WO2004035547A1 - 1位置換―4―ニトロイミダゾール化合物及びその製造法 - Google Patents
1位置換―4―ニトロイミダゾール化合物及びその製造法 Download PDFInfo
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- WO2004035547A1 WO2004035547A1 PCT/JP2003/013134 JP0313134W WO2004035547A1 WO 2004035547 A1 WO2004035547 A1 WO 2004035547A1 JP 0313134 W JP0313134 W JP 0313134W WO 2004035547 A1 WO2004035547 A1 WO 2004035547A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
Definitions
- the present invention relates to a 1-substituted 1-41-2 troimidazole compound and a method for producing the same. Background technology
- X represents a halogen atom or a group S (O) n—.
- n represents 0, 1 or an integer of 2;
- R 1 represents a phenyl group which may have 1 to 3 groups selected from the group consisting of a nitro group, a halogen atom and a lower alkyl group as a substituent on the phenyl ring.
- reaction formula 1 1 Conventionally, as a method for producing a 412 toloimidazole compound represented by the general formula (2), for example, the methods shown in the following reaction formulas 11 and 12 are known (Swinski et al., Polish Journal. Bob's Chemistry, Vol. 56, No. 1261-1272, 1982 (1982) (See Jerzy SUWINSKI, Ewa SALWINSKA, Jan WATRAS and Maria WIDEL, Polish Jounal of Chemistry, 56, 1261-1272 (1982)) . [Reaction formula 1 1]
- the compound (6) and the compound (7) which are reaction intermediates, are chemically unstable compounds and may explode due to impact such as dropping or friction.
- the TNR temperature of compound (6) (Temperature of No Return: safe in equipment in a chemical process) (The maximum temperature that can be handled is around 60 to 70 ° C). Was very dangerous.
- An object of the present invention is to provide a 1-substituted 412-troimidazole compound represented by the following general formula (1) or a salt thereof, and a production method thereof.
- the present invention also provides a method for producing a 4-nitroimidazole compound represented by the general formula (2a) in a high yield and a high purity by a safer method with less risk of explosion and the like. Aim. Further, the present invention provides a novel 1-substituted 1,412-troimidazole compound represented by the general formula (10), which can be used as an intermediate for producing an antituberculous drug, and a compound represented by the general formula (2b) or (2b): An object of the present invention is to provide a 41-2 tromididazole compound represented by 2c).
- the present inventors have proposed a method for producing a 4-nitroimidazole compound represented by the general formula (2a) and a novel intermediate which can be used as an intermediate for producing an antituberculous drug.
- a 4-substituted imidazole compound represented by the following general formula (3) is reduced to obtain a 1-substituted 1-substituted compound represented by the following general formula (la): - by removing iota lambda functionalized nitroimidazole compounds, by reducing the 4 twelve Toro imidazole torquecontrol compound represented by 2 the following general formula (4), represented by 3 the following general formula (1 5)
- the 412-troimidazole compound represented by the general formula (2a) can be converted into an explosion or the like. It has been found that it can be manufactured in a safer method with less danger and with high yield and high purity.
- the present inventors have also found that the 1-substituted-4-nitroimidazole compound represented by the general formula (1) and formed in the course of this method is a novel compound not described in any literature.
- the present invention has been completed based on such findings.
- the present invention provides a compound represented by the general formula
- R may be a hydrogen atom, a lower alkoxy-substituted lower alkyl group, a phenyl-lower alkoxy-substituted lower alkyl group, a cyano-substituted lower alkyl group, or a lower alkoxy group as a substituent on the phenyl ring.
- a phenyl lower alkyl group or group represents CH 2 RA .
- R B represents a hydrogen atom or a lower alkyl group.
- X represents a halogen atom or a group S (O) n—R ⁇ .
- n represents 0 or an integer of 1 or 2.
- R 1 represents a phenyl group which may have 1 to 3 groups selected from the group consisting of a nitro group, a halogen atom and a lower alkyl group as substituents on the phenyl ring.
- R when X represents a halogen atom, R must not be a hydrogen atom.
- the present invention has a general formula
- R A is a lower alkoxy-substituted lower alkyl group, a fuunyl lower alkoxy-substituted lower alkyl group, a cyano-substituted lower alkyl group, or a phenyl which may have a lower alkoxy group as a substituent on the phenyl ring. Shows a lower alkyl group.
- X 1 and X A each represent a halogen atom.
- the present invention provides a compound represented by the general formula
- the present invention provides a compound represented by the general formula (2)
- R B represents a hydrogen atom or a lower alkyl group.
- R u represents a nitro group.
- RE represents a halogen atom or a lower alkyl group.
- a represents 0, 1 or 2. If a represents 2, two R E is to the same derconnection may or may be different. ]
- a method for producing a 1-substituted 1-41-2 troimidazole compound characterized by obtaining a 1-substituted 1-41-2 troimidazole compound represented by the following formula:
- the present invention has a general formula
- the present invention provides a compound represented by the general formula
- R 1 is the same as above.
- the present invention provides a compound represented by the general formula (25), (2b) or (10c)
- R and R 1 are the same as defined above, and oxidize 4-nitroimidazole.
- the present invention provides a compound represented by the general formula
- the present invention relates to a method for producing a 412 troimidazole compound, wherein the nitronium halogenated borate in the above item 8 is nitronium tetrafluoroborate.
- the present invention is a method for producing a 412-troimidazole compound, wherein the nitration in the above item 9 is performed in nitromethane. 1 1.
- the present invention has the general formula
- the present invention has the general formula
- chi beta is a bromine atom, or a group one S (O) nR 1 (R 1 and n are the same.) Shows a. Is the base Or a group (R K and R L each represent a tetrahydrobiranyl group, a tri-lower alkylsilyl group, a lower alkanol group, a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring, or a hydrogen atom ) Is shown. ] It is a 41-2 troimidazole derivative represented by these, or its salt.
- the present invention relates to (S) —2-bromo_1- (2-methyl-2-oxylanyl) Methyl) 14-nitroimidazole or a salt thereof.
- the present invention provides (R) -2-promo-1-1 (2-methyl-21-oxylanylmethyl) -141-troimidazole or a salt thereof.
- the present invention provides (S) _2-chloro-1- (2-methyl-2-oxylaninolemethyl) 141-troimidazole or a salt thereof.
- the present invention provides (R) -2-chloro-11- (2-methyl-21-year-old xylaninolemethyl) -14-nitroimidazole or a salt thereof.
- the 1-substituted 1-41-2 troimidazole compound of the general formula (1) and the 1-substituted 1-4-nitroimidazole compound of the general formula (10) of the present invention are novel compounds not described in the literature.
- the 1-substituted 1-412throimidazole aldehyde compound of the general formula (1) of the present invention is useful as an intermediate for the synthesis of pharmaceuticals and agrochemicals, especially as an intermediate for producing an antituberculous drug. ) Is useful as an intermediate for producing the 412 toroimidazole derivative.
- the 1-substituted 412-troimidazo-rui conjugate of the general formula (10) of the present invention is useful as an intermediate for producing an antituberculous drug.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- Examples of the lower alkoxy-substituted lower alkyl group include methoxymethyl, 3-methoxypropyl, ethoxymethyl, diethoxymethyl, dimethoxymethyl, 1-ethoxyshethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-isopropoxypentyl, 6- ( ⁇ —Propoxy) hexyl, 1,1-dimethyl-2-butoxytinol, 2-methyl-13-tert-butoxypropyl, 2- (n-pentyloxy) ethyl, n-hexyloxymethyl group, etc.
- Examples thereof include straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms in which 1 to 2 straight-chain or branched-chain alkoxy groups are substituted.
- phenyl lower alkoxy-substituted lower alkyl group examples include benzyloxymethyl, (2-phenylethoxy) methyl, (1-phenylethoxy) methyl, 3- (3-phenylpropoxy) propinole, 4- (4-phenylbutoxy) butinole, 5- (5-phenylpentyloxy) pentyl, 6- (6-phenylhexanoloxy) hexyl, 1,1-dimethynolee ( 2-phenynoleethoxy) ethynole, 2-methyl-3- (3-phenylpropoxy) propyl, 2-benzyloxyshenol, 1-benzyloxyxetil, 3-benzyloxypropyl, 4-benzyloxybutyl, 5- A straight chain having 1 to 6 carbon atoms substituted with a phenylalkoxy group in which the alkoxy moiety such as benzyloxypentyl or 6-benzyloxyhexyl group
- phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring
- examples of the phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring include, for example, benzyl, 2-phenylethyl, 1-phenylethylinole, 3-phenylinolepropinole, 4-phenylinolebutinole , 5-phenylenpentole, 6-phenylhexyl, 1,1-dimethyl-12-phenylethyl, 2-methyl-3-phenylpropyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2- (4-ethoxyphenyl) ethyl, 1- (3-propoxyphenyl) ethyl, 3- (2-butoxyphenyl) prop
- cyano-substituted lower alkyl group examples include cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentinole, 6-cyanohexyl, 1,1-dimethyl-2-cyanoethyl, 2-methyl-
- a straight-chain or branched-chain cyanoalkyl group having 1 to 6 carbon atoms in the alkyl moiety such as a 3-cyanopropyl group can be exemplified.
- phenyl group which may have 1 to 3 groups selected from the group include phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, and 3-ethylphenylinole.
- Examples include a nitro group, a halogen atom, and a phenyl group which may have 1 to 3 groups selected from the group consisting of straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms as a substituent. it can.
- a linear or branched C1-C6 group such as methyl, ethyl, propyl, isopropyl, n-butyl, isoptyl, tert-butyl, n-pentyl, n-hexyl, etc.
- a linear or branched C1-C6 group such as methyl, ethyl, propyl, isopropyl, n-butyl, isoptyl, tert-butyl, n-pentyl, n-hexyl, etc.
- the 1-substituted 1-4-nitroimidazole compound represented by the general formula (10) of the present invention includes compounds represented by the following general formulas (10a) and (10b). .
- the method for producing the 412 toloimidazole compound of the general formula (2) of the present invention is described below.
- the 412 troimidazole compound of the general formula (2) is produced by the method shown in the following reaction formula 13.
- X A and X 1 are as defined above.
- X 2 represents a halogen atom or a lower alkoxy group.
- the lower alkoxy group for example, methoxy, ethoxy, propoxy, isopropoxy-n-butoxy, isobutoxy, tert-butoxy, n- Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as pentyloxy and n-hexyloxy groups. Of these, methoxy and ethoxy groups are particularly preferred.
- reaction for converting the compound (5) into the compound (4) can be carried out in a suitable solvent in the presence of a halogenating agent.
- halogenating agent examples include halogen molecules such as bromine, chlorine and iodine, copper compounds such as iodine chloride, sulfuryl chloride, cupric bromide, N-bromosuccinic imid, and N-chlorosuccinic acid
- halogen molecules such as bromine, chlorine and iodine
- copper compounds such as iodine chloride, sulfuryl chloride, cupric bromide, N-bromosuccinic imid, and N-chlorosuccinic acid
- N-halogenated succinic acid imids such as imido
- alkyl halides such as hexachloroethane.
- Such a halogenating agent is usually used in an equimolar to 10-fold molar amount, preferably an equimolar to 5-fold molar amount, relative to compound (5).
- the solvent examples include water, dichloromethane, dichloroethane, black form, halogenated hydrocarbons such as tetrachlorocarbon, ethers such as tetrahydrofuran, getyl ether, dioxane, diethylene glycol dimethyl ether, and dimethoxetane;
- halogenated hydrocarbons such as tetrachlorocarbon
- ethers such as tetrahydrofuran, getyl ether, dioxane, diethylene glycol dimethyl ether, and dimethoxetane
- Examples thereof include aliphatic hydrocarbons such as n-, xane, and cyclohexane; fatty acids such as acetic acid and propionic acid; carbon disulfide; and a mixed solvent thereof.
- an inorganic base such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium carbonate, hydrogen carbonate and the like, an alkyl lithium such as n-butyl lithium, etc. Is preferably added.
- the reaction is usually carried out at around 150 to 150 ° C, preferably around 150 to 100 ° C, and is completed usually within 5 minutes to 10 hours.
- X 2 represents a halogen atom in the reaction between compound (4) and compound (9)
- the reaction is generally performed in a suitable solvent in the presence or absence of a basic compound.
- suitable solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dimethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, and dimethoxetane; dichloromethane, dichloroethane, chloroform, and tetrasalt.
- Halogenated hydrocarbons such as carbon, methanol, ethanol, isopropanol, butanol, lower alcohols such as tert-butanol, acetic acid, ethyl acetate, ethyl acetate, methyl acetate and n-butyl acetate , Acetone, ketones such as methylethyl ketone, acetonitrile, pyridine 2,4,6-collidine, dimethyl sulfoxide, N, N-dimethylformamide N, N-dimethylacetamide, 1-methyl-2- Examples thereof include pyrrolidinone (NMP), hexamethylphosphate triamide, and a mixed solvent thereof.
- NMP pyrrolidinone
- NMP hexamethylphosphate triamide
- Examples of the basic compound include metal carbonates such as sodium carbonate, carbon dioxide, sodium hydrogencarbonate, hydrogen carbonate, sodium hydroxide, metal hydroxide such as sodium hydroxide, calcium hydroxide, sodium hydroxide, and the like.
- Inorganic bases such as metal alcoholates such as potassium, sodium, sodium amide, sodium methylate, sodium ethylate, pyridine, 2,4,6-collidine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] ndenecene-7 (DBU), 1,4 diazabicyclo [2.2.2] o
- Organic bases such as butane (DABCO) can be mentioned.
- the amount of the basic compound used is usually about 1 to 5 mol per 1 mol of the compound (4).
- the amount of compound (9) to be used is generally at least about 1 mol, preferably about 1 to 5 mol, per 1 mol of compound (4).
- the reaction is usually performed at about 50 to 200 ° C, preferably at about -50 to 150 ° C.
- the reaction time is usually about 1 to 30 hours.
- An alkali metal halide such as sodium iodide may be added to the reaction system.
- a sulfonate such as camphorsulfonic acid or P-toluenesulfonic acid may be used under the above reaction conditions instead of a basic compound. It is preferable to use an acid such as an acid.
- the amount of the acid to be used is usually a catalytic amount, preferably about 0.01 to 0.2 mol, per 1 mol of compound (4).
- reaction for converting the compound (3) to the compound (la) and the reaction for converting the compound (4) to the compound (2a) are both carried out in a suitable solvent in the presence of a reducing agent.
- Examples of the reducing agent used include metal sulfites such as sodium sulfite and sodium hydrogen sulfite, tetramethylammonium borohydride, and tetraborohydride hydride. Tetra-ammonium, boron hydride tetra- n -butylammonium, borohydride cyanotetra- n -butylammonium, etc., boron hydride tetra-lower alkyl ammoniums, sodium cyanoborohydride, cyano hydrogen Examples include hydride reducing agents such as lithium borohydride, sodium borohydride, and diborane.
- Examples of the solvent used include water, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, dimethyl ether, tetrahydrofuran, diisopropyl ether, diglyme and 1,4-dioxane. Athenoles such as dimethoxetane, aromatic hydrocarbons such as benzene, tonolene and xylene, dimethyl sulfokind, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-12-pyrro 'Lidinone (NMP) and a mixed solvent thereof.
- lower alcohols such as methanol, ethanol and isopropanol
- ketones such as acetone and methyl ethyl ketone
- dimethyl ether dimethyl ether
- tetrahydrofuran diisopropyl ether
- an anhydrous solvent is preferably used.
- the amount of the reducing agent to be used is generally at least an equimolar amount, preferably about 1 to 10 mol, per 1 mol of the compound (3) or (4).
- the reaction is carried out usually at 0 to: around 150 ° C., preferably at around 0 to 120 ° C., and is generally completed in about 1 to 30 hours.
- a suitable solvent palladium, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, and chromium oxide are used as reducing agents in a suitable solvent.
- a catalytic hydrogen reducing agent such as Raney nickel and palladium acetate
- a fatty acid such as formic acid, sodium formate, ammonium formate and sodium acetate, a fatty acid ammonium salt or a fatty acid alkali metal salt
- the reaction temperature is usually room temperature to 200 ° C. C.
- the compound (la) or (2a) can be obtained by reacting at room temperature to about 150 ° C. for about 1 to 30 hours.
- any of the solvents used in the above-described reduction using a hydride reducing agent or the like can be used.
- An amine such as triethylamine and a phosphorus conjugate such as tri-ortho-tolylphosphine may be added to the reaction.
- the amount of the catalytic hydrogen reducing agent to be used is generally about 0.1 to 40% by weight, preferably about 0.1 to 20% by weight, based on the compound (3) or (4).
- the amount of fatty acid, fatty acid ammonium salt or fatty acid metal salt used depends on the compound (3) or (4).
- the amount is usually at least equimolar, preferably about 1 to 20 mol per mol.
- this reaction can also be carried out by reducing compound (3) or (4) in a suitable solvent in the presence of a catalytic hydrogen reducing agent.
- a suitable solvent in the presence of a catalytic hydrogen reducing agent.
- the solvent used here include water, fatty acids such as acetic acid, alcohols such as methanol and ethanol isopropanol, aliphatic hydrocarbons such as n- hexane and cyclohexane, Ethers such as dioxane, tetrahydrofuran, getinoleatenole, monoglyme, diglyme, and dimethoxetane; esters such as ethyl acetate, methyl acetate, and n-butyl acetate; N, N-dimethylformamide; N, N-dimethyl Examples include non-protonic polar solvents such as acetoamide and 1-methyl-2-pyrrolidinone (NMP), and mixed solvents thereof.
- NMP non
- Examples of the catalytic hydrogen reducing agent to be used include, for example, palladium, palladium acetate, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, chromous acid, Raney nickel, and the like. No.
- the amount of the catalytic hydrogen reducing agent used is generally about 0.02 to 1 times the weight of the compound (3) or (4).
- the reaction temperature is usually about 20 to 100 ° C, preferably about 0 to 80 ° C, and the hydrogen pressure is usually 1 to 10 atm.
- the reaction is generally completed in about 0.5 to 20 hours. .
- the reaction proceeds advantageously when amines such as triethylamine are added to the reaction system.
- the compound (la) or (I) can be obtained by reacting in a suitable solvent in the presence of a catalyst, usually at room temperature to 200 ° C, preferably at room temperature to about 150 ° C for about 1 to 10 hours. 2 a) can be obtained.
- a catalyst usually at room temperature to 200 ° C, preferably at room temperature to about 150 ° C for about 1 to 10 hours.
- the solvent used here any of the solvents used in the above-described reduction using a hydride reducing agent or the like can be used.
- the catalyst include palladium compounds such as palladium acetate-triphenylphosphine and tetrakis (triphenylphosphine) palladium.
- the amount of the catalyst to be used is about 0.01 to 5 mol, preferably about 0.01 to 1 mol, per 1 mol of compound (3) or (4).
- the reaction proceeds advantageously when an alkylsilane compound such as triethylsilane is added to the reaction.
- the reaction for converting the compound (la) to the compound (2a) is carried out in a suitable solvent or without a solvent in the presence of a basic compound or an acidic compound.
- Examples of the solvent used include water, lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; dimethyl ether, dioxane; tetrahydrofuran; ethylene glyconoresmethyl ether; dimethoxetane; Ethers, ethyl acetate, methyl acetate, esters such as 11-butyl acetate, fatty acids such as acetic acid, formic acid, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone (NMP) or a mixed solvent thereof And so on.
- lower alcohols such as methanol, ethanol, and isopropanol
- ketones such as acetone and methyl ethyl ketone
- dimethyl ether, dioxane dioxane
- tetrahydrofuran ethylene glyconoresmethyl ether
- the basic compound known compounds can be widely used, and any of the basic compounds used when X 2 represents a halogen atom in the reaction between the compound (4) and the compound (9) can be used. it can.
- the acid a wide range of known acids can be used, and examples thereof include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and aromatic sulfonic acids such as formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. Can be.
- mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid
- aromatic sulfonic acids such as formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.
- the reaction suitably proceeds generally at about 0 to 150 ° C, preferably about 0 to 100 ° C, and is generally completed in about 5 minutes to 30 hours.
- the 1-substituted 142-troimidazole compound represented by the general formula (10) of the present invention is produced, for example, by the method shown in the following reaction formula 14.
- reaction between the 412 toloimidazole compound represented by the general formula (2) and the compound (11) is carried out in a suitable solvent in the presence of a basic compound.
- solvent used examples include aromatic hydrocarbons such as benzene, toluene, xylene, o-chlorobenzene, m-chlorobanzen, and 2,3-dichlorobenzene, getyl ether, tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether.
- Ethers such as dimethoxetane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, tetrachlorosilane, etc., lower alcohols such as methanol ethanol, isopropanol, butanol, tert-butanol, acetic acid, acetic acid Esters such as ethyl, methyl acetate and n-butyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, 1-methyl-2-pyrrolidinone (NMP), 2,4,6-collidine, dimethyl sulfoxide , NN —Dimethylformamide, N, N-dimethylacetamide, hexamethylphosphate triamide or a mixed solvent thereof.
- Ethers such as dimethoxetane, halogenated hydrocarbons such as dichloromethane, dichloro
- Examples of the inorganic base include alkali metal carbonates such as sodium carbonate and carbon dioxide lime, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and hydrogen carbonate lime, and alkali metal hydroxides such as sodium hydroxide and hydroxylation lime.
- alkali metal carbonates such as sodium carbonate and carbon dioxide lime
- alkali metal hydrogen carbonates such as sodium hydrogen carbonate and hydrogen carbonate lime
- alkali metal hydroxides such as sodium hydroxide and hydroxylation lime.
- Metal alkali metal phosphates such as sodium phosphate, phosphoric acid rim
- alkali metal hydrides such as sodium hydride, hydrogen hydride
- alkali metal amides such as sodium hydride, sodium hydride
- alkali metal amides such as sodium amide
- alkali metal alcoholates such as sodium methylate and sodium ethylate.
- organic base examples include pyridine, trimethylamine, triethylamine N-ethyldiisopropylamine, 2,4,6-collidine, dimethylaniline, dimethylaminopyridine, N-methylmorpholine, N, N-dimethyl-4 Aminoviridine, 1,5-Diazabicyclo [4.3.0] Nonene-5 (DBN), 1 ; 8-Diazabicyclo [5.4.0] Pendene-1 7 (DBU), 1,4-Diazabicyclo [2. 2.2] Octane (DAB CO).
- the amount of compound (2) to be used is generally about 0.1 to 5 mol, preferably about 0.5 to 3 mol, per 1 mol of compound (11).
- the amount of the basic aldehyde compound to be used is generally about 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (11).
- the reaction between the compound (2) and the compound (11) is usually performed at about 0 to 150 ° C, preferably about 0 to 100 ° C, and generally completes in about 1 to 100 hours.
- a halide such as cesium oxide may be added to the reaction system.
- the 1-substituted 4-nitroimidazole compound represented by the general formula (10a) is obtained by reacting the compound (2) with the compound (11a) as shown in the following reaction formula.
- the 1-substituted 1-4-2-tromididazo- / Reich compound represented by the general formula (10b) is represented by the general formula (10b), and the compound (2) is compounded with the compound (lib) as shown in the following reaction formula. Produced by reaction.
- the compound (II) (compound (IIa) and compound (lib)) used as the other one of the starting materials can be easily produced from the known compound (I2) by, for example, the method shown in the following reaction scheme 15. Is done. [Reaction formula 1 5 J
- Compound (11a) is produced by oxidizing compound (12) and then reacting compound (13) with the compound obtained by oxidation.
- the oxidation reaction of compound (12) is carried out in an appropriate solvent in the presence of a dextrorotatory optically active compound using an oxidizing agent.
- oxidizing agent to be used known peroxides can be widely used, and examples thereof include cumene hydroperoxide and tert-butylperoxide.
- the solvent include alcohols such as methanol, ethanol, and isopropanol; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; Ethers such as dimethyl ether, dioxane, tetrahydrofuran, diglyme, and dimethoxetane; saturated hydrocarbons such as n-hexane, n-butane and cyclohexane; ketones such as acetone and methylethyl ketone; N, N Polar solvents such as —dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone (NMP), dimethyl
- dextrorotatory optically active compounds include (D) — (1) diisoprop monotartrate pill, (D) — (1) monotartaric acid, (D) — (1) diparatoluoyltartaric acid, (D) 1) (1) Monomalic acid, (D) — (1) Mandelic acid, (D)-(1) One-strength optically active acid such as 10-sulfonic acid or its alkyl ester, etc. Is mentioned.
- the amount of the oxidizing agent to be used is usually at least 1 relative to 1 mole of the compound (12). It is about 1 mol, preferably about 1 to 3 mol.
- the amount of the optically active compound to be used is usually 0.1 mol per 1 mol of the compound (12).
- It is about 01 mol to 1 mol, preferably about 0.01 to 0.5 mol.
- the oxidation reaction of the compound (12) is generally carried out at a temperature of about 150 ° C. to room temperature, preferably at a temperature of about 130 ° C. to room temperature, and is generally completed in about 1 to 30 hours.
- reaction accelerator examples include alkoxy titaniums such as titanium tetraisopropoxide and the like, molecular sieves 5 A, molecular sieves 4 A, molecular sieves such as molecular sieves 3 A, etc. Used as a mixture of more than one species. The amount of alkoxytitanium used depends on the compound
- the amount of molecular sieves to be used is generally 0.:! ⁇ 1 times the weight.
- reaction between the compound (compound (14a)) obtained by the above oxidation reaction and compound (13) is carried out in a suitable solvent in the presence of a basic compound.
- any of the solvents used in the oxidation reaction of the above compound (12) can be used.
- Examples of the inorganic base include alkali metal carbonates such as sodium carbonate and carbonated lime, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and hydrogenated lime, alkali metal hydroxides such as sodium hydroxide and hydroxylated lime.
- alkali metal carbonates such as sodium carbonate and carbonated lime
- alkali metal hydrogencarbonates such as sodium hydrogencarbonate and hydrogenated lime
- alkali metal hydroxides such as sodium hydroxide and hydroxylated lime.
- products alkali metal phosphates such as sodium phosphate, phosphoric acid rim
- alkali metal hydrides such as sodium hydride
- hydrogenation lime alkali metals
- alkali metals such as potassium and sodium
- alkali metal amides such as sodium amide
- Examples include alkali metal alcoholates such as sodium methylate and sodium methylate.
- organic base examples include pyridine, trimethylamine, triethylamine, N-ethyldiisopropylamine, 2,4,6-collidine, dimethylaniline, dimethinoleaminopyridine, N-methylmonorephorin, ⁇ , ⁇ —Dimethinolee 4-aminoviridine, 1,5-diazabicyclo [4.3.0] nonen-5 (DBN), 1, 8-diazabicyclo [5.4.0] pendene-17 (DBU), 1,4-diazabicyclo [2.2.2] octane (DAB CO) and the like. These basic compounds are used alone or in combination of two or more.
- the amount of compound (13) to be used is generally at least about 1 mol, preferably;!, Relative to 1 mol of compound (12). About 2 moles.
- the amount of the basic compound to be used is generally at least about 1 mol, preferably about 1 to 2 mol, per 1 mol of compound (12).
- the reaction between compound (14a) and compound (13) is usually carried out at a temperature of about 50 ° C to room temperature, preferably _30 ° C to room temperature, and is generally completed in about 1 to 20 hours. .
- the purpose is to react the compound (13) with the reaction mixture without acidifying the compound (14a) after acidifying the compound (12).
- the compound (11a) can be produced.
- a method of reacting the compound (13) with the reaction mixture after oxidizing the compound (12) has been described in terms of workability, efficiency, etc. It is preferable from the viewpoint of.
- Compound (lib) is produced by oxidizing compound (12), and then reacting compound (13) with the compound obtained by oxidation.
- the oxidation reaction of compound (12) is carried out under the same reaction conditions as the oxidation reaction of compound (12) above, except that a levorotatory optically active compound is used instead of the dextrorotatory optically active compound. Be done.
- levorotatory optically active compound used examples include (L)-(+)-diisopropyl tartrate, (L)-(+)-tartaric acid, (L)-((+))-diparatoluyltartaric acid, ( L)-(+)-Malic acid, (L)-(+)-Mandelic acid, (L)-(+) -Camphor 10-Levorotatory optically active acid such as sulfonic acid or its alkyl ester. No.
- reaction of the compound (14b) with the compound (13) is carried out under the same reaction conditions as in the reaction of the compound (14a) with the compound (13).
- the compound (14b) produced after oxidizing the compound (12) The target compound (lib) can be produced by reacting the compound (13) with the reaction mixture without isolating the compound (lib). In these series of reactions, since the solvent used in the reaction is the same, a method of oxidizing the compound (12) and then reacting the reaction mixture with the compound (13) is preferable in terms of workability, efficiency, and the like. Is preferred.
- Compound (4) of the above reaction formula 13 can also be produced by the following reaction formula.
- X 1 is the same as above.
- X 3 and X 4 each represent a halogen atom.
- the reaction for converting the compound (15) into the compound (16) can be carried out under the same conditions as in the reaction for converting the compound (5) in the above Reaction Formula 13 into the compound (4).
- the reaction for converting the compound (16) to the compound (17) is the same as the reaction for converting the compound (3) of the above reaction formula 13 to the compound (la) and the reaction for converting the compound (4) to the compound (2a). Under the following conditions. ,
- the reaction for converting the compound (16) or the compound (17) to the compound (4a) can be generally carried out under the same conditions as in the ditolization reaction of an aromatic compound.
- the reaction can be carried out in a solvent or without a solvent, in the presence of a ditrotide agent.
- the solvent used herein include fatty acids or anhydrides such as acetic acid and acetic anhydride, inorganic acids such as concentrated sulfuric acid, halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride, and nitromethane. .
- nitrifying agent examples include fuming nitric acid, concentrated nitric acid, a mixed acid (sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride and nitric acid), a mixture of sulfuric acid with an alkali metal nitrate such as potassium nitrate and sodium nitrate, and tetranitrate nitrate.
- alkali metal nitrate such as potassium nitrate and sodium nitrate
- tetranitrate nitrate examples include alkylammonium nitrates such as nitrobenzene and nitronium halide borates such as nitrodimethyltetrafluoroborate.
- the amount of the Nitroid agent to be used is preferably at least equimolar to 1 mol of the compound (16) or (17), and generally a large excess.
- alkylammonium nitrates / nitronium halogenated borates use at least equimolar, preferably equimolar to about 5 moles per mole of compound (16) or (17). Good to do.
- the reaction is usually completed at about 30 ° C. to about room temperature for about 10 minutes to 20 hours.
- the amount of anhydrous fatty acid such as trifluoroacetic anhydride in the reaction system should be less than 1 mole per mole of compound (16) or (17). Both are preferably equimolar, preferably about equimolar to about 3 mol.
- the starting compound (15) is a known compound, but can also be produced, for example, by the method of the following reaction formula.
- reaction between the compound (18) and the compound (9) can be performed under the same conditions as in the reaction between the compound (4) and the compound (9) in the aforementioned Reaction Formula 13.
- the reaction for converting the compound (19) to the compound (20) can be carried out under the same conditions as the reaction for converting the compound (5) of the above Reaction Formula 13 to the compound (4).
- the reaction for converting the compound (20) to the compound (15) can be carried out under the same conditions as those for the reaction for converting the compound (1a) of the above Reaction Formula 13 to the compound (2a).
- the 412 toloimidazole compound of the general formula (2) can be prepared by the method shown in the following reaction formula 18 It is also manufactured by
- R A , R 1 and X 2 are the same as above. ⁇ indicates 1 or 2.
- X 5 represents a halogen atom.
- reaction between compound (21) and compound (22) and the reaction between compound (23) and compound (9) are carried out under the same conditions as the reaction between compound (4) and compound (9) in the above Reaction Formula 13. be able to.
- Compound (24) can also be produced by reacting compound (23) with atarilonitrile. This reaction can be carried out in a suitable solvent or without a solvent in the presence of a basic compound. As the solvent and the basic compound used herein, both the solvent and the basic compound used in the reaction of the compound (4) with the compound (9) in the above reaction formula 13 can be used. it can.
- the amount of acrylonitrile to be used is at least equimolar, preferably about equimolar to about 15 mol, per 1 mol of compound (23).
- the reaction is completed usually at about 0 to 150 ° C, preferably at about 0 to 100 ° C, usually for about 10 minutes to 5 hours.
- the reaction for converting the compound (24) to the compound (25) and the reaction for converting the compound (23) to the compound (26) are performed by converting the compound (16) or the compound (17) of the reaction formula 16 into a compound (4
- the reaction can be carried out under the same conditions as in the reaction leading to a).
- the reaction which leads compound (24) to compound (25) the following compound (25 aa) having a nitro group at the 5-position of the imidazono skeleton is obtained at the same time, and this compound (25 aa) is also converted to compound (25).
- Compound (2b) can be obtained by reacting it under the same conditions as those for compound (2b).
- the reaction for converting the compound (25) to the compound (2b) and the reaction for converting the compound (25aa) to the compound (2c) include a reaction for converting the compound (la) of the above reaction formula 13 to the compound (2a). Can be performed under the same conditions.
- the reaction for converting the compound (26) to the compound (2b) can be carried out by heating in a suitable solvent.
- suitable solvent examples include aromatic hydrocarbons such as toluene, xylene, benzene, and benzene.
- the reaction is usually carried out at room temperature to 200 ° C, preferably at room temperature to about 150 ° C.
- the reaction time is usually about 10 minutes to 5 hours.
- the reaction for converting the compound (2b) to the compound (2c) and the reaction for converting the compound (25) to the compound (25a) are carried out in a suitable solvent in the presence of an oxidizing agent.
- the solvent used herein include water, fatty acids such as formic acid, acetic acid, and trifluoroacetic acid; lower alcohols such as methanol, ethanol, isopronolol, butanol, and tert-butanol; liquid form; dichloromethane; and tetrachloride.
- examples thereof include halogenated hydrocarbons such as carbon and a mixed solvent thereof.
- oxidizing agent used examples include peracids such as formic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o-carboxyperbenzoic acid, etc., hydrogen peroxide, and metaperiodic acid.
- Dichromates such as sodium, dichromic acid, sodium dichromate, and potassium dichromate;
- permanganates such as permanganate, permanganate, and permanganate; lead salts such as lead tetraacetate And the like.
- the oxidizing agent is usually used at least in an equimolar amount, preferably in an equimolar to 2-fold molar amount, relative to the compound (25) or the compound (2b).
- the amount of the oxidizing agent to be used is at least 2 times, preferably 2 times to 4 times the amount of compound (25) or compound (2b). It is better to make it twice the mole.
- the reaction is usually carried out at -10 to 40 ° C, preferably 1-10. It is carried out at C to around room temperature and finishes in about 1 to 30 hours.
- the 1-substituted 412-troimidazole derivative represented by the general formula (10) of the present invention can also be produced by the method shown in the following reaction formula 19.
- reaction between the compound (23) and the compound (11) can be carried out under the same conditions as in the reaction between the compound (2) and the compound (11) in the aforementioned Reaction Formula 14.
- the reaction for converting the compound (27) into the compound (10c) may be carried out under the same conditions as in the reaction for converting the compound (16) or the compound (17) in the reaction formula 16 into the compound (4a). it can.
- the reaction for converting the compound (10c) to the compound (10d) can be carried out under the same conditions as those for the reaction for converting the compound (2b) of the reaction formula 18 into the compound (2c).
- the reaction for converting the compound (15) to the compound (2a) can be carried out in a suitable solvent or without solvent in the presence of a ditronium halogenated borate such as nitrodimethyltetrafluoroporate as a ditoxinating agent. Can be done in the presence.
- a ditronium halogenated borate such as nitrodimethyltetrafluoroporate as a ditoxinating agent.
- Examples of the solvent used herein include fatty acids or anhydrides such as acetic acid and acetic anhydride, inorganic acids such as concentrated sulfuric acid, halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride, and nitromethane. . Of these, it is preferable to carry out in nitromethane.
- the amount of the Nitroid agent to be used is at least equimolar, preferably about equimolar to about 5 mol, per 1 mol of compound (15). The reaction is usually completed at about ⁇ 30 ° C. to about room temperature in about 10 minutes to 20 hours.
- nitrating As the reaction, a method of nitrating with nitric acid-sulfuric acid or the like as described above is known. Under these nitration conditions, only the compound (2a) can be obtained in low yield, which is industrially disadvantageous. In the present invention, a high yield and high purity can be obtained by using a nitrium halide borate such as nitridium tetrafluoroborate as a nitrating agent.
- a nitrium halide borate such as nitridium tetrafluoroborate
- the 1-substituted 4-nitroimidazole compounds (compounds (10a) and (10b)) represented by the general formula (10) of the present invention can be prepared, for example, by the method shown in the following reaction formula 112.
- the compounds (30a) and (30b) useful as antituberculous agents can be obtained.
- R B and X are the same as above.
- R 2 is represented by the following general formula (A), (B), (C) (D), (E), (F) or (G) R D and one (CH 2 ) 2 R 2 are bonded to each other via a nitrogen atom together with an adjoining carbon atom to form a spiro ring represented by the following general formula (H). Is also good.)
- Phenyl C1-6 alkyl group (on the phenyl ring, phenyl C1-6 alkoxy group; halogen-substituted or unsubstituted C1-6 alkyl group; hahagen-substituted or unsubstituted A group selected from the group consisting of a C 1-6 alkoxy group and a phenoxy group [the phenyl ring may be substituted with at least one halogen-substituted or unsubstituted C 1-6 alkoxy group.]
- A5 a biphenylyl C1-6 alkyl group;
- a benzenesulfonyl group optionally substituted by a C1-6 alkyl group
- A10) Group represented by general formula (Aa): (Where R 4 is a C 1-6 alkoxycarbonyl group; phenyl C 1-6 alkoxycarbonyl group [a phenyl C 1-6 alkoxy group, halogen-substituted or unsubstituted C 1-6 alkyl At least one selected from the group consisting of a group and a halogenated or unsubstituted C 1-6 alkoxy group may be substituted] or a phenyl C 1-6 alkyl group [on the phenyl ring A phenyl Cl-6 alkoxy group, a halogen-substituted or unsubstituted C1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxy group. And one of them may be substituted.]);
- Benzoxazolyl C 1-6 alkyl group (at least one oxo group may be substituted on the benzoxazole ring);
- Oxazolyl C1-6 alkyl group (at least one of a group selected from the group consisting of a phenyl group and a C1-6 alkyl group is substituted on the oxazole ring. ).
- R 5 represents a tetrazolyl group [a C .1-6 alkyl group or a phenyl group which may have a halogen atom may be substituted on the tetrazole ring] or a benzoxazolyl group
- R represents a C 1-6 alkyl group.
- phenyl C 1-6 alkyl group (on the phenyl ring, a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a haegen-substituted or unsubstituted C 1-6 alkoxy group At least one of the selected groups may be substituted);
- Phenyl group (Halogen atom, halogen-substituted or unsubstituted C1-6 alkyl group, halogen-substituted or unsubstituted C1-6 alkoxy group. Cl-6 alkanol group, carboxyl group 1 to 3 groups selected from the group consisting of C1-6 alkoxycarbonyl group, phenyl C1-6 alkoxycarbonyl group, carbamoyl group, C1-6 alkyl carpamoyl group, aminosulfonyl group and morpholino group May be substituted);
- D10) Scales 7 and 8 form the following (D10-1) to (D10-3) by bonding to each other with or without adjacent heteroatoms or carbon atoms, together with adjacent nitrogen atoms. Or a benzene-fused heterocyclic group shown in (D10-4) to (D10-7) shown below.
- (Da3) Phenyl C 1-6 alkyl group (Halogen atom, nitrogen-substituted or unsubstituted C 1-6 alkyl group, and haegen-substituted or unsubstituted C:!-6 alkoxy group At least one of the groups selected from the group consisting of: may be substituted);
- (Da4) a phenyl group (selected from the group consisting of a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group At least one of the groups may be substituted); (Da5) C:!-6 anorecoxycarbonyl group;
- phenyl C 1-6 alkoxycarbonyl group (a phenyl ring may contain a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group At least one of the groups selected from the group may be substituted);
- (Db2) a phenyl group (at least one of a group selected from the group consisting of halogen, halogen-substituted or unsubstituted (DC 1-6 alkyl group and halogen-substituted or unsubstituted C 1-6 alkoxy group Species may be substituted);
- (Db3) a phenoxy group (at least one halogen-substituted or unsubstituted C 1-6 alkyl group may be substituted on the phenyl ring);
- X represents a halogen atom or an amino-substituted C1-6 alkyl group which may have a C1-6 alkyl group as a substituent.
- m represents an integer of 0 to 3.
- R 11 is E1) a hydrogen atom;
- W represents a group C O— or a C 1-6 alkylene group.
- O represents 0 or 1
- R 12 and R 13 are the same or different
- (Ea5) a phenyl C 1-6 alkyl group (a halogen atom on the phenyl ring; a halogen-substituted or unsubstituted C 1-6 alkyl group; a halogen-substituted or unsubstituted C:!-6 alkoxy group and A phenoxy group (on the phenyl ring, a substituent is selected from the group consisting of a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxy group. At least one of the groups may be substituted.] In addition, at least one of the groups selected from the group consisting of: may be substituted. The amino group may be substituted.);
- Benzoyl group (Halunyl atom, halogen substitution or Unsubstituted C :! may be substituted with at least one group selected from the group consisting of! 6 alkyl groups and unsubstituted or unsubstituted C1-6 alkoxy groups.
- Pyridyl group (at least one halogen atom may be substituted on the pyridine ring);
- (Ea9) a phenyl C 1-6 alkyl group (selected on the phenyl ring from a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group, and a halogen-substituted or unsubstituted C 1-6 alkoxy group At least one of the substituted groups may be substituted);
- (EalO) phenoxy C 1-6 alkyl group (a group consisting of a halogen atom, a hydrogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C:!-6 alkoxy group on the phenyl ring) At least one of the more selected groups may be substituted);
- Benzyl C 1-6 alkyl group (a group consisting of a halogen atom, a hydrogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted group on the phenyl ring:! -6 alkoxy group At least one of the selected groups may be substituted)
- R 14 A is a hydrogen atom, a hydroxyl group, a Cl-6 alkoxy group or a phenyl group [a halogen atom may be substituted on the phenyl ring. Les ,. ].
- the dotted line indicates that it may be a double bond. When the dotted line indicates a double bond, it is assumed that only R 14 is substituted. 1 1 4 and 1 1 4, it may also form a C. 1 to 4 alkylenedioxy O alkoxy groups bonded to each other together with the carbon atom to which they are adjacent Rere.
- R 14 is
- (Eaa3) a phenoxy group (a halogen atom on the phenyl ring; a halogen-substituted or unsubstituted C1-6 alkyl group; a halogen-substituted or unsubstituted C1-6 alkoxy group; C 1-6 alkoxy canoleponyl group; cyano group; C 2-6 alkenyl group; nitro group; phenyl group; phenyl group, C 1-6 alkyl group, carbamoyl group and An amino group which may have a group selected from the group consisting of C1-6 alkanoyl groups; a C1-6 alkanoinole-substituted C1-6 alkyl group; a hydroxyl group; a C1-6 alkoxycarbonyl-substituted C1-6 alkyl group C-6!
- phenylcarbamoyl group (on the phenyl ring, a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group are selected. At least one of the groups may be substituted);
- (Eaal3) naphthyloxy group (at least one C 1-6 alkyl group may be substituted on the naphthalene ring);
- (Eaa27) a phenyl C 2-6 alkenyl group (a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group At least one of the groups selected from the group consisting of may be substituted)
- (Eab2) C1-6 alkyl group (Alkyl group may be substituted by morpholino group, benzoyl group, or carbamoyl group or cyano group which may have C1-6 alkyl group as a substituent) ;
- phenyl C 1-6 alkyl group (Halogen atom, cyano group, phenyl group, nitro group, C 1-6 alkylthio group, C 1-6 alkyl Honyl group, phenyl C 1-6 alkoxy group, C 2-6 alkanoyloxy group, halogen-substituted or unsubstituted C 1-6 alkyl group, halogen-substituted or unsubstituted C 1-6 alkoxy group and 1 , 2,3-Thiadiazole group may be substituted with at least one group selected from the group consisting of);
- (Eab6) a phenyl group (a group consisting of a halogen atom, a cyano group, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group on the phenyl ring) At least one of the selected groups may be substituted);
- phenyl C 2-6 alkanol group (a group consisting of a halogen atom, halogen-substituted or unsubstituted C:!-6 alkyl group and halogen-substituted or unsubstituted C 1-6 alkoxy group on the phenyl ring At least one of the selected groups may be substituted));
- (Eab9) benzoyl group selected from the group consisting of halogen atoms, halogen-substituted or unsubstituted C1-6 alkyl groups and halogen-substituted or unsubstituted C1-6 alkoxy groups on the benzene ring (EablO) C 1-20 alkoxycarbonyl group (Alkoxy group may have a halogen atom, and may have a C 1-6 alkyl group as a substituent.) Amino group and C;! -6 alkoxy substituted at least one of groups selected from the group consisting of C1-6 alkoxy groups may be substituted);
- (Eabl2) phenyl C 3-6 alkenyloxycarbonyl group (on the phenyl ring, At least one group selected from the group consisting of halogen atom, halogen-substituted or unsubstituted C:!-6 alkyl group and halogen-substituted or unsubstituted C1-6 alkoxy group may be substituted. );
- (Eabl3) a phenoxycarbonyl group (a group selected from the group consisting of a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group At least one of which may be substituted);
- phenylcarbamoyl group (on the phenyl ring, selected from the group consisting of halogen atoms, halogen-substituted or unsubstituted C:!-6 alkyl groups and halogen-substituted or unsubstituted C1-6 alkoxy groups At least one of the groups may be substituted,);
- R 1 D represents the same group as R i D.
- (Eel) phenyl C 1-6 alkyl group (halogen atom, halogen Substituted or unsubstituted C: at least one selected from the group consisting of! -6 alkyl groups and halogen-substituted or unsubstituted C1-6 alkoxy groups may be substituted);
- R 4 6 is, on the phenyl group [phenyl ring, a halogen atom as a substituent, C port Gen substituted or unsubstituted C:! ⁇ 6 C 1 ⁇ 6 alkyl group and halogen-substituted or unsubstituted replacement At least one of the groups selected from the group consisting of alkoxy groups may be substituted.]; Phenyl C 1-6 alkyl group [halogen atom, halogen-substituted or unsubstituted C 1 At least one of a group selected from the group consisting of an alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group may be substituted.]; Phenyl C 1-6 alkoxycarbonyl A group (at least one of a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted
- a phenoxy group (a group selected from the group consisting of a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group on the phenyl ring) May be substituted); E17) Benzyl group (a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group on the phenyl ring) E18) 8-azabicyclo [3,2,1] octinole group (8-azabicyclo [3,2,1] octane ring At least one phenoxy group (selected from the group consisting of a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and
- R 47 and R 48 are the same or different and are each a hydrogen atom; a C 1-6 alkyl group; a phenyl group [A halogen atom, halogen-substituted or unsubstituted C:!-6 At least one selected from the group consisting of an alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group may be substituted] or a pyridyl group [on the pyridine ring, halogen is substituted as a substituent.
- R, 7 and R 48 are, together with the adjacent nitrogen atom, other hetero atoms. They may be bonded to each other via an atom or without an atom to form a 5- to 7-membered saturated heterocyclic ring, wherein at least one phenyl group as a substituent on the heterocyclic ring Is a halogen atom, halogen-substituted or Substituted C; at least one group selected from the group consisting of! -6 alkyl groups and nodogen-substituted or unsubstituted C1-6 alkoxy groups may be substituted.] Yore.);
- Phenyl C 1-6 alkoxy group (a group consisting of a halogen atom, a nitrogen-substituted or unsubstituted C 1-6 alkyl group and a haegen-substituted or unsubstituted C 1-6 alkoxy group on the phenyl ring At least one of the more selected groups may be substituted));
- E22 represents an oxazolidinyl group (at least one oxo group may be substituted on the oxazolidine ring).
- Phenyl C1-6 alkyl group (a phenyl group on the phenyl ring [a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 At least one of the groups selected from the group consisting of alkoxy groups may be substituted]; a halogen atom; a halogen-substituted or unsubstituted C;!
- a phenyl group on the phenyl ring, a halogen atom, halogen-substituted or unsubstituted C 1 And at least one group selected from the group consisting of a C.sub.1-6 alkyl group and a halogen-substituted or unsubstituted C.sub.1-6 alkoxy group may be substituted.
- a group consisting of a C.sub.1-6 alkyl group On the amino group, a phenyl group (on the phenyl ring, a halogen atom, halogen-substituted or unsubstituted C 1 And at least one group selected from the group consisting of a C.sub.1-6 alkyl group and a halogen-substituted or unsubstituted C.sub.1-6 alkoxy group may be substituted.) And a group consisting of a C.sub.1-6 alkyl group.
- Phenoxy C 1-6 alkyl group (a group consisting of a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a haegen-substituted or unsubstituted C 1-6 alkoxy group on the phenyl ring At least one of the more selected groups may be substituted);
- C 1-6 alkyl group (C 1-6 alkyl group, C 1-6 alkoxycarbonyl group and phenyl group on the amino group [Halogen atom or halogen-substituted or unsubstituted on the phenyl ring At least one group selected from the group consisting of C 1-6 alkyl groups of the above may be substituted.) At least one group selected from the group consisting of
- Phenyl group (Halogen atom, phenoxy group on phenyl ring [halogen atom, halogen-substituted or unsubstituted C:!-6 alkyl group and halogen-substituted or unsubstituted C1-6 At least one group selected from the group consisting of an alkoxy group may be substituted.] And at least one group selected from the group consisting of a C1-6 alkoxycarbonyl group is substituted. Also good);
- Phenyl C 1-6 alkoxycarbonyl group (Halogen atom, halogen-substituted or unsubstituted C 1-6 alkyl group and halogen-substituted or unsubstituted C 1-6 At least one group selected from the group consisting of 6 alkoxy groups may be substituted);
- R is a C 1-6 alkoxycarbonyl group; a phenyl C 1-6 alkoxycarbonyl group (a halogen atom, a cyano group, halogen-substituted or unsubstituted C 1-6 alkyl on the phenyl ring) And at least one group selected from the group consisting of a C 1-6 alkoxy group substituted or unsubstituted or unsubstituted may be substituted); a phenyl C 1-6 alkyl group (a phenyl ring Above are halogen atoms and ha At least one of the groups selected from the group consisting of substituted or unsubstituted C 1-6 alkyl groups may be substituted, or a phenyl group (a halogen atom on the phenyl ring , A cyano group, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or
- F10 A 1-substituted 4-piperidyl group represented by the general formula (F b): (Wherein, R 2 2 is, C 1 to 6 alkoxycarbonyl group; the phenyl C 1 to 6 alkoxide aryloxycarbonyl group (on the phenyl ring, a halogen atom, halogen-substituted or and C.
- 1 to 6 alkyl group unsubstituted At least one group selected from the group consisting of halogen-substituted or unsubstituted C 1-6 alkoxy groups may be substituted; or a phenyl group (a halogen atom, a cyano group, a halogen atom on the phenyl ring) A substituted or unsubstituted C 1-6 alkyl group or at least one group selected from the group consisting of halogen-substituted or unsubstituted C 1-6 alkoxy groups may be substituted) ); Or
- piperidyl C 1-6 alkyl group (at least one phenoxy group on the piperidine ring (at least one halogen-substituted or unsubstituted C 1-6 alkyl group on the phenyl ring May be substituted) may be substituted)
- (Fcl) a C 1-6 alkyl group; (Fc2) a phenyl C 1-6 alkyl group (a phenyl ring includes a halogen atom, a nitrogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group At least one of the groups selected from the group may be substituted);
- -6 alkyl groups and halogen-substituted or unsubstituted C1-6 alkoxy groups may be substituted,], phenyl C 1-6A Coxy group [having at least one group selected from the group consisting of a halogen atom, halogen-substituted or unsubstituted C;! -6 alkyl group and halogen-substituted or unsubstituted C;! -6 alkoxy group on the phenyl ring.
- Species may be substituted) and a piperidyl group [at least one amino group may be substituted on the piperidine ring]
- a phenyl C 1-6 alkyl group (phenyl The ring is substituted with at least one selected from the group consisting of a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group.
- at least one of the groups selected from the group consisting of) and Cl-6 alkyl groups may be substituted. Good);
- phenyl C 1-6 alkoxy group (a phenyl ring comprises a halogen atom, a nitrogen-substituted or unsubstituted C 1-6 alkyl group, and a halogen-substituted or unsubstituted C:!-6 alkoxy group At least one of the groups selected from the group may be substituted);
- (Fc7) a fuunoxy group (selected from the group consisting of a halogen atom, a cyano group, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group on the phenyl ring; Or at least one of the groups may be substituted);
- Benzoyl group (selected from the group consisting of halogen atoms, halogen-substituted or unsubstituted C:!-6 alkyl groups and halogen-substituted or unsubstituted C:!-6 alkoxy groups on the phenyl ring.
- Fc9 a C1-6 alkoxycarbonyl group; at least one of the groups may be substituted;
- halogen atom may be substituted on the phenyl ring.
- Fcl2 Phenylcarbamoyl group (On the phenyl ring, a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and At least one group selected from the group consisting of halogen-substituted or unsubstituted C 1-6 alkoxy groups may be substituted);
- R 24 and R 25 are each
- phenyl group (on the phenyl ring, a halogen atom, a cyano group, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C;! -6 alkoxy group At least one of the selected groups may be substituted);
- (Fca6) f a phenyl C 2-6 alkanoyl group which may be substituted by at least one halogen atom on the phenyl ring;
- (Fca7) benzoyl group (selected on the phenyl ring from a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group, and a halogen-substituted or unsubstituted C 1-6 alkoxy group. At least one of the substituted groups may be substituted);
- phenyl C 1-6 alkoxycarbonyl group (on the phenyl ring, a phenyl, a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group At least one of the groups selected from the group may be substituted);
- piperidyloxycarbonyl group on the piperidine ring, a fuenyl group as a substituent [on the phenyl ring, at least one halogen-substituted or unsubstituted C 1-6 alkyl group may be substituted]] At least one may be substituted.
- R 2 4 and R 2 5 is 5 to 6-membered ring via a nitrogen atom to which they are adjacent May form a saturated heterocycle.
- a C 1-6 alkoxycarboxy group On the heterocyclic ring, a C 1-6 alkoxycarboxy group; a benzoyl group (on the phenyl ring, a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6
- a phenyl group (a halogen atom, halogen-substituted or unsubstituted C 1-6 alkyl on the phenyl ring may be substituted with at least one group selected from the group consisting of 6 alkoxy groups).
- At least one group selected from the group consisting of a group and a halogen-substituted or unsubstituted C 1-6 alkoxy group may be substituted); a phenyl Cl-6 alkyl group (on the phenyl ring A halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group. There); off sulfonyl C
- alkoxycarbonyl groups selected from the group consisting of halogen atoms, halogen-substituted or unsubstituted C:!-6 alkyl groups and hagogen-substituted or unsubstituted C1-6 alkoxy groups on the phenyl ring
- a phenyl C 2-6 alkenyl group (a halogen atom, a nitrogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted phenyl ring on the phenyl ring may be substituted).
- At least one of the groups selected from the group consisting of unsubstituted C1-6 alkoxy groups may be substituted) and a phenyl group (a halogen atom, halogen-substituted or unsubstituted on the phenyl ring)
- At least one group selected from the group consisting of C 1-6 alkyl groups and halogen-substituted or unsubstituted C 1-6 alkoxy groups may be substituted)
- at least one may be substituted groups
- F12-2) 4-monosubstituted mono-1-piperazinyl group represented by the general formula (F d):
- (Fd8) biphenyl C 1-6 alkyl group (a halogen atom, a nitrogen-substituted or unsubstituted C 1-6 alkyl group, a halogen-substituted or unsubstituted C 1-6 alkoxy group and As a group: at least one of groups selected from the group consisting of amino groups which may have 6 to 6 alkyl groups may be substituted);
- (FdlO) phenyl group (Halogen atom; cyano group; amino group which may have a C 1-6 alkyl group as a substituent; halogen-substituted or unsubstituted C:!-6 alkyl group A halogen-substituted or unsubstituted C 1-6 alkoxy group; a C 1-6 alkoxycarbonyl group; a carboxyl group; a phenoxy group [a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group on a phenyl ring; And at least one selected from the group consisting of Cl-substituted or unsubstituted Cl-6 alkoxy groups may be substituted]; amino C1-6 alkyl group [on the amino group Is a phenyl group (a group selected from the group consisting of a halogen atom, a halogen-substituted or unsubstitute
- phenyl C1-6 alkoxy group phenyl ring Above are a halogen atom, halogen-substituted or unsubstituted C1-6 alkyl group and nitrogen-substituted or C: at least one of the groups selected from the group consisting of! -6 alkoxy groups may be substituted.) At least one of the groups selected from the group consisting of ;
- (Fdl2) Amino group, amino group substituted by C 1-6 alkoxycarbonyl group, phenyl C 1-6 alkylamino group (having at least one halogen-substituted or unsubstituted C 1-6 alkyl group on the phenyl ring) Or a phenylamino group (at least one group selected from the group consisting of a halogen atom and a nitrogen-substituted or unsubstituted C1-6 alkyl group on the phenyl ring) May be substituted);
- (Fdl5) thiazolyl C 1-6 alkyl group (at least one group selected from the group consisting of halogen-substituted or unsubstituted phenyl group and C;!-6 alkyl group is substituted on the thiazole ring. );
- (Fdl6) oxazolyl C1-6 alkyl group (on the oxazole ring, at least one group selected from the group consisting of halogen-substituted or unsubstituted phenyl group and C1-6 alkyl group is substituted. Also good);
- phenyl C 2-6 alkanol group having a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group on the phenyl ring At least one of the groups selected from the group may be substituted);
- Benzyl group (Halogen atom, halogen-substituted or unsubstituted C1-6 alkyl group, halogen-substituted or unsubstituted C1-6 alkoxy group and C1-6 alkyl group as substituent At least one of the groups selected from the group consisting of amino groups that may have a substituent may be substituted);
- (Fd35) benzenesulfonyl group (the benzene ring may be substituted with at least one group selected from the group consisting of halogen atoms and C1-6 alkyl groups);
- R, R 29 and R 30 are each a hydrogen atom; a C 1-6 alkyl group; a phenyl group [A halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and And at least one of the groups selected from the group consisting of halo-substituted or unsubstituted C 1-6 alkoxy groups may be substituted.]
- phenyl C 1-6 alkyl group (on the phenyl ring, a nitrogen atom, a nitrogen-substituted or unsubstituted C 1-6 alkyl group, a halogen-substituted or unsubstituted 1-6 alkoxy group, halogen Substituted or unsubstituted C1-6 alkylthio group, phenyl C1-6 alkoxy group, hydroxy group, C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, C1-6 alkylsulfonyloxy group In the cyano group, C1-6 alkanoyl group, benzoyl group, alkyl moiety, phenyl which may have 1-6 alkoxy groups, C1-6 alkyl group, amino group, nitro group, carbamoyl group, C1-6 Alkanoylamino group, Cl-6 alkoxycarbonyl group, C1-6 alkylaminocarbonyl group,
- (Fdal1) phenyl C2-6 alkynyl group (although at least one halogen-substituted or unsubstituted C:!-6 alkyl group may be substituted on the phenyl ring); (Fdal2) A pyridyl C 1-6 alkyl group;
- a phenyl ring is formed from a group consisting of a halogen atom, a cyano group, a halogen-substituted or unsubstituted C1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxy group.
- a phenyl C 1-6 alkyl group [a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group on the phenyl ring, or at least one of the selected groups may be substituted] And at least one group selected from the group consisting of halogen-substituted or unsubstituted C1-6 alkoxy groups may be substituted.] Or benzoyl group [halogen atom, halogen-substituted on the phenyl ring] Or at least one group selected from the group consisting of an unsubstituted C1-6 alkyl group and a nitrogen-substituted or unsubstituted C1-6 alkoxy group may be substituted.];
- Piperidino C 1-6 alkyl group (The piperidine ring is substituted by a phenoxy group which may have at least one halogen-substituted or unsubstituted alkyl group as a substituent on the phenyl ring. May be);
- Amino C 1-6 alkyl group (C 1-6 alkyl group on amino group and halogen-substituted or unsubstituted C 1-6 alkoxy group as substituent on phenyl ring) At least one group selected from the group consisting of a fluorine group which may have a silyl group may be substituted);
- (Fda22) oxazolyl C 1-6 alkyl group (a halogen atom or a halogen-substituted or unsubstituted fuunyl group may be substituted on the oxazole ring); May be substituted with a halogen-substituted or unsubstituted fuunyl group);
- indolinyl C1-6 alkyl group at least one of groups selected from the group consisting of C1-6 alkyl group and oxo group may be substituted on the indoline ring
- Benzoxazolyl C 1-6 alkyl group At least one of the groups selected from the group consisting of halogen atom, C 1-6 alkyl group and oxo group is substituted on the benzoxal ring.
- Tetrazolyl C1-6 alkyl group (Even if at least one kind of group selected from the group consisting of halogen-substituted or unsubstituted phenyl group and C1-6 alkyl group is substituted on the tetrazole ring, Good)
- R 32 and R 33 may be the same or different,
- phenyl C 1-6 alkyl group (on the phenyl ring, halogen atom, nitrogen-substituted or unsubstituted C:!-6 alkyl group and nitrogen-substituted or unsubstituted C 1-6 alkoxy group At least one of the groups selected from the group consisting of:
- phenyl C2-6 alkenyl group Halogen atom, halogen-substituted or unsubstituted C1-6 alkyl group and halogen-substituted or unsubstituted C1-6 alkoxy group At least one of the groups selected from the group consisting of );
- R 3 2 and R 3 3 are, they piperidine ring linked to each other through the other carbon atom together with the adjacent nitrogen atom, or 1, 2, 3, 6-tetrahydro pyridine ring You may form it.
- a phenyl group may be substituted on the piperidine ring and the 1,2,3,6-tetrahydrido pyridine ring, and the phenyl group has a halogen atom and a halogen-substituted or unsubstituted C 1-6 alkyl. At least one of the groups selected from the group consisting of groups may be substituted. );
- R 34 represents a hydrogen atom or a C:!-6 lower alkyl group.
- R 3 6, 'and R 3 8 are each a hydrogen atom; C 1 to 6 alkyl radical; The full Weniru group [on the phenyl ring, a halogen atom, C 1 to 6 Anorekinore halogen-substituted or unsubstituted Group, halogen-substituted or unsubstituted C1-6 alkoxy group, C1-4 alkylenedioxy group, C1-6 alkylsulfonyl group, halogen-substituted or unsubstituted C1-6 alkylthio group, nitro group And at least one group selected from the group consisting of amino groups which may have a C 1-6 alkanoyl group as a substituent may be substituted with 1 to 5]; a benzofuryl group [on a benzofuran ring In At least one group selected from the group consisting of a halogen atom, a halogen-substituted or unsubstit
- a biphenylyl group or a furyl group [a phenyl group which may have a halogen atom as a substituent may be substituted on the furan ring] or a thiazolyl group [having a halogen atom on the thiazole ring] And at least one phenyl group which may be substituted may be substituted].
- (Ff4) a phenyl group (a halogen atom on the phenyl ring; a halogen-substituted or unsubstituted C 1-6 alkyl group; a C 3-8 cycloalkyl group; a hydroxyl group; a nodogen-substituted or unsubstituted C: C-8 cycloalkoxy group; C:!-4 alkylenedioxy group; cyano group; nitro group; phenyl C2-6 alkenyl group; C2-6 alkanoyloxy group; An amino group which may have a C 1-6 alkyl group as a substituent; a C 1-6 alkylsulfonylamino group; a phenyl C 1-6 alkoxy group; a phenoxy group; Amino group substituted by one; Amino group substituted by at least one phenyl group; Amino C 1-6 alkoxy group [At least one C 1-6 alkyl
- (Ff5) a naphthyl group (a group consisting of a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkoxy group and an amino group which may have a C 1-6 alkyl group as a substituent on the naphthalene ring At least one of the selected groups is substituted Good);
- (Ff6) bifurdyl group (a bifuryl ring has a halogen atom, a halogen-substituted or unsubstituted C 1-9 alkyl group, and a hagage-substituted or unsubstituted C 1-6 alkoxy group At least one selected group may be substituted);
- (Ff8) benzofuryl group (on the benzofuran ring, a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl and a haegen-substituted or unsubstituted C 1-6 alkoxy group, At least one of them may be substituted);
- (Ff9) benzothenyl group (on the benzothiophene ring, selected from the group consisting of a halogen atom, a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group At least one of the groups may be substituted);
- (FflO) pyridyl group (a halogen atom, halogen-substituted or unsubstituted C 1-6 alkyl group on a pyridine ring, phenyl group; a cyl group [a nitrogen atom, a halogen-substituted or unsubstituted group on a phenyl ring] At least one group selected from the group consisting of a substituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group may be substituted, At least one of the groups selected from the group may be substituted);
- (Ffll) a furyl group (an alkyl group of C 1 to C 6, a nitro group and a phenyl group on a furan ring [a halogen atom, a halogen-substituted or unsubstituted C:!-6 alkyl group on a phenyl ring, At least one group selected from the group consisting of a halogen-substituted or unsubstituted C 1-6 alkoxy group and a nitro group may be substituted.] The group selected from the group consisting of 1-3 May be substituted);
- (Ffl5) pyrrolyl group (selected from the group consisting of a phenyl group and a C1-6 alkyl group which may have at least one halogen-substituted or unsubstituted C1-6 alkyl group on the pyrrole ring. At least one of the groups may be substituted);
- (Ffl9) Thiazolyl group At least one phenyl group may be substituted on the thiazole ring. On the phenyl ring, selected from the group consisting of a halogen atom, a nitro group and a phenyl group (Ff20) quinolyl group; at least one of the groups may be substituted.
- R 4 5 is, C. 1 to 6 alkoxycarbonyl
- the phenyl group [on the phenyl ring, a halogen atom, halogen-substituted or unsubstituted C 1 to 6 alkyl groups and C port Gen substituted or unsubstituted C At least one of groups selected from the group consisting of 1 to 6 alkoxy groups may be substituted.];
- An amino-substituted C 1 to 6 alkyl group [an amino group is a phenyl group (a phenyl ring is At least one group selected from the group consisting of a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1-6 alkoxy group.
- At least one group selected from the group consisting of C1-6 alkyl groups may be substituted); benzoyl group [halogen atom, halogen-substituted or unsubstituted on phenyl ring] C 1-6 alkyl group and A halogen-substituted or unsubstituted C; at least one of groups selected from the group consisting of!
- -6 alkoxy groups may be substituted]; a phenyl Cl-6 alkyl group [on the phenyl ring, At least one selected from the group consisting of a halogen atom, a nitrogen-substituted or unsubstituted C:!-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group; A phenyl C 1-6 alkoxycarbonyl group [having a halogen atom, a halogen-substituted or unsubstituted C 1-6 alkyl group and a halogen-substituted or unsubstituted C 1- At least one of the groups selected from the group consisting of 6 alkoxy groups may be substituted] or phenyl C 2-6 alkenyl group [halogen atom, halogen-substituted or unsubstituted C:!- 6 alkyl groups Shows the least one even group selected from the group consisting
- Homopiperazinyl group (chosen from the group consisting of Cl-6 alkoxyl propyl group, phenyl C:!-6 alkoxycarbonyl group and phenyl-substituted or unsubstituted phenyl group on the homopidazine ring Or at least one of the groups may be substituted));
- Piperazinyl group (an oxo group, a C1-6 alkyl group, a phenyl C1-6 alkyl group on the piperazine ring [a halogenated or unsubstituted 1-6 alkyl group on the phenyl ring At least one of which may be substituted.) At least one of the groups selected from the group consisting of:
- Piperidyl group (the piperidine ring may be substituted with at least one oxo group);
- R 1 9 ⁇ Pi R 2 (3 is bonded to one another without which they are over or through a hetero atom together with the adjacent nitrogen atom, the following (F13- 1) shown in ⁇ (F13- 11) It may form a cyclic imid or amide.
- (F13-4) imidazolidinyl group (an oxo group, a phenyl Cl-6 alkyl group on the imidazolidine ring [a group selected from the group consisting of a halogen atom and a C1-6 alkoxy group on the phenyl ring] And at least one group selected from the group consisting of 1 and 3 may be substituted) and phenyl group);
- ⁇ 6 alkoxy force Rubonyl group and piperidyl group [C 1-6 alkyl group on piperidine ring, 1-3 halogen atoms substituted on phenyl ring
- at least one group selected from the group consisting of a phenyl group, an optionally substituted phenyl group, a C 1-6 alkenyloxycarbonyl group and a phenyl C 1-6 alkoxycarbonyl group may be substituted. At least one selected group may be substituted);
- indolinyl group (the indoline ring may be substituted with at least one group selected from the group consisting of a Cl-6 alkyl group, a halogen atom and an oxo group);
- R 9 is a hydrogen atom; a phenyl which may have a halogen atom as a substituent on the Hunyl ring; C:!-6 alkyl group; a halogen atom which has a halogen atom as a substituent on the phenyl ring.
- R 40 represents a C 1-6 alkyl group or a halogen-substituted or unsubstituted phenyl group.
- H3 a phenyl C 1-6 alkyl group which may have a phenyl group as a substituent on the phenyl ring;
- phenyl group (on the phenyl ring, halogen atom, halogen-substituted or unsubstituted C:!-6 alkyl group and halogen-substituted or unsubstituted C1-6 alkoxy group, amino group [on the amino group, C 1-6 alkyl group and phenyl group (having a halogen atom, halogen-substituted or unsubstituted C 1-6 alkyl group and hydrogen-substituted or unsubstituted Cl-6 alkoxy group on the phenyl ring Group of groups selected from the group At least one kind may be substituted, or at least one kind of group selected from the group consisting of :), a phenoxy group [a halogen atom, a halogen-substituted or Unsubstituted C; at least one group selected from the group consisting of!
- -6 alkyl groups and nitrogen-substituted or unsubstituted C1-6 alkoxy groups may be substituted] and piperidyl group [piperidine ring At least one phenoxy group (consisting of a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group on the phenyl ring) H5) piperazinyl; at least one of the groups selected from the group consisting of: may be substituted.
- C 1 to 6 alkyl groups (C 1 to 6 alkoxycarbonyl groups and phenyl C 1 to 6 alkoxycarbonyl groups on the piperazine ring [no, logen atoms, nodogen-substituted or unsubstituted C 1 1 to 3 alkyl groups, nitrogen-substituted or unsubstituted C 1-6 alkoxy groups and phenyl groups may be substituted by 1 to 3 groups]. At least one of which may be substituted);
- Phenylcarbamoyl C1-6 alkyl group (at least one halogen-substituted or unsubstituted C1-6 alkyl group may be substituted on the phenyl ring);
- Benzoxazolyl C 1-6 alkyl group (at least one oxo group may be substituted on the benzoxazole ring);
- Tetrazolyl group (at least one phenyl group on the tetrazole ring May be substituted);
- Phenylsulfonyl group (at least one C1-6 alkyl group may be substituted on the phenyl ring); 'H13) Phenylthiol-rubamoyl group (at least on the phenyl ring One halogen atom may be substituted);
- Phenyl C 1-6 alkoxycarbonyl group (Halogen atom, C 1-6 alkoxycarbonyl group on the phenyl ring, amino group optionally having C 1-6 alkoxycarbonyl group as a substituent, halogen At least one group selected from the group consisting of a substituted or unsubstituted C1-6 alkyl group, a halogen-substituted or unsubstituted C1-6 alkoxy group, a nitro group and a C1-6 alkylthio group; );
- Benzoyl group (Halogen-substituted or unsubstituted C 1- 6 alkyl groups may be substituted at least one);
- Phenyl C1-6 alkanoyl group (at least one halogen-substituted or unsubstituted C1-6 alkyl group may be substituted on the phenyl ring); H26) Phenyl C1-6 6 alkanoyl groups (Halogen atoms on the phenyl ring may be substituted with:! To 3);
- Piperazinyl C 2-6 alkanoyl group ( ⁇ 1-6 alkanoyl group, phenyl C 1-6 alkyl group on piperazine ring [phenyl group, halogen atom, halogen-substituted or unsubstituted on phenyl ring C: at least one selected from the group consisting of!
- -6 alkyl groups and halogen-substituted or unsubstituted C1-6 alkoxy groups may be substituted]
- phenyl C1-6 alkoxycarbonyl group At least one group selected from the group consisting of a halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group and a halogen-substituted or unsubstituted C1-6 alkoxy group is present on the phenyl ring.
- phenylcarbamoyl C:!-6 alkyl group [Halogen atom, halogen-substituted or unsubstituted C1-6 alkyl group and halogen on the phenyl ring
- phenylcarbamoyl group [halogen atom, halogen substitution on phenyl ring]
- phenylcarbamoyl group [halogen atom, halogen substitution on phenyl ring]
- At least one group selected from the group consisting of bibenzoxazolyl groups may be substituted);
- H28 Furylcarbamoyl group (Halogen atom on the phenyl ring, amino group which may have a C1-6 alkyl group as a substituent, carboxyl group, C1-6 alkoxycarbonyl group, halogen-substituted or unsubstituted A C 1-6 alkyl group, a halogen-substituted or unsubstituted C 1-6 alkoxy group, a piperazinyl group having a C 1-6 alkyl group as a substituent on a piperazine ring, and a morpholino group. 1 to 3 selected groups may be substituted);
- phenyl C 1-6 alkyl group rubamoyl group having a halogen-substituted or unsubstituted C 1-6 alkyl group and a non-substituted or unsubstituted C At least one group selected from the group consisting of 16 alkoxy groups may be substituted;
- R 1 represents a hydrogen atom and R 2 represents a group represented by the general formula (A), must not be an isopropyl group.
- R 1 represents a hydrogen atom
- R 2 represents a group represented by formula (E)
- m represents 0, R 11 must not be a hydrogen atom.
- R 1 represents a hydrogen atom
- R 1 9 shall show and R 20 is tert- butoxycarbonyl group represents a hydrogen atom.
- reaction of compound (10a) or compound (10b) with compound (28) is carried out in a suitable solvent or without a solvent, in the presence or absence of a basic compound.
- solvent used here examples include water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, and other alcohols, benzene, tonolene, xylene, tetralin, o-chlorobenzenole, m —Aromatic hydrocarbons such as chlorobenzene, 2,3-dichlorobenzene, etc .; dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, etc., Jetylether, dioxane, tetrahydrofuran, Ethers such as diglyme, dipropyl ether and dimethoxetane, saturated hydrocarbons such as n-xane, n-butane, cyclohexane, liquid paraffin, ketones such as acetone and methyl ethyl ketone, N, N-dimethyl Formamide,
- the inorganic base examples include alkali metal carbonates such as sodium carbonate and carbonated lime, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and hydrogenated lime, sodium hydroxide, alkali metal hydroxides such as hydroxylated lime and the like.
- Alkali metal metal phosphates such as sodium chloride, sodium phosphate, phosphoric acid rim, alkali metal hydrides such as sodium hydride and lithium hydride, alkali metals such as potassium and sodium, alkali metals such as sodium amide
- Examples include amides, alkali metal alcoholates such as sodium methylate, sodium ethylate, and sodium tert-butoxide.
- organic base examples include sodium acetate, acetate such as acetate acetate, pyridine, trimethylamine, triethynoleamine, diisopropylethylamine, dimethinorea diline, 1-methylpyrrolidine, N-methyl Morpholine, N, N-dimethyl-4-aminopyridine, 1,5-diazavicic mouth [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] ndenecene-7 (DBU) : 1,4-diazabic mouth [2.2.2] octane (DABCO) etc.
- the amount of compound (28) to be used is usually at least one mole per mole of compound (10a) or compound (10b). It is about 1 mol, preferably about 1-5 mol.
- the amount of the basic compound to be used is generally about 0.1 to 1 mol, preferably about 0.1 to 0.5 mol, per 1 mol of compound (10a) or compound (10b).
- the reaction between the compound (10a) or the compound (10b) and the compound (28) is carried out usually at room temperature to 150 ° C, preferably at room temperature to about 120 ° C, and generally for about 10 minutes to 24 hours. Ends with
- reaction for converting the compound (29a) to the compound (30a) and the reaction for converting the compound (29b) to the compound (30b) are carried out in a suitable solvent or in the absence of a solvent in the presence of a basic compound. .
- the solvent and the basic compound used herein may be the same as the solvent and the basic compound used in the reaction of the compound (10a) or the compound (10b) with the compound (28). it can.
- the amount of the basic compound to be used is generally at least about 1 mol, preferably about 1 to 2 mol, per 1 mol of compound (29a) or (29b).
- the reaction is usually carried out at 0 to 150 ° C, preferably at about 0 to 120 ° C, and is completed generally in about 10 minutes to 48 hours.
- the 4-nitroimidazole conjugate represented by the general formula (2) of the present invention is also useful as an antituberculous drug described in WO 97/01562 (Japanese Translation of PCT Application No. 11-508270). 38).
- X is oxygen, zeo or NR 2 , wherein R 2 is hydrogen, lower alkyl, aryl, cycloalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, COR 3 , S0 2 R 4 or CONR 4 R 5 , where R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, aryl, alkylaryl, alkoxyanolalkyl, alkoxyaryl, Selected from alkoxyaryl, alkylheterocycles, and alkoxyheterocycles: -n is 1, 2 or 3;
- Y and Z are independently oxygen CH 2
- C_ ⁇ is selected from CR 4 R 5 or NR 4,, wherein, R 4 Oyopi 1 5 are the same as defined above;
- R 6, R 7, 1 8 Oyobi 1 9 are independently hydrogen, lower alkyl, ⁇ reel, alkyl ⁇ reel, alkoxyalkyl, alkoxyalkyl ⁇ reel, heterocycle alkoxyalkyl, Arukirua Reel Alkya Reel, Alkya Selected from linole, aryl, alkylcycloalkyl, alkoxyaryl, alkylheterocycle and alkoxyheterocycle. ).
- Compound (38) can be produced, for example, by the method of the following reaction formula 13:
- R D ′ and R E ′ each represent a tetrahydrovinylanyl group, a tri-lower alkylsilyl group, a lower alkenyl group, or a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring.
- R r represents a substituted or unsubstituted arylalkyl group, an alkyl group, a substituted or unsubstituted arylalkylalkyl group, or a substituted or unsubstituted heterocyclic alkyl group.
- Is 3 shows the 4-dihydro-2 H- pyran or R 1.
- R 1 represents a tri-lower alkylsilyl group, a lower alkanol group or a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring.
- the tri-lower alkylsilyl group here, for example, tert- Buchirujimechi Rushiriru, trimethylsilyl, n- heptyl E chill trimethylsilyl, tert- butyl distearate professional building silyl, n - pentyl Rougier chill silyl, hexyl propyl methylcarbamoyl Rushiriru group to n- And a straight- or branched-chain alkyl group having 1 to 6 carbon atoms, such as a substituted or unsubstituted silyl group.
- Examples of the lower alkanoyl group include a straight-chain or branched-chain alkanol group having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butylinole, isoptyryl, pentanoyl, tert-butylcarbonyl, and hexanol.
- X 2 is a halogen atom in the reaction of the compound (4) with the compound (9).
- the reaction leading to (34a) when RD represents a trialkylalkylsilyl group, the reaction is carried out in a suitable solvent in the presence of a desilylation agent.
- a suitable solvent in the presence of a desilylation agent.
- the solvent to be used any of the solvents used in the reaction for converting the compound (la) of the above-mentioned reaction formula-3 into the compound (2a) can be used.
- the desilylating agent include alkyl ammonium halides such as tetrabutylammonium fluoride.
- the amount of the desilylating agent to be used is at least equimolar, preferably 1-2 mol, per 1 mol of compound (33b) or (33d).
- the reaction is completed usually at 0 to 100 ° C, preferably at about 0 to 70 ° C for about 1 to 30 hours.
- RD represents a tetrahydropyranyl group, a lower alkanol group or a phenyl lower alkyl group which may have a lower paper alkoxy group as a substituent on the phenyl ring
- the compound (la) of the above reaction formula 13 The reaction can be carried out under the same conditions as in the reaction leading to (2a).
- reaction of (31c) can be carried out under the same conditions as in the reaction of the compound (4) with the compound (9) in the reaction formula 13 when X 2 represents a halogen atom. .
- Reaction of compound (33a) with compound (32) and compound (33c) with compound The reaction with (32) can be carried out under the same conditions as in the reaction of compound (40a) with compound (32) in Reaction Scheme 14 described below.
- the reaction leading to 36a), the reaction between compound (36) and compound (37) and the reaction between compound (36a) and compound (37) are described in WO 97/01562 (Japanese Translation of PCT International Publication No. 11-508270). It can be manufactured by a method.
- X is a bromine atom or a group S (O) nR 1 (R 1 and n Is the same as described above.)
- the 4-nitroimidazole derivative is a novel compound, and as described above, is a useful compound as an intermediate for the synthesis of antituberculous drugs.
- the compound (31a) or (31d) as a starting material can be produced, for example, by the method shown in the following Reaction Scheme 14.
- the solvent used is a compound in the case where X 2 represents a halogen atom in the reaction between compound (4) and compound (9).
- the reaction can be carried out using a solvent or a solvent, and the reaction is completed usually at 0 to 100 ° C, preferably at about 0 to 70 ° C for about 1 to 30 hours.
- the reaction advantageously proceeds by adding as a catalyst a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as pyridinum p-toluenesulfonic acid.
- a mineral acid such as hydrochloric acid or sulfuric acid
- an organic acid such as pyridinum p-toluenesulfonic acid.
- the compounds (40a) and (40b) can also be produced by reacting in a suitable solvent in the presence of imidazole. it can.
- any solvent used in the reaction between compound (4) and compound (9) in the above-mentioned reaction formula 13 is used. be able to.
- Compound (32) is used in an amount of at least 1 mol, preferably about 1 to 2 mol, per 1 mol of compound (39a) or compound (39b) or compound (40a) or compound (40b). Good.
- the imidazole is used in an amount of at least 1 mol, preferably about 1 to 2 mol per 1 mol of the compound (39a) or the compound (39b) or the compound (40a) or the compound (40b).
- the reaction usually proceeds suitably at 0 to 100 ° C., preferably around 0 to 70 ° C., and is generally completed in about 1 to 30 hours.
- the target compound obtained in each of the above reactions is separated from the reaction mixture by a usual separation means, and can be further purified.
- separation and purification means include distillation, recrystallization, column chromatography, ion-exchange chromatography, gel chromatography, affinity chromatography, preparative thin-layer chromatography, and solvent extraction. Can be.
- the compound having a basic group can easily form a salt with an ordinary pharmacologically acceptable acid.
- an acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, and hydrobromic acid, acetic acid, ⁇ -toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, and fumaric acid.
- organic acids such as citric acid, succinic acid, malic acid, tartaric acid, malonic acid, lactic acid and benzoic acid.
- the 1-substituted 4-nitroimidazole compound represented by the general formula (1) of the present invention includes stereoisomers and optical isomers.
- the 1-substituted 4-nitroimidazole conjugate represented by the general formula (1) of the present invention is used for synthesizing an antituberculous drug as shown in the above reaction formulas 12 and 13. It can be suitably used as an intermediate.
- the 1-substituted 1-41-2 troimidazole compound represented by the general formula (10) of the present invention is produced by using the compound (11) as a starting material.
- the target 412 toloimidazole compound of general formula (2a) can be manufactured, without going through an intermediate which has the danger of explosion.
- the production method of the present invention is simple in operation and does not require complicated purification steps. According to the production method of the present invention, the desired general formula
- the 4-nitroimidazole compound of (2a) can be produced.
- the method of the present invention is industrially extremely advantageous.
- Triethylamine (219 ml) was added to the reaction mixture, and a solution of 412 trobenzenesulfolyl chloride (332 g) in toluene (830 ml) was added.
- C-1 The mixture was added dropwise at 6 ° C and stirred at 110 ° C for 1 hour.
- the reaction suspension was filtered through celite, and the filtrate was washed successively with a 15% aqueous tartaric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated saline solution.
- the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a brown oil (695 g).
- the optical purity was measured by high performance liquid chromatography (HPLC) under the following conditions.
- trimethinolephosphite (18.lml) was added dropwise at 115 ° C to — 5 ° C and excess The oxide was reduced. The end point of this reduction reaction was confirmed by zinc iodide starch paper.
- reaction suspension was filtered through celite, and the filtrate was washed successively with a 15% aqueous tartaric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a brown oil (1%). 29.2 g) was obtained.
- reaction mixture was extracted with ethyl acetate, washed successively with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a yellow solid.
- Test Example 1 Antibacterial test by agar plate dilution method
- the minimum inhibitory concentration against (M. tuberculosisH37Rv) was determined using 7H11 medium (BBL). The above strain is prepared in advance in 7H9 medium
- the cells were cultured at (BB ⁇ M), the viable cell count was calculated, and the final viable cell count was adjusted to about 10 6 CFU / ml using the bacterial solution frozen and stored at 180 ° C.
- the bacterial solution thus prepared was inoculated in an amount of 5 ⁇ l on a 7H11 agar medium containing a test compound, cultured at 37 ° C for 14 days, and then subjected to a test for measuring the minimum inhibitory concentration.
- the minimum inhibitory concentration for M. tuberculosisH37Rv was 0.024 ⁇ g / ml.
- 2-Imperium 4-l-imidazole 43 lmg is suspended in 2.5 ml of concentrated nitric acid (d. 1.38), 2.5 ml of concentrated sulfuric acid is added while cooling with ice, and the mixture is added at room temperature. Stirred for hours. Thereafter, the precipitate was collected by filtration and dried to obtain 348 mg (yield: 67.0%) of 2-chloro-5-iodo412-troimidazole as a yellow solid.
- 2- (2-Difluorophenylthio) imidazole 50 Omg and tetra-n-butylammonium nitrate 1.0 g ⁇ ⁇ , and then stirred at 110 ° C for 30 minutes. Ice water was added to the reaction solution, and the mixture was stirred for a while, then, ethyl acetate was added, and the mixture was separated. The ethyl acetate layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate.
- the ethyl acetate layer was washed with water, saturated aqueous sodium bicarbonate, and saturated saline, and dried over anhydrous sodium sulfate.
- the ethyl acetate 'layer was washed with a 5% aqueous potassium carbonate solution, water, and saturated saline, and dried over anhydrous sodium sulfate.
- a solution of 25-mg of imidazonole and 25 mL of imidazonole was prepared by stirring a solution of benzene in 5 mL of benzene at 85-95 ° C for 20 minutes.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
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CA2494710A CA2494710C (en) | 2002-10-15 | 2003-10-14 | 1-substituted-4-nitroimidazole compound and method for preparing the same |
BR0313566-7A BR0313566A (pt) | 2002-10-15 | 2003-10-14 | Composto de 4-nitroimidazol 1-substituìdo, método para preparar um composto de 4-nitroimidazol, método para preparar um composto de 4-nitroimidazol 1-substituìdo, derivado de 4-nitroimidazol, e, composto |
AU2003301282A AU2003301282B2 (en) | 2002-10-15 | 2003-10-14 | 1-substituted 4-nitroimidazole compound and process for producing the same |
EP03756610A EP1553088A4 (en) | 2002-10-15 | 2003-10-14 | 1-SUBSTITUTED 4-NITROIMIDAZOLE COMPOUND AND PROCESS FOR PRODUCING THE SAME |
UAA200503528A UA80839C2 (en) | 2002-10-15 | 2003-10-14 | 1-substituted 4-nitroimidazole compound and process for producing the same |
MXPA05002414A MXPA05002414A (es) | 2002-10-15 | 2003-10-14 | Compuesto de 4-nitroimidazol 1-sustituido y procedimiento para su produccion. |
US10/523,008 US7368579B2 (en) | 2002-10-15 | 2003-10-14 | 1-substituted-4-nitroimidazole compound and process for producing the same |
EGNA2005000131 EG24885A (en) | 2002-10-15 | 2005-04-12 | Substituted 4-nitroimidazole compound and process for producing the same |
HK06103740A HK1083830A1 (en) | 2002-10-15 | 2006-03-24 | 1-Substituted 4-nitroimidazole compound and process for producing the same |
US11/905,446 US8129544B2 (en) | 2002-10-15 | 2007-10-01 | 1-substituted-4-nitroimidazole compound and method for preparing the same |
US12/007,776 US7807843B2 (en) | 2002-10-15 | 2008-01-15 | 1-substituted-4-nitroimidazole compound and method for preparing the same |
US13/362,646 US20120130082A1 (en) | 2002-10-15 | 2012-01-31 | 1-Substituted-4-Nitroimidazole Compound and Method for Preparing the Same |
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US11/905,446 Division US8129544B2 (en) | 2002-10-15 | 2007-10-01 | 1-substituted-4-nitroimidazole compound and method for preparing the same |
US12/007,776 Continuation US7807843B2 (en) | 2002-10-15 | 2008-01-15 | 1-substituted-4-nitroimidazole compound and method for preparing the same |
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EP (2) | EP2644599B1 (ja) |
JP (1) | JP5014315B2 (ja) |
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AR (1) | AR041605A1 (ja) |
AU (1) | AU2003301282B2 (ja) |
BR (1) | BR0313566A (ja) |
CA (1) | CA2494710C (ja) |
EG (1) | EG24885A (ja) |
ES (1) | ES2526892T3 (ja) |
HK (2) | HK1083830A1 (ja) |
MX (1) | MXPA05002414A (ja) |
MY (1) | MY145079A (ja) |
PL (1) | PL375103A1 (ja) |
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Cited By (7)
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WO2005042542A1 (en) * | 2003-10-31 | 2005-05-12 | Otsuka Pharmaceutical Co., Ltd. | 2,3-dihydro-6-nitroimidazo (2,1-b) oxazole compounds for the treatment of tuberculosis |
WO2005077913A1 (en) * | 2004-02-18 | 2005-08-25 | Otsuka Pharmaceutical Co., Ltd. | Method for producing 4-nitroimidazole compound |
CN100338039C (zh) * | 2004-11-29 | 2007-09-19 | 南京圣和药业有限公司 | 奥硝唑光学对映体的制备及纯化方法 |
WO2011093529A1 (en) | 2010-01-29 | 2011-08-04 | Otsuka Pharmaceutical Co., Ltd. | Synthetic intermediate of oxazole compound and method for producing the same |
JP2012500183A (ja) * | 2008-08-21 | 2012-01-05 | デイナミート ノーベル ゲゼルシャフト ミット ベシュレンクテル ハフツング エクスプロジーフシュトッフ− ウント ジステームテヒニク | 2−ハロ−4−ニトロイミダゾール及びその中間体の製造方法 |
CN101675044B (zh) * | 2007-05-08 | 2012-10-03 | 大塚制药株式会社 | 环氧化合物及其制备方法 |
US9572809B2 (en) | 2012-07-18 | 2017-02-21 | Spero Trinem, Inc. | Combination therapy to treat Mycobacterium diseases |
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RU2324682C2 (ru) * | 2002-10-15 | 2008-05-20 | Оцука Фармасьютикал Ко., Лтд. | Производное 1-замещенного 4-нитроимидазола и способ его получения |
TW200624422A (en) * | 2004-09-27 | 2006-07-16 | Otsuka Pharma Co Ltd | Process for production of 2-chloro-4-nitroimidazole |
MX2008001210A (es) * | 2005-07-28 | 2008-03-24 | Otsuka Pharma Co Ltd | Composicion farmaceutica que comprende derivados de 2,3-dihidro-6-nitroimidazo{2,1-b]oxazol. |
CN103396369B (zh) * | 2013-08-14 | 2016-03-23 | 盐城工学院 | 一种制备2-氯-4-硝基咪唑的方法 |
US20200190073A1 (en) | 2017-04-26 | 2020-06-18 | Basf Se | Substituted succinimide derivatives as pesticides |
EP3696177A1 (en) | 2019-02-12 | 2020-08-19 | Basf Se | Heterocyclic compounds for the control of invertebrate pests |
CN113874341B (zh) * | 2019-04-01 | 2024-05-31 | 科学与工业研究委员会 | 制备作为有用中间体的1,1-二烷基乙烷-1,2-二醇的衍生物的方法 |
WO2020223267A1 (en) | 2019-05-01 | 2020-11-05 | Boehringer Ingelheim International Gmbh | (r)-(2-methyloxiran-2-yl)methyl 4-bromobenzenesulfonate |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4021442A (en) * | 1974-03-25 | 1977-05-03 | Basf Aktiengesellschaft | Production of 1-alkyl-5-nitroimidazoles |
US4925949A (en) * | 1988-01-15 | 1990-05-15 | Rhone-Poulenc Sante | Process for preparing 1-alkyl-5-nitroimidazoles |
US5380866A (en) * | 1993-04-20 | 1995-01-10 | Eli Lilly And Company | Alkyl substituted nitroimidazole acetic acids |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3341548A (en) * | 1964-04-29 | 1967-09-12 | Hoffmann La Roche | Nitroimidazoles and their preparation |
US3435049A (en) * | 1965-05-19 | 1969-03-25 | Hoffmann La Roche | Nitroimidazole derivatives |
US4183941A (en) * | 1978-08-21 | 1980-01-15 | John R. A. Simoons | Treatment of rheumatoid arthritis and related diseases |
US5668127A (en) | 1995-06-26 | 1997-09-16 | Pathogenesis Corporation | Nitroimidazole antibacterial compounds and methods of use thereof |
TWI347946B (en) * | 2002-10-11 | 2011-09-01 | Otsuka Pharma Co Ltd | 2,3-dihydro-6-nitroimidazo[2,1-b]oxazole compound |
RU2324682C2 (ru) | 2002-10-15 | 2008-05-20 | Оцука Фармасьютикал Ко., Лтд. | Производное 1-замещенного 4-нитроимидазола и способ его получения |
TWI300409B (en) * | 2004-02-18 | 2008-09-01 | Otsuka Pharma Co Ltd | Method for producing 4-nitroimidazole compound |
-
2003
- 2003-10-14 RU RU2005114534/04A patent/RU2324682C2/ru not_active IP Right Cessation
- 2003-10-14 US US10/523,008 patent/US7368579B2/en not_active Expired - Fee Related
- 2003-10-14 MX MXPA05002414A patent/MXPA05002414A/es active IP Right Grant
- 2003-10-14 MY MYPI20033919A patent/MY145079A/en unknown
- 2003-10-14 BR BR0313566-7A patent/BR0313566A/pt not_active IP Right Cessation
- 2003-10-14 EP EP13174291.8A patent/EP2644599B1/en not_active Expired - Lifetime
- 2003-10-14 AR ARP030103730A patent/AR041605A1/es unknown
- 2003-10-14 ES ES13174291.8T patent/ES2526892T3/es not_active Expired - Lifetime
- 2003-10-14 CA CA2494710A patent/CA2494710C/en not_active Expired - Fee Related
- 2003-10-14 PL PL03375103A patent/PL375103A1/xx unknown
- 2003-10-14 EP EP03756610A patent/EP1553088A4/en not_active Withdrawn
- 2003-10-14 TW TW097117703A patent/TW200838855A/zh unknown
- 2003-10-14 AU AU2003301282A patent/AU2003301282B2/en not_active Ceased
- 2003-10-14 KR KR1020057006493A patent/KR100655670B1/ko not_active IP Right Cessation
- 2003-10-14 WO PCT/JP2003/013134 patent/WO2004035547A1/ja active Application Filing
- 2003-10-14 TW TW092128442A patent/TWI331607B/zh not_active IP Right Cessation
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2005
- 2005-04-12 EG EGNA2005000131 patent/EG24885A/xx active
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2006
- 2006-03-24 HK HK06103740A patent/HK1083830A1/xx not_active IP Right Cessation
-
2007
- 2007-10-01 US US11/905,446 patent/US8129544B2/en not_active Expired - Fee Related
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2008
- 2008-01-15 US US12/007,776 patent/US7807843B2/en not_active Expired - Fee Related
- 2008-11-28 JP JP2008305239A patent/JP5014315B2/ja not_active Expired - Fee Related
-
2012
- 2012-01-31 US US13/362,646 patent/US20120130082A1/en not_active Abandoned
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2014
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4021442A (en) * | 1974-03-25 | 1977-05-03 | Basf Aktiengesellschaft | Production of 1-alkyl-5-nitroimidazoles |
US4925949A (en) * | 1988-01-15 | 1990-05-15 | Rhone-Poulenc Sante | Process for preparing 1-alkyl-5-nitroimidazoles |
US5380866A (en) * | 1993-04-20 | 1995-01-10 | Eli Lilly And Company | Alkyl substituted nitroimidazole acetic acids |
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Publication number | Priority date | Publication date | Assignee | Title |
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US8163753B2 (en) | 2003-10-31 | 2012-04-24 | Otsuka Pharmaceutical Co., Ltd. | 2,3-dihydro-6-nitroimidazo (2,1-b) oxazole compounds for the treatment of tuberculosis |
KR100851802B1 (ko) * | 2003-10-31 | 2008-08-13 | 오쓰까 세이야꾸 가부시키가이샤 | 결핵의 치료를 위한2,3-디히드로-6-니트로이미다조[2,1-b]옥사졸 화합물 |
WO2005042542A1 (en) * | 2003-10-31 | 2005-05-12 | Otsuka Pharmaceutical Co., Ltd. | 2,3-dihydro-6-nitroimidazo (2,1-b) oxazole compounds for the treatment of tuberculosis |
WO2005077913A1 (en) * | 2004-02-18 | 2005-08-25 | Otsuka Pharmaceutical Co., Ltd. | Method for producing 4-nitroimidazole compound |
US7569702B2 (en) | 2004-02-18 | 2009-08-04 | Otsuka Pharmaceutical Co., Ltd. | Method for producing 4-nitroimidazole compound |
CN100338039C (zh) * | 2004-11-29 | 2007-09-19 | 南京圣和药业有限公司 | 奥硝唑光学对映体的制备及纯化方法 |
US8344148B2 (en) | 2007-05-08 | 2013-01-01 | Otsuka Pharmaceutical Co., Ltd. | Epoxy compound and method for manufacturing the same |
CN101675044B (zh) * | 2007-05-08 | 2012-10-03 | 大塚制药株式会社 | 环氧化合物及其制备方法 |
US8552188B2 (en) | 2007-05-08 | 2013-10-08 | Otsuka Pharmaceutical Co., Ltd. | Epoxy compound and method for manufacturing the same |
JP2012500183A (ja) * | 2008-08-21 | 2012-01-05 | デイナミート ノーベル ゲゼルシャフト ミット ベシュレンクテル ハフツング エクスプロジーフシュトッフ− ウント ジステームテヒニク | 2−ハロ−4−ニトロイミダゾール及びその中間体の製造方法 |
WO2011093529A1 (en) | 2010-01-29 | 2011-08-04 | Otsuka Pharmaceutical Co., Ltd. | Synthetic intermediate of oxazole compound and method for producing the same |
US8598358B2 (en) | 2010-01-29 | 2013-12-03 | Otsuka Pharmaceutical Co., Ltd. | Synthetic intermediate of oxazole compound and method for producing the same |
US9572809B2 (en) | 2012-07-18 | 2017-02-21 | Spero Trinem, Inc. | Combination therapy to treat Mycobacterium diseases |
US9937192B2 (en) | 2012-07-18 | 2018-04-10 | Spero Trinem, Inc. | Combination therapy to treat mycobacterium diseases |
Also Published As
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JP5014315B2 (ja) | 2012-08-29 |
JP2009102329A (ja) | 2009-05-14 |
PL375103A1 (en) | 2005-11-28 |
AU2003301282A1 (en) | 2004-05-04 |
CA2494710A1 (en) | 2004-04-29 |
AU2003301282B2 (en) | 2009-04-30 |
KR100655670B1 (ko) | 2007-02-28 |
RU2005114534A (ru) | 2006-01-20 |
KR20050046013A (ko) | 2005-05-17 |
EP2644599B1 (en) | 2014-12-10 |
EP2644599A1 (en) | 2013-10-02 |
AR041605A1 (es) | 2005-05-26 |
US20060079697A1 (en) | 2006-04-13 |
US20120130082A1 (en) | 2012-05-24 |
CA2494710C (en) | 2011-05-03 |
TW200838855A (en) | 2008-10-01 |
EP1553088A1 (en) | 2005-07-13 |
RU2324682C2 (ru) | 2008-05-20 |
HK1188993A1 (en) | 2014-05-23 |
TWI331607B (en) | 2010-10-11 |
MXPA05002414A (es) | 2005-06-22 |
TW200410943A (en) | 2004-07-01 |
MY145079A (en) | 2011-12-15 |
US20080097107A1 (en) | 2008-04-24 |
HK1083830A1 (en) | 2006-08-11 |
US7807843B2 (en) | 2010-10-05 |
BR0313566A (pt) | 2005-06-21 |
US7368579B2 (en) | 2008-05-06 |
EP1553088A4 (en) | 2011-03-02 |
ES2526892T3 (es) | 2015-01-16 |
US20080200689A1 (en) | 2008-08-21 |
US8129544B2 (en) | 2012-03-06 |
EG24885A (en) | 2010-12-06 |
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