or in water, hydrochloric acid, either present under reflux of acid such as sulfuric acid, hydroxide sodium ⁇ , Al, such as hydroxide force Riumu Ii)
  • acid such as sulfuric acid, hydroxide sodium ⁇ , Al, such as hydroxide force Riumu Ii
  • the compound having 1 CN on the spiro ring is reacted with water, an acid such as hydrochloric acid, sulfuric acid, etc., sodium hydroxide, Heat reflux in the presence of Al Than,
  • a compound in which the substituent on the spiro ring is 1 C 0 NH 2 is heated to reflux in an aqueous alcohol solvent or water in the presence of an acid such as hydrochloric acid or sulfuric acid or an alkali such as sodium hydroxide or potassium hydroxide. Can be manufactured.
  • a compound in which the substituent on the spiro ring is one COOH is reacted with borane in diglyme (2-methoxylethyl ether) or in ether, tetrahydrofuran, toluene, lithium aluminum hydride, bis hydride (2-Methoxyethoxy) It can be produced by reacting with aluminum sodium at room temperature or under reflux with heating.
  • a compound having one COOH substituent on the spiro ring is converted into a compound such as methylene chloride, chloroform, or a solvent-free solvent such as thionyl chloride, phosphorus pentachloride, etc.
  • the halogenating agent is heated to reflux to form a halide compound represented by one COF (F represents a halogen).
  • dimethylformamide, dimethylacetamide, methylene chloride, and chloroform are used.
  • it can be produced by reacting an amine represented by HN (R 6 ) (R 7 ) in the presence of an organic or inorganic base or a deoxidizing agent.
  • the compound in which the substituent on the spiro ring is one CH 2 — G requires the compound in which the substituent on the spiro ring is —CH 20 H in a chlorinated hydrocarbon solvent such as chloroform and in the absence of a solvent. If present, it can be produced by reacting a halogenating agent such as thionyl chloride or phosphorus pentachloride under heating and reflux.
  • a compound in which the substituent on the spiro ring is one CH 2 — G (G represents a halogen) is required in a solvent such as dimethylformamide, dimethylacetamide, methylene chloride, and chloroform, or in the absence of a solvent.
  • a solvent such as dimethylformamide, dimethylacetamide, methylene chloride, and chloroform
  • the compound can be produced by reacting a compound in which the substituent of the spiro ring is one CONR 6 R 7 in the same manner as in (5) -ii).
  • R ′ in the spiro compound (R ′ is not a hydrogen atom) obtained by each of the above production methods can be easily eliminated according to a known or known method. Further, a spiro compound having a substituent R 8 ′ at the nitrogen atom in ⁇ can be easily produced from a compound in which R 8 is a hydrogen atom according to a known method, or a final compound in which R 8 is a hydrogen atom.
  • the target compound (I) in which R s is not hydrogen JK can also be obtained.
  • the spiro compound (V) produced in this manner can be isolated and purified by ordinary methods such as recrystallization, distillation, various chromatographic methods, etc. Can also be used. Further, a quinolone and a naphthyridine derivative having a mother nucleus of definition Q, which is another synthetic raw material used in the present invention, are disclosed in JP-B-62-56154, JP-A-11-19997 JP-A-58-103393, JP-A-62-187472, JP-A-3-22383, JP-A-3- It is synthesized according to the method described in, for example, JP-A-222322.
  • the compound (I) of the present invention thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization, chromatography and the like.
  • the compound (I) of the present invention can be prepared by a conventional method using inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid) , Tartaric acid, cunic acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.), inorganic bases (sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, hydroxide) Treated with magnesium, copper hydroxide, zinc hydroxide, iron hydroxide, gold hydroxide, silver hydroxide, platinum hydroxide, manganese hydroxide, or amino acids (ly
  • the compound of the present invention When the compound of the present invention has a chiral carbon atom as described above, it is usually obtained as a racemic body.
  • the racemate can be separated into optical isomers by a conventional method.
  • Such optical isomers can also be produced by using an optically active starting compound.
  • the individual diastereomers can be purified by fractional recrystallization or chromatography.
  • the compound of the present invention when used as an antibacterial agent, it may be orally administered in the form of a conventional preparation containing a therapeutically effective amount of the compound of the present invention and an organic or inorganic, solid or liquid pharmaceutically acceptable carrier. It can be administered parenterally or externally.
  • Such preparations include, for example, solid preparations and suspensions such as tablets, granules, powders and capsules, and liquid preparations such as syrups, emulsions and limonade.
  • solid preparations and suspensions such as tablets, granules, powders and capsules
  • liquid preparations such as syrups, emulsions and limonade.
  • the dosage of the compound of the present invention will vary depending on the age and symptoms of the patient, or on the type of disease and the type of compound administered, but generally 1 mg to about 40,000 mg or more per day can be administered to the patient. it can.
  • the average single dose of the compound of the present invention is about 50 mg, 100 mg, 250 mg, 500 mg, 100 mg, 200 mg, and is used for treatment of diseases caused by pathogenic microorganisms. Can be.
  • the usefulness of the compound of the present invention as an antibacterial agent will be described in detail in the following examples. The following are used as test compounds.
  • the in vitro antibacterial activity (minimum inhibitory concentration, MIC, g ml) of the test compound was measured in accordance with the Japanese Society of Chemotherapy Standard Method (Chemottierapy, Vol. 29, pp. 76-79, 1989). Table 1 shows the results of the antibacterial spectrum. Table 1 Antibacterial activity (MIC: ⁇ g / ml) Compound Compound Compound Compound Control
  • E. faecal is LS- ⁇ 0.10 0.10 0.10 0.10 0.78
  • Example 3 Acute toxicity
  • mice Male d dY mice were used as a group of 5 mice, and the compound of Example 18 was administered orally at 200 mg / kg. No deaths occurred and no abnormality was observed.
  • the compound of the general formula (I) and salts, hydrates or optical isomers thereof obtained by the present invention can be converted into conventional pyridone carboxylic acids. While maintaining the strong antibacterial activity of acid-based antibacterial agents against gram-negative bacteria, it has enhanced efficacy and broad antibacterial activity against gram-positive bacteria in vitro and in vivo. In addition, since it has almost no problematic side effects and shows low toxicity, it is expected to be more clinically useful as an antibacterial agent.
  • the compounds of the present invention have particularly strong antibacterial activity against staphylococci such as methicillin- and cefm-resistant Staphylococcus aureus, staphylococcus epidermidis, and gram-positive bacteria such as pneumococci and staphylococci, and are further anaerobic. Since it has strong antibacterial activity against bacteria, mycoplasmas, and acid-fast bacteria, it can be used for the treatment of various infections caused by these pathogenic bacteria.
  • staphylococci such as methicillin- and cefm-resistant Staphylococcus aureus, staphylococcus epidermidis, and gram-positive bacteria such as pneumococci and staphylococci, and are further anaerobic. Since it has strong antibacterial activity against bacteria, mycoplasmas, and acid-fast bacteria, it can be used for the treatment of various infections caused by these pathogenic bacteria.
  • the desired product was obtained as an oil from the 5-benzyl-1-oxa-5-azaspiro [2.4] heptane and methylamine obtained in Production Example 9 in the same manner as in Production Example 2. '.
  • Production Example 11 2-benzyl-9-methyl-8-oxo-6-oxa-1,2,9-diazaspiro [4.5]
  • the desired product was obtained as an oil from decane in the same manner as in Production Example 6. Was.
  • the desired product was obtained from 1-benzyl-3-piperidone in the same manner as in Production Example 14.
  • the desired product was obtained from 3-benzamide 1-benzyl-13-cyanopiperidine obtained in Production Example 32 in the same manner as in Production Example 15.
  • the desired product was obtained from 3-benzamide 1-benzyl-3-ethoxycarbodirubiperidine obtained in Production Example 33 in the same manner as in Production Example 16.
  • the desired product was obtained from 1-benzyl-3-aminobenzyl 3-hydroxymethylbiperidine obtained in Production Example 34 in the same manner as in Production Example 17.
  • the desired product was obtained from 1-benzyl-3- (N-benzyl) chloroacetamide 3-chloroacetoxymethylbiperidine obtained in Production Example 35 in the same manner as in Production Example 18.
  • pandecane obtained in Production Example 18 was dissolved in 40 ml of tetrahydrofuran. — At 70 ° C, 5.3 mL of 1.5 M lithium diisopropylamide monotetrahydrofuran complex cyclohexane solution was added dropwise, the temperature was raised to 110 ° C, and then cooled to 170 ° C again. Methyl chloride 681 mg was added dropwise. Further, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with black-mouthed form.
  • the mixture was stirred at the same temperature for 30 minutes, poured into 30 ml of ice water, extracted with ethyl acetate, washed with water, dried and concentrated. The residue was dissolved in methanol (20 ml), and sulfuric acid (5.4 ml) was added under ice cooling. The mixture was stirred at the same temperature for 30 minutes, poured into 300 ml of ice water, and made alkaline with an aqueous sodium hydroxide solution. Extracted with ethyl acetate, washed with water, dried and concentrated to obtain an oil. The product was further purified using silica gel to obtain the desired product as an oil.
  • Nonan Production Example 4 8-benzyl-2-diphenylmethyl-7-oxo-1-5-oxa-1,2,8-diazaspiro [3.5] nonane '1 ethanol solvate obtained in 7-1 2) It was dissolved in a solution of 0 Oml and 50 ml of acetic acid, 10 g of a 10% palladium-carbon catalyst was added, and hydrogenation was performed under normal pressure. After absorbing the theoretical amount of hydrogen, the catalyst was removed and the solvent was distilled off under reduced pressure. Ethyl acetate was added, extracted with water, and the aqueous layer was made alkaline with ammonia water. The mixture was extracted with black-mouthed form, dried and concentrated under reduced pressure to obtain the desired product as an oil.
  • Production Example 5 3 2-Cyl-1,3-dioxer 8-azaspiro [4.5] decane 8-Bencil-2-methyl-1,3-dioxer 8-azaspiro obtained in Production Example 52 [4.5] 1.7 g of decane was dissolved in 30 ml of ethanol, and 1 g of a 10% paradigm carbon catalyst was added and hydrogenated. After the completion of the reaction, the catalyst was removed under reduced pressure to obtain the desired product as an oil.
  • Example 7 1-cyclopropyl-1-6-fluoro-1,4-dihydro-7- (1-oxo-1,4,9-diazaspiro [5.5] indekut-91-yl) obtained in Example 7 —4—oxo-3-quinolinecarboxylic acid
  • acetic anhydride To a solution of 1.5 g and 3 Om 1 of acetic acid, add 0.458 g of acetic anhydride and stir at room temperature for 2 hours. After concentration, ethanol is added and the precipitated crystals are collected by filtration to obtain the desired product. Melting point 2 8 8-2 9 1 ° C
  • Example 11 1-cyclopropyl-6-fluoro-1,4-dihydro obtained in Example 11 1 7- (4-oxa-1,9-diazspiro [5.5] INDECUT 91-yl) 1-4-oxo-1 3-quinolinecarboxylic acid 10 Omg and 37% formalin solution 0.8 ml, formic acid 0.4 ml of the mixture was heated at 100 ° C. for 2 hours. The formic acid and formalin solutions were distilled off, 25% aqueous ammonia was added to the residue, and the insolubles were filtered off. Ethanol was added to the filtrate, and the precipitated crystals were collected by filtration to obtain 56 mg of the desired product. 2 56 ° C (decomposition)
  • Example 14 7- (4-tert-butoxycarbonyl-1,4,9-triazaspiro [5.5] indec-9-yl) obtained in 4 (2) -1 1-cyclopropyl-1 6 — Fluorine-1,4-dihydro-8-methoxy-4-oxo-13-quinolinecarboxylate (264 mg) was treated with 4N hydrochloric acid in dioxane under ice-cooling, and the obtained crystals were recrystallized from 95% ethanol. 74 mg of the desired product was obtained. Melting point 2 29 ° C (decomposition)
  • Example 16 Example 14 7- (4-tert-butoxycarbonyl-1,4,9-triazaspiro [5.5] indec-9-yl) obtained in 4 (2) -1 1-cyclopropyl-1 6 — Fluorine-1,4-dihydro-8-methoxy-4-oxo-13-quinolinecarboxylate (264 mg) was treated with 4N hydrochloric acid in dioxane under ice-

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Abstract

Composé de pyridonecarboxylate représenté par la formule générale (I), son utilisation pharmaceutique et composé spiro utilisé comme intermédiaire dans sa synthèse. Dans ladite formule, R1 représente hydrogène, alkyle, etc.; R2 représente hydrogène ou alkyle; X et Y, pouvant être identiques ou différents représentent chacun oxygène, soufre ou -NR8- represente hydrogène, alkyle, etc; l et m représentent chacun un nombre entier compris entre 0 et 3; n représente 0, 1 ou 2; et Q représente un groupe de la formule générale (IV), dans laquelle R9 représente alkyle; R10 représente hydrogène; R11 représente -COOR?13 où R13¿ représente hydrogène, alkyle, etc; R12 représente hydrognène, halogène, etc.; Hal représente halogène; et A représente =N- ou =CR?14- où R14¿ représente hydrogène, halogène, etc.; ou R9 peut être combiné avec R?10 ou R14¿ pour former un cycle, ou R10 peut être combiné avec R11 pour former un cycle.
PCT/JP1992/001739 1991-12-27 1992-12-24 Compose de pyridonecarboxylate, son utilisation pharmaceutique et compose spiro WO1993013101A1 (fr)

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Cited By (17)

* Cited by examiner, † Cited by third party
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WO1999002494A1 (fr) * 1997-07-11 1999-01-21 Janssen Pharmaceutica N.V. Benzamides monocycliques gastrocinetiques de derives 4-(aminomethyl)-piperidine
US6291469B1 (en) 1995-09-29 2001-09-18 Eli Lilly And Company Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
WO2002074769A1 (fr) * 2001-03-19 2002-09-26 Ono Pharmaceutical Co., Ltd. Medicaments contenant comme principe actif des derives du triazaspiro [5.5] undecane
EP1236726A4 (fr) * 1999-12-03 2003-01-15 Ono Pharmaceutical Co Derives triazaspiro 5.5]undecane et medicaments contenant ces derives en tant que principe actif
WO2005047286A1 (fr) * 2003-11-13 2005-05-26 Ono Pharmaceutical Co., Ltd. Compose spiranique heterocyclique
JP2017516819A (ja) * 2014-06-02 2017-06-22 ラボラトリオス・デル・デエレ・エステベ・エセ・ア 疼痛に対する多様な活性を有する１−オキサ−４，９−ジアザスピロウンデカン化合物のアルキルおよびアリール誘導体
JP2017535566A (ja) * 2014-11-21 2017-11-30 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ 疼痛に対する多様な活性を有する１，９−ジアザスピロウンデカン化合物
US20190002475A1 (en) * 2015-10-23 2019-01-03 Laboratorios Del Dr. Esteve S.A. Oxa-diazaspiro compounds having activity against pain
US10730863B2 (en) 2017-11-01 2020-08-04 Bristol-Myers Squibb Company Bridged bicyclic compounds as farnesoid X receptor modulators
US11078198B2 (en) 2017-11-01 2021-08-03 Bristol-Myers Squibb Company Spirocyclic compounds as farnesoid X receptor modulators
US11168079B2 (en) 2017-11-01 2021-11-09 Bristol-Myers Squibb Company Alkene compounds as farnesoid x receptor modulators
US11254663B2 (en) 2019-02-15 2022-02-22 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US11286252B2 (en) 2017-11-01 2022-03-29 Bristol-Myers Squibb Company Alkene spirocyclic compounds as farnesoid X receptor modulators
US11370785B2 (en) 2017-11-01 2022-06-28 Bristol-Myers Squibb Company Multicyclic compounds as farnesoid X receptor modulators
US12030835B2 (en) 2019-02-15 2024-07-09 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators
US12227496B2 (en) 2019-02-15 2025-02-18 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12319676B2 (en) 2019-02-15 2025-06-03 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators

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JPS63258855A (ja) * 1987-04-02 1988-10-26 バイエル・アクチエンゲゼルシヤフト ５−置換キノロン−及びナフチリドンカルボン酸誘導体

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SU1066997A1 (ru) * 1982-07-09 1984-01-15 Ордена Трудового Красного Знамени Институт Тонкой Органической Химии Им.А.Л.Мнджояна Новые гетероциклические триазаспиро-конденсированные системы
JPS5967269A (ja) * 1982-09-09 1984-04-16 ワ−ナ−−ランバ−ト・コンパニ− 抗細菌化用化合物
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JPS63258855A (ja) * 1987-04-02 1988-10-26 バイエル・アクチエンゲゼルシヤフト ５−置換キノロン−及びナフチリドンカルボン酸誘導体

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6693109B2 (en) 1995-09-29 2004-02-17 Eli Lilly And Company Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
US6291469B1 (en) 1995-09-29 2001-09-18 Eli Lilly And Company Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
US6528534B2 (en) 1995-09-29 2003-03-04 Millennium Pharmaceuticals, Inc. Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
US6452013B1 (en) 1997-07-11 2002-09-17 Janssen Pharmaceutica N.V. Gastrokinetic monocyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
WO1999002494A1 (fr) * 1997-07-11 1999-01-21 Janssen Pharmaceutica N.V. Benzamides monocycliques gastrocinetiques de derives 4-(aminomethyl)-piperidine
US6750349B2 (en) 1997-07-11 2004-06-15 Janssen Pharmaceutics, N.V. Gastrokinetic monocyclic benzamides of 3-or 4-substituted 4-(aminoethyl)-piperidine derivatives
US7119091B2 (en) 1999-12-03 2006-10-10 Ono Pharmaceutical Co., Ltd. Triazaspiro[5.5]undecane derivatives and pharmaceutical compositions comprising thereof, as an active ingredient
EP1236726A4 (fr) * 1999-12-03 2003-01-15 Ono Pharmaceutical Co Derives triazaspiro 5.5]undecane et medicaments contenant ces derives en tant que principe actif
US7285552B2 (en) 2001-03-19 2007-10-23 Ono Pharmaceuticals Co., Ltd. Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient
WO2002074769A1 (fr) * 2001-03-19 2002-09-26 Ono Pharmaceutical Co., Ltd. Medicaments contenant comme principe actif des derives du triazaspiro [5.5] undecane
WO2005047286A1 (fr) * 2003-11-13 2005-05-26 Ono Pharmaceutical Co., Ltd. Compose spiranique heterocyclique
US10703765B2 (en) 2014-06-02 2020-07-07 Esteve Pharmaceuticals, S.A. Alkyl and aryl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain
JP2017516819A (ja) * 2014-06-02 2017-06-22 ラボラトリオス・デル・デエレ・エステベ・エセ・ア 疼痛に対する多様な活性を有する１−オキサ−４，９−ジアザスピロウンデカン化合物のアルキルおよびアリール誘導体
JP2017535566A (ja) * 2014-11-21 2017-11-30 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ 疼痛に対する多様な活性を有する１，９−ジアザスピロウンデカン化合物
US10689398B2 (en) * 2015-10-23 2020-06-23 Esteve Pharmaceuticals, S.A. OXA-Diazaspiro compounds having activity against pain
US20190002475A1 (en) * 2015-10-23 2019-01-03 Laboratorios Del Dr. Esteve S.A. Oxa-diazaspiro compounds having activity against pain
US10730863B2 (en) 2017-11-01 2020-08-04 Bristol-Myers Squibb Company Bridged bicyclic compounds as farnesoid X receptor modulators
US11078198B2 (en) 2017-11-01 2021-08-03 Bristol-Myers Squibb Company Spirocyclic compounds as farnesoid X receptor modulators
US11168079B2 (en) 2017-11-01 2021-11-09 Bristol-Myers Squibb Company Alkene compounds as farnesoid x receptor modulators
US11286252B2 (en) 2017-11-01 2022-03-29 Bristol-Myers Squibb Company Alkene spirocyclic compounds as farnesoid X receptor modulators
US11370785B2 (en) 2017-11-01 2022-06-28 Bristol-Myers Squibb Company Multicyclic compounds as farnesoid X receptor modulators
US11254663B2 (en) 2019-02-15 2022-02-22 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US11713312B2 (en) 2019-02-15 2023-08-01 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12030835B2 (en) 2019-02-15 2024-07-09 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators
US12227496B2 (en) 2019-02-15 2025-02-18 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12319676B2 (en) 2019-02-15 2025-06-03 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators

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