WO2014119681A1 - アゾールベンゼン誘導体 - Google Patents
アゾールベンゼン誘導体 Download PDFInfo
- Publication number
- WO2014119681A1 WO2014119681A1 PCT/JP2014/052154 JP2014052154W WO2014119681A1 WO 2014119681 A1 WO2014119681 A1 WO 2014119681A1 JP 2014052154 W JP2014052154 W JP 2014052154W WO 2014119681 A1 WO2014119681 A1 WO 2014119681A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- thiazole
- phenyl
- carboxylic acid
- group
- Prior art date
Links
- 0 *c1c(C(O)=O)[s]c(-c(cc2)cc(N*=N)c2I)n1 Chemical compound *c1c(C(O)=O)[s]c(-c(cc2)cc(N*=N)c2I)n1 0.000 description 15
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61P1/04—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
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/04—Drugs for disorders of the urinary system for urolithiasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a novel compound having xanthine oxidase inhibitory activity, a method for producing the same, and a xanthine oxidase inhibitor containing the compound as an active ingredient.
- the present invention includes gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy,
- the present invention relates to an azolebenzene derivative useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease.
- Xanthine oxidase is an enzyme that catalyzes the conversion of hypoxanthine to xanthine and further to uric acid in nucleic acid metabolism.
- xanthine oxidase inhibitors reduce uric acid synthesis by inhibiting uric acid synthesis. That is, it is effective in treating hyperuricemia and various diseases caused by it.
- pathological conditions that occur as a result of persistent hyperuricemia and deposition of urate crystals include gout arthritis called gout and gout nodules. Hyperuricemia is regarded as an important factor in lifestyle-related diseases and metabolic syndrome related to obesity, hypertension, dyslipidemia, and diabetes.
- nephropathy, urolithiasis, cardiovascular disease It is being clarified that it is a risk factor for the treatment of hyperuricemia and gout (2nd edition).
- xanthine oxidase inhibitors due to their reactive oxygen species generation inhibitory activity, are useful for treating diseases involving reactive oxygen species, for example, useful for treating cardiovascular diseases through improving vascular function.
- Expected (Circulation. 2006; 114: 2508-2516).
- the problem to be solved by the present invention is to provide a novel compound having xanthine oxidase inhibitory activity. Furthermore, the subject of this invention is providing the compound which has the outstanding uric acid reduction effect
- action. Another subject of the present invention is gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, diabetic nephropathy, etc. It is intended to provide a compound useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as renal diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
- diseases involving xanthine oxidase such as renal diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
- this azolebenzene derivative is useful for gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, and kidneys such as diabetic nephropathy.
- the present invention has been completed by discovering that it can be a good therapeutic or preventive drug for diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
- the present invention is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
- R 1 represents OR, NRR ′ which may form a ring, or SR, wherein R and R ′ independently represent a hydrogen atom, one or more alkoxy groups having 1 to 8 carbon atoms, An alkyl group having 1 to 8 carbon atoms which may be substituted with a halogen atom or a hydroxyl group, one or more alkyl groups having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or a halogen atom. And a heteroaryl group which may be substituted with one or more alkyl groups having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or a halogen atom.
- R 2 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- X 1 , X 2 , and X 3 are independently CR 3 or a nitrogen atom, or X 1 is CR 3 or a nitrogen atom, and X 2 and X 3 together form a benzene ring.
- R 3 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- the present invention is also a pharmaceutical composition
- a pharmaceutical composition comprising the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the present invention is a xanthine oxidase inhibitor comprising as an active ingredient a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
- the present invention also includes gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension, containing as an active ingredient the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
- gout hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension
- Xanthine dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease It is a therapeutic or prophylactic agent for diseases involving oxidase.
- the present invention is a compound represented by the following formula (II), which can be used as an intermediate for producing the compound represented by the above formula (I).
- R 1 represents OR, NRR ′ which may form a ring, or SR, wherein R and R ′ independently represent a hydrogen atom, one or more alkoxy groups having 1 to 8 carbon atoms, An alkyl group having 1 to 8 carbon atoms which may be substituted with a halogen atom or a hydroxyl group, one or more alkyl groups having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or a halogen atom. And a heteroaryl group which may be substituted with one or more alkyl groups having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or a halogen atom.
- R 2 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- X 1 , X 2 , and X 3 are independently CR 3 or a nitrogen atom, or X 1 is CR 3 or a nitrogen atom, and X 2 and X 3 together form a benzene ring.
- R 3 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- R 4 represents a protecting group for a carboxyl group.
- the present invention is a compound represented by the following formula (III), which can be used as an intermediate for producing the compound represented by the above formula (I).
- R 2 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- X 1 , X 2 , and X 3 are independently CR 3 or a nitrogen atom, or X 1 is CR 3 or a nitrogen atom, and X 2 and X 3 together form a benzene ring.
- R 3 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- R 4 represents a protecting group for a carboxyl group.
- R 5 represents a protecting group for a phenolic hydroxyl group.
- the present invention provides a novel compound having high xanthine oxidase inhibitory activity and a method for producing the same. Furthermore, the compounds of the present invention are particularly useful for gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, kidneys such as diabetic nephropathy, etc. It is useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase such as diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
- Xanthine oxidase is generally used in the broad sense of an enzyme that catalyzes an oxidation reaction from hypoxanthine to xanthine and further to uric acid, and in the narrow sense of an oxidase-type xanthine oxidoreductase that is one of the enzymes that catalyze the reaction.
- xanthine oxidase is a general term for enzymes that catalyze an oxidation reaction from hypoxanthine to xanthine and further to uric acid, unless otherwise specified.
- xanthine oxidoreductase responsible for this reaction, an oxidase type and a dehydrogenase type, both of which are included in the xanthine oxidase of the present invention.
- xanthine oxidase inhibitory activity xanthine oxidase inhibitor
- xanthine oxidase inhibitor has the same meaning as defined above unless otherwise specified.
- halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- the “alkyl group” means a monovalent saturated linear, cyclic or branched aliphatic hydrocarbon group
- examples of the “alkyl group having 1 to 8 carbon atoms” include, for example, methyl group, ethyl Group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1 -Ethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethyl Butyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3
- the “alkoxy group” means a monovalent saturated linear, cyclic or branched aliphatic hydrocarbon oxy group.
- Examples of the “alkoxy group having 1 to 8 carbon atoms” include methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, n-hexaoxy group, isopropoxy group, isobutoxy group, s- Butoxy group, t-butoxy group, isopentyloxy group, 2-methylbutoxy group, neopentyloxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclopropylmethoxy group, Examples include a cyclobutylmethoxy group, a cyclopentylmethoxy group, and a cyclohexylmethoxy group.
- the “aryl group” means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms.
- the aryl group include a phenyl group, a naphthyl group, an indenyl group, a tetrahydronaphthyl group, an indanyl group, and an azulenyl group.
- heteroaryl group means a monocyclic or bicyclic aromatic heterocyclic group having 1 to 5 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom.
- Heteroaryl groups include pyridyl, pyrazyl, pyrimidyl, furyl, thienyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoimidazolyl, benzoxazolyl, pyranyl, imidazolyl Group, oxazolyl group, thiazolyl group, triazinyl group, triazolyl group, benzoxazolyl group, benzoisoxazolyl group and the like.
- the “optionally substituted alkyl group having 1 to 8 carbon atoms” represents an alkyl group having 1 to 8 carbon atoms which may have one or more substituents at substitutable positions.
- substituents for the alkyl group having 1 to 8 carbon atoms include an alkoxy group having 1 to 8 carbon atoms, a halogen atom, and a hydroxyl group. When a plurality of substituents are present, each substituent may be the same or different.
- the “optionally substituted aryl group” means an aryl group which may have one or more substituents at substitutable positions.
- substituents for the aryl group include an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and a halogen atom.
- each substituent may be the same or different.
- the “optionally substituted heteroaryl group” means a heteroaryl group optionally having one or more substituents at substitutable positions.
- substituent for the heteroaryl group include an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and a halogen atom.
- each substituent may be the same or different.
- carboxyl-protecting group refers to, for example, PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc.
- General carboxyl group protecting groups described in, for example, methyl group, ethyl group, isopropyl group, heptyl group, t-butyl group, methoxymethyl group, methylthiomethyl group, methoxyethoxymethyl group, methoxyethyl group, A benzyl group etc. can be mentioned.
- the “protective group for phenolic hydroxyl group” means, for example, PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc.
- R 1 represents OR, NRR ′ which may form a ring, or SR.
- R and R ′ are independently a hydrogen atom, one or a plurality of alkoxy groups having 1 to 8 carbon atoms, a halogen atom or an alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, 1 or A plurality of alkyl groups having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or an aryl group optionally substituted with a halogen atom, or one or more alkyl groups having 1 to 8 carbon atoms, 8 represents a heteroaryl group which may be substituted with an alkoxy group or a halogen atom.
- R 1 is preferably OR.
- R preferably represents one or more alkoxy groups having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms which may be substituted with a halogen atom or a hydroxyl group, or 1 Alternatively, a plurality of alkyl groups having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an aryl group optionally substituted with a halogen atom. More preferably, it is an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 8 carbon atoms or a hydroxyl group.
- NRR ′ in which R 1 may form a ring
- R ′ forms a ring means that R and R ′ together with the nitrogen atom to which they are bonded form a nitrogen-containing saturated ring To do.
- R and R ′ are preferably independently an alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group
- R ′ is independently a methyl group, an ethyl group, an isopropyl group, or R and R ′ together with the nitrogen atom to which they are attached are a pyrrolidin-1-yl group, piperidin-1-yl More preferably, a group, a morpholin-1-yl group is formed.
- R 2 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- R 2 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- alkyl group having 1 to 8 carbon atoms are as defined above.
- a hydrogen atom or an alkyl group having 1 to 3 carbon atoms is preferred, and specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. More preferably, they are a hydrogen atom and a methyl group. Particularly preferred is a methyl group.
- X 1 , X 2 , and X 3 are independently CR 3 or a nitrogen atom, or X 1 is CR 3 or a nitrogen atom, and X 2 and X 3 are together To form a benzene ring.
- R 3 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- X 1 , X 2 , and X 3 are preferably independently CR 3 or a nitrogen atom. More preferably, X 1 is a nitrogen atom, X 2 is CR 3 or a nitrogen atom, and X 3 is CR 3 . In any combination, R 3 is preferably a hydrogen atom. When X 1 is a nitrogen atom, X 2 is CH or a nitrogen atom, and X 3 is CH, it can be represented by the following structural formula.
- R 1 is OR, NRR ′ which may form a ring, or SR, and in any case, preferred R, R ′, R 2 , X 1 , X 2 and X 3
- the combination is a combination of the preferred groups described above for each, wherein R 3 is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
- R 3 is a hydrogen atom.
- R, R ′, R 2 , X 1 , X 2 , and X 3 are combinations of more preferable groups, in which R 3 is a hydrogen atom or a group having 1 to 8 carbon atoms. It is an alkyl group. In such a more preferable combination of R, R ′, R 2 , X 1 , X 2 , and X 3 , R 3 is more preferably a hydrogen atom.
- R, R ′, R 2 , X 1 , X 2 , and X 3 are such that R is an isopropyl group, isobutyl group or neopentyl group, R 2 is a methyl group, and X 1 is a nitrogen atom Yes, X 2 is CR 3 or a nitrogen atom, and X 3 is a combination of CR 3 , where R 3 is a hydrogen atom.
- R 1 is preferably OR.
- R 1 , R, R ′, R 2 , X 1 , X 2 , and X 3 in the formula (I) according to the present invention include the following combinations 1) to 9): Can do.
- R 1 is OR;
- R is an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 8 carbon atoms, a halogen atom or a hydroxyl group, or one or more An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or an aryl group optionally substituted with a halogen atom;
- R 2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
- X 1 is a nitrogen atom;
- X 2 is CR 3 or a nitrogen atom;
- X 3 is CR 3 ;
- R 3 is a hydrogen atom;
- R 1 is OR;
- R is an alkyl group having
- the compound of the present invention is a compound exhibiting excellent xanthine oxidase inhibitory activity. Further, the compound of the present invention has an excellent uric acid lowering action. Furthermore, the compounds of the present invention have a long-lasting uric acid lowering action.
- preferable compounds include the following compounds.
- more preferable compounds are compound numbers 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 and 53, more preferably compound numbers 1, 9, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 and 53, Particularly preferably, compound numbers 17, 24, 25 and 26 A.
- R 1 , R, R ′, R 2 , X 1 , X 2 , X 3 and CR 3 are the same as defined in the above formula (I).
- R 4 represents a protecting group for a carboxyl group.
- the definition of the protective group of a carboxyl group is as above-mentioned, Preferably they are a methyl group, an ethyl group, and a benzyl group.
- R 2 , X 1 , X 2 , X 3 , CR 3 has the same definition as in formula (I) above.
- R 4 represents a protecting group for a carboxyl group.
- the definition of the protective group of a carboxyl group is as above-mentioned, Preferably they are a methyl group, an ethyl group, and a benzyl group.
- R 5 represents a protecting group for a phenolic hydroxyl group.
- the definition of the protecting group of a phenolic hydroxyl group is as above-mentioned, Preferably they are a methyl group, a methoxymethyl group, and a benzyl group.
- Y 1 and Y 2 represent a leaving group.
- the leaving group represented by Y 1 and Y 2 includes a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- Etc. This reaction is a method of synthesizing compound (A-2) by reacting the phenolic hydroxyl group in compound (A-1) with an alkylating reagent having a leaving group in the presence of a base.
- Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and metal alkoxides such as sodium ethoxide, sodium methoxide, and t-butoxy potassium.
- Organic amines such as triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) are used. .
- This reaction is carried out by reacting compound (A-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And is usually allowed to react for 0.5 to 16 hours.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N -Dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water or a mixed solvent thereof.
- Compound (A-2) can also be synthesized according to a synthesis method as described below, for example. Synthesis of compound (A-2)
- Y 1 and Y 3 represent a leaving group.
- the leaving group represented by Y 1 and Y 3 includes a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- Etc. This reaction is a method of synthesizing compound (A-2) by lithiating, sodiumating or potassiumating alcohols with a base and then reacting with compound (A-3).
- Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and metal alkoxides such as sodium ethoxide, sodium methoxide, and t-butoxy potassium.
- Organic amines such as triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) are used. . This reaction is carried out at ⁇ 20 ° C. to 120 ° C.
- reaction in a solvent inert to the reaction by reacting an equal amount or an excess amount of alcohol with an equal amount or a slight excess of the compound (A-3). And is usually allowed to react for 0.5 to 16 hours.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Examples thereof include ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- Y 1 represents a leaving group.
- This reaction is a method of synthesizing compound (A-5) by a substitution reaction of compounds (A-2) and (A-4).
- Examples of the leaving group represented by Y 1 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- the compounds (A-2) and (A-4) are used in an equal amount, or one of them in excess, and in a solvent inert to the reaction, in the presence of a base, at room temperature to heating under reflux, usually 0.5 It is carried out by reacting for a time to 2 days.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the base include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide, sodium methoxide, triethylamine, pyridine, 4 Organic amines such as aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) are used.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethylsulfoxide (DMSO), or these And the like.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-di
- This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (A-5) with a sulfur source under acidic conditions.
- compound (A-5) and a sulfur source are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for a day.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source.
- an inorganic acid such as hydrochloric acid or sulfuric acid, an organic acid such as acetic acid, or an aqueous solution of these acids
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Examples thereof include ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- An acid such as acetic acid can also be used as a solvent.
- R 4 represents a protecting group of carboxyl group.
- Y 4 represents a leaving group.
- a halogen atom as the leaving group represented by Y 4 methanesulfonyloxy group, p- toluenesulfonyloxy Group, trifluoromethanesulfonyloxy group and the like.
- This reaction is a ring-forming reaction of thiazole ring, and the compounds (A-6) and (A-7) are used in equal amounts or in excess, and the reaction is carried out in a solvent inert to the reaction at room temperature to heating under reflux. The reaction is usually carried out for 0.5 hours to 2 days. Further, an equal amount or an excess amount of a base can be added.
- the solvent is not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane,
- Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
- inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate
- metal alkoxides such as sodium ethoxide and sodium methoxide
- triethylamine N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
- R 4 represents a protecting group for a carboxyl group.
- the protecting group R 4 of the compound (A-8) is deprotected with an acid or a base, whereby the compound (A- 9).
- compound (A-8) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) , N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons
- Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
- Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases diluted with water or an organic solvent. Examples include solutions.
- the leaving group represented by Y 2 and Y 5 includes a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- Etc. This reaction is a method of synthesizing compound (B-2) by reacting a phenolic hydroxyl group in compound (B-1) with an alkylating reagent having a leaving group in the presence of a base.
- Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and metal alkoxides such as sodium ethoxide, sodium methoxide, and t-butoxy potassium.
- Organic amines such as triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) are used. .
- This reaction is carried out by reacting the compound (B-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And is usually allowed to react for 0.5 to 16 hours.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N -Dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water or a mixed solvent thereof.
- Compound (B-2) can also be synthesized, for example, according to a synthesis method as described below.
- Y 3 and Y 5 represent a leaving group.
- the leaving group represented by Y 3 and Y 5 includes a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- Etc. This reaction is a method for synthesizing compound (B-2) by lithiating, sodiumating or potassiumating alcohols with a base and then reacting with compound (B-3).
- Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and metal alkoxides such as sodium ethoxide, sodium methoxide, and t-butoxy potassium.
- Organic amines such as triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) are used. . This reaction is carried out at ⁇ 20 ° C. to 120 ° C.
- the reaction is usually carried out for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Examples thereof include ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- R 4 represents a protecting group for a carboxyl group
- Y 5 represents a leaving group.
- a compound (B-2) and (B-4) are coupled to produce a compound ( This is a method for synthesizing B-5).
- the leaving group represented by Y 5 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- compounds (B-2) and (B-4) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, carboxylic acid And a copper (I-valent or II-valent) salt are added, and the reaction is carried out at room temperature to heating under reflux, usually for 0.5 hour to 2 days.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) , N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons
- Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbons) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole.
- alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salt
- transition metal catalyst examples include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium.
- ligand examples include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine.
- Copper (I or II) salts include copper (I) chloride, copper bromide (I), copper iodide (I), copper acetate (I), copper (II) fluoride, copper (II) chloride.
- Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
- This synthesis method is a method of synthesizing compound (B-6) by reducing the nitro group of compound (B-5).
- This reaction is carried out by reacting compound (B-5) in a solvent inert to the reaction, in the presence of a transition metal catalyst, in a hydrogen gas atmosphere at room temperature to heating under reflux, usually for 0.5 hour to 2 days. Done.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) N-methylpyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate, or a mixed solvent thereof.
- transition metal catalyst palladium-carbon, palladium hydroxide, palladium black, platinum-carbon, Raney nickel and the like are preferable.
- R 6 represents a methyl group or a p-tolyl group.
- This synthesis method is described in HETEROCYCLES, Vol. 48, no. 4, 1998 P695-702 can be referred to. That is, the compound (B-9) is synthesized by condensing the compounds (B-7) and (B-8). In this reaction, the compounds (B-7) and (B-8) are used in an equal amount or in excess, and the reaction is inert to the reaction at 0 ° C. to heating under reflux, usually 0.5 hours to 1 day. This is done by reacting. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethylsulfoxide (DMSO), acetic acid, Examples include propionic acid or a mixed solvent thereof.
- compound (B-6) and compound (B-9) are reacted to form 1 , 2,3-triazole ring.
- the compound (B-6) and the compound (B-9) are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of a base, at room temperature to heating under reflux, usually 0. It is carried out by reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5, Organic amines such as 4,0] -7-undecene (DBU) are used.
- carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate
- triethylamine pyridine
- 4-aminopyridine N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5, Organic amines such as 4,0] -7-undecene (DBU) are used.
- Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, Examples include 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, Examples include 1,2-diethoxye
- R 4 represents a protecting group for a carboxyl group.
- the protecting group R 4 of the compound (B-10) is deprotected with an acid or a base, whereby the compound (B- 11).
- compound (B-10) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) , N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons
- Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
- Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases diluted with water or an organic solvent. Examples include solutions.
- R 4 represents a protecting group for a carboxyl group
- R 7 represents an alkyl group such as a methyl group or an ethyl group.
- a compound (B-6), an orthoformate ester and an azide compound are reacted.
- This is a method for synthesizing a tetrazole ring.
- compound (B-6), orthoformate ester and azide compound are used in equal amounts, or in excess, either in an inert solvent for reaction, in the presence of an acid, at room temperature to heating under reflux, usually 0 By reacting for 5 hours to 2 days.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- Examples of the orthoformate ester include trimethyl orthoformate and triethyl orthoformate.
- Examples of the azide compound include sodium azide and trimethylsilyl azide.
- Examples of the acid to be used include organic acids such as formic acid and acetic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and Lewis acids such as indium triflate, yttrium triflate, zinc triflate and trichloroindium.
- the solvent used in these reactions is not particularly limited, and examples thereof include benzene, toluene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy.
- examples include ethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- An acid such as acetic acid may be used as a solvent. Good.
- R 4 represents a protecting group for a carboxyl group.
- the protecting group R 4 of compound (C-1) is deprotected with an acid or a base, whereby the compound (C— This is a method of synthesizing 2).
- compound (C-1) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) , N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons
- Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
- Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases diluted with water or an organic solvent. Examples include solutions.
- R 4 represents a protecting group for a carboxyl group
- R 5 represents a protecting group for a phenolic hydroxyl group.
- the protecting group R 5 of the compound (C-3) is protected with an acid or a base.
- compound (C-4) is synthesized by deprotection.
- compound (C-3) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) , N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons
- Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
- Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases diluted with water or an organic solvent. Examples include solutions.
- Compound (C-1) can also be synthesized, for example, according to a synthesis method as described below.
- R 4 represents a protecting group for a carboxyl group.
- This synthesis method is a method of synthesizing compound (C-1) by reacting compound (C-4) with alcohols by Mitsunobu reaction or the like. It is.
- This reaction is a method of synthesizing compound (C-1) by reacting alcohols with triphenylphosphine and carbodiimide and then reacting with compound (C-4).
- Examples of the carbodiimide used include diethyl carbodiimide and diisopropyl carbodiimide.
- an equivalent amount or an excess amount of alcohol, triphenylphosphine and carbodiimide is usually added to 0.5 to 12 in a solvent inert to the reaction at ⁇ 20 ° C. to 120 ° C. This is done by reacting for hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Examples thereof include ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- R 4 represents a protecting group for a carboxyl group
- Y 3 and Y 5 represent a leaving group.
- the leaving group represented by Y 3 and Y 5 includes a halogen atom, a methanesulfonyloxy group, p-toluene.
- a sulfonyloxy group, a trifluoromethanesulfonyloxy group, etc. are mentioned.
- This synthesis method is a method of synthesizing compound (D-1) by coupling compounds (B-3) and (B-4).
- compounds (B-3) and (B-4) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, carboxylic acid And a copper (I-valent or II-valent) salt are added, and the reaction is carried out at room temperature to heating under reflux, usually for 0.5 hour to 2 days.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) , N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons
- Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbons) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole.
- alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salt
- transition metal catalyst examples include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium.
- ligand examples include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine.
- Copper (I or II) salts include copper (I) chloride, copper bromide (I), copper iodide (I), copper acetate (I), copper (II) fluoride, copper (II) chloride.
- Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
- R 4 represents a protecting group for a carboxyl group
- Y 3 represents a leaving group.
- the leaving group represented by Y 3 includes a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, trifluoromethane. A sulfonyloxy group etc. are mentioned.
- This reaction is a method of synthesizing compound (D-2) by lithiation, sodiumation, potassiumation or cesiumation of thiols with a base, followed by reaction with compound (D-1).
- Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and metal alkoxides such as sodium ethoxide, sodium methoxide, and t-butoxy potassium.
- Organic amines such as triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5,4,0] -7-undecene (DBU) are used. . This reaction is carried out at ⁇ 20 ° C. to 120 ° C.
- reaction in an inert solvent for the reaction, after reacting compound (D-1) with an equal amount or a small excess of the base, and then an equal amount or an excess amount of thiols. And the reaction is usually carried out for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Examples thereof include ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- ethers such as 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- This synthesis method is a method of synthesizing compound (D-3) by reducing the nitro group of compound (D-2).
- This reaction is carried out by reacting compound (D-2) in a solvent inert to the reaction in the presence of a transition metal catalyst in a hydrogen gas atmosphere at room temperature to heating under reflux, usually for 0.5 hour to 2 days. Done.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- transition metal catalyst palladium-carbon, palladium hydroxide, palladium black, platinum-carbon, Raney nickel and the like are preferable.
- This synthesis method involves reacting compound (D-3), an orthoformate ester and an azide compound. This is a method for synthesizing a tetrazole ring. In this reaction, the compound (D-3), orthoformate ester and azide compound are used in an equal amount or in excess of either, and usually 0 in a solvent inert to the reaction in the presence of an acid at room temperature to heating under reflux. By reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- Examples of the orthoformate ester include trimethyl orthoformate and triethyl orthoformate.
- Examples of the azide compound include sodium azide and trimethylsilyl azide.
- Examples of the acid to be used include organic acids such as formic acid and acetic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and Lewis acids such as indium triflate, yttrium triflate, zinc triflate and trichloroindium.
- the solvent is not particularly limited.
- R 4 represents a protecting group for a carboxyl group.
- the protecting group R 4 of the compound (D-4) is deprotected with an acid or a base, whereby the compound (D- This is a method of synthesizing 5).
- compound (D-4) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
- the solvent is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF) , N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1, Ethers such as 2-diethoxyethane, halogenated hydrocarbons
- Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
- Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases diluted with water or an organic solvent. Examples include solutions.
- Y 3 and Y 5 represent a leaving group.
- the leaving group represented by Y 3 and Y 5 includes a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- Etc. This reaction is a method of synthesizing compound (E-2) by lithiating, sodiumating or potassiumating amines with a base and then reacting with compound (B-3).
- Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and metal alkoxides such as sodium ethoxide, sodium methoxide, and t-butoxy potassium.
- Organic amine salts such as triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) It is done. This reaction is carried out at ⁇ 20 ° C. to 120 ° C.
- reaction in a solvent inert to the reaction by reacting the amine (E-1) with an equal amount or a slight excess of the base, and then reacting the compound (B-3).
- the reaction is usually carried out for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
- diethoxyethane N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- DMF N-di
- R 4 represents a protecting group for a carboxyl group
- Y 5 represents a leaving group.
- a compound (E-2) and (B-4) are coupled to form a compound ( This is a method of synthesizing E-3).
- the leaving group represented by Y 5 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- compounds (E-2) and (B-4) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, a carboxylic acid And a copper (I-valent or II-valent) salt are added, and the reaction is carried out at room temperature to under reflux with heating, usually for 0.5 hour to 2 days.
- This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
- the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
- Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbons) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole.
- alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salt
- transition metal catalyst examples include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium.
- ligand examples include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine.
- Copper (I or II) salts include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) fluoride, copper (II) chloride , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof.
- the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
- This synthesis method is a method of synthesizing compound (E-4) by reducing the nitro group of compound (E-3). This reaction is carried out by reacting compound (E-3) in a solvent inert to the reaction in the presence of a transition metal catalyst in a hydrogen gas atmosphere at room temperature to heating under reflux, usually for 0.5 hour to 2 days. Is called.
- the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, ethyl acetate, N, N-dimethylformamide ( DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2
- Examples of the orthoformate ester include trimethyl orthoformate and triethyl orthoformate.
- Examples of the azide compound include sodium azide and trimethylsilyl azide.
- Examples of the acid to be used include organic acids such as formic acid and acetic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and Lewis acids such as indium triflate, yttrium triflate, zinc triflate and trichloroindium.
- Solvents used in these reactions include toluene, benzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-di- Examples thereof include ethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO) or a mixed solvent thereof, and an acid such as acetic acid may be used as a solvent.
- THF tetrahydrofuran
- 1,4-dioxane 1,2-dimethoxyethane
- 1,2-di- Examples thereof include ethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO) or a mixed solvent thereof, and an acid such as ace
- R 4 represents a protecting group for a carboxyl group.
- the protecting group R 4 of the compound (E-5) is deprotected with an acid or a base, whereby the compound (E- 6).
- compound (E-5) is usually reacted for 0.5 to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done by.
- the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
- aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
- Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
- Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
- the compounds of the formulas (A-8), (B-10), (C-1), (C-4), (D-4), and (E-5) corresponds to the compound of formula (II), which is a production intermediate of the compound represented by formula (I), and the compound of formula (C-3) corresponds to the compound of formula (III).
- preferred compounds and pharmaceutically acceptable salts thereof are not particularly limited as long as they are pharmaceutically acceptable salts.
- Salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, carbonic acid; maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid , Salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, formic acid; salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, aspartic acid Salt with alkali metal such as sodium, potassium and lithium; salt with alkaline earth metal such as calcium and magnesium; aluminum and zinc Salts with metals such as iron; salts with organic oniums such as tetramethylammonium and choline; ammonia, propanediamine, pyrrolidine,
- the compound represented by the formula (I) and salts thereof include various hydrates and solvates.
- the solvent of the solvate is not particularly limited, but methanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, Examples include diethyl ether, t-butylmethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, benzene, toluene, DMF, DMSO and the like.
- the compounds of the present invention also include stereoisomers, racemates, and all possible optically active compounds of the compounds represented by formula (I) and salts thereof.
- the compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof have particularly excellent xanthine oxidase inhibitory activity. Due to its excellent xanthine oxidase inhibitory activity, the compounds represented by the formula (I) of the present invention and pharmaceutically acceptable salts thereof are useful as xanthine oxidase inhibitors.
- the compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof are clinically applicable as a xanthine oxidase inhibitor, gout, hyperuricemia, oncolysis syndrome, urolithiasis , Hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease Etc., and can be used as a medicament for the treatment or prevention of diseases involving xanthine oxidase.
- the compound represented by the formula (I) and a pharmaceutically acceptable salt thereof can be made into a pharmaceutical composition together with a pharmaceutically acceptable carrier and / or diluent.
- This pharmaceutical composition can be formed into various dosage forms and administered orally or parenterally.
- Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, or rectal administration.
- Formulations containing one or more of the compounds represented by the formula (I) of the present invention or salts thereof as active ingredients are prepared using carriers, excipients and other additives that are usually used for formulation.
- the carrier or excipient for the preparation may be either solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, etc.
- Administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, liquids, or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories, and transdermal. Good.
- the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the type of disease, administration route, patient symptom, age, sex, body weight, etc. It can be administered in the range of 0.01 to 1000 mg per dose or divided into several doses. However, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or a dose exceeding the above range may be required.
- HPLC high-performance liquid chromatography
- TOF-MS time-of-flight mass spectrometer
- HPLC retention time The retention time (unit: minute) of a compound in HPLC analysis under the following analysis conditions is shown as HPLC retention time.
- Mass that is, actual measurement in which proton (H + ) was added to the molecular mass (M) of the compound, which was observed by the following apparatus and analysis conditions. Value) and the calculated value of “M + + H” (Pred. Mass), as well as the composition formula (Formula) calculated from the actually measured value of “M + + H”.
- Example 1 2- [3- (1H-imidazol-1-yl) -4- (2-methylpropoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 1 ) (Synthesis method (A)) (1) 41.1 mg of 3-fluoro-4-hydroxybenzonitrile, 33.4 mg of isobutyl bromide and 62.2 mg of potassium carbonate were suspended in 1 mL of dimethylformamide and heated at 110 ° C. for 5 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
- reaction mixture was stirred by adding 0.2 mL of 2M hydrochloric acid, and then 3 mL of water was added and extracted with 4 mL of ethyl acetate.
- the organic phase was concentrated and purified by a conventional method, and 2- [3- (1H-imidazol-1-yl) -4- (2-methylpropoxy) phenyl] -4-methyl-1,3-thiazole-5- 2.50 mg of carboxylic acid was obtained.
- Example 2-6 In the same manner as in Example 1, Compound Nos. 2 to 6 were synthesized.
- Example 8 Compound No. 8 was synthesized in the same manner as Example 7.
- Example 15 Compound No. 15 was synthesized in the same manner as Example 7.
- Example 16 4-Methyl-2- [4- (propan-2-yloxy) -3- (1H-1,2,3-triazol-1-yl) phenyl] -1,3-thiazole-5 Synthesis of carboxylic acid (Compound No. 16 ) (Synthesis Method (B)) (1) 2.18 g of 4-bromo-2-nitrophenol and 2.07 g of potassium carbonate were suspended in 40 mL of dimethylformamide, 2.04 g of isopropyl iodide was added under a nitrogen atmosphere, and the mixture was heated at 110 ° C. for 14 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
- reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give ethyl 2- [3-amino-4- (propan-2-yloxy) phenyl] -4-methyl-1,3-thiazole-5-carboxy. A rate of 1.26 g was obtained.
- reaction mixture was stirred by adding 0.2 mL of 2M hydrochloric acid, and then 3 mL of water was added and extracted with 4 mL of ethyl acetate.
- the organic phase was concentrated and purified by a conventional method, and 2- [4- (3-hydroxy-2-methylpropoxy) -3- (1H-1,2,3,4-tetrazol-1-yl) phenyl]- 15.4 mg of 4-methyl-1,3-thiazole-5-carboxylic acid was obtained.
- Example 30 2- [4- (2-Hydroxy-2-methylpropoxy) -3- (1H-1,2,3,4-tetrazol-1-yl) phenyl] -4-methyl-1,3 Synthesis of thiazole-5-carboxylic acid (Compound No. 30 ) (Synthesis Method (C)) (1) Ethyl 2- [4-hydroxy-3- (1H-1,2,3,4-tetrazol-1-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylate 33.1 mg Was dissolved in 1.0 mL of dimethylformamide, 20.7 mg of potassium carbonate and 16.2 mg of 3-bromo-2-methylpropene were added, and the mixture was stirred at 100 ° C.
- reaction mixture was stirred by adding 0.2 mL of 2M hydrochloric acid, and then 3 mL of water was added and extracted with 4 mL of ethyl acetate.
- the organic phase was concentrated and purified by a conventional method, and 2- [4- (2-hydroxy-2-methylpropoxy) -3- (1H-1,2,3,4-tetrazol-1-yl) phenyl]- 4.8 mg of 4-methyl-1,3-thiazole-5-carboxylic acid was obtained.
- Example 33 4-Methyl-2- [4-phenoxy-3- (1H-1,2,3,4-tetrazol-1-yl) phenyl] -1,3-thiazole-5-carboxylic acid (compound No. 33 ) (Synthesis method (C)) (1) To 2.20 g of 5-bromo-2-fluoronitrobenzene, 2.10 g of potassium hydrogen carbonate, 44 mg of palladium (II) chloride and 205 mg of copper (I) dimethyl sulfide complex were added and suspended in 20 mL of toluene. .
- reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 1.05 g of ethyl 2- (3-amino-4-phenoxyphenyl) -4-methyl-1,3-thiazole-5-carboxylate. It was.
- Example 49 4-methyl-2- ⁇ 4-[(2-methylpropyl) sulfanyl] -3- (1H-1,2,3,4-tetrazol-1-yl) phenyl ⁇ -1,3- Synthesis of thiazole-5-carboxylic acid (Compound No. 49 ) (Synthesis Method (D)) (1) 15 mL of ethyl 2- [4-fluoro-3-nitrophenyl] -4-methyl-1,3-thiazole-5-carboxylate and 244.4 mg of cesium carbonate in 1.5 mL of N, N-dimethylformamide 29.6 mg of 2-methylpropylthiol was added and heated at 80 ° C. for 5 hours under nitrogen atmosphere.
- Example 50-51 In the same manner as in Example 49, compound numbers 50 and 51 were synthesized.
- Example 52 4-Methyl-2- [4- (N, N-diethylamino) -3- (1H-1,2,3,4-tetrazol-1-yl) phenyl] -1,3-thiazole- Synthesis of 5-carboxylic acid (Compound No. 52 ) (1) 220 mg of 5-bromo-2-fluoronitrobenzene and 276 mg of potassium carbonate are suspended in 2 mL of N, N-dimethylformamide, 88 mg of N, N-diethylamine is added, and nitrogen is added. It heated at 40 degreeC under atmosphere for 14 hours. After cooling to room temperature, 3 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
- Example 53 Compound No. 53 was synthesized in the same manner as Example 52.
- Example 54 About the compound synthesize
- Preparation of test compound A test compound was dissolved in DMSO (manufactured by Sigma) so as to have a concentration of 20 mM, and then adjusted to a target concentration at the time of use.
- (2) Measurement method The xanthine oxidase inhibitory activity of the compounds of the present invention was evaluated by partially modifying the method described in the literature (Method Enzymatic Analysis, 1,521-522, 1974). This evaluation was performed by measuring oxidase type xanthine oxidoreductase activity.
- a xanthine (manufactured by Sigma) solution prepared to 10 mM in a 20 mM sodium hydroxide solution in advance was prepared to 30 ⁇ M using a 100 mM phosphate buffer, and 75 ⁇ L / well was added to a 96-well plate.
- Each test compound diluted with DMSO to 100 times the final concentration was added at 1.5 ⁇ L / well, and after mixing, the absorbance at 290 nm was measured with a microplate reader SPECTRA max Plus 384 (manufactured by Molecular Devices).
- oxidase type xanthine oxidoreductase (from buttermilk, Calbiochem) was prepared to 30.6 mU / mL using 100 mM phosphate buffer, and 73.5 ⁇ L / well was added. Immediately after mixing, the change in absorbance at 290 nm was measured for 5 minutes. The inhibition rate of the test compound was calculated by setting the enzyme activity when DMSO was added instead of the test compound solution as 100%, and the 50% inhibitory concentration for the oxidase type xanthine oxidoreductase was calculated by fitting to the dose response curve. The results are shown in the following table. However, the symbols (+, ++, ++) in the table represent the inhibitory activity values as follows. 10.0 nM ⁇ IC 50 : + 5.0 nM ⁇ IC 50 ⁇ 10.0 nM: ++ 1.0 nM ⁇ IC 50 ⁇ 5.0 nM: +++
- Example 55 Blood uric acid lowering effect (normal rat) Regarding the compounds of Compound Nos. 17, 24, 25 and 26, the blood uric acid lowering action was confirmed.
- Test compounds suspended in 0.5% methylcellulose solution were forcibly administered to male Sprague-Dawley rats (Charles River Japan Co., Ltd.) 8-9 weeks old using an oral sonde. Two hours after administration, blood was collected from the tail vein, and plasma was separated.
- the blood uric acid level was measured using a uric acid measurement kit (L type Wako UA • F: Wako Pure Chemical Industries) with an absorptiometer by the uricase method, and the uric acid reduction rate was determined by the following equation.
- Uric acid reduction rate (%) (Uric acid value of control animal ⁇ Uric acid value of test compound-administered animal) ⁇ 100 / Uric acid value of control animal Compound Nos. 17, 24, 25 and 26 were all administered at a dose of 10 mg / kg. The uric acid reduction rate was 50% or more. Further, the compounds of Compound Nos. 24, 25 and 26 showed a uric acid reduction rate of 50% or more even at a dose of 1 mg / kg. From this result, it was shown that the compound of the present invention has a strong blood uric acid lowering effect.
- Example 57 Blood uric acid lowering action (hyperuricemia beagle dog) Compound No. 25 was confirmed to have a blood uric acid lowering action in beagle dogs that caused hyperuricemia due to oxonic acid.
- a test compound suspended in 0.5% methylcellulose solution was orally administered by gavage to a beagle dog (Kitayama Labes). Potassium oxonate (50 mg / kg) was administered subcutaneously before administration of the compound and 4 hours after administration. 8 hours after administration of the compound, blood was collected from the cephalic vein, and plasma was separated. The blood uric acid level was measured using the LC-MS / MS method, and the uric acid reduction rate was determined by the following equation.
- Uric acid reduction rate (%) (Uric acid level of control animals ⁇ Uric acid level of animals receiving test compound) ⁇ 100 / Uric acid level of control animals 8 hours after administration, Compound 25 exhibited a uric acid lowering effect at a dose of 10 mg / kg. . From this result, it was shown that the compound of the present invention has a strong blood uric acid lowering effect in dogs.
- Example 58 Persistence of Xanthine Oxidase Inhibitory Activity in Tissue and Plasma Regarding “xanthine oxidase” of the present invention, only in this example, the oxidation reaction catalytic activity of oxidase-type xanthine oxidoreductase, and both oxidase-type and dehydrogenase-type xanthine oxidoreductase In order to distinguish from the oxidation reaction catalytic activity carried by, the former is referred to as “XO activity” and the latter as “XOR activity”.
- tissue XO activity includes liver, kidney, adipose tissue, intestine, blood vessel. From the following results, it is understood that the XOR activity inhibition rate and the XO activity inhibition rate in the same sample are about the same value for the compound of the present invention. Tissue XO activity, tissue XOR activity and plasma XO activity were confirmed for the compounds of Compound Nos. 17, 25 and 26.
- Test compounds suspended in 0.5% methylcellulose solution were forcibly administered to male Sprague-Dawley rats (Charles River Japan, Ltd.) 7-9 weeks old using an oral sonde. Blood was collected from the abdominal aorta and tissues were collected 24 hours or 27 hours after administration. The obtained blood was centrifuged and plasma was collected. Tissue XO activity, tissue XOR activity, and plasma XO activity were measured using reactions in which pterin was oxidized by each type of xanthine oxidoreductase to produce isoxanthopterin, which is a fluorescent substance. PH 7.
- XO inhibitory activity and XOR inhibitory activity were determined by the following equations.
- XO inhibitory activity (%) (XO activity or XOR activity of control animal ⁇ XO activity or XOR activity of test compound-administered animal) ⁇ 100 / XO activity or XOR activity of control animal About 27 hours after administration of Compound 17, 25, 26 Tissue and plasma XO inhibitory activity is shown in the following table.
- the following table shows the XOR inhibitory activity of the intestine, adipose tissue and blood vessels 24 hours after administration of Compound 25.
- Compounds Nos. 17, 25 and 26 all inhibited liver XO activity by 27% after administration at a dose of 10 mg / kg by 80% or more compared to control animals. All of the compounds of Compound Nos. 17, 25 and 26 inhibited the XO activity of the kidney 27 hours after administration by 70% or more compared with the control animals at a dose of 10 mg / kg. Compound Nos. 17, 25 and 26 all inhibited plasma XO activity by 27% after administration at a dose of 10 mg / kg by 40% or more compared to control animals. In addition, Compound 25 inhibited intestinal XOR activity at 24 hours after administration by 80% or more at a dose of 10 mg / kg compared to control animals.
- Compound 25 inhibited adipose tissue XOR activity by 24% after administration at a dose of 10 mg / kg by 60% or more compared to control animals.
- Compound 25 inhibited vascular XOR activity 24 hours after administration at a dose of 10 mg / kg by more than 40% compared to control animals.
- Compound 25 inhibited liver XOR activity and XO activity in liver at 24 hours after administration by 80% or more compared with control animals at a dose of 10 mg / kg.
- Compound 25 inhibited renal XOR activity and XO activity in the kidney 24 hours after administration by 70% or more at a dose of 10 mg / kg as compared to control animals.
- Compounds Nos. 17, 25, and 26 inhibited liver XO activity by 27% after administration at a dose of 1 mg / kg by 80% or more compared to control animals.
- Compounds Nos. 17, 25, and 26 all inhibited renal XO activity at a dose of 1 mg / kg by 60% or more compared to control animals at 27 hours after administration. All of the compounds of Compound Nos. 17, 25 and 26 inhibited plasma XO activity by 27% or more at a dose of 1 mg / kg by 25% or more compared to control animals.
- Compound 25 inhibited intestinal XOR activity at 24 hours after administration by 60% or more at a dose of 1 mg / kg compared with control animals.
- Compound 25 inhibited adipose tissue XOR activity 24 hours after administration at a dose of 1 mg / kg by 30% or more compared to control animals.
- Compound 25 inhibited vascular XOR activity 24 hours after administration at a dose of 1 mg / kg by more than 25% compared to control animals.
- Compound 25 inhibited liver XOR activity and XO activity in liver at 24 hours after administration by 80% or more compared with control animals at a dose of 1 mg / kg.
- Compound 25 inhibited kidney XOR activity and XO activity by 24% after administration at a dose of 1 mg / kg by 60% or more compared to control animals. From these results, it was shown that the compound of the present invention has a long-lasting XO activity and XOR activity inhibitory action.
- the compound represented by the above formula (I) of the present invention and a pharmaceutically acceptable salt thereof have xanthine oxidase inhibitory activity and are clinically applicable as xanthine oxidase inhibitors.
- Respiratory organs such as uricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy, chronic obstructive pulmonary disease It can be used as a therapeutic or prophylactic agent for diseases involving xanthine oxidase such as diseases, inflammatory bowel diseases or autoimmune diseases.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
特に、本発明は、痛風、高尿酸血症、腫瘍崩壊症候群、尿路結石、高血圧症、脂質異常症、糖尿病、動脈硬化症や心不全等の心血管疾患、糖尿病性腎症等の腎疾患、慢性閉塞性肺疾患等の呼吸器疾患、炎症性腸疾患または自己免疫性疾患等、キサンチンオキシダーゼの関与する疾患の治療薬または予防薬として有益なアゾールベンゼン誘導体に関する。
キサンチンオキシダーゼの作用に対して、キサンチンオキシダーゼ阻害剤は尿酸合成を阻害することで血中尿酸値を低下させる。すなわち高尿酸血症およびこれに起因する各種疾患の治療に有効である。一方、高尿酸血症が持続して尿酸塩結晶が沈着した結果として起こる病態として、痛風と呼ばれる痛風関節炎、痛風結節がある。また、高尿酸血症は肥満、高血圧、脂質異常症および糖尿病などに関連した生活習慣病やメタボリックシンドロームの因子として重要視されており、最近では疫学調査により腎障害、尿路結石、心血管疾患の危険因子であることが明らかにされつつある(高尿酸血症・痛風の治療ガイドライン 第2版)。また、キサンチンオキシダーゼ阻害剤は、その活性酸素種発生阻害活性により、活性酸素種が関与する疾患の治療への有用性、例えば、血管機能改善作用を通じた心血管疾患の治療への有用性、が期待されている(Circulation. 2006;114:2508-2516)。
臨床では、高尿酸血症の治療薬としてアロプリノール、フェブキソスタットが使用されているが、アロプリノールには、スティーブンス・ジョンソン症候群、中毒性表皮壊死症、肝障害、腎機能障害等の副作用が報告されている(Nippon Rinsho, 2003; 61, Suppul.1:197-201)。
キサンチンオキシダーゼ阻害活性を有する化合物としては、例えば、2-フェニルチアゾール誘導体(特許文献1~3)が報告されている。
一方、特許文献4および特許文献5には、中央にベンゼン環を有するジチアゾールカルボン酸誘導体が報告されている。また、特許文献6および特許文献7には、ビフェニルチアゾールカルボン酸誘導体が報告されている。
R1は、OR、環を形成していてもよいNRR’、またはSRを表し、ここで、RおよびR’は独立して、水素原子、1もしくは複数の炭素数1~8のアルコキシ基、ハロゲン原子もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基、1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいアリール基、または1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいヘテロアリール基を表す。
R2は、水素原子または炭素数1~8のアルキル基を表す。
X1、X2、およびX3は、独立して、CR3もしくは窒素原子であるか、またはX1がCR3もしくは窒素原子であり、X2とX3が一緒になってベンゼン環を形成する。ここで、R3は、水素原子または炭素数1~8のアルキル基を表す。]
R1は、OR、環を形成していてもよいNRR’、またはSRを表し、ここで、RおよびR’は独立して、水素原子、1もしくは複数の炭素数1~8のアルコキシ基、ハロゲン原子もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基、1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいアリール基、または1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいヘテロアリール基を表す。
R2は、水素原子または炭素数1~8のアルキル基を表す。
X1、X2、およびX3は、独立して、CR3もしくは窒素原子であるか、またはX1がCR3もしくは窒素原子であり、X2とX3が一緒になってベンゼン環を形成する。ここで、R3は、水素原子または炭素数1~8のアルキル基を表す。
R4は、カルボキシル基の保護基を表す。]
R2は、水素原子または炭素数1~8のアルキル基を表す。
X1、X2、およびX3は、独立して、CR3もしくは窒素原子であるか、またはX1がCR3もしくは窒素原子であり、X2とX3が一緒になってベンゼン環を形成する。ここで、R3は、水素原子または炭素数1~8のアルキル基を表す。
R4は、カルボキシル基の保護基を表す。
R5は、フェノール性水酸基の保護基を表す。]
1)R1がORであり;Rが、1もしくは複数の炭素数1~8のアルコキシ基、ハロゲン原子もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基、または1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいアリール基であり;R2が水素原子または炭素数1~3のアルキル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である;
2)R1がORであり;Rが1もしくは複数の炭素数1~8のアルコキシ基もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基であり;R2が水素原子または炭素数1~3のアルキル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である;
3)R1がORであり;Rがイソプロピル基、イソブチル基、ネオペンチル基であり;R2が水素原子およびメチル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である;
4)R1がSRであり;Rが、1もしくは複数の炭素数1~8のアルコキシ基、ハロゲン原子もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基、または1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいアリール基であり;R2が水素原子または炭素数1~3のアルキル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である;
5)R1がSRであり;Rが1もしくは複数の炭素数1~8のアルコキシ基もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基であり;R2が水素原子または炭素数1~3のアルキル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である;
6)R1がSRであり;Rがイソプロピル基、イソブチル基、ネオペンチル基であり;R2が水素原子およびメチル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である;
7)R1が環を形成していてもよいNRR’であり;RおよびR’は、独立して、1もしくは複数の炭素数1~8のアルコキシ基もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基であり;R2が水素原子または炭素数1~3のアルキル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である;
8)R1が環を形成していてもよいNRR’であり;RおよびR’が、独立して、メチル基、エチル基もしくはイソプロピル基であるか、またはRおよびR’が、それらが結合する窒素原子と一緒になってピロリジン-1-イル基、ピペリジン-1-イル基、モルホリン-1-イル基を形成し;R2が水素原子または炭素数1~3のアルキル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である;
9)R1が環を形成していてもよいNRR’であり;RおよびR’が、独立して、メチル基、エチル基もしくはイソプロピル基であるか、またはRおよびR’が、それらが結合する窒素原子と一緒になってピロリジン-1-イル基、ピぺリジン-1-イル基、モルホリン-1-イル基を形成し;R2が水素原子およびメチル基であり;X1が窒素原子であり;X2がCR3または窒素原子であり;X3がCR3であり:R3が水素原子である。
本発明の式(I)の化合物および中間体は、例えば、以下に記載されるような合成法のいずれかに従って合成することができる。なお、各式中、R1、R、R’、R2、X1、X2およびX3は、式(I)の定義のとおりである。また、化学式中に記載の条件としての試薬または溶媒などは、本文にも記載のとおり例示にすぎない。各置換基は必要に応じて、適切な保護基で保護されていても良く、適切な段階において脱保護を行ってよい。なお、適切な保護基およびその除去方法は、この分野で汎用される各置換基の保護基および公知の方法を採用することができ、例えば、PROTECTIVE GROUPS in ORGANIC SYNTHESIS,THIRD EDITION、John Wiley&Sons,Inc.に記載されている。
化合物(A-2)の合成
化合物(A-2)の合成
化合物(B-2)の合成
化合物(C-1)の合成
化合物(D-1)の合成
化合物(E-2)の合成
以下、前記式(I)で表される化合物のうち、好ましい化合物およびその製薬学的に許容される塩としては、製薬学的に許容される塩であれば特に限定されないが、かかる塩としては、例えば、塩化水素、臭化水素、硫酸、硝酸、リン酸、炭酸などの無機酸との塩;マレイン酸、フマル酸、クエン酸、リンゴ酸、酒石酸、乳酸、コハク酸、安息香酸、シュウ酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、酢酸、トリフルオロ酢酸、ギ酸などの有機酸との塩;グリシン、リジン、アルギニン、ヒスチジン、オルニチン、グルタミン酸、アスパラギン酸などのアミノ酸との塩;ナトリウム、カリウム、リチウムなどのアルカリ金属との塩;カルシウム、マグネシウムなどのアルカリ土類金属との塩;アルミニウム、亜鉛、鉄などの金属との塩;テトラメチルアンモニウム、コリンなどのような有機オニウムとの塩;アンモニア、プロパンジアミン、ピロリジン、ピペリジン、ピリジン、エタノールアミン、N,N-ジメチルエタノールアミン、4-ヒドロキシピペリジン、t-オクチルアミン、ジベンジルアミン、モルホリン、グルコサミン、フェニルグリシルアルキルエステル、エチレンジアミン、N-メチルグルカミン、グアニジン、ジエチルアミン、トリエチルアミン、ジシクロヘキシルアミン、N,N’-ジベンジルエチレンジアミン、クロロプロカイン、プロカイン、ジエタノールアミン、N-ベンジルフェニルアミン、ピペラジン、トリス(ヒドロキシメチル)アミノメタンなどの有機塩基との塩が挙げられる。
1H NMRスペクトル(300MHzまたは400MHz、DMSO-d6またはCDCl3)を測定したものについては、その化学シフト(δ:ppm)およびカップリング定数(J:Hz)を示す。質量分析の結果については、M++H、すなわち化合物分子質量(M)にプロトン(H+)が付加した値として観測された測定値を示す。なお、以下の略号はそれぞれ次のものを表す。
s=singlet、d=doublet、t=triplet、q=quartet、brs=broad singlet、m=multiplet。
下記分析条件でのHPLC分析における化合物の保持時間(単位:分)を、HPLC保持時間として示す。
HPLC測定条件
測定装置:Hewlett-Packard 1100HPLC
カラム:Imtakt Cadenza CD-Cl8 100mm×4.6mm 3μm
UV:PDA検出(254nm)
カラム温度:40度
グラジエント条件:
溶媒:A:H2O/アセトニトリル=95/5
0.05%TFA(トリフルオロ酢酸)
B:H2O/アセトニトリル=5/95
0.05%TFA(トリフルオロ酢酸)
流速:1.0mL/分
勾配:0~1分、溶媒B:2% 溶媒A:98%
1~14分、溶媒B:2%→100% 溶媒A:98%→0%
14~17分、溶媒B:100% 溶媒A:0%
17~19分、溶媒B:100%→2% 溶媒A:0%→98%
また、質量分析の結果については、以下に示す装置および分析条件により観測された「M++H」の値(Obs.Mass:すなわち化合物の分子質量(M)にプロトン(H+)が付加した実測値)、「M++H」の計算値(Pred.Mass)と共に、実測された「M++H」の値から算出された組成式(Formula)も示す。
TOF-MS測定条件
質量分析装置:島津製作所 LCMS-IT-TOF
LC:Prominence
カラム:Phenomenex Synergi Hydro-RP 4.0mm×20mm 2.5μm
UV:PDA検出(254nm)
流量:0.6mL/分
カラム温度:40度
検出電圧:1.63kV
グラジェント条件:
溶媒:A:H2O/アセトニトリル=95/5
0.1%HCOOH
B:H2O/アセトニトリル=5/95
0.1%HCOOH
流速:0.5mL/分
勾配:0~0.2分、溶媒B:2% 溶媒A:98%
0.2~2.5分、溶媒B:2%→100% 溶媒A:98%→0%
2.5~3.8分、溶媒B:100% 溶媒A:0%
3.8~4.0分、溶媒B:100%→2% 溶媒A:0%→98%
4.0~5.0分、溶媒B:2% 溶媒A:98%
p-トルエンスルホニルヒドラジン1.86gをプロピオン酸4mLに溶解し、0℃に冷却させた後に、ジクロロアセトアルデヒド水和物1.36gをプロピオン酸8mLに溶解させた溶液をゆっくりと滴下させた。この反応溶液を0℃で1時間撹拌させた後に、析出した固体を濾過し、トルエン10mLで洗浄後、減圧乾燥させることで、N’-[(1E)-2,2-ジクロロエチリデン]-4-メチルベンゼン-1-スルホンヒドラジン1.98gを得た。
1H-NMR(400MHz,CDCl3)δ(ppm):2.45(3H,s),6.11(1H,d,J=8.0Hz),7.19(1H,d,J=4.0Hz), 7.35(1H,d,J=8.0Hz),7.80(1H,d,J=8.0Hz),7.92(1H,s)
(1)3-フルオロ-4-ヒドロキシベンゾニトリル41.1mg、臭化イソブチル33.4mgおよび炭酸カリウム62.2mgをジメチルホルムアミド1mLに懸濁させ、窒素雰囲気下、110℃で5時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、3-フルオロ-4-(2-メチルプロポキシ)ベンゾニトリルの粗体を得た。
(2)上記で得られた3-フルオロ-4-(2-メチルプロポキシ)ベンゾニトリルの粗体に水素化ナトリウム15.7mg、イミダゾール24.5mgを加え、ジメチルスルホキシド1mLに懸濁させ、窒素雰囲気下、110℃で5時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、3-(1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)ベンゾニトリルの粗体を得た。
ESI/MS m/e:242.1(M++H,C14H16N3O)
(3)上記で得られた3-(1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)ベンゾニトリルの粗体を酢酸0.2mL、チオ酢酸0.5mLに懸濁させ、窒素雰囲気下、50℃で14時間加熱した。その後、減圧濃縮を行い、3-(1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)ベンゼン-1-カルボチオアミドの粗体を得た。
ESI/MS m/e:276.1(M++H,C14H18N3OS)
(4)上記で得られた3-(1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)ベンゼン-1-カルボチオアミドの粗体にエチル-2-クロロアセトアセテート74.1mgを加え、エタノール1mLに懸濁させ、窒素雰囲気下、80℃で5時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、エチル 2-[3-(1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレートの粗体を得た。
ESI/MS m/e:386.1(M++H,C20H24N3O3S)
(5)上記で得られたエチル 2-[3-(1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレートの粗体をテトラヒドロフラン/メタノール=1/1の混合溶液1mLに溶解し、2M水酸化ナトリウム水溶液0.2mLを加えて、室温で4時間撹拌した。反応混合液に2M塩酸0.2mLを加えて撹拌した後に、水3mLを加え、酢酸エチル4mLで抽出した。有機相を濃縮した後に常法により精製し、2-[3-(1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸2.50mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm):0.89(6H,d,J=6.4Hz),1.96-2.02(1H,m),2.65(3H,s),3.92(2H,d,J=6.4Hz),7.13(1H,s),7.37(1H,d,J=8.8Hz),7.55(1H,s),7.95-8.07(3H,m)
HPLC保持時間:8.15分
Obs Mass(M++H):358.1215
Pred Mass(M++H):358.1220
Formula(M):C18H19N3O3S
実施例1と同様にして、化合物番号2~6を合成した。
(1)3-クロロ-4-フルオロベンゾニトリル77.8mg、フェノール51.8mgおよび炭酸カリウム82.9mgをジメチルスルホシキド2mLに懸濁させ、窒素雰囲気下、100℃で14時間加熱した。続いて、反応混合液に水素化ナトリウム24.0mg、イミダゾール40.8mgを加え、窒素雰囲気下、140℃で5時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、得られた粗体をシリカゲルカラムクロマトグラフィーで分離精製することで、3-(1H-イミダゾール-1-イル)-4-フェノキシベンゾニトリル65.2mgを得た。
ESI/MS m/e:262.2(M++H,C16H12N3O)
(2)上記で得られた3-(1H-イミダゾール-1-イル)-4-フェノキシベンゾニトリル65.2mgを酢酸0.3mL、チオ酢酸1.0mLに懸濁させ、窒素雰囲気下、50℃で14時間加熱した。その後、減圧濃縮を行い、3-(1H-イミダゾール-1-イル)-4-フェノキシベンゼン-1-カルボチオアミドの粗体を得た。
ESI/MS m/e:296.1(M++H,C16H14N3OS).
(3)上記で得られた3-(1H-イミダゾール-1-イル)-4-フェノキシベンゼン-1-カルボチオアミドの粗体にエチル-2-クロロアセトアセテート123.2mgを加え、エタノール2mLに懸濁させ、窒素雰囲気下、80℃で5時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、得られた粗体をシリカゲルカラムクロマトグラフィーで分離精製することで、エチル 2-[3-(1H-イミダゾール-1-イル)-4-フェノキシフェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート72.2mgを得た。
ESI/MS m/e:406.1(M++H,C22H20N3O3S).
(4)上記で得られたエチル 2-[3-(1H-イミダゾール-1-イル)-4-フェノキシフェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート20.2mgをテトラヒドロフラン/メタノール=1/1の混合溶液1mLに溶解し、2M水酸化ナトリウム水溶液0.2mLを加えて、50℃で2時間撹拌した。反応混合液に2M塩酸0.2mLを加えて撹拌した後に、水3mLを加え、酢酸エチル4mLで抽出した。有機相を濃縮した後に常法により精製し、2-[3-(1H-イミダゾール-1-イル)-4-フェノキシフェニル]-4-メチル-1,3-チアゾール-5-カルボン酸9.0mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm):2.61(3H,s),7.07-7.13(3H,m),7.20(1H,t,J=6.8Hz),7.42(2H,t, J=8.0Hz),7.59(2H,s),7.74(1H,d,J=7.6Hz),7.86(1H,dd,J=1.2,8.4Hz),8.08(1H,s)
HPLC保持時間:7.86分
Obs Mass(M++H):378.0906
Pred Mass(M++H):378.0907
Formula(M):C20H15N3O3S
実施例7と同様にして、化合物番号8を合成した。
実施例1と同様にして、化合物番号9-14を合成した。
実施例7と同様にして、化合物番号15を合成した。
(1)4-ブロモ-2-ニトロフェノール2.18gおよび炭酸カリウム2.07gをジメチルホルムアミド40mLに懸濁させ、窒素雰囲気下、ヨウ化イソプロピル2.04gを加えて、110℃で14時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、得られた粗体をシリカゲルカラムクロマトグラフィーで分離精製することで、4-ブロモ-2-ニトロ-1-(プロパン-2-イルオキシ)ベンゼン2.08gを得た。
(2)上記で得られた4-ブロモ-2-ニトロ-1-(プロパン-2-イルオキシ)ベンゼン2.08gに炭酸水素化カリウム1.05g、塩化パラジウム(II)22mg、臭化銅(I)ジメチルスフフィド錯体102mgを加え、トルエン15mLに懸濁させた。その後にエチル 4-メチル-1,3-チアゾール-5-カルボキシレート1.02g、イソ酪酸46.2μL及びジ-t-ブチルシクロヘキシルホスフィン114mgを加えて、窒素雰囲気下、120℃で14時間加熱した。反応混合液をセライトろ過して不溶物を取り除き、ろ液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に常法により精製し、エチル 4-メチル-2-[3-ニトロ-4-(プロパン-2-イルオキシ)フェニル]-1,3-チアゾール-5-カルボキシレート1.38gを得た。
ESI/MS m/e:351.0(M++H,C16H19N2O5S)
(3)エチル 4-メチル-2-[3-ニトロ-4-(プロパン-2-イルオキシ)フェニル]-1,3-チアゾール-5-カルボキシレート1.38gをエタノール15mLに懸濁させ、パラジウム/炭素(10%wt)100mgを加えた後に、水素雰囲気下、50℃で14時間撹拌した。反応混合液をセライトろ過し、ろ液を減圧濃縮することで、エチル 2-[3-アミノ-4-(プロパン-2-イルオキシ)フェニル]- 4-メチル-1,3-チアゾール-5-カルボキシレート1.26gを得た。
ESI/MS m/e:321.1(M++H,C16H21N2O3S)
(4)エチル 2-[3-アミノ-4-(プロパン-2-イルオキシ)フェニル]- 4-メチル-1,3-チアゾール-5-カルボキシレート1.26gをメタノール10mLに懸濁させた後、トリエチルアミン1.12mLを加え、反応溶液を0℃に冷却した。その後にN’-[(1E)-2,2-ジクロロエチリデン]-4-メチルベンゼン-1-スルホンヒドラジン1.01gをメタノール10mLに溶解させた溶液をゆっくり加えて、窒素雰囲気下、40℃で2時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、得られた粗体をシリカゲルカラムクロマトグラフィーで分離精製することで、エチル 4-メチル-2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボキシレート501mgを得た。
ESI/MS m/e:373.1(M++H,C18H21N4O3S)
(5)エチル 4-メチル-2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボキシレート501mgをテトラヒドロフラン/メタノール=1/1の混合溶液10mLに溶解し、2M水酸化ナトリウム水溶液1.35mLを加えて、室温で3時間撹拌した。反応混合液に2M塩酸1.35mLを加えて撹拌した後に、水8mLを加え、酢酸エチル20mLで抽出した。有機相を濃縮した後に常法により精製し、4-メチル-2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸415mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm): 1.28(6H,d,J=5.6Hz),2.66(3H,s),4.83-4.89(1H,m),7.46(1H,d,J=8.8Hz),7.95(1H,s),8.06(1H,dd,J=2.0,8.8Hz),8.22(1H,d,J=2.8Hz),8.52(1H,s),13.39(1H,s)
HPLC保持時間:9.96分
Obs Mass(M++H):345.1005
Pred Mass(M++H):345.1016
Formula(M):C16H16N4O3S
実施例16と同様にして、化合物番号17-21を合成した。
実施例7と同様にして、化合物番号22、23を合成した。
(1)エチル 2-[3-アミノ-4-(プロパン-2-イルオキシ)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート1.23gを酢酸20mLに懸濁させた後、アジ化ナトリウム478mg、オルソギ酸トリエチル1.09gを加え、窒素雰囲気下、70℃で2時間加熱した。室温まで冷却させた後に反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に常法により精製し、エチル 4-メチル-2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボキシレート1.13gを得た。
ESI/MS m/e:374.1(M++H,C17H20N5O3S)
(2)エチル 4-メチル-2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボキシレート1.13gをテトラヒドロフラン/メタノール=1/1の混合溶液15mLに溶解し、2M水酸化ナトリウム水溶液3.0mLを加えて、室温で3時間撹拌した。反応混合液に2M塩酸3.0mLを加えて撹拌した後に、水7mLを加え、酢酸エチル30mLで抽出した。有機相を濃縮した後に常法により精製し、4-メチル-2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸920mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm): 1.28(6H,d,J=6.0Hz),2.65(3H,s),4.84-4.90(1H,m),7.50(1H,d,J=9.6Hz),8.13(1H,dd,J=2.4,8.8Hz),8.27(1H,d,J=2.4Hz),9.79(1H,s),13.41(1H,s)
HPLC保持時間:9.99分
Obs Mass(M++H):346.0958
Pred Mass(M++H):346.0968
Formula(M):C15H15N5O3S
実施例24と同様にして、化合物番号25-28を合成した。
(1)実施例16および24と同様にして、4-ブロモ-2-ニトロフェノール4.36gからエチル [4-(メトキシメトキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート1.97gを得た。
ESI/MS m/e:376.0(M++H,C16H18N5O4S)
1H-NMR(400MHz,CDCl3)δ(ppm): 1.40(6H,d,J=7.2Hz),2.78(3H,s),3.48(3H,s),4.36(2H,q,J=6.8Hz),5.34(2H,s),7.45(1H,d,J=8.8Hz),8.05(1H,dd,J=2.4,8.8Hz),8.44(1H,d,J=2.4Hz),9.17(1H,s)
(2)エチル [4-(メトキシメトキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート1.97gを1,4-ジオキサン25mLに溶解し、2M塩酸5.0mLを加えて、60℃で8時間撹拌した。反応混合液を室温まで冷却した後、析出した固体をろ過することにより、エチル 2-[4-ヒドロキシ-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート1.49gを得た。
ESI/MS m/e:332.0(M++H,C14H14N5O3S)
1H-NMR(400MHz,DMSO d6)δ(ppm): 1.39(6H,d,J=7.2Hz),2.76(3H,s),4.35(2H,q,J=7.2Hz),7.22(1H,d,J=8.4Hz),7.39(1H,s),7.90(1H,dd,J=2.4,8.8Hz),8.45(1H,d,J=2.8Hz),9.44(1H,s)
(3)2-メチルプロパン-1,3-ジオール13.5mgをテトラヒドロフラン1mLに溶解し、トリフェニルホスフィン39.3mg、ジエチル アゾジカルボキシレートの40%トルエン溶液65μLを加えて、室温で30分間撹拌した後、エチル 2-[4-ヒドロキシ-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート33.1mgを加えて、室温で3時間撹拌した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に常法により精製し、エチル 2-[4-(3-ヒドロキシ-2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート67.7mgを得た。
ESI/MS m/e:404.1(M++H,C18H22N5O4S)
(4)エチル 2-[4-(3-ヒドロキシ-2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート34.1mgをテトラヒドロフラン/メタノール=1/1の混合溶液1.0mLに溶解し、2M水酸化ナトリウム水溶液0.2mLを加えて、室温で3時間撹拌した。反応混合液に2M塩酸0.2mLを加えて撹拌した後に、水3mLを加え、酢酸エチル4mLで抽出した。有機相を濃縮した後に常法により精製し、2-[4-(3-ヒドロキシ-2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸15.4mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm): 0.82(3H,d,J=6.8Hz),1.90-1.98(1H,m),2.66(3H,s),3.25-3.28(2H,m),4.04-4.15(2H,m),4.62(1H,m),7.48(1H,d,J=8.8Hz),8.17(1H,dd,J=2.0,8.8Hz),8.28(1H,d,J=2.0Hz),9.80(1H,s),13.37(1H,brs)
HPLC保持時間:8.23分
Obs Mass(M++H):376.1074
Pred Mass(M++H):376.1074
Formula(M):C16H17N5O4S
(1)エチル 2-[4-ヒドロキシ-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート33.1mgをジメチルホルムアミド1.0mLに溶解し、炭酸カリウム20.7mg、3-ブロモ-2-メチルプロペン16.2mgを加えて、100℃で4時間撹拌した。反応混合液を室温まで冷却した後に、水3mL、酢酸エチル4mLを加えて撹拌し、有機相を濃縮し、エチル 4-メチル-2-{4-[(2-メチルプロペン-1-イル)オキシ]-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル}-1,3-チアゾール-5-カルボキシレート34.1mgを得た。
(2)エチル 4-メチル-2-{4-[(2-メチルプロペン-1-イル)オキシ]-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル}-1,3-チアゾール-5-カルボキシレート34.1mgに35%硫酸水溶液1.0mLを加えて、80℃で4時間撹拌した。反応混合液を室温まで冷却した後に、水3mL、酢酸エチル4mLを加えて撹拌し、有機相を濃縮した後に常法により精製し、エチル 2-[4-(2-ヒドロキシ-2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート9.9mgを得た。
ESI/MS m/e:404.1(M++H,C18H22N5O4S)
(3)エチル 2-[4-(2-ヒドロキシ-2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート9.9mgをテトラヒドロフラン/メタノール=1/1の混合溶液1.0mLに溶解し、2M水酸化ナトリウム水溶液0.2mLを加えて、室温で3時間撹拌した。反応混合液に2M塩酸0.2mLを加えて撹拌した後に、水3mLを加え、酢酸エチル4mLで抽出した。有機相を濃縮した後に常法により精製し、2-[4-(2-ヒドロキシ-2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸4.8mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm): 1.08(6H,s),2.66(3H,s),3.96(2H,s),4.80(1H,s),7.50(1H,d,J=8.8Hz),8.15(1H,dd,J=2.8,8.8Hz),8.31(1H,d,J=2.4Hz),9.90(1H,s),13.44(1H,brs)
HPLC保持時間:8.29分
Obs Mass(M++H):376.1073
Pred Mass(M++H):376.1074
Formula(M):C16H17N5O4S
実施例24と同様にして、化合物番号31および32を合成した。
(1)5-ブロモ-2-フルオロニトロベンゼン2.20gに炭酸水素化カリウム2.10g、塩化パラジウム(II)44mg、臭化銅(I)ジメチルスルフィド錯体205mgを加え、トルエン20mLに懸濁させた。その後にエチル 4-メチル-1,3-チアゾール-5-カルボキシレート2.05g、イソ酪酸92.5μL及びジ-t-ブチルシクロヘキシルホスフィン228mgを加えて、窒素雰囲気下、120℃で14時間加熱した。反応混合液をセライトろ過して不溶物を取り除き、ろ液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、得られた粗体をシリカゲルカラムクロマトグラフィーで分離精製することで、エチル 2-(4-フルオロ-3-ニトロフェニル)-4-メチル-1,3-チアゾール-5-カルボキシレート2.28gを得た。
ESI/MS m/e:311.0(M++H,C13H12FN2O4S)
(2)エチル 2-(4-フルオロ-3-ニトロフェニル)-4-メチル-1,3-チアゾール-5-カルボキシレート931mg、フェノール339mgおよび炭酸カリウム622mgをジメチルホルムアミド15mLに懸濁させ、窒素雰囲気下、100℃で14時間加熱した。室温まで冷却させた後に反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、得られた粗体をシリカゲルカラムクロマトグラフィーで分離精製することで、エチル 2-(3-ニトロ-4-フェノキシフェニル)-4-メチル-1,3-チアゾール-5-カルボキシレート1.14gを得た。
ESI/MS m/e:385.0(M++H,C19H17N2O5S)
(3)エチル 2-(3-ニトロ-4-フェノキシフェニル)-4-メチル-1,3-チアゾール-5-カルボキシレート1.14gをエタノール15mLに懸濁させ、パラジウム/炭素(10%wt)300mgを加えた後に、水素雰囲気下、室温で14時間撹拌した。反応混合液をセライトろ過し、ろ液を減圧濃縮することで、エチル 2-(3-アミノ-4-フェノキシフェニル)- 4-メチル-1,3-チアゾール-5-カルボキシレート1.05gを得た。
ESI/MS m/e:355.1(M++H,C19H19N2O3S)
(4)エチル 2-(3-アミノ-4-フェノキシフェニル)-4-メチル-1,3-チアゾール-5-カルボキシレート1.05gを用いて、実施例24と同様にして、4-メチル-2-[4-フェノキシ-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸458mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm): 2.67(3H,s),7.11-7.29(4H,m),7.43-7.48(2H,m),8.15(1H,dd,J=2.4,8.8Hz),8.42(1H,d,J=2.0Hz),9.97(1H,s)
HPLC保持時間:10.79分
Obs Mass(M++H):380.0803
Pred Mass(M++H):380.0812
Formula(M):C18H13N5O3S
実施例33と同様にして、化合物番号34-48を合成した。
(1)エチル 2-[4-フルオロ-3-ニトロフェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート155.2mgと炭酸セシウム244.4mgをN,N-ジメチルホルムアミド1.5mLに懸濁させ、2-メチルプロピルチオール49.6mgを加え、窒素雰囲気下、80℃で5時間加熱した。室温まで冷却させた後に反応混合液に水3mLを加え、酢酸エチルで抽出した。有機層を減圧濃縮することでエチル 2-[4-(2-メチルプロピルチオ)-3-ニトロフェニル]-4-メチル-1,3-チアゾール-5-カルボキシレートの粗体を得た。
(2)上記で得られたエチル 2-[4-(2-メチルプロピルチオ)-3-ニトロフェニル]-4-メチル-1,3-チアゾール-5-カルボキシレートの粗体を水素雰囲気下、パラジウム炭素で還元することによりエチル 2-[3-アミノ-4-(2-メチルプロピルチオ)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレートを得た。
(3)上記で得られたエチル 2-[3-アミノ-4-(2-メチルプロピルチオ)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレートを酢酸2.0mLに懸濁させた後、アジ化ナトリウム65mg、オルソギ酸トリエチル148mgを加え、窒素雰囲気下、70℃で5時間加熱した。室温まで冷却させた後に反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に常法により精製し、エチル 4-メチル-2-{4-[(2-メチルプロピル)スルファニル]-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル}-1,3-チアゾール-5-カルボキシレート123mgを得た。
(4)上記で得られたエチル 4-メチル-2-{4-[(2-メチルプロピル)スルファニル]-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル}-1,3-チアゾール-5-カルボキシレート123mgをテトラヒドロフラン/メタノール=1/1の混合溶液2mLに溶解し、2M水酸化ナトリウム水溶液0.5mLを加えて、室温で3時間撹拌した。反応混合液に2M塩酸0.5mLを加えて撹拌した後に、水3mLを加え、酢酸エチルで抽出した。有機相を濃縮した後に常法により精製し、4-メチル-2-{4-[(2-メチルプロピル)スルファニル]-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル}-1,3-チアゾール-5-カルボン酸67.9mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm):0.91(6H,d,J=8.0Hz),1.75(1H,septet,J=8.0Hz),2.66(3H,s),2.93(2H,d,J=8.0Hz),7.78(1H,d,J=8.0Hz),8.17-8.19(2H,m),9.89(1H,s),13.48(1H,brs)
HPLC保持時間:11.19分
Obs Mass(M++H):376.0887
Pred Mass(M++H):376.0896
Formula(M):C16H17N5O2S2
実施例49と同様にして、化合物番号50、51を合成した。
(1)5-ブロモ-2-フルオロニトロベンゼン220mgと炭酸カリウム276mgをN,N-ジメチルホルムアミド2mLに懸濁させ、N,N-ジエチルアミン88mgを加え、窒素雰囲気下、40℃で14時間加熱した。室温まで冷却させた後に反応混合液に水3mLを加え、酢酸エチルで抽出した。有機層を減圧濃縮することで5-ブロモ-2-(N,N-ジエチルアミノ)ニトロベンゼンの粗体を得た。
(2)上記で得られた5-ブロモ-2-(N,N-ジエチルアミノ)ニトロベンゼンの粗体に炭酸水素化カリウム210.3mg、塩化パラジウム(II)5.3mg、臭化銅(I)ジメチルスルフィド錯体49.3mg、2-(ジ-tert-ブチルホスフィノ)ビフェニル21.5mgを加え、トルエン2mLに懸濁させた。その後にエチル 4-メチル-1,3-チアゾール-5-カルボキシレート188.3mg、イソ酪酸10.6mgを加え、窒素雰囲気下、130℃で13時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を減圧濃縮した後に、得られた粗体をシリカゲルカラムクロマトグラフィーで分離精製することで、エチル 2-[4-(N,N-ジエチルアミノ)-3-ニトロフェニル]-4-メチル-1,3-チアゾール-5-カルボキシレート256.1mgを得た
(3)上記で得られたエチル 2-[4-(N,N-ジエチルアミノ)-3-ニトロフェニル]-4-メチル-1,3-チアゾール-5-カルボキシレートを水素雰囲気下、パラジウム炭素で還元することによりエチル 2-[3-アミノ-4-(N,N-ジエチルアミノ)フェニル]-4-メチル-1,3-チアゾール-5-カルボキシレートを得た。
(4)上記で得られたエチル 2-[3-アミノ-4-(N,N-ジエチルアミノ)フェ
ニル]-4-メチル-1,3-チアゾール-5-カルボキシレートを酢酸3.0mLに懸濁させた後、アジ化ナトリウム91.6mg、オルソギ酸トリエチル209.2mgを加え、窒素雰囲気下、70℃で5時間加熱した。室温まで冷却させた後に反応混合液に水および飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に常法により精製し、エチル 2-[4-(N,N-ジエチルアミノ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボキシレート295.9mgを得た。
(5)上記で得られたエチル 2-[4-(N,N-ジエチルアミノ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボキシレート295.9mgをテトラヒドロフラン/メタノール=1/1の混合溶液3mLに溶解し、2M水酸化ナトリウム水溶液2.0mLを加えて、室温で2時間撹拌した。反応混合液に2M塩酸2.0mLを加え、常法により精製することで4-メチル-2-[4-(N,N-ジエチルアミノ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル] -1,3-チアゾール-5-カルボン酸199.9mgを得た。
1H-NMR(400MHz,DMSO d6)δ(ppm):0.85(6H,d,J=8.0Hz),2.64(3H,s),2.80(4H,d,J=8.0Hz),7.41(1H,d,J=8.0Hz),8.02(1H,d,J=4.0Hz),8.08(1H,dd,J=8.0, 4.0Hz),9.82(1H,s)
HPLC保持時間:10.50分
obs Mass(M++H):359.1289
Pred Mass(M++H):359.1285
Formula(M):C16H18N6O2S
実施例52と同様にして、化合物番号53を合成した。
以上の実施例の方法に従って合成された化合物について、キサンチンオキシダーゼ阻害活性を測定した。
(1)試験化合物の調製
試験化合物をDMSO(シグマ社製)に20mMの濃度になるように溶解した後、使用時の目的の濃度に調製して用いた。
(2)測定方法
本発明化合物のキサンチンオキシダーゼ阻害活性評価を文献記載の方法(Method Enzymatic Analysis,1,521-522,1974)を一部改変して実施した。本評価は、オキシダーゼ型のキサンチンオキシドレダクターゼ活性の測定により行われた。すなわち、あらかじめ20mM水酸化ナトリウム溶液にて10mMに調製したキサンチン(シグマ社製)溶液を100mMリン酸緩衝液を用いて30μMに調製し、96穴プレートに75μL/穴ずつ加えた。最終濃度の100倍になるようにDMSOにて希釈した各試験化合物を1.5μL/穴ずつ添加し、ミキシング後にマイクロプレートリーダーSPECTRA max Plus384(モレキュラーデバイス社製)にて290nmの吸光度を測定した。続けてオキシダーゼ型キサンチンオキシドレダクターゼ(バターミルク由来、Calbiochem社製)を100mMリン酸緩衝液を用いて30.6mU/mLに調製し、73.5μL/穴ずつ加えた。ミキシング後速やかに290nmにおける吸光度変化を5分間測定した。試験化合物溶液の代わりにDMSOを添加したときの酵素活性を100%として試験化合物の阻害率を計算し、用量応答曲線にフィットさせてオキシダーゼ型キサンチンオキシドレダクターゼに対する50%阻害濃度を計算した。
この結果を以下の表に示す。但し、表中の記号(+、++、+++)は以下の通りの阻害活性値を表しているものとする。
10.0nM≦IC50:+
5.0nM≦IC50<10.0nM:++
1.0nM≦IC50<5.0nM:+++
血中尿酸低下作用(正常ラット)
化合物番号17、24、25および26の化合物について、血中尿酸低下作用を確認した。8~9週齢のSprague-Dawley系雄性ラット(日本チャールス・リバー株式会社)に0.5%メチルセルロース液に懸濁した試験化合物を経口ゾンデを用いて強制投与した。投与後2時間に尾静脈より採血した後、血漿を分離した。血中尿酸値は尿酸測定キット(LタイプワコーUA・F:和光純薬工業)を用いて、ウリカーゼ法にて吸光度計を用いて測定し、尿酸低下率を下式により求めた。
尿酸低下率(%)=(対照動物の尿酸値-試験化合物投与動物の尿酸値)x100/対照動物の尿酸値
化合物番号17、24、25および26の化合物はいずれも、10mg/kgの用量において尿酸低下率50%以上を示した。
さらに、化合物番号24、25及び26の化合物は1mg/kgの用量においても、尿酸低下率50%以上を示した。
この結果から、本発明の化合物が強力な血中尿酸低下効果を有することが示された。
血中尿酸低下作用の持続性(正常ラット)
化合物番号17、25及び26の化合物を用いて、実施例55と同じ方法でSprague-Dawley系雄性ラットに試験化合物を投与した。投与後24時間に尾静脈より採血した後、血漿を分離した。血中尿酸値は尿酸測定キット(LタイプワコーUA・F:和光純薬工業)を用いて、ウリカーゼ法にて吸光度計を用いて測定し、尿酸低下率を下式により求めた。尿酸低下率(%)
=(対照動物の尿酸値-試験化合物投与動物の尿酸値)x100/対照動物の尿酸値 化合物番号17、25及び26の化合物はいずれも、10mg/kgの用量において、投与後24時間において、尿酸低下率50%以上を示した。
さらに、化合物番号25及び26の化合物はいずれも、3mg/kgの用量においても、投与後24時間において、尿酸低下率40%以上を示した。
この結果から、本発明の化合物が長時間にわたる持続的な血中尿酸低下効果を有することが示された。
血中尿酸低下作用(高尿酸血症ビーグル犬)
化合物番号25について、オキソン酸により高尿酸血症を惹起したビーグル犬における血中尿酸低下作用を確認した。ビーグル犬(北山ラベス)に0.5%メチルセルロース液に懸濁した試験化合物を強制経口投与した。化合物投与前および投与4時間後にオキソン酸カリウム(50mg/kg)を皮下投与した。化合物投与8時間後、橈側皮静脈より採血した後、血漿を分離した。血中尿酸値はLC-MS/MS法を用いて測定し、尿酸低下率を下式により求めた。
尿酸低下率(%)=(対照動物の尿酸値-試験化合物投与動物の尿酸値)x100/対照動物の尿酸値
投与8時間後において、化合物25は10mg/kgの用量において尿酸低下作用を示した。
この結果から、本発明の化合物がイヌにおいて強力な血中尿酸低下効果を有することが示された。
組織および血漿におけるキサンチンオキシダーゼ阻害活性の持続性
本発明の「キサンチンオキシダーゼ」について、本実施例に限り、オキシダーゼ型のキサンチンオキシドレダクターゼが担う酸化反応触媒活性と、オキシダーゼ型とデヒドロゲナーゼ型両方のキサンチンオキシドレダクターゼが担う酸化反応触媒活性とを区別するために、前者を「XO活性」、後者を「XOR活性」と称する。「組織XO活性」、「血漿XO活性」、「組織XO阻害活性」、「組織XOR阻害活性」等についても、「XO活性」および「XOR活性」は同じ意味を有する。「組織」には、肝臓、腎臓、脂肪組織、腸、血管が含まれる。なお、下記の結果より、本発明の化合物について、同一サンプルにおけるXOR活性阻害率とXO活性阻害率は同程度の数値となるものと解される。
化合物番号17、25および26の化合物について、組織XO活性、組織XOR活性および血漿XO活性を確認した。7~9週齢のSprague-Dawley系雄性ラット(日本チャールス・リバー株式会社)に0.5%メチルセルロース液に懸濁した試験化合物を経口ゾンデを用いて強制投与した。投与後24時間または27時間後に腹大動脈からの採血および組織の採材を行った。得られた血液は遠心分離し、血漿を採取した。
組織XO活性、組織XOR活性および血漿XO活性は、pterinがそれぞれの型のキサンチンオキシドレダクターゼにより酸化され蛍光物質であるisoxanthopterinが生成される反応を用いて測定した。組織を各組織濃度が肝臓:25mg/mL、腎臓:25mg/mL、脂肪:5mg/mL、腸:5mg/mL、血管:30mg/mLとなるように、1mMEDTAおよびプロテアーゼ阻害剤を含んだpH7.4のリン酸カリウム溶液でホモジナイズし、4℃、12000rpmで15分遠心した。XO活性の測定時は組織ホモジネートの上清または血漿を50μM pterinを含んだ溶液と混合し37℃で反応させた。XOR活性の測定時は、組織ホモジネートの上清を50μM pterinおよび50μM Methylene Blueを含んだ溶液と混合し37℃で反応させた。コントロールとしてオキシダーゼ型キサンチンオキシドレダクターゼ(バターミルク由来、Calbiochem社製)と50μM pterinを含んだ溶液を同様の方法で反応させた。生成されたisoxanthopterinの蛍光強度を測定し、コントロールの酵素活性およびタンパク濃度で補正しXOまたはXOR活性として算出した。
XO阻害活性およびXOR阻害活性は下式により求めた。
XO阻害活性(%)=(対照動物のXO活性またはXOR活性-試験化合物投与動物のXO活性またはXOR活性)x100/対照動物のXO活性またはXOR活性
化合物17,25,26投与約27時間後の組織および血漿XO阻害活性を次の表に示す。
化合物番号17、25及び26の化合物はいずれも、10mg/kgの用量において、投与後27時間の腎臓のXO活性を対照動物と比較して70%以上阻害した。
化合物番号17、25及び26の化合物はいずれも、10mg/kgの用量において、投与後27時間の血漿のXO活性を対照動物と比較して40%以上阻害した。
また、化合物25は10mg/kgの用量において、投与後24時間の腸のXOR活性を対照動物と比較して80%以上阻害した。
化合物25は10mg/kgの用量において、投与後24時間の脂肪組織のXOR活性を対照動物と比較して60%以上阻害した。
化合物25は10mg/kgの用量において、投与後24時間の血管のXOR活性を対照動物と比較して40%以上阻害した。
化合物25は10mg/kgの用量において、投与後24時間の肝臓のXOR活性およびXO活性それぞれを対照動物と比較して80%以上阻害した。
化合物25は10mg/kgの用量において、投与後24時間の腎臓のXOR活性およびXO活性それぞれを対照動物と比較して70%以上阻害した。
さらに、化合物番号17、25及び26の化合物はいずれも、1mg/kgの用量において、投与後27時間の肝臓のXO活性を対照動物と比較して80%以上阻害した。
化合物番号17、25及び26の化合物はいずれも、1mg/kgの用量において、投与後27時間の腎臓のXO活性を対照動物と比較して60%以上阻害した。
化合物番号17、25及び26の化合物はいずれも、1mg/kgの用量において、投与後27時間の血漿のXO活性を対照動物と比較して25%以上阻害した。
また、化合物25は1mg/kgの用量において、投与後24時間の腸XOR活性を対照動物と比較して60%以上阻害した。
化合物25は1mg/kgの用量において、投与後24時間の脂肪組織XOR活性を対照動物と比較して30%以上阻害した。
化合物25は1mg/kgの用量において、投与後24時間の血管XOR活性を対照動物と比較して25%以上阻害した。
化合物25は1mg/kgの用量において、投与後24時間の肝臓のXOR活性およびXO活性それぞれを対照動物と比較して80%以上阻害した。
化合物25は1mg/kgの用量において、投与後24時間の腎臓のXOR活性およびXO活性それぞれを対照動物と比較して60%以上阻害した。
この結果から、本発明の化合物が長時間にわたる持続的なXO活性、XOR活性阻害作用を有することが示された。
Claims (19)
- 式(I)で表される化合物またはその製薬学的に許容される塩。
R1は、OR、環を形成していてもよいNRR’、またはSRを表し、ここで、RおよびR’は、独立して、水素原子、1もしくは複数の炭素数1~8のアルコキシ基、ハロゲン原子もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基、1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいアリール基、または1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいヘテロアリール基を表す。
R2は、水素原子または炭素数1~8のアルキル基を表す。
X1、X2、およびX3は、独立して、CR3もしくは窒素原子であるか、またはX1がCR3もしくは窒素原子であり、X2とX3が一緒になってベンゼン環を形成する。ここで、R3は、水素原子または炭素数1~8のアルキル基を表す。] - R1がORである、請求項1に記載の化合物またはその製薬学的に許容される塩。
- R1がSRである、請求項1に記載の化合物またはその製薬学的に許容される塩。
- R1が、環を形成していてもよいNRR’である、請求項1に記載の化合物またはその製薬学的に許容される塩。
- RおよびR’が、独立して、1もしくは複数の炭素数1~8のアルコキシ基、ハロゲン原子もしくは水酸基で置換されていてもよい炭素数1-8のアルキル基、または1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいアリール基である、請求項1~4のいずれかに記載の化合物またはその製薬学的に許容される塩。
- RおよびR’が、独立して、1もしくは複数の炭素数1~8のアルコキシ基、ハロゲン原子もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基である、請求項5に記載の化合物またはその製薬学的に許容される塩。
- R1が、ORまたはSRであり、Rが、イソプロピル基、イソブチル基またはネオペンチル基である、請求項6に記載の化合物またはその製薬学的に許容される塩。
- R2が、水素原子または炭素数1~3のアルキル基である、請求項1~7のいずれかに記載の化合物またはその製薬学的に許容される塩。
- R2がメチル基である、請求項8に記載の化合物またはその製薬学的に許容される塩。
- X1、X2、およびX3が、独立して、CR3または窒素原子である、請求項1~9のいずれかに記載の化合物またはその製薬学的に許容される塩。
- X1が窒素原子であり、X2がCR3または窒素原子であり、X3がCR3である、請求項10に記載の化合物またはその製薬学的に許容される塩。
- R3が水素原子である、請求項1~11のいずれかに記載の化合物またはその製薬学的に許容される塩。
- 以下の(1)~(53)より選択されるいずれかの化合物またはその製薬学的に許容される塩。
(1) 2-[3-(1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(2) 2-[4-(2,2-ジメチルプロポキシ)-3-(1H-イミダゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(3) 2-[4-(シクロブチルメトキシ)-3-(1H-イミダゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(4) 2-[4-(シクロペンチルメトキシ)-3-(1H-イミダゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(5) 2-[4-(シクロペンチルオキシ)-3-(1H-イミダゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(6) 2-[4-(シクロヘキシルオキシ)-3-(1H-イミダゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(7) 2-[3-(1H-イミダゾール-1-イル)-4-フェノキシフェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(8) 2-[4-(2-フルオロフェノキシ)-3-(1H-イミダゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(9) 4-メチル-2-[3-(2-メチル-1H-イミダゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-1,3-チアゾール-5-カルボン酸
(10) 4-メチル-2-[3-(5-メチル-1H-1,2,3,4-テトラゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-1,3-チアゾール-5-カルボン酸
(11) 2-[3-(1H-1,3-ベンゾジアゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(12) 4-メチル-2-[3-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-1,3-チアゾール-5-カルボン酸
(13) 4-メチル-2-[4-(2-メチルプロポキシ)-3-(1H-1,2,4-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(14) 4-メチル-2-[3-(5-メチル-1H-1,2,4-トリアゾール-1-イル)-4-(2-メチルプロポキシ)フェニル]-1,3-チアゾール-5-カルボン酸
(15) 4-メチル-2-[4-フェノキシ-3-(1H-1,2,4-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(16) 4-メチル-2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(17) 4-メチル-2-[4-(2-メチルプロポキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(18) 2-[4-(2,2-ジメチルプロポキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(19) 2-[4-(シクロブチルメトキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(20) 2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(21) 2-[4-(2-メチルプロポキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(22) 4-メチル-2-[4-フェノキシ-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(23) 2-[4-(2-フルオロフェノキシ)-3-(1H-1,2,3-トリアゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(24) 4-メチル-2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(25) 4-メチル-2-[4-(2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(26) 2-[4-(2,2-ジメチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(27) 2-[4-(シクロブチルメトキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(28) 2-[4-(シクロペンチルオキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(29)2-[4-(3-ヒドロキシ-2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(30)2-[4-(2-ヒドロキシ-2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(31)2-[4-(プロパン-2-イルオキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(32) 2-[4-(2-メチルプロポキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(33) 4-メチル-2-[4-フェノキシ-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(34) 2-[4-(2-フルオロフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(35) 2-[4-(2-メトキシフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(36) 2-[4-(2,6-ジフルオロフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(37) 2-[4-(3-フルオロフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(38) 2-[4-(3-メチルフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(39) 2-[4-(2-クロロフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(40) 2-[4-(4-フルオロ-3-メチルフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-
カルボン酸
(41) 2-[4-(4-フルオロ-2-メチルフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-
カルボン酸
(42) 2-[4-(2,4-ジフルオロフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(43) 2-[4-(2-フルオロ-6-メトキシフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5
-カルボン酸
(44) 2-[4-(2-メチルフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(45) 2-[4-(4-メチルフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(46) 2-[4-(3-フルオロ-5-メチルフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-
カルボン酸
(47) 2-[4-(2,5-ジフルオロフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(48) 2-[4-(2-フルオロ-5-メチルフェノキシ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-
カルボン酸
(49) 4-メチル-2-{4-[(2-メチルプロピル)スルファニル]-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル}-1,3-チアゾール-5-カルボン酸
(50) 4-メチル-2-[4-(プロパン-2-イルスルファニル)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸
(51) 4-メチル-2-{4-[(4-メチルフェニル)スルファニル]-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル}-1,3-チアゾール-5-カルボン酸
(52) 2-[4-(N,N-ジエチルアミノ)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-メチル-1,3-チアゾール-5-カルボン酸
(53) 4-メチル-2-[4-(ピロリジン-1-イル)-3-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-1,3-チアゾール-5-カルボン酸 - 請求項1~13のいずれかに記載の化合物またはその製薬学的に許容される塩と、製薬学的に許容される担体を含有する、医薬組成物。
- 請求項1~13のいずれかに記載の化合物またはその製薬学的に許容される塩を有効成分として含有する、キサンチンオキシダーゼ阻害剤。
- 請求項1~13のいずれかに記載の化合物またはその製薬学的に許容される塩を有効成分として含有する、痛風、高尿酸血症、腫瘍崩壊症候群、尿路結石、高血圧症、脂質異常症、糖尿病、心血管疾患、腎疾患、呼吸器疾患、炎症性腸疾患または自己免疫性疾患の治療薬または予防薬。
- 請求項1~13のいずれかに記載の化合物またはその製薬学的に許容される塩を有効成分として含有する、痛風または高尿酸血症の治療薬または予防薬。
- 式(II)で表される化合物。
R1は、OR、環を形成していてもよいNRR’、またはSRを表し、ここで、RおよびR’は、独立して、水素原子、1もしくは複数の炭素数1~8のアルコキシ基、ハロゲン原子もしくは水酸基で置換されていてもよい炭素数1~8のアルキル基、1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいアリール基、または1もしくは複数の炭素数1~8のアルキル基、炭素数1~8のアルコキシ基もしくはハロゲン原子で置換されていてもよいヘテロアリール基を表す。
R2は、水素原子または炭素数1~8のアルキル基を表す。
X1、X2、およびX3は、独立してCR3もしくは窒素原子であるか、またはX1がCR3もしくは窒素原子であり、X2とX3が一緒になってベンゼン環を形成する。ここで、R3は、水素原子または炭素数1~8のアルキル基を表す。
R4は、カルボキシル基の保護基を表す。]
Priority Applications (31)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020157019782A KR102199258B1 (ko) | 2013-01-31 | 2014-01-30 | 아졸벤젠 유도체 |
EP14746209.7A EP2952513B1 (en) | 2013-01-31 | 2014-01-30 | Azole benzene derivative |
LT14746209T LT2952513T (lt) | 2013-01-31 | 2014-01-30 | Azolo benzeno darinys |
SI201431281T SI2952513T1 (sl) | 2013-01-31 | 2014-01-30 | Derivati azol benzena |
ES14746209T ES2744817T3 (es) | 2013-01-31 | 2014-01-30 | Derivado de azol benceno |
MYPI2015702266A MY181731A (en) | 2013-01-31 | 2014-01-30 | Azole benzene derivative |
AU2014213396A AU2014213396B2 (en) | 2013-01-31 | 2014-01-30 | Azole benzene derivative |
NZ70940714A NZ709407A (en) | 2013-01-31 | 2014-01-30 | Azole benzene derivative |
CA2897928A CA2897928C (en) | 2013-01-31 | 2014-01-30 | Azole benzene derivative having xanthine oxidase inhibitory activity |
JP2014557920A JP5734532B2 (ja) | 2013-01-31 | 2014-01-30 | アゾールベンゼン誘導体 |
DK14746209.7T DK2952513T3 (da) | 2013-01-31 | 2014-01-30 | Azolbenzenderivat |
RSP20191244 RS59371B1 (sr) | 2013-01-31 | 2014-01-30 | Derivat azol benzena |
UAA201507650A UA117124C2 (uk) | 2013-01-31 | 2014-01-30 | Азолові похідні бензолу |
RU2015132105A RU2641891C2 (ru) | 2013-01-31 | 2014-01-30 | Азоловые производные бензола |
MEP-2019-262A ME03516B (me) | 2013-01-31 | 2014-01-30 | Derivat azol benzena |
PL14746209T PL2952513T3 (pl) | 2013-01-31 | 2014-01-30 | Azolowe pochodne benzenu |
MX2015009655A MX364483B (es) | 2013-01-31 | 2014-01-30 | Derivado de azol benceno. |
US14/442,752 US9388174B2 (en) | 2013-01-31 | 2014-01-30 | Azole benzene derivative |
CN201480006601.1A CN104968662B (zh) | 2013-01-31 | 2014-01-30 | 唑苯衍生物 |
BR112015018033-7A BR112015018033B1 (pt) | 2013-01-31 | 2014-01-30 | Composto, composição farmacêutica, e, uso de um composto |
MA38295A MA38295B1 (fr) | 2013-01-31 | 2014-01-30 | Dérivé d'azole et de benzène |
SG11201505993PA SG11201505993PA (en) | 2013-01-31 | 2014-01-30 | Azole benzene derivative |
IL239940A IL239940B (en) | 2013-01-31 | 2015-07-14 | History of 2-[3-(diazolyl)phenyl]-3,1-thiazole-5-carboxylic acid and intermediates obtained in the process for their preparation |
ZA2015/05240A ZA201505240B (en) | 2013-01-31 | 2015-07-21 | Azole benzene derivative |
PH12015501640A PH12015501640A1 (en) | 2013-01-31 | 2015-07-23 | Azole benzene derivative |
SA515360829A SA515360829B1 (ar) | 2013-01-31 | 2015-07-29 | مشتق بنزين أزول |
HK16103729.4A HK1215806A1 (zh) | 2013-01-31 | 2016-04-01 | 唑苯衍生物 |
PH12018500261A PH12018500261B1 (en) | 2013-01-31 | 2018-02-05 | Azole benzene derivative |
IL259824A IL259824B (en) | 2013-01-31 | 2018-06-05 | History of 2-[3-(azolyl)phenyl]-3,1-thiazole-5-carboxylic acid for use as drugs |
HRP20191554 HRP20191554T1 (hr) | 2013-01-31 | 2019-08-28 | Derivat azol benzena |
CY20191100944T CY1122015T1 (el) | 2013-01-31 | 2019-09-10 | Παραγωγο αζολιου βενζολιου |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013-017167 | 2013-01-31 | ||
JP2013017167 | 2013-01-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014119681A1 true WO2014119681A1 (ja) | 2014-08-07 |
Family
ID=51262388
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2014/052154 WO2014119681A1 (ja) | 2013-01-31 | 2014-01-30 | アゾールベンゼン誘導体 |
Country Status (36)
Country | Link |
---|---|
US (1) | US9388174B2 (ja) |
EP (1) | EP2952513B1 (ja) |
JP (1) | JP5734532B2 (ja) |
KR (1) | KR102199258B1 (ja) |
CN (1) | CN104968662B (ja) |
AR (1) | AR095098A1 (ja) |
AU (1) | AU2014213396B2 (ja) |
BR (1) | BR112015018033B1 (ja) |
CA (1) | CA2897928C (ja) |
CL (1) | CL2015002117A1 (ja) |
CY (1) | CY1122015T1 (ja) |
DK (1) | DK2952513T3 (ja) |
ES (1) | ES2744817T3 (ja) |
HK (1) | HK1215806A1 (ja) |
HR (1) | HRP20191554T1 (ja) |
HU (1) | HUE047028T2 (ja) |
IL (2) | IL239940B (ja) |
LT (1) | LT2952513T (ja) |
MA (1) | MA38295B1 (ja) |
ME (1) | ME03516B (ja) |
MX (1) | MX364483B (ja) |
MY (1) | MY181731A (ja) |
NZ (1) | NZ709407A (ja) |
PE (1) | PE20151329A1 (ja) |
PH (2) | PH12015501640A1 (ja) |
PL (1) | PL2952513T3 (ja) |
PT (1) | PT2952513T (ja) |
RS (1) | RS59371B1 (ja) |
RU (1) | RU2641891C2 (ja) |
SA (1) | SA515360829B1 (ja) |
SG (1) | SG11201505993PA (ja) |
SI (1) | SI2952513T1 (ja) |
TW (1) | TWI606048B (ja) |
UA (1) | UA117124C2 (ja) |
WO (1) | WO2014119681A1 (ja) |
ZA (1) | ZA201505240B (ja) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016017696A1 (ja) * | 2014-07-30 | 2016-02-04 | 帝人ファーマ株式会社 | アゾールベンゼン誘導体の結晶 |
WO2016017826A1 (ja) * | 2014-07-30 | 2016-02-04 | 帝人ファーマ株式会社 | キサンチンオキシダーゼ阻害薬 |
WO2016017708A1 (ja) * | 2014-07-30 | 2016-02-04 | 帝人ファーマ株式会社 | アゾールベンゼン誘導体およびその結晶 |
WO2017142091A1 (ja) | 2016-02-19 | 2017-08-24 | 国立大学法人鳥取大学 | 認知症治療薬または予防薬 |
WO2018097294A1 (ja) | 2016-11-28 | 2018-05-31 | 帝人ファーマ株式会社 | 糖尿病性腎症の治療薬または予防薬 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20151781A1 (es) | 2013-01-31 | 2015-12-02 | Vertex Pharma | Piridonamidas como moduladores de canales de sodio |
KR102435145B1 (ko) | 2013-12-13 | 2022-08-24 | 버텍스 파마슈티칼스 인코포레이티드 | 나트륨 채널의 조절제로서의 피리돈 아미드의 프로드럭 |
IL270680B (en) | 2017-05-16 | 2022-06-01 | Vertex Pharma | Deuterium-converted pyridone amides and their prodrugs as sodium channel modulators |
US20190343817A1 (en) | 2018-02-12 | 2019-11-14 | Vertex Pharmaceuticals Incorporated | Method of treating pain |
BR112022010924A2 (pt) | 2019-12-06 | 2022-09-06 | Vertex Pharma | Tetra-hidrofuranos substituídos como moduladores de canais de sódio |
PE20241335A1 (es) | 2021-06-04 | 2024-07-03 | Vertex Pharma | N-(hidroxialquil (hetero)aril) tetrahidrofurano carboxamidas como moduladores de canales de sodio |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992009279A1 (en) | 1990-11-30 | 1992-06-11 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
WO1996031211A1 (fr) | 1995-04-07 | 1996-10-10 | Teijin Limited | Agent protecteur pour organe ou tissu |
JP2002105067A (ja) | 2000-09-28 | 2002-04-10 | Teijin Ltd | 2−フェニルチアゾール誘導体、およびそれを有効成分とする医薬組成物 |
WO2007043400A1 (ja) * | 2005-10-07 | 2007-04-19 | Kissei Pharmaceutical Co., Ltd. | 含窒素芳香族複素環化合物およびそれを含有する医薬組成物 |
WO2008126770A1 (ja) * | 2007-04-05 | 2008-10-23 | Astellas Pharma Inc. | トリアリールカルボン酸誘導体の製造方法 |
WO2008126899A1 (ja) * | 2007-04-11 | 2008-10-23 | Kissei Pharmaceutical Co., Ltd. | 5員環へテロ環誘導体及びその医薬用途 |
WO2010018458A2 (en) | 2008-08-12 | 2010-02-18 | Crystalgenomics, Inc. | Phenol derivatives and methods of use thereof |
WO2010128163A2 (en) | 2009-05-08 | 2010-11-11 | Pike Pharma Gmbh | Small molecule inhibitors of influenza a and b virus and respiratory syncytial virus replication |
WO2011101867A2 (en) | 2010-02-19 | 2011-08-25 | Cadila Healthcare Limited | Substantially pure salts of febuxostat and processes for preparation thereof |
WO2011139886A2 (en) | 2010-04-29 | 2011-11-10 | Dr. Reddy's Laboratories Ltd. | Preparation of febuxostat |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SK282425B6 (sk) * | 1995-04-21 | 2002-01-07 | Neurosearch A/S | Benzimidazolové zlúčeniny, farmaceutické zmesi obsahujúce tieto zlúčeniny a použitie týchto zlúčenín |
-
2014
- 2014-01-29 TW TW103103559A patent/TWI606048B/zh active
- 2014-01-30 ES ES14746209T patent/ES2744817T3/es active Active
- 2014-01-30 MY MYPI2015702266A patent/MY181731A/en unknown
- 2014-01-30 PL PL14746209T patent/PL2952513T3/pl unknown
- 2014-01-30 WO PCT/JP2014/052154 patent/WO2014119681A1/ja active Application Filing
- 2014-01-30 KR KR1020157019782A patent/KR102199258B1/ko active IP Right Grant
- 2014-01-30 SI SI201431281T patent/SI2952513T1/sl unknown
- 2014-01-30 EP EP14746209.7A patent/EP2952513B1/en active Active
- 2014-01-30 UA UAA201507650A patent/UA117124C2/uk unknown
- 2014-01-30 MX MX2015009655A patent/MX364483B/es active IP Right Grant
- 2014-01-30 CA CA2897928A patent/CA2897928C/en active Active
- 2014-01-30 AR ARP140100314A patent/AR095098A1/es unknown
- 2014-01-30 BR BR112015018033-7A patent/BR112015018033B1/pt active IP Right Grant
- 2014-01-30 RU RU2015132105A patent/RU2641891C2/ru active
- 2014-01-30 MA MA38295A patent/MA38295B1/fr unknown
- 2014-01-30 NZ NZ70940714A patent/NZ709407A/en not_active IP Right Cessation
- 2014-01-30 HU HUE14746209A patent/HUE047028T2/hu unknown
- 2014-01-30 ME MEP-2019-262A patent/ME03516B/me unknown
- 2014-01-30 PE PE2015001576A patent/PE20151329A1/es active IP Right Grant
- 2014-01-30 LT LT14746209T patent/LT2952513T/lt unknown
- 2014-01-30 JP JP2014557920A patent/JP5734532B2/ja active Active
- 2014-01-30 PT PT14746209T patent/PT2952513T/pt unknown
- 2014-01-30 RS RSP20191244 patent/RS59371B1/sr unknown
- 2014-01-30 CN CN201480006601.1A patent/CN104968662B/zh active Active
- 2014-01-30 AU AU2014213396A patent/AU2014213396B2/en active Active
- 2014-01-30 DK DK14746209.7T patent/DK2952513T3/da active
- 2014-01-30 US US14/442,752 patent/US9388174B2/en active Active
- 2014-01-30 SG SG11201505993PA patent/SG11201505993PA/en unknown
-
2015
- 2015-07-14 IL IL239940A patent/IL239940B/en active IP Right Grant
- 2015-07-21 ZA ZA2015/05240A patent/ZA201505240B/en unknown
- 2015-07-23 PH PH12015501640A patent/PH12015501640A1/en unknown
- 2015-07-29 SA SA515360829A patent/SA515360829B1/ar unknown
- 2015-07-29 CL CL2015002117A patent/CL2015002117A1/es unknown
-
2016
- 2016-04-01 HK HK16103729.4A patent/HK1215806A1/zh unknown
-
2018
- 2018-02-05 PH PH12018500261A patent/PH12018500261B1/en unknown
- 2018-06-05 IL IL259824A patent/IL259824B/en active IP Right Grant
-
2019
- 2019-08-28 HR HRP20191554 patent/HRP20191554T1/hr unknown
- 2019-09-10 CY CY20191100944T patent/CY1122015T1/el unknown
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992009279A1 (en) | 1990-11-30 | 1992-06-11 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
WO1996031211A1 (fr) | 1995-04-07 | 1996-10-10 | Teijin Limited | Agent protecteur pour organe ou tissu |
JP2002105067A (ja) | 2000-09-28 | 2002-04-10 | Teijin Ltd | 2−フェニルチアゾール誘導体、およびそれを有効成分とする医薬組成物 |
WO2007043400A1 (ja) * | 2005-10-07 | 2007-04-19 | Kissei Pharmaceutical Co., Ltd. | 含窒素芳香族複素環化合物およびそれを含有する医薬組成物 |
WO2008126770A1 (ja) * | 2007-04-05 | 2008-10-23 | Astellas Pharma Inc. | トリアリールカルボン酸誘導体の製造方法 |
WO2008126899A1 (ja) * | 2007-04-11 | 2008-10-23 | Kissei Pharmaceutical Co., Ltd. | 5員環へテロ環誘導体及びその医薬用途 |
WO2010018458A2 (en) | 2008-08-12 | 2010-02-18 | Crystalgenomics, Inc. | Phenol derivatives and methods of use thereof |
WO2010128163A2 (en) | 2009-05-08 | 2010-11-11 | Pike Pharma Gmbh | Small molecule inhibitors of influenza a and b virus and respiratory syncytial virus replication |
WO2011101867A2 (en) | 2010-02-19 | 2011-08-25 | Cadila Healthcare Limited | Substantially pure salts of febuxostat and processes for preparation thereof |
WO2011139886A2 (en) | 2010-04-29 | 2011-11-10 | Dr. Reddy's Laboratories Ltd. | Preparation of febuxostat |
Non-Patent Citations (6)
Title |
---|
.: "PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION,", JOHN WILEY & SONS, INC |
CIRCULATION, vol. 114, 2006, pages 2508 - 2516 |
HETEROCYCLES, vol. 48, no. 4, 1998, pages 695 - 702 |
METHOD ENZYMATIC ANALYSIS, vol. 1, 1974, pages 521 - 522 |
NIPPON RINSHO, vol. 61, no. 1, 2003, pages 197 - 201 |
See also references of EP2952513A4 |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9815826B2 (en) | 2014-07-30 | 2017-11-14 | Teijin Pharma Limited | Crystal of azole benzene derivative |
US10179780B2 (en) | 2014-07-30 | 2019-01-15 | Teijin Pharma Limited | Azole benzene derivative and crystalline form thereof |
WO2016017708A1 (ja) * | 2014-07-30 | 2016-02-04 | 帝人ファーマ株式会社 | アゾールベンゼン誘導体およびその結晶 |
CN106536519A (zh) * | 2014-07-30 | 2017-03-22 | 帝人制药株式会社 | 唑苯衍生物的晶体 |
KR20170033320A (ko) * | 2014-07-30 | 2017-03-24 | 데이진 화-마 가부시키가이샤 | 아조르벤젠 유도체 및 그 결정 |
KR102474325B1 (ko) | 2014-07-30 | 2022-12-05 | 데이진 화-마 가부시키가이샤 | 아조르벤젠 유도체 및 그 결정 |
WO2016017826A1 (ja) * | 2014-07-30 | 2016-02-04 | 帝人ファーマ株式会社 | キサンチンオキシダーゼ阻害薬 |
AU2015297489B2 (en) * | 2014-07-30 | 2019-09-19 | Teijin Limited | Crystal of azole benzene derivative |
WO2016017696A1 (ja) * | 2014-07-30 | 2016-02-04 | 帝人ファーマ株式会社 | アゾールベンゼン誘導体の結晶 |
US10301300B2 (en) | 2014-07-30 | 2019-05-28 | Teijin Limited | Xanthine oxidase inhibitor |
US11344539B2 (en) | 2016-02-19 | 2022-05-31 | National University Corporation Tottori University | Therapeutic or prophylactic drug for dementia |
WO2017142091A1 (ja) | 2016-02-19 | 2017-08-24 | 国立大学法人鳥取大学 | 認知症治療薬または予防薬 |
KR20190073473A (ko) | 2016-11-28 | 2019-06-26 | 데이진 화-마 가부시키가이샤 | 당뇨병성 신증의 치료약 또는 예방약 |
JPWO2018097294A1 (ja) * | 2016-11-28 | 2019-07-11 | 帝人ファーマ株式会社 | 糖尿病性腎症の治療薬または予防薬 |
WO2018097294A1 (ja) | 2016-11-28 | 2018-05-31 | 帝人ファーマ株式会社 | 糖尿病性腎症の治療薬または予防薬 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5734532B2 (ja) | アゾールベンゼン誘導体 | |
JP6134072B2 (ja) | キサンチンオキシダーゼ阻害薬 | |
JP6230713B2 (ja) | アゾールベンゼン誘導体の結晶 | |
JP6091603B2 (ja) | ピラゾール誘導体 | |
RU2701515C2 (ru) | Производное азолобензола и его кристаллическая форма | |
WO2016017699A1 (ja) | アゾールカルボン酸誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14746209 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2014557920 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14442752 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2897928 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 239940 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 20157019782 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2014213396 Country of ref document: AU Date of ref document: 20140130 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 38295 Country of ref document: MA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2015/009655 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15173318 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2014746209 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: P968/2015 Country of ref document: AE Ref document number: 001576-2015 Country of ref document: PE |
|
ENP | Entry into the national phase |
Ref document number: 2015132105 Country of ref document: RU Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: IDP00201504724 Country of ref document: ID |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112015018033 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201507650 Country of ref document: UA |
|
ENP | Entry into the national phase |
Ref document number: 112015018033 Country of ref document: BR Kind code of ref document: A2 Effective date: 20150728 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12018500261 Country of ref document: PH |