Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to an imidazopyridine compound useful as a gastric acid secretion inhibitor, or a salt thereof or a hydrate thereof.
• the present invention also relates to an imidazopyridine compound useful as a therapeutic or preventive agent for acid related diseases (especially gastroesophageal reflux disease, symptomatic gastroesophageal reflux disease, gastric ulcer or duodenal ulcer), or a salt thereof or a hydrate thereof.
• acid related diseases especially gastroesophageal reflux disease, symptomatic gastroesophageal reflux disease, gastric ulcer or duodenal ulcer
• Peptic ulcer such as gastric ulcer and duodenal ulcer
• gastric ulcer and duodenal ulcer is considered to have developed as a result of self-digestion caused by imbalance between aggressive factors, such as acid and pepsin, and protective factors, such as mucus and blood.
• drugs specifically inhibiting H + -, K + -ATPase, an enzyme present in gastric parietal cells and in charge of the final step of gastric acid secretion, suppressing the acid secretion and thereby preventing self-digestion for example, omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, etc., have been recently developed and clinically used.
• An object of the present invention is to provide a new compound having an excellent inhibitory effect on gastric acid secretion which is useful as a therapeutic or preventive agent for the treatment of acid related diseases.
• an imidazopyridine compound having a novel chemical structure has an excellent inhibition effect on gastric acid secretion and is useful as a therapeutic or preventive agent particularly for gastroesophageal reflux disease, symptomatic gastroesophageal reflux disease, gastric ulcer or duodenal ulcer, and thus completed the present invention.
• the present invention is directed to a compound having the following general formula (1), or a salt thereof or a hydrate thereof.
• the present invention is also directed to a drug comprising the compound having the above described general formula (1), or a salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier.
• the present invention is further directed to a gastric acid secretion inhibitor comprising a compound having the above described general formula (1), or a salt thereof or a hydrate thereof.
• the present invention is still further directed to a method using a compound of formula (1), or a therapeutic or preventive agent comprising a compound having the above described general formula (1), or a salt thereof or a hydrate thereof, for diseases caused by gastric acid, specifically, gastric ulcer, duodenal ulcer, stomal ulcer, gastroesophageal reflux disease, Zollinger-Ellison syndrome, symptomatic gastroesophageal reflux disease, endoscopy-negative gastroesophageal reflux disease, gastroesophageal regurgitation, paresthesia of pharyngolarynx, Barrett's esophagus, non-steroidal antiinflammatory drug (NSAID) ulcer, gastritis, stomach bleeding, gastrointestinal bleeding, peptic ulcer, bleeding ulcer, stress ulcer, gastric hyperacidity, dyspepsia, gastraparesis, senile ulcer, intractable ulcer, heartburn, bruxism, stomachache, heavy stomach, temporomandibular arthrosis or erosive
• Suitable examples of “acid related diseases” include, for example, gastric ulcer, duodenal ulcer, stomal ulcer, gastroesophageal reflux disease, Zollinger-Ellison syndrome or symptomatic gastroesophageal reflux disease, and more suitable examples include gastroesophageal reflux disease, symptomatic gastroesophageal reflux disease, gastric ulcer or duodenal ulcer, and still more suitable examples include (1) gastroesophageal reflux disease or symptomatic gastroesophageal reflux disease, or (2) gastric ulcers or duodenal ulcer.
• the present invention is directed to a mono therapeutic or combination therapeutic agent for the eradication of Helicobacter Pylori comprising a compound having the above described general formula (1), or a salt thereof or a hydrate thereof.
• preventive agent includes an agent administered before onset of the disease, as well as a maintenance therapy agent or a relapse preventing agent after the disease is cured.
• the above mentioned “combination therapeutic agent for the eradication of Helicobacter Pylori ” means a drug suitably adjusting the environment so that an eradicating agent, which is difficult to exhibit the effect under acidic condition, can exhibit its effect.
• a “C1-C6 alkyl group” as used in this specification for convenience sake means a straight chain or branched chain alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group.
• C1-C3 alkyl group as used in this specification for convenience sake means a straight chain or branched chain alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl or isopropyl.
• a “C2-6 alkenyl group” as used in this specification for convenience sake means a vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1,3-pentadienyl group or 1,4-hexadienyl group.
• C2-C6 alkynyl group as used in this specification for convenience sake means an alkynyl group having 2 to 6 carbon atoms and 1 to 2 triple bonds such as ethynyl group, 1-propynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, 1,3-pentadiynyl group, 1,4-hexadiynyl group, pentynyl group, or hexynyl group.
• C3-6 cycloalkyl group as used in this specification for convenience sake means a cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group.
• halogen atom as used in this specification for convenience sake means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
• a “C1-C6 alkoxy group” as used in this specification for convenience sake means a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy group.
• R 1 is an unsubstituted C1-C6 alkyl group, a C2-C6 alkynyl group or a C1-C6 alkyl group which may be substituted with halogen or a phenyl group which may have a substituent selected from the above described ⁇ group, and more preferably methyl group, 2,2,2-trifluoroethyl group, 2,2-difluoroethyl group, 2-(phenyl)propyl group, 2-(phenyloxy)ethyl group, 2-butynyl group, 3-fluorophenyl group, 4-fluorophenyl group or 4-methoxyphenyl group, and more preferably methyl group, 2,2,2-trifluoroethyl group or 2,2-difluoroethyl group, and most preferably methyl group.
• R 2 is a hydrogen atom, methyl group, ethyl group, or propyl group, and more preferably a hydrogen atom or methyl group.
• R 3 is preferably a methyl group.
• R 4 is preferably a methyl group.
• the structural formula of a compound may represent a particular isomer in this specification for convenience sake, the present invention encompasses all the isomers including geometric isomers, optical isomers, stereoisomers and tautomer, and mixtures of isomers generated by the structure of the compound, and the compound is not limited to the particular formula described for convenience sake and may be either one of the isomer or a mixtures of isomers. Therefore, the compound of the present invention, which may be an optically active object and racemate, is not limited to a particular one and may include either one. Similarly, crystal polymorphism which may exist is not limited, and the crystal may comprise a single crystal form or may be a mixture, and the compound of the present invention may include an anhydride as well as a hydrate.
• metabolite which is generated by the decomposition of Compound (1) of the present invention in a living body is also included by the present invention.
• prodrug which will lead to Compound (1) of the present invention through metabolism such as oxidization, reduction, hydrolysis and conjugation in a living body is also included by the present invention.
• the compound of the present invention forms a salt in the above described general formula (1) at 1- or 3-position NH group in the imidazopyridine skeleton.
• the “salt” is not particularly limited as long without any treatment is pharmacologically acceptable, and includes, for example, an inorganic base salt or an organic base salt.
• inorganic base salt examples include alkaline metal salts such as sodium salt and potassium salt, alkaline-earth-metals salts such as calcium salt or magnesium salt, aluminum salt or ammonium salt, and preferable examples of organic base salt include diethylamine salt, diethanolamine salt, meglumine salt or N,N′-dibenzylethylenediamine salt, etc.
• Preferable compounds among the specific compounds of the present invention, or a salt thereof or a hydrate thereof are 5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine, 2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine, or 5-(2,2-difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine, or a salt thereof or a hydrate thereof (especially a sodium salt thereof).
• the compound of the present invention Since the compound of the present invention has excellent gastric acid secretion inhibitory activity, more sustainable gastric acid secretion inhibitory activity, higher safety (for example, causing less induction of cytochrome P450) and more suitable physicochemical stability, it is useful as a pharmaceutical agent, particularly a therapeutic or preventive agent for acid related diseases and a mono therapeutic or combination therapeutic agent for the eradication of Helicobacter Pylori.
• the compound of the present invention can be produced by the process indicated below. However, process for producing the compound the present invention is not limited thereto.
• Compound (1) of the present invention can be produced by the following Process A.
• R 1 , R 2 , R 3 , R 4 and R 5 represent the same as defined above, and X 1 represents a leaving group and is preferably an alkylsulfonyloxy group which may be substituted or a benzenesulfonyloxy group which may be substituted (for example, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy group, etc.) or a chlorine atom, a bromine atom or an iodine atom, and more preferably a chlorine atom and a methanesulfonyloxy group.
• X 1 represents a leaving group and is preferably an alkylsulfonyloxy group which may be substituted or a benzenesulfonyloxy group which may be substituted (for example, methanesulfonyloxy, ethanesulfon
• This step is a step where Compound (2) and Compound (3) or a salt thereof (particularly, a hydrochloride salt) is made to react in the presence or absence of a base, in the absence of a solvent or in an inert solvent to produce Compound (4).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; N,N-dimethylformamide; dimethylsulfoxide; water; or mixtures of these solvents, and is preferably alcohols and most preferably m
• the usable base includes, for example, inorganic bases such as sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide; and organic bases such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethyl aniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undeca-7-ene
• reaction temperature may vary depending on starting materials, solvent and base catalyst, it is typically 0 to 100° C., and is preferably 10 to 40° C.
• reaction time may vary depending on starting materials, solvent, base catalyst and reaction temperature, it is typically 30 minutes to 20 hours, and is preferably 1 to 8 hours.
• This step is a step where an oxidizing reagent is made to react with Compound (4) in the absence of a solvent or in an inert solvent to produce Compound (1) of the present invention.
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; aromatic hydrocarbons such as benzene, toluene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, and is preferably an aromatic hydrocarbon, an alcohol or a mixture of these solvents, and most preferably is a mixture of toluene and
• the usable oxidizing reagent includes, for example, aqueous hydrogen peroxide solution, t-butyl hydroperoxide, sodium periodate, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, urea-hydrogen peroxide addition compound ((NH 2 ) 2 CO.H 2 O 2 ), etc., and it is preferably metachloroperbenzoic acid.
• a commonly used asymmetric oxidizing agent can also be used.
• reaction temperature may vary depending on starting materials, solvent, and oxidizing reagents, typically, it is ⁇ 100 to 100° C., and preferably ⁇ 70 to 70° C.
• reaction time may vary depending on starting materials, solvent, oxidizing reagent and reaction temperature, it is typically 30 minutes to 24 hours, and is preferably 1 to 5 hours.
• the compound obtained above can be converted to a salt by an ordinary method.
• a base is made to react with Compound (1) in the absence of a solvent or in an inert solvent.
• An alcohol such as methanol or ethanol, water or a mixture of these solvents, preferably a mixture of ethanol and water is used as a solvent
• an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, an alkaline-earth-metals hydroxide such as magnesium hydroxide, an alkoxide such as sodium methoxide, sodium t-butoxide and magnesium methoxide, preferably sodium hydroxide
• the reaction temperature is ⁇ 50 to 50° C., and is preferably 10 to 40° C.
• the reaction time is 5 minutes to 2 hours, and is preferably 10 to 30 minutes.
• Compound (2) and compound (3) which are intermediates in the above described Process A may be commercial products or easily produced from commercial products by a process which those skilled in the art usually employs, and they can also be produced by Processes B, C, D or E described below.
• Compound (2) can be produced by the following Process B.
• R 1 and R 2 represent the same as defined above, and R 2a represents a methyl group, vinyl group or allyl group, and X 2 represents a leaving group, preferably a chlorine atom, a bromine atom or an iodine atom, and more preferably a chlorine atom.
• X 3 represents a leaving group, preferably a chlorine atom, a bromine atom or an iodine atom, and more preferably an iodine atom.
• This step is a step where ammonia is made to react with Compound (4) in the presence or absence of an alkaline metal carbonate, in the absence of a solvent or in an inert solvent, to produce Compound (5).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide; t-butyl alcohol, water, etc., and is preferably a mixture of t-butyl alcohol and water or a mixture of N,N-dimethylformamide and water.
• aliphatic hydrocarbons such as he
• the usable alkaline metal carbonate includes, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc., and is preferably potassium carbonate.
• reaction temperature may vary depending on starting materials, solvent, and alkaline metal carbonate, it is typically 0 to 100° C., and is preferably 40 to 80° C.
• reaction time may vary depending on starting materials, solvent, alkaline metal carbonate, and reaction temperature, it is typically 6 to 48 hours and is preferably 12 to 36 hours.
• Step B-2 R 1 —O Group Introducing Reaction
• Reaction conditions may be changed depending on the type of R 1 —OH.
• This step is a step where Compound (5) and alcohol R 1 —OH (wherein R 1 represent the same as defined above) are made to react in the presence of a base in the absence of a solvent or in an inert solvent to produce Compound (6).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, alcohols which form the desired R 1 —O— such as methanol and ethanol; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, N-methylpyrrolidone; dimethylsulfoxide, water, or a mixture
• the usable base includes, for example, alkaline metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkaline metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium-t-butoxide; alkaline metal hydrides such as sodium hydride, potassium hydride; alkaline metal alkoxides prepared from alkaline metals; n-butyl lithium, lithium diisopropylamide, etc., and it is preferably an alkaline metal hydride and most preferably sodium hydride.
• reaction temperature may vary depending on starting materials, solvent, and bases, it is typically 0 to 100° C., and when R 1 —OH is a primary alcohol, it is 10 to 40° C., and in the case of secondary alcohol, it is 50 to 100° C.
• reaction time may vary depending on starting materials, solvent, base, and reaction temperature, it is typically 6 to 48 hours and is preferably 12 to 24 hours.
• This step is a step where Compound (5) and a phenol R 1 —OH (wherein R 1 represent the same as defined above) are made to react in the presence of a palladium catalyst, ligand, and an alkaline metal phosphate in the absence of a solvent or in an inert solvent to produce Compound (6).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene;
• the usable palladium catalyst includes, for example, a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-t-butylphosphine)palladium(0), palladium black; a palladium catalyst precursor (which generates a palladium catalyst within a system) such as dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II), dichlorobis(tri-o-tolylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II) etc., and is preferably palladium(II) acetate.
• the usable ligand includes, for example, triphenylphosphine, tri-t-butylphosphine, tri(4-methylphenyl)phosphine, 2-(di-t-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, di-t-butylphosphoniumtetrafluoroborate, etc., and is preferably 2-(di-t-butylphosphino)biphenyl.
• the usable alkaline metal phosphate includes, for example, sodium phosphate, potassium phosphate, etc., and is preferably potassium phosphate.
• reaction temperature may vary depending on starting materials, solvent, palladium catalysts, etc., it is typically 50 to 200° C., and preferably 120 to 180° C.
• reaction time may vary depending on starting materials, solvent, palladium catalyst, reaction temperature, etc., it is typically 6 to 48 hours and is preferably 12 to 24 hours.
• This step is a step where a brominating agent or an iodizing agent is made to react with Compound (6) in the absence of a solvent or in an inert solvent to produce Compound (7).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitrile such as ace
• the usable brominating or iodizing agent includes, for example, bromine (Br 2 ), iodine (I 2 ), N-bromosuccinimide, N-iodosuccinimide, etc., and is preferably N-iodosuccinimide or N-bromosuccinimide.
• reaction temperature may vary depending on starting materials, solvent, brominating or iodizing agent, it is typically 0 to 60° C., and preferably 10 to 40° C.
• reaction time may vary depending on starting materials, solvent, brominating agent or iodizing agent, reaction temperature, etc., it is typically 2 to 24 hours and preferably 5 to 24 hours.
• This step is a step where Compound (7) and a desired trialkylboroxin are made to react in the presence of a palladium catalyst and a base in the absence of a solvent or in an inert solvent to produce Compound (8).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as dioxane, dimethoxyethane, tetrahydrofuran; amides such as N,N-dimethylformamide, and it is preferably tetrahydrofuran or N,N-dimethylformamide.
• aromatic hydrocarbons such as benzene, toluene, xylene
• ethers such as dioxane, dimethoxyethane, tetrahydrofuran
• amides such as N,N-dimethylformamide, and it is preferably tetrahydrofuran or N,N-dimethylformamide.
• the usable palladium catalyst includes, for example, a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-t-butylphosphine)palladium(0), palladium black, etc., and preferably dichlorobis(triphenylphosphine)palladium(II) or tetrakis(triphenylphosphine)palladium(0).
• a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)
• the usable base includes, for example, bases such as potassium t-butoxide, sodium t-butoxide, cesium carbonate, and preferably cesium carbonate.
• reaction temperature may vary depending on starting materials, solvent, palladium catalysts, etc., it is typically 50 to 200° C., and preferably 70 to 150° C.
• reaction time may vary depending on starting materials, solvent, palladium catalyst, reaction temperature, etc., it is typically 30 minutes to 48 hours, and preferably 5 to 12 hours.
• This step is a step where Compound (7) and tributyl (vinyl) tin or allyltributyltin are made to react in the presence of a palladium catalyst in the absence of a solvent or in an inert solvent to produce Compound (8).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as dioxane, dimethoxyethane, tetrahydrofuran; amides such as N,N-dimethylformamide, and it is preferably tetrahydrofuran or N,N-dimethylformamide.
• aromatic hydrocarbons such as benzene, toluene, xylene
• ethers such as dioxane, dimethoxyethane, tetrahydrofuran
• amides such as N,N-dimethylformamide, and it is preferably tetrahydrofuran or N,N-dimethylformamide.
• the usable palladium catalyst includes, for example, a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-t-butylphosphine)palladium(0), palladium black, etc., and preferably dichlorobis(triphenylphosphine)palladium(II) or tetrakis(triphenylphosphine)palladium(0).
• a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)
• reaction temperature may vary depending on starting materials, solvent, palladium catalysts, etc., it is typically 50 to 200° C., and preferably 70 to 150° C.
• reaction time may vary depending on starting materials, solvent, palladium catalyst, reaction temperature, etc., it is typically 30 minutes to 48 hours, and is preferably 5 to 12 hours.
• This step is a step where hydrogen is made to react with Compound (8) in the absence of a solvent or in an inert solvent, in the presence of a reduction catalyst, or a reducing agent is made to react with Compound (8) in the absence of a solvent or in an inert solvent, and a nitro group and an alkenyl group is converted into an amino group and an alkyl group.
• step where when R 1 is a C2-C6 alkynyl group, only a nitro group is reduced without reducing the triple bond.
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; organic acid esters such as ethyl acetate, and preferably ethers, aliphatic hydrocarbons, alcohols, organic acid ester, or a mixture of these, and
• the usable catalyst includes, for example, palladium-carbon, Raney nickel, nickel (II) chloride, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, etc., and preferably palladium/carbon or nickel (II) chloride.
• a reduction catalyst can also be used in an amount of the weight ratio to the materials of about 1/2.
• reaction temperature in the case of using a reduction catalyst may vary depending on starting materials and solvents, it is typically 0 to 60° C., and preferably 10 to 40° C.
• reaction time in the case of using a reduction catalyst may vary depending on starting materials, solvent, and reaction temperature, it is typically 1 to 60 hours and preferably 5 to 24 hours.
• the hydrogen pressure at the time of the reaction in the case of using a reduction catalyst is 0.5 to 5 atm, and preferably 1 to 2 atm.
• nickel (II) chloride is used as a catalyst and the reaction can be performed with sodium borohydride, etc., at ⁇ 30 to 40° C. (preferably ⁇ 15 to 25° C.) for 30 minutes to 1 hour.
• reaction when R 1 is a C2-C6 alkynyl group, and in the case that only the nitro group is reduced without reducing the triple bond, the reaction can be performed using iron-hydrochloric acid, zinc-acetic acid, iron-ammonium chloride, etc., at 0 to 30° C. for 10 to 50 hours.
• the compound obtained at the B-5 step can be used in the following B-6 step by merely filtering the catalyst off.
• This step is a step where carbon bisulfide is made to react with the compound obtained at the above described B-5 step in the absence of a solvent or in an inert solvent to produce Compound (2) which is an intermediate in the above described Process A.
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; amides such as formamide, N,N-dimethylformamide
• reaction temperature may vary depending on starting materials and solvent, it is typically 0 to 60° C., and preferably 10 to 40° C.
• reaction time may vary depending on starting materials, solvent, and reaction temperature, it is typically 12 to 60 hours and preferably 24 to 48 hours.
• This step is a step where ammonia is made to react with Compound (4a) in the presence or absence of alkaline metal carbonate in the absence of a solvent or in an inert solvent to produce Compound (6).
• This step can be performed according to the B-1 step.
• Compound (2a) in which R 2 of Compound (2) is methyl group can be produced by the following Process C.
• R 1 is as defined above, X 4 represents a leaving group, preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and more preferably a fluoride atom.
• This step is a step where Compound (9), and an alcohol or phenol R 1 —OH (wherein R 1 is as defined above) is made to react with produce Compound (10).
• This process can be performed according to the above described B-2 step.
• This step is a step where fuming nitric acid is made to react with Compound (10) in the presence or absence of concentrated sulfuric acid, in the absence of a solvent to produce Compound (11).
• reaction temperature may vary depending on starting materials and solvent, it is typically ⁇ 20 to 100° C., and more preferably 0 to 80° C.
• reaction time may vary depending on starting materials, solvent, and reaction temperature, it is typically 6 to 48 hours and preferably 7 to 36 hours.
• This step is a step where hydrogen is made to react with Compound (11) in the presence of a reduction catalyst in the absence of a solvent or in an inert solvent to produce Compound (12). This process can be performed according to the above described step B-5.
• This step is a step where Compound (12) is made to react in an anhydrous acetic acid at 0 to 40° C. for 1 to 10 hours to obtain a compound converted into N-acetyl form (Step C-4-1), subsequently fuming nitric acid is made to react with Compound (12) in the presence or the absence of concentrated sulfuric acid, in the absence of a solvent at 0 to 40° C. for 1 to 10 hours to obtain Compound (13) (Step C-4-2), and further, the compound obtained at the preceeding step is made to react with an alkaline metal hydroxide such as sodium hydroxide in an alcohol such as methanol and ethanol or a mixture of the alcohol and water at 0 to 40° C. for 5 to 30 minutes to produce Compound (13).
• an alkaline metal hydroxide such as sodium hydroxide in an alcohol such as methanol and ethanol or a mixture of the alcohol and water at 0 to 40° C. for 5 to 30 minutes to produce Compound (13).
• This step is a step where hydrogen gas is made to react with Compound (13) in the presence of a reduction catalyst in the absence of a solvent or in an inert solvent, to convert a nitro group into an amino group.
• This process can be performed according to the above described step B-5.
• This step is a step where carbon bisulfide is made to react with the compound obtained at the above described step C-5 in the absence of a solvent or in an inert solvent to produce Compound (2a) in which R 2 is methyl group among the intermediates of the above described Process A.
• This process can be performed according to the above described step B-6.
• Compound (3a) in which R 3 of Compound (3) is ethyl group can be produced by the following Process D.
• R 4 , R 5 and X 1 represent the same as defined above, Y 1 represents a trialkylsilyl group, preferably trimethylsilyl group and X 6 represents an alkylsulfonyl group which may be substituted with a halogen atom or a benzene sulfonyl group which may be substituted (for example, with trifluoromethanesulfonyl, methanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl group, etc.).
• This step is a step where Compound (14) and a leaving group introduction agent are made to react in the presence of a base in the absence of a solvent or in an inert solvent to produce Compound (15).
• Compound (14) a commercially available compound or a compound synthesized based on a process known by publication can be used.
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; aromatic, hydrocarbon such as benzene, toluene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, pyridine, etc., and preferably a halogenated hydrocarbon and most preferably dichloromethane.
• halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride
• aromatic, hydrocarbon such
• the usable leaving group introduction agent includes, for example, sulfonyl halides such as methanesulfonylchloride, p-toluenesulfonylchloride, trifluoromethanesulfonylchloride, N-phenyl-bis(trifluoromethanesulfonimide), and preferably N-phenyl-bis(trifluoromethanesulfonimide).
• sulfonyl halides such as methanesulfonylchloride, p-toluenesulfonylchloride, trifluoromethanesulfonylchloride, N-phenyl-bis(trifluoromethanesulfonimide), and preferably N-phenyl-bis(trifluoromethanesulfonimide).
• the usable base includes, for example, tertiary alkylamines such as trimethylamine and triethylamine, pyridines, etc., and it is preferably triethylamine.
• reaction temperature may vary depending on starting materials, solvent, leaving group introduction agent and bases, it is typically 0 to 100° C., and preferably 0 to 40° C.
• reaction time may vary depending on starting materials, solvent, leaving group introduction agent, base, and reaction temperature, it is typically 6 to 48 hours and preferably 12 to 30 hours.
• This step is a step where Compound (15) and (trialkylsilyl)acetylene are made to react in the presence of a palladium catalyst, a copper catalyst and a base in the absence of a solvent or in an inert solvent, and under nitrogen atmosphere to produce Compound (16).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, pyridine, etc., and preferably an amide and most preferably N,N-dimethylformamide.
• ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether
• amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, pyridine, etc., and preferably an amide and most preferably N,N-dimethylform
• the usable palladium catalyst includes, for example, dichlorobis(triphenylphosphine)palladium(0), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-t-butylphosphine)palladium(0), palladium black, etc., and preferably dichlorobis(triphenylphosphine)palladium(0).
• the usable copper catalyst includes, for example, copper (powder), copper(I) chloride, copper(II) chloride, copper(I) iodide, copper(I) oxide, copper(II) oxide, copper(II) acetate, copper(II) sulfate pentahydrate, copper(II) acetylacetonate, copper(I) thiocyanate, etc., and preferably copper(I) iodide.
• the usable base includes, for example, N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethyl aniline, N,N-diethyl aniline, 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) etc., and it is preferably triethylamine.
• the usable (trialkylsilyl)acetylene includes, for example, (trimethylsilyl)acetylene, (triethylsilyl)acetylene, etc., and it is preferably (trimethylsilyl)acetylene.
• reaction temperature may vary depending on starting materials, solvent, a palladium catalyst, copper catalyst, base and (trialkylsilyl)acetylene, it is typically 10 to 100° C., and preferably 30 to 80° C.
• reaction time may vary depending on starting materials, solvent, palladium catalyst, copper catalyst, base, (trialkylsilyl)acetylene and reaction temperature, it is typically 10 minutes to 4 hours, and preferably 30 minutes to 3 hours.
• This process consists of the following 2 reaction steps.
• This step is a step where a desilylating agent was made to react to Compound (16) in the absence of a solvent or in an inert solvent to produce a desilylated compound.
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide,
• the usable desilylating agent includes, for example, hydrogen fluoride, tetrabutylammonium fluoride, etc., and it is preferably tetrabutylammonium fluoride.
• reaction temperature may vary depending on starting materials, solvent, and desilylating agent, it is typically 0 to 100° C., and preferably 10 to 40° C.
• reaction time may vary depending on starting materials, solvent, and desilylating agent, it is typically 30 minutes to 6 hours, and preferably 2 to 3 hours.
• the compound obtained in this step may be a low boiling point compound, and in that case, the solution is typically used for the subsequent process without any treatment of concentration after reaction, extraction, column chromatography, etc.
• This step is a step where hydrogen gas is made to react with the compound obtained at the above described step (1) in the presence of a reduction catalyst in an inert solvent to produce Compound (17).
• This process can be performed according to the above described step B-2.
• the reduction catalyst is typically used in a weight ratio of about 5-10% to the compound obtained at the above described step (1).
• This step is a step where an oxidizing reagent is made to react with Compound (17) in the absence of a solvent or in an inert solvent to produce Compound (18).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide; organic acids such as acetic acid, etc., and it is preferably an organic acid and most preferably acetic acid.
• aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum
• the usable oxidizing reagent includes, for example, hydrogen peroxide, t-butyl hydroperoxide, sodium periodate, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, urea-hydrogen peroxide addition compound, etc., and it is preferably hydrogen peroxide or urea-hydrogen peroxide addition compound.
• urea-hydrogen peroxide addition compound it is usually desirable to use the compound along with anhydrous trifluoroacetic acid and the like.
• reaction temperature may vary depending on starting materials, solvent, and oxidizing reagent, it is typically 30 to 150° C., and preferably 50 to 100° C.
• reaction time may vary depending on starting materials, solvent, oxidizing reagent and reaction temperature, it is typically 12 to 60 hours and preferably 24 to 36 hours.
• This step is a step where fuming nitric acid is made to react with Compound (18) in the absence or presence of concentrated sulfuric acid in the absence of a solvent or in an inert solvent to produce Compound (19).
• This step can be performed according to the above described step C-2.
• This step is a step where an alcoholic R 4 —OH (wherein R 4 is as defined above) is made to react with Compound (19) in the presence of a base in the absence of a solvent or in an inert solvent to produce Compound (20).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide,
• the usable base includes, for example, alkaline metal alkoxide such as sodium methoxide and sodium ethoxide, and it is preferably sodium alkoxide (desired R 4 —ONa).
• reaction temperature may vary depending on starting materials, solvent and base, it is typically 0 to 100° C., and preferably 10 to 60° C.
• reaction time may vary depending on the starting materials, solvent, base and reaction temperature, it is typically 5 to 24 hours and preferably 8 to 14 hours.
• This step is a step where anhydrous acetic acid is made to react with Compound (20) in the absence of a solvent to produce an acetic acid ester of Compound (21).
• reaction temperature may vary depending on starting materials and solvent, it is typically 20 to 150° C., and preferably 50 to 100° C.
• reaction time may vary depending on starting materials, solvent and reaction temperature, it is typically 10 minutes to 3 hours, and preferably 1 to 2 hours.
• the residue after the reaction obtained by evaporating anhydrous acetic acid is typically used for the subsequent step without any treatment.
• This step is a step where a base is made to react with the compound obtained at the above described step D-7 process in the absence of a solvent or in an inert solvent to produce Compound (21).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, water; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, di
• the usable base includes, for example, alkaline metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkaline metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide; metal alkoxide such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide; ammonia such as aqueous ammonia solution, concentrated ammonia-methanol, etc., and it is preferably an alkaline metal hydroxide and most preferably sodium hydroxide.
• alkaline metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate
• alkaline metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide
• metal alkoxide such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide
• ammonia such as aqueous ammonia solution, concentrated ammonia-methanol, etc.
• reaction temperature may vary depending on starting materials, solvent and base, it is typically 0 to 60° C., and preferably 10 to 40° C.
• reaction time may vary depending on the starting materials, solvent, base and reaction temperature, it is typically 10 minutes to 2 hours, and preferably 30 minutes to 1 hour.
• This step is a step where a chlorinating agent is made to react with Compound (21) in the absence of a solvent or in an inert solvent to produce Compound (3a) in which R 3 is an ethyl group among the intermediates of the above described Process A.
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, and it is preferably a halogenated hydrocarbon and most preferably dichloromethane.
• halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, and it is preferably a halogenated hydrocarbon and most preferably dichloromethane.
• the usable chlorinating agent includes, for example, chlorine, oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc., and it is preferably thionyl chloride.
• reaction temperature may vary depending on starting materials, solvent and chlorinating agents, it is typically ⁇ 20 to 30° C., and preferably 0 to 10° C.
• reaction time may vary depending on starting materials, solvent, chlorinating agent and reaction temperature, it is typically 30 minutes to 6 hours, and preferably 1 to 2 hours.
• Compound (3a) of this step can be obtained as a hydrochloride salt, and can also be used without any treatment.
• This step is a step where Compound (21) and a leaving group introduction agent are made to react in the presence of base in the absence of a solvent or in an inert solvent to produce Compound (3a) in which R 2 is methyl group.
• This step can be performed such as the above described step D-1.
• R 1b is as defined above, and X 5 represents a leaving group and is a chlorine atom, a bromine atom or an iodine atom, and preferably a chlorine atom.
• This step is a step where an oxidizing reagent is made to react with Compound (22) or Compound (22a) in the absence of a solvent or in an inert solvent to produce Compound (23) or Compound (23a).
• This step can be performed according to the above described step D-4.
• Step E-2 Leaving Group Introduction Reaction (Illustrated by Chlorination Reaction as a Representative Reaction)
• This step is a step where a chlorinating agent is made to react with Compound (23) or Compound (23a) in the presence of a base in the absence of a solvent or in an inert solvent to produce Compound (24).
• the usable solvent is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, and includes, for example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, and it is preferably a halogenated hydrocarbon and most preferably dichloromethane.
• halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, and it is preferably a halogenated hydrocarbon and most preferably dichloromethane.
• the usable base includes, for example, N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethyl aniline, N,N-diethyl aniline, 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), etc., and it is preferably triethylamine.
• the usable chlorinating agent includes, for example, chlorine, oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc., and it is preferably thionyl chloride.
• reaction temperature may vary depending on starting materials, solvent and chlorinating agents, it is typically ⁇ 20 to 30° C., and preferably 0 to 10° C.
• reaction time may vary depending on starting materials, solvent, chlorinating agent and reaction temperature, it is typically 30 minutes to 6 hours, and preferably 1 to 2 hours.
• This step is a step where fuming nitric acid is made to react with Compound (24) in the absence or presence of concentrated sulfuric acid in the absence of a solvent to produce Compound (25).
• This process can be performed according to the above described step C-2.
• This step is a step where aqueous ammonia solution is made to react with Compound (25) in the presence of alkaline metal carbonate in the absence of a solvent or in an inert solvent to produce Compound (26).
• This step can be performed according to the above described step B-1.
• This step is a step where Compound (26) and an alcohol or phenol R 1 —OH (wherein R 1 is as defined above) is made to react, to produce Compound (27).
• This step can be performed according to the above described step B-2.
• This step is a step where hydrogen is made to react with Compound (27) in the presence of a reduction catalyst in the absence of a solvent or in an inert solvent, and a nitro group is converted to an amino group.
• This step can be performed according to the above described step B-5.
• This step is a step where carbon bisulfide is made to react with the compound obtained at the above described step B-5 in the absence of a solvent or in an inert solvent to produce Compound (2b) in which R 2 is methyl group among the intermediates of the above described Process A.
• This step can be performed according to the above described step B-6.
• the object compound of each step can be extracted from the reaction mixture according to ordinary process after each step of each of the above processes is ended.
• the reaction mixture when the whole reaction mixture is a liquid, the reaction mixture is optionally allowed to be cooled to room temperature or ice-cooled, and the acid, alkali, oxidizing reagent, or reducing agent is suitably neutralized, and an organic solvent which is immiscible like water and ethyl acetate and does not react with the object compound is added, and the layer containing the object compound is separated.
• an organic solvent which is immiscible like water and ethyl acetate and does not react with the object compound is added, and the layer containing the object compound is separated.
• a solvent which does not mix with the obtained layer and does not react with the object compound is added, the layer containing the object compound is washed, and the layer concerned is separated.
• the layer concerned is an organic layer, it can be dried using a drying agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate, and the object compound can be taken out by evaporating the solvent. If the layer concerned is an aqueous layer, after it is electrically desalted, the object compound can be obtained by freeze-drying.
• a drying agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate
• the object compound in the case that the whole reaction mixture is a liquid, and if possible, the object compound can be taken out only by evaporating substances other than the object compound (for example, solvent, reagents, etc.) under ordinary or reduced pressure.
• the object compound when only the object compound has precipitated as a solid, or when the above described whole reaction mixture is a liquid and only the object compound has precipitated as a solid in process of obtaining the compound, first, the object compound is taken out by filtering method and the obtained object compound is washed with a suitable organic or inorganic solvent, and then dried, and the mother liquid is treated just like the above described case where the whole reaction mixture is a liquid to further obtain the object compound.
• the reagent or catalyst when only a reagent or catalyst exists as a solid, or when the above described whole reaction mixture is a liquid and only a reagent or catalyst precipitates as a solid in process of extraction and the object compound is dissolving in the solution, the reagent or catalyst is first filtered off by the filtering method, and the object compound is washed with a suitable organic or inorganic solvent, and the resulting washing liquid is combined with the mother liquid, and the resulting mixed solution is treated just like the above described case where the whole reaction mixture is a liquid to obtain the object compound.
• the reaction mixture can also be used without any treatment for the subsequent step without particularly isolating the object compound.
• recrystallization method For the purpose of improving the purity of the object compound extracted by the above described method, recrystallization method, various chromatography methods, and distillation method can be suitably performed.
• the purity of the object compound can typically be improved by recrystallization method.
• a single solvent or two or more mixtures which do not react with the object compound can be used.
• the object compound is first dissolved in a single or multiple solvents which do not react with the object compound at room temperature or under heating.
• the resulting mixed solution is cooled with iced water or allowed to leave at room temperature, and the object compound is allowed to recrystallize from the mixed solution.
• the purity of the object compound can be improved by various chromatography methods.
• weak acidic silica-gels such as Silica Gel 60 produced by Merck Co. (70-230 mesh or 340-400 mesh) or BW-300 produced by Fuji Silysia Chemical Co., Ltd. (300 mesh) can be used.
• the object compound has basic properties, and the above described silica gels are excessively adsorptive, propylamine coating silica gel (200-350 mesh) by Fuji Silysia Chemical Co., Ltd. etc., can also be used.
• the object compound has bipolarity, or when it is required to be eluted with a high polarity solvent such as methanol, NAM-200H or NAM-300H produced by NAMU Research Institute can also be used.
• a high polarity solvent such as methanol, NAM-200H or NAM-300H produced by NAMU Research Institute can also be used.
• the object compound whose purity is improved can be obtained by using these silica gels and eluting the object compound with a single or multiple solvents which do not react with the object compound, and evaporating the solvent.
• the purity of the object compound can be improved also by distillation method.
• the object compound can be distilled under reduced pressure at room temperature or under heating in the distillation method.
• various isomers for example, geometric isomer, optical isomer, rotational isomer, stereoisomer, tautomer, etc.
• obtainable for Compound (1) of the present invention can be purified and isolated by using usual separation means, for example, recrystallization, diastereomer salt method, enzymatic dividing method, and various chromatography (for example, thin layer chromatography, column chromatography, gas chromatography, etc.).
• suitable additive agents are mixed with the compound of the present invention to form preparation.
• this does not deny the use of the compound of the present invention without any treatment as a drug.
• additive agent generally used for drugs, excipient, binder, lubricant, disintegrating agent, colorant, flavor, emulsifier, surfactant, dissolution auxiliary agent, suspending agent, isotonizing agent, buffering agent, antiseptic, anti-oxidizing agent, stabilizing agent, absorption improver, etc. can be mentioned, and these can also be optionally used in a suitable combination.
• excipients examples include lactose, sucrose, glucose, cornstarch, mannitol, sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminometasilicate, calcium hydrogen phosphate, etc.
• binder examples include polyvinyl alcohol, methyl cellulose, ethyl cellulose, gum arabic, gum tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, macrogol, etc.
• Examples of the above described lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, colloidal silica, etc.
• disintegrating agent examples include crystal cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, low substituted hydroxypropylcellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch, carboxymethyl starch sodium, etc.
• Examples of the above described colorant include those permitted to add to drugs such as iron sesquioxide, yellow iron sesquioxide, carmine, caramel, beta-carotene, titanium oxide, talc, riboflavin sodium phosphate, and yellow aluminum lake.
• drugs such as iron sesquioxide, yellow iron sesquioxide, carmine, caramel, beta-carotene, titanium oxide, talc, riboflavin sodium phosphate, and yellow aluminum lake.
• Examples of the above described flavor include cocoa powder, peppermint, aromatic powder, peppermint oil, camphol, cinnamon powder, etc.
• emulsifier or surfactant examples include stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, glyceryl monostearate, sucrose fatty acid ester, glycerin fatty acid ester, etc.
• dissolution auxiliary agent examples include polyethylene glycol, propylene glycol, benzoic acid benzyl ester, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, Polysorbate 80, nicotinamide, etc.
• suspending agent examples include, besides the above described surfactant, hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose.
• hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose.
• Examples of the above described isotonizing agent include glucose, sodium chloride, mannitol, sorbitol, etc.
• buffering agent examples include buffer solution such as phosphate, acetate, carbonate, citrate, etc.
• antiseptic examples include methylparaben, propyl paraben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
• anti-oxidizing agent examples include sulfurous acid salt, ascorbic acid, alpha-tocopherol, etc.
• Examples of the above described stabilizing agent include those generally used for drugs.
• Examples of the above described absorption improver include those generally used for drugs.
• oral agent such as tablet, powder drug, granule agent, capsule agent, syrup agent, troche agent, and inhalation agent
• external preparations such as suppository, ointment, eye ointment, tapes, eye drop, nose drop, ear drop, pap agent, lotion or an injection agent.
• the above described oral agent is prepared by suitably combining the above described additives.
• the surface of it may be coated if needed.
• the above described external preparations is prepared by suitably combining the above described additives, particularly excipient, binder, flavor, emulsifier, surfactant, dissolution auxiliary agent, suspending agent, isotonizing agent, antiseptic, anti-oxidizing agent, stabilizing agent or absorption improver.
• injection agent prepared by suitably combining the above described additives, particularly emulsifier, surfactant, dissolution auxiliary agent, suspending agent, isotonizing agent, buffering agent, antiseptic, anti-oxidizing agent, stabilization agent or absorption improver.
• the dosage varies depending on condition or age, and typically, 0.15 to 5000 mg (preferably 0.5 to 1500 mg) in the case of oral agent, 0.5 to 1500 mg (preferably 1.5 to 500 mg) in the case of external preparation, 0.3 to 5000 mg (preferably 1 to 500 mg) for one time or divided to 2 to 6 times per day in the case of injection agent.
• 0.15 to 5000 mg preferably 0.5 to 1500 mg
• 0.5 to 1500 mg preferably 1.5 to 500 mg
• external preparation preferably preferably 1 to 500 mg for one time or divided to 2 to 6 times per day in the case of injection agent.
• Compound (1) of the present invention can be produced, for example, by the process indicated in the following Examples, and the effect of the compound can be confirmed by the method indicated for the following Test Examples. However, they are illustrative and present invention are not limited to these specific examples below in any case.
• 6-Methoxy-5-methyl-2-nitro-3-pyridineamine (5.40 g, 29.5 mmol) was dissolved in methanol (300 ml), 10% Pd-on-carbon powder (50% water content article) (2.73 g) was added, and the reaction mixture was stirred under hydrogen atmosphere for 5 hours and 25 minutes. After the reaction was completed, the reaction mixture was filtered, carbon bisulfide (110 ml) was added, and stirred at room temperature for 65 hours and 40 minutes under nitrogen atmosphere, and the solvent was evaporated, thereby yielding the title compound (5.59 g, 28.6 mmol, 97.1%) as a brown solid.
• 2,2,2-Trifluoroethanol (340 mg, 3.4 mmol) was dissolved in the tetrahydrofuran (10 ml), sodium hydride (60%) (120 mg, 3.0 mmol) was added thereto, and the reaction mixture was stirred for 30 minutes at room temperature under nitrogen atmosphere.
• a solution of 6-chloro-5-methyl-3-nitro-2-pyridineamine crude product (400 mg) in tetrahydrofuran (10 ml) was dropped, and the reaction mixture was stirred at room temperature for 2.5 days. Water was added to the reaction solution and extracted with ethyl acetate, and after washed with a sodium bicarbonate solution, dried over magnesium sulfate.
• 6-Methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine-2-thol (238 mg, 0.90 mmol) and 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride salt (243 mg, 1.17 mmol) was dissolved in methanol (20 ml), sodium hydroxide (218 mg, 5.45 mmol) was added thereto, and the mixture was stirred at room temperature overnight. An ammonium chloride solution was added, and the mixture was extracted with chloroform (100 ml), and dried over magnesium sulfate.
• 6-(2,2-Difluoroethoxy)-5-methyl-3-nitro-2-pyridineamine (685 mg, 3.07 mmol) was dissolved in methanol (30 ml), 10% Pd-on-carbon powder (50% water content article) (300 mg) was added thereto, and the reaction mixture was stirred under hydrogen atmosphere for 2 hours and 30 minutes. After the reaction was completed, the mixture was filtered through celite, carbon bisulfide (7 ml) was added, and the mixture was stirred at room temperature under nitrogen atmosphere for 2.5 days. Thereafter, the solvent was evaporated to yield the title compound (700 mg, 2.85 mmol) as a purple gray solid.
• Test compounds were dissolved or suspended in 0.5% methyl-cellulose solution (solvent) and prepared the concentration of 5 mg/ml. Histamine was dissolved in brine (solvent) and prepared the concentration of 10 mg/ml. 0.5% methyl-cellulose solution or test compound solution (10 mg/kg) in a volume of 0.2 ml per 100 g body weight was injected into the duodenum at the time of ligation, and then histamine solution (20 mg/kg) in a volume of 0.2 ml per 100 g body weight was administered subcutaneously. Then the abdomen was sutured.
• HS medium was replaced with Hepato-STIM (trademark, BD Biosciences) supplemented with EGF, penicillin (100U/mL), streptomycin (100 ⁇ g/mL) and glutamine (2 mM) (HS medium) and the cells were cultured for about 24 hr.
• the cells were treated with the test compounds and ⁇ -naphtoflavone ( ⁇ -NF, positive control for human CYP1A1 and CYP1A2, SIGMA) prepared by HS medium for about 48 hr.
• ⁇ -NF ⁇ -naphtoflavone
• the final concentration of ⁇ -NF was set to 10 ⁇ M. All compounds were dissolved in dimethylsulfoxide (DMSO, Wako), resulting in a final vehicle concentration of 0.1% (v/v).
• DMSO dimethylsulfoxide
• Oligo dT was employed for reverse transcription (RT) reaction. The RT reaction was carried using TaqMan Reverse Transcription Reagents (Applied Biosystems) at 25° C. for 10 min followed by 60-min reaction at 48° C., and then the enzyme was inactivated at 95° C. for 5 min in Gene Amp PCR System 9700. The resulting cDNA was subjected to polymerase chain reaction (PCR) in ABI7700 Sequence Detection System (Applied Biosystems).
• PCR polymerase chain reaction
• Test Example 2 to assess CYP induction in liver, which is one of the problems in the development of new drug, induction of mRNAs of CYP1A isozymes was studied using human cryopreserved hepatocytes. As the results, test compound showed week induction potency, resulted in less than 12% at 3 uM and less than 30% at 10 uM as compared with positive control (100%). TABLE 6 Sample Conc.
• CYP1A1 CYP1A2 Control 0.1% DMSO (1.00) (1.00) ⁇ NF 10 ⁇ M 100(79.97) 100(14.16)
• Table 6 represents the % of the positive control (100%).
• Figures in parentheses show the fold induction by positive control as compared with control.
• the compound of the present invention Since the compound of the present invention has an excellent gastric acid secretion inhibitory activity, higher safety and more suitable physicochemical stability, it can serve as a drug particularly useful for acid related diseases.

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