WO2011148962A1 - Composé hétérocyclique inédit ou son sel - Google Patents

Composé hétérocyclique inédit ou son sel Download PDF

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WO2011148962A1
WO2011148962A1 PCT/JP2011/061939 JP2011061939W WO2011148962A1 WO 2011148962 A1 WO2011148962 A1 WO 2011148962A1 JP 2011061939 W JP2011061939 W JP 2011061939W WO 2011148962 A1 WO2011148962 A1 WO 2011148962A1
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group
formula
oxo
naphthyridin
compound
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PCT/JP2011/061939
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English (en)
Japanese (ja)
Inventor
寿也 野口
文仁 牛山
裕正 堀切
恵子 山本
直哉 小野
哲男 高山
朋子 神山
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大正製薬株式会社
富山化学工業株式会社
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Priority to JP2012517290A priority Critical patent/JP5685589B2/ja
Publication of WO2011148962A1 publication Critical patent/WO2011148962A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present invention relates to a novel compound having a strong antibacterial activity against gram positive bacteria, gram negative bacteria and resistant bacteria, or a salt thereof, and an antibacterial agent containing them.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant enterococci
  • PRSP penicillin-resistant pneumococci
  • Non-Patent Document 1 discloses a quinolone compound effective for MRSA.
  • Patent Documents 2-7 disclose a compound having a mechanism of action different from existing drugs.
  • Patent Document 8 discloses a compound having a spiro ring skeleton characteristic of the structure.
  • a bond including a dotted line connecting X 2 and Y 1 represents a single bond or a double bond
  • Z 1 represents a nitrogen atom or formula CR 1
  • Z 2 represents a nitrogen atom or formula CR 2
  • Z 3 represents a nitrogen atom or formula CR 3
  • Z 4 represents a nitrogen atom or formula CR 4 .
  • Z 5 represents a nitrogen atom or formula CR 5
  • Z 6 represents a nitrogen atom or formula CR 6
  • X 1 represents a C 1-4 alkylene group which may be substituted with an oxo group
  • X 2 represents a bond when
  • X 3 represents a C 1-4 alkylene group, a formula NR 10 (CH 2 ) m , a formula SO n , or a bond
  • R 10 is the same or different and represents a hydrogen atom or a C 1-6 alkyl group
  • m and n are the same or different and represent 0, 1, or 2
  • R 7 represents a C 3-6 cycloalkyl group, a C 3-6 cycloalkenyl group, an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group
  • the C 3-6 cycloalkyl group, C 3-6 cycloalkenyl group, aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group are a C 1-6 alkoxy group, a hydroxy group, a halogen atom, A C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 2
  • the compound of the formula [I] or a salt thereof has a strong antibacterial activity against gram positive bacteria, gram negative bacteria and resistant bacteria.
  • C xy means that the carbon number is from x to y.
  • C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert -Butoxy, pentyloxy, isopentyloxy, hexyloxy and the like.
  • the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. , Pentyl, isopentyl, hexyl and the like.
  • the C 1-6 hydroxyalkyl group means a group in which any one hydrogen atom of the C 1-6 alkyl group is substituted with a hydroxy group.
  • the C 1-6 haloalkyl group means a group in which any hydrogen atom of the C 1-6 alkyl group is substituted with a halogen atom, and examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl and the like. Can do.
  • the number of halogen atom substitutions is preferably 1 to 3.
  • the C 1-6 haloalkoxy group means a group in which any hydrogen atom of the above C 1-6 alkoxy group is substituted with a halogen atom, and examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like. .
  • the number of halogen atom substitutions is preferably 1 to 3.
  • the C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the C 3-6 cycloalkenyl group is cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • the C 2-7 alkanoyl group means a linear or branched alkanoyl group having 2 to 7 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, isovaleryl, pivaloyl and the like.
  • the C 1-4 alkylene group means a linear or branched alkylene group having 1 to 4 carbon atoms, and examples thereof include methylene, ethylene, propylene, butylene and the like.
  • monocyclic heterocyclic groups include furyl, thienyl, 2-pyrrolyl, imidazolyl, 3-pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, imidazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, piperazinyl, 2-piperidyl , 3-piperidyl, 4-piperidyl, 2-piperazinyl, 2-morpholinyl, 2-thiomorpholinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl and the like.
  • the monocyclic heterocyclic group includes 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms, and is preferably 5- or 6-membered.
  • Bicyclic heterocyclic groups include, for example, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, 1H-indazolyl, purinyl, coumarinyl, chromenyl Quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, quinuclidinyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl, benzomorpholinyl, benzomorpholonyl, 2 , 3-dihydro (1,4) dioxino (2,3-c) pyridin-7-yl, 3,4-d
  • aryl group examples include phenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
  • Examples of the salt of the compound of the formula [I] include a salt of a known basic group such as an amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group.
  • Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid
  • salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid
  • salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
  • salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogenous organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine and N, N′-dibenzylethylenediamine Can be mentioned.
  • alkali metals such as sodium and potassium
  • alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogenous organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohex
  • preferred salts of the compound of the formula [I] include pharmacologically acceptable salts.
  • the compound of the present invention or a salt thereof may form a hydrate or a solvate, and these are also included in the present invention.
  • preferable compounds include the following compounds.
  • a compound in which Z 1 is formula CR 1 is preferred, and a compound in which formula CH is more preferred.
  • a compound in which Z 2 is a nitrogen atom or the formula CH is preferred.
  • Compounds in which Z 3 is a nitrogen atom or the formula CH are preferred.
  • Compounds in which Z 4 is formula CR 4 are preferred, and compounds of formula CH are more preferred.
  • a compound in which Z 5 is formula CR 5 is preferable, and a compound in which R 5 is a C 1-6 alkoxy group or a halogen atom is more preferable.
  • a compound in which Z 6 is formula CR 6 is preferred, and a compound in which formula CH is more preferred.
  • a compound in which X 1 is a C 1-2 alkylene group which may be substituted with an oxo group is preferable, and a C 1-2 alkylene group substituted with an oxo group is more preferable.
  • a compound in which X 2 is a bond (a bond including a dotted line connecting X 2 and Y 1 is a single bond) is preferable.
  • Y 1 is a hydroxy group, a halogen atom, a C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 2-7 alkanoyl group, a phenyl group, a formula —NR 13 R 14 , a formula —CO 2 R 13 , and
  • a compound which is a spiro ring group selected from the following formula group [III], optionally substituted by 1 to 3 groups selected from the group consisting of formula —CONR 13 R 14 is preferably an unsubstituted formula group
  • a compound having a spiro ring group selected from [III] is more preferable,
  • a compound having a spiro ring group selected from the following formula group [IV] is even more preferable.
  • a compound in which X 3 is a C 1-4 alkylene group, a formula NR 10 , a formula SO n , or a bond is preferred, and a compound in which a bond is preferred.
  • R 7 is an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group, and the aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group are a C 1-6 alkoxy group, a hydroxy group, Halogen atom, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group, C 2-7 alkanoyl group, monocyclic heterocyclic group, formula —NR 11 R 12 , formula —CO 2 R 11 and a compound optionally substituted with 1 to 5 substituents selected from the group consisting of —CONR 11 R 12, preferably 1 to 3 selected from a halogen atom and a C 1-6 alkyl group
  • formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed.
  • excipients such as excipients, carriers and diluents usually used for formulation
  • these are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, It can be administered orally or parenterally in the form of a patch, ointment or injection.
  • the administration method, the dose and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient.
  • oral administration or parenteral administration for example, injection, infusion, administration to the rectal site, etc.
  • 0.01 to 1000 mg / kg per day can be divided into 1 to several doses. Good.
  • the compound of the formula [I] of the present invention is a gram-positive bacterium, a gram-negative bacterium, an anaerobic bacterium, or a non-drug-containing bacterium such as a multidrug-resistant Staphylococcus aureus, a multidrug-resistant pneumococci, or a vancomycin-resistant enterococci. Excellent antibacterial activity against typical acid-fast bacteria.
  • Z 1 -Z 6 , X 3 , and R 7 are as defined above.
  • X 1a represents a C 1-3 alkylene group
  • Y 1b represents a spiro ring group having a nitrogen atom in the spiro ring and bonded to the adjacent hydrogen atom.
  • the compound of the formula [1a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
  • the present compound of the formula [1] can be produced by reacting the compound of the formula [1a] with the compound of the formula [1b] in the presence of a reducing agent.
  • This reaction may be performed by a method described in WO 06/46552 pamphlet or the like or a method according thereto.
  • the amount of the compound of the formula [1b] and the reducing agent used may be 1 to 20 times mol with respect to the compound of the formula [1a].
  • L 1 represents a leaving group, and examples of L 1 include a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • the compound of the formula [2a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
  • the compound of the present invention of the formula [2] can be produced by reacting the compound of the formula [2a] with the formula [1b] in the presence or absence of a base.
  • This reaction may be performed by the method described in US Pat. No. 6,603,005 or the like, or a method analogous thereto.
  • the amount of the compound of the formula [1b] and optionally used base may be 1-20 times mol with respect to the compound of the formula [2a].
  • Z 1 -Z 6 , X 1a , X 3 , Y 1b and R 7 are as defined above.
  • the compound of the present invention of the formula [3] can be produced by reacting the compound of the formula [3a] with the compound of the formula [1b] using a condensing agent in the presence or absence of a base.
  • This reaction is carried out according to the method described in WO03 / 010138, WO03 / 087098 and Izumiya et al., Basics and Experiments of Peptide Synthesis, 89-142, 1985, Maruzen et al. What is necessary is just to perform according to the method.
  • the use amount of the base, the compound of formula [1b], and the condensing agent that are optionally used may be 1 to 20 moles compared to the compound of formula [3a].
  • Z 1 -Z 6 , X 1 -X 3 , Y 1 , R 7 , and L 1 are as defined above.
  • the compound of the formula [4a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
  • the compound of the present invention of the formula [I] can be produced by reacting the compound of the formula [4a] with the compound of the formula [4b] in the presence or absence of a base.
  • the use amount of the base and the compound of the formula [4b] used as required may be 1 to 20 times the mol of the compound of the formula [4a].
  • Z 1 -Z 6 , X 1 , X 2 , R 7 , and L 1 are as defined above.
  • Y 1a represents a spiro ring group having a nitrogen atom in the spiro ring, and the nitrogen atom is bonded to an adjacent hydrogen atom, and
  • X 3b represents a C 1-4 alkylene group.
  • the compound of the present invention of the formula [5] can be produced by reacting the compound of the formula [5a] with the compound of the formula [5b] in the presence or absence of a base.
  • This reaction may be performed by the method described in US Pat. No. 6,603,005 or the like, or a method analogous thereto.
  • the amount of the compound of the formula [5b] and optionally used base may be 1-20 times mol with respect to the compound of the formula [5a].
  • Z 1 -Z 6 , X 1 , X 2 , R 7 , and Y 1a are as defined above.
  • X 3c represents a C 1-3 alkylene group.
  • the compound of the present invention of the formula [6] can be produced by reacting the compound of the formula [5a] with the compound of the formula [6b] in the presence of a reducing agent.
  • This reaction may be carried out by the method described in WO 06/46552 pamphlet or the like or a method analogous thereto.
  • the amount of the compound of the formula [6b] and the reducing agent used may be 1-20 times mol with respect to the compound of the formula [5a].
  • a base when using a base in the reaction of each production method, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, potassium hydroxide
  • sodium hydroxide, lithium hydroxide, sodium amide, sodium methoxide, tert-butoxypotassium, sodium hydride, lithium hydride, triethylamine, diisopropylethylamine, dimethylaniline, diethylaniline, pyridine, pyrrolidine and N-methylmorpholine can be mentioned.
  • lithium aluminum hydride for example, lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, etc., boranes, sodium And sodium amalgam and the like.
  • electrolytic reduction using copper or platinum as a cathode catalytic reduction using Raney nickel, platinum oxide or palladium black, reduction using “zinc-acid”, or the like can also be used.
  • the solvent is not particularly limited as long as it is stable under the reaction conditions and is inert and does not interfere with the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether Ethers such as; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate; N, N-dimethylformamide, N, N-dimethylacetoa
  • amides and water such as de and 1-methyl-2-pyrrolidone, and the like, it may be used which are mixed.
  • reaction can be carried out by selecting an appropriate temperature in the range of ⁇ 78 ° C. to the boiling point of the solvent used for the reaction, under normal pressure or under pressure, under microwave irradiation, or the like.
  • the mixing ratio in the eluent is a volume ratio.
  • each abbreviation has the following meaning.
  • DMSO-d6 heavy dimethyl sulfoxide
  • the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate], and ethyl (7-methoxy-2-oxo-2H-quinolin-1-yl) ethyl acetate 322 mg was obtained.
  • the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate] and (2-oxo-2H- (1,7) -naphthyridin-1-yl) 112 mg of ethyl acetate was obtained.
  • a colorless oil of 3- (7-methoxy-2) was prepared in the same manner as in Reference Example 7 using 300 mg of 7-methoxy-1H- (1,5) -naphthyridin-2-one and 463 mg of ethyl 3-bromopropionate. There was obtained 207 mg of ethyl -oxo-2H- (1,5) -naphthyridin-1-yl) propionate.
  • N-Butyllithium (2.77 mol / L n-hexane solution) (463 ⁇ L) was added dropwise to a tetrahydrofuran (5.0 mL) solution of diisopropylethylamine (172 ⁇ L) under ice cooling, and the mixture was stirred for 10 minutes. After cooling to ⁇ 78 ° C., 300 mg of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate was added and stirred for 1 hour.
  • 6-iodo-2,3-dihydrobenzo (1,4) dioxin 341 mg, tert-butyl 1-oxo-2,6-diazaspiro (3.5) nonane-6-carboxylate 300 mg, copper iodide 25 mg, phosphorus 660 mg of potassium acid n-hydrate and 41.1 ⁇ L of (1R, 2R) -N, N′-dimethylcyclohexane-1,2-diamine were suspended in 10 mL of N, N-dimethylformamide and incubated at 110 ° C. for 15.5 hours. Stir. 30 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated.
  • tert-Butyl 9- (2- (7-Fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -3,9-diazaspiro (5.5) undecane-3-carboxylate 1- (2- (3,9-diazaspiro (5.5) undecan-3-yl) ethyl) -7-fluoro-1H- (1,5) was prepared in the same manner as in Reference Example 13 using 438 mg. 318 mg of naphthyridin-2-one hydrochloride was obtained.
  • tert-butyl 7- (2- (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,7-diazaspiro (4.4) nonane-2-carboxylate Using 105 mg, in the same manner as in Reference Example 13, colorless solid 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-fluoro-1H— 92 mg of hydrochloride of (1,5) -naphthyridin-2-one was obtained.
  • a yellow oil was obtained. This was suspended in 50 mL of 2-propanol, 10 mL of 2-propanol solution of 2 mol / L hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 21 hours.
  • tert-Butyl 8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,8-diazaspiro (4.5) decane-2-carboxylate 290 mg was dissolved in 5 mL of 1,4-dioxane, 5 mL of 1,4-dioxane solution of 4 mol / L hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours.
  • tert-butyl 3-oxo-2,8-diazaspiro (4.5) decane-8-carboxylate was dissolved in 2 mL of N, N-dimethylformamide, and 14 mg of 60% sodium hydride was added. Further, a solution of 60 mg of 7-chloromethyl-2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine in 2 mL of N, N-dimethylformamide-2 mL of tetrahydrofuran was added, and the mixture was stirred at 70 ° C. for 15 hours. Stir.
  • reaction mixture was returned to room temperature, 10 mL of water and 10 mL of ethyl acetate were added, and the organic layer was separated.
  • the organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2- (2,3-dihydro- (1,4) dioxyno (2, 3-c) 108 mg of pyridin-7-ylmethyl) -3-oxo-2,8-diazaspiro (4.5) decane-8-carboxylate was obtained.
  • tert-Butyl 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) -5′-oxo-8-azaspiro (bicyclo (3.2.1) octane-3, 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) -8 was prepared in the same manner as in Reference Example 15 using 3 mg of 3′-pyrrolidine) -8-carboxylate. -181 mg of azaspiro (bicyclo (3.2.1) octane-3,3'-pyrrolidin) -5'-one was obtained.
  • Benzyl 4-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-ylamino) methyl) -4-hydroxypiperidine-1-carboxylate 51 mg was dissolved in 2 mL of chloroform. , 0.05 mL of triethylamine and 38 mg of bis (trichloromethyl) carbonate were added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (3 mL) and chloroform (5 mL) were added to the reaction mixture, and the organic layer was separated.
  • Benzyl 3- (2,3-dihydro- (1,4) dioxino (2,3-c) pyridin-7-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane -8-Carboxylate (63 mg) was dissolved in ethanol (3 mL), 7.5% palladium carbon (22 mg) was added, and the mixture was stirred at 40 ° C. for 6 hours under hydrogen atmosphere. Insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure to give 3- (2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl)-as a white solid.
  • tert-Butyl (2- (3-methoxy-6-oxo-6H-pyrido (2,3-b) pyrazin-5-yl) acetate (980 mg) was dissolved in ethyl acetate (5 mL), and 4 mol / L hydrochloric acid in ethyl acetate 10 mL was added, and the mixture was stirred at room temperature for 20 hours, the insoluble material was collected by filtration, washed with 50 mL of ethyl acetate, and dried to give (2- (3-methoxy-6-oxo-6H-pyrido (2 , 3-b) Pyrazin-5-yl) acetic acid hydrochloride 504 mg was obtained.
  • tert-butyl 1-oxa-6-azaspiro (2.5) octane-6-carboxylate 210 mg and 2,3-dihydro- (1,4) dioxyno (2,3-b) pyridin-6-amine 150 mg
  • tert-butyl 4-(((2,3-dihydro- (1,4) dioxyno (2,3-b) pyridin-6-yl) amino in the form of a brown oil was used.
  • 294 mg of methyl) -4-hydroxypiperidine-1-carboxylate were obtained.
  • tert-Butyl 3- (2,3-dihydro- (1,4) dioxino (2,3-b) pyridin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5 )
  • 153 mg of decane-8-carboxylate was dissolved in 2 mL of chloroform, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it basic.
  • 2-Bromo-5H-pyrido (3,2-d) pyrimidin-6-one (200 mg) and sodium hydrogen carbonate (297 mg) are suspended in a mixed solvent of 60 mL of ethanol and 60 mL of tetrahydrofuran, and 20 mg of 10% palladium on carbon is added under a hydrogen atmosphere. Stir for hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 220 mg of 5H-pyrido (3,2-d) pyrimidin-6-one (crude purified product) as a light brown solid.
  • tert-butyl 3- (2,3-dihydrobenzo (b) (1,4) dithiin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane-8-
  • the same operation as in Reference Example 58 was carried out using 33 mg of carboxylate, to give a pale brown solid of 3- (2,3-dihydrobenzo (b) (1,4) dithiin-6-yl) -1-oxa-3 , 8-diazaspiro (4.5) decan-2-one 14 mg was obtained.
  • tert-Butyl 6-Amino-2-azaspiro (3.3) heptane-2-carboxylate 119 mg and 2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde 89 mg was dissolved in chloroform (5 mL), acetic acid (46 ⁇ L) was added, and the mixture was stirred at room temperature for 3 hr. 250 mg of sodium triacetoxyborohydride was added and stirred at room temperature for 2 hours.
  • tert-butyl 6-(((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) methyl) amino) -2-azaspiro (3.3) heptane-2 -Using a carboxylate of 130 mg and following the same procedure as in Reference Example 58, a pale yellow oily N-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) 88 mg of methyl) -2-azaspiro (3.3) heptane-6-amine were obtained.
  • tert-Butyl 7- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,7-diazaspiro (4.4) nonane-2-carboxylate Using 105 mg, in the same manner as in Reference Example 13, 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-methoxy-1H— in the form of a brown solid 125 mg of (1,5) naphthyridin-2-one hydrochloride was obtained.
  • Second Step 140 mg of the residue obtained in the first step and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3,8-diazaspiro (4.5) decane- 173 mg of 2-one was suspended in 10 mL of chloroform, 0.42 mL of triethylamine, 204 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 35 mg of 1-hydroxybenzotriazole monohydrate were added, Stir for days. Chloroform 100mL and water 20mL were added to the reaction liquid, and the organic layer was fractionated.
  • Example 5 105 mg ethyl (2-oxo-2H- (1,7) -naphthyridin-1-yl) acetate and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3,
  • the same operation as in Example 5 was carried out using 124 mg of 8-diazaspiro (4.5) decan-2-one, and 1- (2- (3- (2,3-dihydrobenzo (1,4 ) Dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -1H- (1,7) -naphthyridine-2- On 204 mg was obtained.
  • reaction mixture was ice-cooled, 43 mg of sodium triacetoxyborohydride was added, and the mixture was allowed to warm to room temperature and stirred for 3 hr.
  • the reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate] to give 1- (2- (2- (2,3-Dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,7-diazaspiro (3.5) non-7-yl) ethyl) -7-methoxy-1H 32 mg of (1,5) naphthyridin-2-one was obtained.
  • the reaction mixture was diluted with 100 mL of ethyl acetate, washed successively with 10 mL of water and 10 mL of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: chloroform]. Further, 10 mL of chloroform and 150 mL of hexane were added to the purified product, and the precipitate was collected by filtration and dried to give 3- (3-fluoro-4-methylphenyl) -8- (2- (7-methoxy-2-) as a white solid.
  • Test example 1 Sensitivity measurement test 1 The test substance was dissolved in dimethyl sulfoxide, and antibacterial activity (MIC) was measured by a micro liquid dilution method according to the standard method of CLSI (Clinical and Laboratory Standards Institute).
  • the test strain used was Staphylococcus aureus (MSSA, MRSA).
  • MSSA Staphylococcus aureus
  • the cells cultured overnight at 35 ° C. on a heart infusion agar plate were suspended in Mueller Hinton medium so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution.
  • About 0.005 mL of the inoculated bacterial solution was inoculated into a cation-adjusted Mueller Hinton medium (100 ⁇ L / well) containing a test substance, and cultured overnight at 35 ° C.
  • the lowest test substance concentration at which no bacterial growth was observed macroscopically was defined as MIC ( ⁇ g / mL). The results are shown in Table 1. The part where the numerical value is not described indicates that the test is not performed.
  • Test Example 2 Staphylococcus aureus Mouse Systemic Infection Test
  • a group of 8 animals was used. (4) Judgment of effect The infection treatment effect was based on the survival number 7 days after bacterial inoculation. In the non-treatment group, all cases died by 1 day after the bacterial inoculation, but in Example 4, 7 out of 8 cases were observed 7 days after the bacterial inoculation, indicating in vivo antibacterial activity.
  • Test Example 3 Measurement of inhibitory activity against Staphylococcus aureus-derived topoisomerase IV S. aureus Topoisomerase IV Decatenation Kit (Inspiralis) was used for measurement.
  • 198 ⁇ L of 5 ⁇ Assay Buffer 198 ⁇ L of 5 ⁇ Assay Buffer, 66 ⁇ L of 0.1 ⁇ g / ⁇ L kinetoplast DNA solution and 462 ⁇ L of sterilized ultrapure water were added to prepare a reaction base solution A.
  • 22 ⁇ L of reaction base solution A and 3 ⁇ L of the compound of Example 26 or cyproxacin (CPFX) prepared to a 10-fold concentration were added.
  • topoisomerase IV solution diluted to 0.16 U / ⁇ L using Dilution Buffer was added. The whole volume was incubated at 37 ° C. for 30 minutes. After the reaction, 5 ⁇ L of a reaction stop solution (0.5 M EDTA containing 0.1% BPB) was added, and 20 ⁇ L was electrophoresed on a 1% agarose gel. After electrophoresis, the agarose gel was stained in a 2 ⁇ g / mL ethidium bromide solution, an image was captured, and the amount of each DNA was determined.
  • a reaction stop solution 0.5 M EDTA containing 0.1% BPB
  • the amounts of single-stranded and circular DNA bands in the enzyme-free group and the enzyme-added group not containing the compound of Example 26 or CPFX were 0% and 100%, respectively, and the drug concentration when the reaction product was 50%. It was calculated some IC 50 (IC 50 deca Te National activity). Both the compound of Example 26 and CPFX had an IC 50 of 1 ⁇ g / mL or less.
  • Test Example 4 Measurement of inhibitory activity against S. aureus-derived DNA gyrase S. aureus DNA Gyrase Supercoiling Assay Kit (Inspiralis) was used for measurement.
  • a basic reaction solution B was prepared by adding 210 ⁇ L of 5 ⁇ Assay Buffer, 17.5 ⁇ L of relaxed pBR322 DNA solution and 542.5 ⁇ L of sterilized ultrapure water to an Eppendorf tube.
  • 22 ⁇ L of reaction base solution B and 3 ⁇ L of the compound of Example 26 or CPFX prepared to a 10-fold concentration were added.
  • 5 ⁇ L of DNA gyrase solution diluted to 0.25 U / ⁇ L using Dilution Buffer was added.
  • the whole volume was incubated at 37 ° C. for 30 minutes. After the reaction, 5 ⁇ L of a reaction stop solution was added, and 20 ⁇ L was electrophoresed on a 1% agarose gel. After electrophoresis, the agarose gel was stained in a 2 ⁇ g / mL ethidium bromide solution, an image was taken in, and the amount of each DNA was determined. That is, the drug concentration when the reaction product is 50% when the amount of the supercoiled DNA band in the enzyme-free group and the enzyme-added group not containing the compound of Example 26 or CPFX is 0% and 100%, respectively. It was calculated IC 50 (IC 50 of supercoiling activity). The IC 50 of the compound of Example 26 was 1 ⁇ g / mL or less. On the other hand, IC 50 of CPFX was 12 [mu] g / mL.
  • the heterocyclic compound of the present invention or a salt thereof is useful as an excellent antibacterial agent because it has strong antibacterial activity and high safety.

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Abstract

La présente invention concerne un médicament doté d'une forte activité antibactérienne contre les bactéries à gram positif, les bactéries à gram négatif et les bactéries résistantes. Un composé de formule [I] ou son sel peut être utilisé en tant qu'agent antibactérien. Dans la formule [I], une liaison représentée par une ligne en pointillés et reliant X2 à Y1 représente une simple liaison ou une double liaison ; Z1, Z2, Z3, Z4, Z5 et Z6 représentent chacun un atome d'azote, le composé CH ou équivalent ; X1 représente un groupe alkylène en C1-C4 pouvant être substitué par un groupe oxo ; X2 représente une extrémité de liaison ou un composé CH ; Y1 représente un groupe spirocyclique choisi parmi les groupes de formule (II) ; X3 représente un groupe alkylène en C1-C4, le composé de formule NR10 (CH2) m, le composé de formule SOn ou une extrémité de liaison ; et R7 représente un groupe cycloalkyle en C3-C6, un groupe cycloalcényle en C3-C6, un groupe aryle, un groupe hétérocyclique monocyclique, un groupe hétérocyclique bicyclique ou équivalent.
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WO2014181266A1 (fr) 2013-05-08 2014-11-13 Actelion Pharmaceuticals Ltd Dérivés de phtalide antibactériens
WO2015136947A1 (fr) 2014-03-14 2015-09-17 Raqualia Pharma Inc. Dérivés azaspiro en tant qu'antagonistes de trpm8
WO2017029602A3 (fr) * 2015-08-16 2017-04-13 Glaxosmithkline Intellectual Property Development Limited Composés à utiliser dans des applications antibactériennes
CN113214257A (zh) * 2021-04-22 2021-08-06 上海合全药业股份有限公司 一种1-氧亚基-2,6-二氮杂螺[3.5]壬烷-6-甲酸叔丁酯的合成方法
WO2024092040A1 (fr) * 2022-10-26 2024-05-02 Protego Biopharma, Inc. Composés hétéroaryle bicycliques contenant un spirocycle

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014181266A1 (fr) 2013-05-08 2014-11-13 Actelion Pharmaceuticals Ltd Dérivés de phtalide antibactériens
US10093678B2 (en) 2014-03-14 2018-10-09 Raqualia Pharma Inc. Azaspiro derivatives as TRPM8 antagonists
WO2015136947A1 (fr) 2014-03-14 2015-09-17 Raqualia Pharma Inc. Dérivés azaspiro en tant qu'antagonistes de trpm8
US10364254B2 (en) 2015-08-16 2019-07-30 Glaxosmithkline Intellectual Property Development Limited Compounds for use in antibacterial applications
CN108137616A (zh) * 2015-08-16 2018-06-08 葛兰素史克知识产权开发有限公司 包含吡嗪并[2,3-b][1,4]噁嗪-3-酮或相关环系的抗菌剂
AU2016307969B2 (en) * 2015-08-16 2019-02-14 Glaxosmithkline Intellectual Property Development Limited Antibacterial agents comprising a pyrazino[2,3-b][1,4]oxazin-3-one or a related ring system
WO2017029602A3 (fr) * 2015-08-16 2017-04-13 Glaxosmithkline Intellectual Property Development Limited Composés à utiliser dans des applications antibactériennes
AU2016307969C1 (en) * 2015-08-16 2019-09-05 Glaxosmithkline Intellectual Property Development Limited Antibacterial agents comprising a pyrazino[2,3-b][1,4]oxazin-3-one or a related ring system
EA033314B1 (ru) * 2015-08-16 2019-09-30 Глаксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед АНТИБАКТЕРИАЛЬНЫЕ АГЕНТЫ, СОДЕРЖАЩИЕ ПИРАЗИНО[2,3-b][1,4]ОКСАЗИН-3-ОН ИЛИ РОДСТВЕННУЮ КОЛЬЦЕВУЮ СИСТЕМУ
AU2019200226B2 (en) * 2015-08-16 2020-01-23 Glaxosmithkline Intellectual Property Development Limited Antibacterial agents comprising a pyrazino[2,3-b][1,4]oxazin-3-one or a related ring system
US10683307B2 (en) 2015-08-16 2020-06-16 Glaxosmithkline Intellectual Property Development Limited Compounds for use in antibacterial applications
CN108137616B (zh) * 2015-08-16 2020-06-26 葛兰素史克知识产权开发有限公司 包含吡嗪并[2,3-b][1,4]噁嗪-3-酮或相关环系的抗菌剂
CN113214257A (zh) * 2021-04-22 2021-08-06 上海合全药业股份有限公司 一种1-氧亚基-2,6-二氮杂螺[3.5]壬烷-6-甲酸叔丁酯的合成方法
WO2024092040A1 (fr) * 2022-10-26 2024-05-02 Protego Biopharma, Inc. Composés hétéroaryle bicycliques contenant un spirocycle

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