WO2014077285A1 - ピリジン誘導体 - Google Patents
ピリジン誘導体 Download PDFInfo
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- WO2014077285A1 WO2014077285A1 PCT/JP2013/080706 JP2013080706W WO2014077285A1 WO 2014077285 A1 WO2014077285 A1 WO 2014077285A1 JP 2013080706 W JP2013080706 W JP 2013080706W WO 2014077285 A1 WO2014077285 A1 WO 2014077285A1
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- imidazole
- carboxylic acid
- methyl
- dichlorobenzyl
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- 0 CC(*)C(*)c1ccccc1 Chemical compound CC(*)C(*)c1ccccc1 0.000 description 4
- XCADABREZOMZON-UHFFFAOYSA-N CCN(CC)Cc1c(C(O)=O)[n](Cc(cc(cc2)Cl)c2Cl)c(-c2cc(Cl)cnc2)n1 Chemical compound CCN(CC)Cc1c(C(O)=O)[n](Cc(cc(cc2)Cl)c2Cl)c(-c2cc(Cl)cnc2)n1 XCADABREZOMZON-UHFFFAOYSA-N 0.000 description 1
- CVHULNTZGUQUOH-UHFFFAOYSA-N CCN(CC)Cc1c(C(OC)=O)[n](Cc(cc(cc2)Cl)c2Cl)c(-c2cc(Cl)cnc2)n1 Chemical compound CCN(CC)Cc1c(C(OC)=O)[n](Cc(cc(cc2)Cl)c2Cl)c(-c2cc(Cl)cnc2)n1 CVHULNTZGUQUOH-UHFFFAOYSA-N 0.000 description 1
- OFRSZTUDKLDCCM-UHFFFAOYSA-N CCNC1(CCC1)O Chemical compound CCNC1(CCC1)O OFRSZTUDKLDCCM-UHFFFAOYSA-N 0.000 description 1
- ONYREYXVQCJIGY-UHFFFAOYSA-N COC(c1c(CBr)nc(-c2cncc(Cl)c2)[n]1Cc(cc(cc1)Cl)c1Cl)=O Chemical compound COC(c1c(CBr)nc(-c2cncc(Cl)c2)[n]1Cc(cc(cc1)Cl)c1Cl)=O ONYREYXVQCJIGY-UHFFFAOYSA-N 0.000 description 1
- YGZVKEJMLUDIMI-UHFFFAOYSA-N COC(c1c(CO)nc(-c2cc(Cl)cnc2)[n]1Cc(cc(cc1)Cl)c1Cl)=O Chemical compound COC(c1c(CO)nc(-c2cc(Cl)cnc2)[n]1Cc(cc(cc1)Cl)c1Cl)=O YGZVKEJMLUDIMI-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Definitions
- the present invention relates to a pyridine derivative useful as a pharmaceutical product. More specifically, it has URAT1 inhibitory activity, and is associated with URAT1-related diseases such as gout, hyperuricemia, hypertension, interstitial nephritis, and other renal diseases, such as diabetes, arteriosclerosis, or Lesch-Nyhan syndrome.
- URAT1-related diseases such as gout, hyperuricemia, hypertension, interstitial nephritis, and other renal diseases, such as diabetes, arteriosclerosis, or Lesch-Nyhan syndrome.
- the present invention relates to a pyridine derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof useful for treatment or prevention.
- Uric acid is the final product produced by the degradation of purines in the liver.
- the main excretion route of uric acid in the living body is kidney, about 2/3 is excreted in urine, and the rest is excreted from feces.
- blood uric acid levels in healthy individuals are maintained, hyperuricemia occurs due to excessive uric acid production or decreased uric acid excretion.
- Hyperuricemia which results in a high blood uric acid level, is a factor that causes gout and urinary calculi, and is also said to be a cause of kidney damage and arteriosclerosis.
- a gene (SLC22A12) encoding a human kidney urate transporter has been identified.
- the transporter (ureate transporter 1, URAT1) encoded by this gene is a 12-transmembrane molecule belonging to the OAT family, which expresses mRNA specifically in the kidney, and further, the proximal tubule in human kidney tissue sections Localization on the luminal side was observed.
- Experiments using the Xenopus oocyte expression system showed uric acid uptake via URAT1.
- probenecid or benzbromarone that inhibits URAT1 is useful as a therapeutic or prophylactic agent for hyperuricemia and gout (Non-patent Document 2).
- An object of the present invention is to provide a novel compound having URAT1 inhibitory activity. Another object of the present invention is to provide gout, hyperuricemia, hypertension, interstitial nephritis and other renal diseases such as gout, hyperuricemia, interstitial nephritis, diabetes, arteriosclerosis, or To provide a therapeutic or prophylactic agent for diseases involving URAT1, such as Lesch-Nyhan syndrome.
- the present invention is a pyridine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof.
- A represents a single bond, an oxygen atom, a sulfur atom, NH or CH 2 .
- R 1 represents a nitrogen atom or CH.
- X 1 to X 5 one represents a nitrogen atom and the remaining four represent CR 2 .
- R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group, A cyano group, an alkylcarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a nitro group, an amino group, a dialkylamino group having 1 to 6 carbon atoms which may form a ring, a formyl group, A hydroxyl group, an alkoxy group having 1-6 carbon atoms (which may be substituted by one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1-6 carbon atoms, a phenyl group (carbon
- R 2 when two CR 2 are adjacent to each other, R 2 may be bonded to each other to form a ring.
- R 3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (hydroxyl group, amino group, dialkylamino group having 1 to 6 carbon atoms which may form a ring, imidazole ring, pyrazole ring, pyrrolidine ring, piperidine ring, Substituted by one or more of a morpholine ring and a piperazine ring (which may be substituted by one or more of a C 1-6 alkyl group and a C 1-6 alkylsulfonyl group)
- the alkenyl group having 2-6 carbon atoms, the alkynyl group having 2-6 carbon atoms, the alkoxy group having 1-6 carbon atoms (which may be substituted with one or more of a hydroxyl group and a halogen atom).
- R 4 represents a carboxyl group,
- R 3 is a C 1-6 alkyl group substituted with a hydroxyl group and R 4 is a carboxyl group
- R 3 and R 4 may be condensed to form a lactone ring.
- R 5 in R 3 and R 4 each independently represents an alkyl group having 1 to 6 carbon atoms.
- Z represents any of the substituents represented by the following Z1 to Z7.
- each of R 6 and R 7 independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, or a cyano group.
- R 6 and R 7 are hydrogen atoms at the same time is excluded.
- R 8 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- R 9 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- R 10 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- R 11 and R 12 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- R 13 and R 14 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- R 15 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- Y represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- W represents a sulfur atom, an oxygen atom or NR 16 (R 16 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group).
- the present invention also provides a prodrug of a pyridine derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof.
- a pharmaceutical composition comprising a pyridine derivative represented by the above formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
- the present invention is represented by the following formulas (II) and (III) useful for the synthesis of a pyridine derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof.
- a compound is provided.
- R 1 and R 3 are the same as defined in formula (I).
- R 17 represents a chlorine atom, a bromine atom or an iodine atom.
- R 18 represents a formyl group or —CO 2 R 5 .
- R 5 in R 3 and R 18 each independently represents an alkyl group having 1 to 6 carbon atoms.
- Z represents any of the substituents represented by the following Z1 to Z7.
- R 6 -R 15 , Y and W are the same as defined in formula (I).
- 2-chloro-1- (thiophen-2-ylmethyl) -1H-pyrrole-5-carbaldehyde, ethyl 2-bromo-1- (4-methylbenzyl) -1H-pyrrole-5-carboxylate, and dimethyl Except 2-bromo-1- (2-chlorobenzyl) -1H-imidazole-4,5-dicarboxylate. ]
- R 19 represents —CO 2 R 5 .
- R 5 in R 3 and R 19 each independently represents an alkyl group having 1 to 6 carbon atoms.
- Za is 2,5-dichlorobenzyl group, 3,5-dichlorobenzyl group, 2,5-dimethylbenzyl group, 2,5-bis (trifluoromethyl) benzyl group, 2-chloro-5-methylbenzyl group, Naphthalen-1-ylmethyl group, (2-methylnaphthalen-1-yl) methyl group, (4-methylnaphthalen-1-yl) methyl group, (8-methylnaphthalen-1-yl) methyl group, (8-bromo) Naphthalen-1-yl) methyl group, benzo [b] thiophen-3-ylmethyl group, (4-methylbenzo [b] thiophen-3-yl) methyl group, (4-chlorobenzo [b] thiophen-3-yl) methyl Group, (4-bromobenzo [b] thioph
- a therapeutic or prophylactic agent for diseases involving URAT1 such as gout, hyperuricemia, hypertension, renal disease such as interstitial nephritis, diabetes, arteriosclerosis, or Lesch-Nyhan syndrome
- diseases involving URAT1 such as gout, hyperuricemia, hypertension, renal disease such as interstitial nephritis, diabetes, arteriosclerosis, or Lesch-Nyhan syndrome
- URAT1 diseases involving URAT1
- gout hyperuricemia
- hypertension such as interstitial nephritis
- renal disease such as interstitial nephritis
- diabetes arteriosclerosis
- Lesch-Nyhan syndrome Useful novel pyridine derivatives or prodrugs thereof, or pharmaceutically acceptable salts thereof, or solvates thereof are provided.
- the alkyl group in the present invention refers to a linear, branched, or cyclic aliphatic saturated hydrocarbon group.
- Examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, cyclopropyl group, and cyclopropyl.
- Specific examples of the group include a methyl group, a cyclopentyl group, and a cyclohexyl group.
- the alkenyl group means an aliphatic unsaturated hydrocarbon group containing at least one carbon-carbon double bond which is linear, branched or cyclic.
- the alkenyl group having 2 to 6 carbon atoms include ethenyl group, 1-propenyl group, 2-propenyl group, 2-methyl-1-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 3 -Methyl-2-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 4-methyl-3-pentenyl group, 1-hexenyl group, 3-hexenyl group, 5-hexenyl group Specific examples of the group include 1-cyclopenten-1-yl group, 3-cyclopenten-1-yl group, 2-cyclohexen-1-yl group, and 3-cyclohexen-1-yl group.
- the alkynyl group means an aliphatic unsaturated hydrocarbon group containing at least one carbon-carbon triple bond that is linear or branched.
- the alkynyl group having 2 to 6 carbon atoms include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 2-pentynyl group, Specific examples of the 3-pentynyl group, 4-pentynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, and 5-hexynyl group can be given.
- the alkylcarbonyl group refers to a group in which the alkyl group is bonded via a carbonyl group.
- the alkylcarbonyl group having 2 to 7 carbon atoms include acetyl group, propanoyl group, butanoyl group, isobutanoyl group, sec-butanoyl group, tert-butanoyl group, pentanoyl group, isopentanoyl group, hexanoyl group, cyclopropylcarbonyl A group, a cyclohexylcarbonyl group, etc. can be mentioned as specific groups.
- the alkylsulfonyl group refers to a group in which the alkyl group is bonded via a sulfonyl group.
- Specific examples of the alkylsulfonyl group having 1 to 6 carbon atoms include a methylsulfonyl group, an ethylsulfonyl group, an isopropylsulfonyl group, and a cyclopropylsulfonyl group.
- the alkylsulfinyl group in the present invention refers to a group in which the alkyl group is bonded via a sulfinyl group.
- Specific examples of the alkylsulfinyl group having 1 to 6 carbon atoms include a methylsulfinyl group, an ethylsulfinyl group, an isopropylsulfinyl group, and a cyclopropylsulfinyl group.
- the alkoxy group means a linear, branched or cyclic aliphatic saturated hydrocarbon oxy group.
- alkoxy group having 1 to 6 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, cyclopropoxy, cyclo Specific examples include a propylmethoxy group or a cyclohexyloxy group.
- the alkylthio group in the present invention refers to a linear, branched or cyclic aliphatic saturated hydrocarbon sulfide group.
- alkylthio group having 1 to 6 carbon atoms include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, cyclopropylthio, cyclo Specific examples include a propylmethylthio group or a cyclohexylthio group.
- the dialkylamino group in the present invention is a group obtained by substituting an amino group with two identical or different alkyl groups.
- the dialkylamino group having 1-6 carbon atoms in the present invention is a group in which the amino group is substituted with two identical or different alkyl groups having 1-6 carbon atoms.
- the dialkylamino group in the present invention may form a ring.
- Specific examples of the dialkylamino group having 1 to 6 carbon atoms that may form a ring include a dimethylamino group, a diethylamino group, a pyrrolidin-1-yl group, and a piperidin-1-yl group. be able to.
- the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- “when two CR 2 are adjacent to each other, R 2 is bonded to form a ring” means that R 2 is bonded to each other together with the carbon atom on the pyridine ring to which they are bonded.
- Forming a non-aromatic ring or aromatic ring By combining R 2 with each other to form a ring, a bicyclic ring condensed with the pyridine ring is formed.
- Such a non-aromatic ring or aromatic ring may be a hydrocarbon ring or a heterocyclic ring having an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent atom.
- substituted with an imidazole ring, a pyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring, or a piperazine ring means substituted with a group in which one hydrogen atom is removed from each ring. .
- A represents a single bond, an oxygen atom, a sulfur atom, NH or CH 2 .
- A is preferably a single bond or an oxygen atom, and more preferably a single bond.
- R 1 represents a nitrogen atom or CH, and is preferably a nitrogen atom.
- X 1 to X 5 one represents a nitrogen atom and the remaining four represent CR 2 .
- X 1 or X 2 is preferably a nitrogen atom, and X 2 is more preferably a nitrogen atom.
- R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group Group, alkylcarbonyl group having 2 to 7 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, nitro group, amino group, dialkylamino group having 1 to 6 carbon atoms which may form a ring, formyl group, hydroxyl group An alkoxy group having 1 to 6 carbon atoms (which may be substituted with one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6 carbon atoms, and a phenyl group (the number of carbon atoms
- R 2 when two CR 2 are adjacent to each other, R 2 may be bonded to each other to form a ring.
- the ring formed by two adjacent CR 2 is preferably an aromatic hydrocarbon ring, and more preferably a benzene ring.
- R 2 is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, a nitro group, or a C 1-6 which may form a ring.
- a dialkylamino group, a hydroxyl group, an alkoxy group having 1-6 carbon atoms (which may be substituted by one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1-6 carbon atoms , A phenyl group (which may be substituted with one or more of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen atom), or a phenoxy group (C 1-6 And may be substituted with one or more of an alkyl group, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom).
- R 2 is more preferably a hydrogen atom, methyl group, ethyl group, cyclopropyl group, methoxy group, ethoxy group, methylthio group, fluorine atom, chlorine atom, bromine atom, cyano group, hydroxyl group, pyrrolidin-1-yl group , Trifluoromethyl group, difluoromethyl group, nitro group, phenyl group, or phenoxy group.
- R 2 is more preferably a hydrogen atom, methyl group, ethyl group, cyclopropyl group, fluorine atom, chlorine atom, bromine atom, methoxy group, ethoxy group, methylthio group, trifluoromethyl group, difluoromethyl group, nitro group. Or a phenyl group.
- X 4 can be mentioned as a preferred position of the remaining CR 2 .
- the combination of the nitrogen atom and the remaining CR 2 position is preferably when X 2 is a nitrogen atom and X 4 is CR 2 .
- R 3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (hydroxyl group, amino group, dialkylamino group having 1 to 6 carbon atoms which may form a ring, imidazole ring, pyrazole ring, pyrrolidine ring, piperidine ring, Substituted by one or more of a morpholine ring and a piperazine ring (which may be substituted by one or more of a C 1-6 alkyl group and a C 1-6 alkylsulfonyl group)
- the alkenyl group having 2-6 carbon atoms, the alkynyl group having 2-6 carbon atoms, the alkoxy group having 1-6 carbon atoms (which may be substituted with one or more of a hydroxyl group and a halogen atom).
- R 3 is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a hydroxyl group, an amino group, a dialkylamino group having 1 to 6 carbon atoms which may form a ring, an imidazole ring, a pyrazole ring, or a pyrrolidine ring.
- a piperidine ring, a morpholine ring, and a piperazine ring (which may be substituted with one or more of a C 1-6 alkyl group and a C 1-6 alkylsulfonyl group) 1-6 carbon atoms, alkoxy groups having 1-6 carbon atoms, alkylthio groups having 1-6 carbon atoms, halogen atoms, trifluoromethyl groups, difluoromethyl groups, cyano groups, phenyl groups (1-6 carbon atoms).
- R 3 is more preferably a hydrogen atom, methyl group, ethyl group, isopropyl group, cyclopropyl group, trifluoromethyl group, difluoromethyl group, chlorine atom, bromine atom, iodine atom, methoxy group, methylthio group, ethylthio group.
- Cyano group, phenyl group, carboxyl group, —CO 2 R 5 hydroxymethyl group, 2-hydroxypropan-2-yl group, 3-hydroxypentan-3-yl group, or morpholin-4-ylmethyl group.
- R 4 represents a carboxyl group, a tetrazolyl group, —CONHSO 2 R 5 or —CO 2 R 5 , or any of the following substituents.
- R 3 and R 4 may be condensed to form a lactone ring.
- R 4 is preferably a carboxyl group (when R 3 is a C 1-6 alkyl group substituted with a hydroxyl group, it may be condensed with R 3 to form a lactone ring), a tetrazolyl group, -CONHSO 2 CH 3 , -CONHSO 2 -cyclopropyl, or -CO 2 R 5 .
- R 5 in R 3 and R 4 each independently represents an alkyl group having 1 to 6 carbon atoms.
- Z represents any of the substituents represented by the following Z1 to Z7.
- R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, or a cyano group. However, the case where R 6 and R 7 are hydrogen atoms at the same time is excluded.
- R 6 and R 7 are each preferably a methyl group, a fluorine atom, a chlorine atom, a bromine atom, or a trifluoromethyl group.
- R 6 and R 7 are more preferably a chlorine atom, a methyl group, or a trifluoromethyl group, respectively.
- substitution positions on the benzene ring of R 6 and R 7 are 2,5-disubstituted and 3,5-disubstituted, more preferably 2,5-disubstituted.
- Preferred combinations of R 6 and R 7 and their substitution positions on the benzene ring are 2,5-dichloro substitution, 3,5-dichloro substitution, 2,5-dimethyl substitution, 2,5-bis (trifluoromethyl) ) Substitution, or 2-chloro-5-methyl substitution.
- Y represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Y is preferably a hydrogen atom.
- R 8 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- a preferred combination of R 8 and the substitution position on the naphthalene ring is a hydrogen atom, 2-methyl group, 4-methyl group, 8-methyl group, or 8-bromo group.
- R 9 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- W represents a sulfur atom, an oxygen atom or NR 16 (R 16 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group), and preferably a sulfur atom.
- Preferred combinations of R 9 and the substitution position on the benzothiophene, benzofuran, or indole ring include a hydrogen atom, 4-methyl group, 4-chloro group, 4-bromo group, 4-trifluoromethyl group, and 5-methyl group. , 5-chloro group, or 5-trifluoromethyl group.
- R 10 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- W represents a sulfur atom, an oxygen atom or NR 16 (R 16 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group), and preferably a sulfur atom.
- R 10 and its substitution position on the benzothiophene, benzofuran, or indole ring is a hydrogen atom or a 5-fluoro group.
- R 11 and R 12 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- W represents a sulfur atom, an oxygen atom or NR 16 (R 16 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group), and preferably a sulfur atom.
- R 11 and R 12 and their substitution positions on the thiophene, furan or pyrrole ring is 2,5-dichloro substitution.
- R 13 and R 14 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- W represents a sulfur atom, an oxygen atom or NR 16 (R 16 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group), and preferably a sulfur atom.
- R 13 and R 14 and their substitution positions on the thiophene, furan or pyrrole ring is 2,4-dichloro substitution.
- R 15 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group.
- R 15 is preferably a hydrogen atom.
- Z1 to Z7 Z1 to Z6 are preferable, and Z1 to Z4 are more preferable.
- Preferable Z is specifically, for example, 2,5-dichlorobenzyl group, 3,5-dichlorobenzyl group, 2,5-dimethylbenzyl group, 2,5-bis (trifluoromethyl) benzyl group, 2- Chloro-5-methylbenzyl group, naphthalen-1-ylmethyl group, (2-methylnaphthalen-1-yl) methyl group, (4-methylnaphthalen-1-yl) methyl group, (8-methylnaphthalen-1-yl) ) Methyl group, (8-bromonaphthalen-1-yl) methyl group, benzo [b] thiophen-3-ylmethyl group, (4-methylbenzo [b] thiophen-3-yl) methyl group, (4-chlorobenzo [b ] Thiophen-3-yl) methyl group, (4-bromobenzo [b] thiophen-3-yl) methyl group, (4- (trifluoromethyl) benzo [b] thiophen
- Preferred combinations of A, X 1 -X 5 , R 1 -R 4 , and Z present in the formula (I) according to the present invention include the following combinations 1) to 11).
- A is a single bond;
- R 1 is a nitrogen atom;
- X 1 is a nitrogen atom;
- X 4 is CR 2 and X 2 , X 3 and X 5 are CH;
- R 2 is a hydrogen atom;
- A is a single bond;
- R 1 is a nitrogen atom;
- X 2 is a nitrogen atom;
- X 4 is CR 2 and X 1 , X 3 and X 5 are CH;
- R 2 is a hydrogen atom;
- A is a single bond;
- R 1 is CH;
- X 1 is a nitrogen atom;
- X 4 is CR 2 and X 2 , X 3 and X 5 are CH;
- R 2 is a hydrogen atom, carbon A C 1-6 alkyl group, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, a nitro group, a C 1-6 dialkylamino group which may form a ring, a hydroxyl group, 6 alkoxy groups (which may be substituted by one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6 carbon atoms, a phenyl group (an alkyl having 1 to 6 carbon atoms) Group, optionally substituted by one or more of a C 1-6 alkoxy group, and a halogen atom
- A is a single bond;
- R 1 is CH;
- X 2 is a nitrogen atom;
- X 4 is CR 2 and X 1 , X 3 and X 5 are CH;
- R 2 is a hydrogen atom, carbon A C 1-6 alkyl group, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, a nitro group, a C 1-6 dialkylamino group which may form a ring, a hydroxyl group, 6 alkoxy groups (which may be substituted by one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6 carbon atoms, a phenyl group (an alkyl having 1 to 6 carbon atoms) Group, optionally substituted by one or more of a C 1-6 alkoxy group, and a halogen atom
- A is an oxygen atom;
- R 1 is a nitrogen atom;
- X 1 is a nitrogen atom;
- X 4 is CR 2 and X 2 , X 3 and X 5 are CH;
- R 2 is a hydrogen atom;
- R 4 is alkyl group of a carboxyl group (R 3 carbon atoms substituted by hydroxyl groups 1-6, R 3 is fused May form a lactone ring), a tetrazolyl group, —CONHSO 2 CH 3 , —CONHSO 2 -cyclopropyl, or —CO 2 R 5 ;
- Z is a 2,5-dichlorobenzyl group, 3,5 -Dichlorobenzyl group, 2,5-dimethylbenzyl group, 2,5-bis (trifluoromethyl) benzyl group, 2-chloro-5-methylbenzyl group, naphthalen-1-ylmethyl group, (2-methylnaphthalene-1 -Yl) methyl group, (4-methylnaphthalen-1-yl) methyl group, (8-methylnaphthalen-1-yl) methyl group, (8-bromonaphthalen-1-yl) methyl
- A is an oxygen atom;
- R 1 is a nitrogen atom;
- X 2 is a nitrogen atom;
- X 4 is CR 2 and X 1 , X 3 and X 5 are CH;
- R 2 is a hydrogen atom;
- R 4 is alkyl group of a carboxyl group (R 3 carbon atoms substituted by hydroxyl groups 1-6, R 3 and condensation May form a lactone ring), a tetrazolyl group, —CONHSO 2 CH 3 , —CONHSO 2 -cyclopropyl, or —CO 2 R 5 ;
- Z is a 2,5-dichlorobenzyl group, 3, 5-dichlorobenzyl group, 2,5-dimethylbenzyl group, 2,5-bis (trifluoromethyl) benzyl group, 2-chloro-5-methylbenzyl group, naphthalen-1-ylmethyl group, (2-methylnaphthalene- 1-yl) methyl group, (4-methylnaphthalen-1-yl) methyl group, (8-methylnaphthalen-1-yl) methyl group, (8-bromonaphthalen-1-yl) ) Me
- A is an oxygen atom;
- R 1 is CH;
- X 1 is a nitrogen atom;
- X 4 is CR 2 and X 2 , X 3 and X 5 are CH;
- R 2 is a hydrogen atom, carbon A C 1-6 alkyl group, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, a nitro group, a C 1-6 dialkylamino group which may form a ring, a hydroxyl group, 6 alkoxy groups (which may be substituted by one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6 carbon atoms, a phenyl group (an alkyl having 1 to 6 carbon atoms) Group, optionally substituted by one or more of a C 1-6 alkoxy group, and a halogen atom
- A is an oxygen atom;
- R 1 is CH;
- X 2 is a nitrogen atom;
- X 4 is CR 2 and X 1 , X 3 and X 5 are CH;
- R 2 is a hydrogen atom, carbon A C 1-6 alkyl group, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, a nitro group, a C 1-6 dialkylamino group which may form a ring, a hydroxyl group, 6 alkoxy groups (which may be substituted by one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6 carbon atoms, a phenyl group (an alkyl having 1 to 6 carbon atoms) Group, optionally substituted with one or more of a C 1-6 alkoxy group, and a halogen atom
- R 2 is a hydrogen atom, a methyl group, an ethyl group, a cyclopropyl group, a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, an ethoxy group, a methylthio group, a trifluoromethyl group, A difluoromethyl group, a nitro group, or a phenyl group;
- R 3 is a hydrogen atom, methyl group, ethyl group, isopropyl group, cyclopropyl group, trifluoromethyl group, difluoromethyl group, chlorine atom, bromine atom, iodine atom, methoxy group , Methylthio group, ethylthio group, cyano group, phenyl group, carboxyl group, —CO 2 R 5 , hydroxymethyl group, 2-hydroxypropan-2-yl group, 3-hydroxypentan-3-yl group, or morpholine-4 -An ylmethyl group.
- Z is 2,5-dichlorobenzyl group, 2,5-dimethylbenzyl group, naphthalen-1-ylmethyl group, (4-chlorobenzo [b] thiophen-3-yl) methyl Group, or a benzo [b] thiophen-7-ylmethyl group.
- R 1 and R 3 are the same as defined in formula (I).
- R 17 represents a chlorine atom, a bromine atom or an iodine atom.
- R 18 represents a formyl group or —CO 2 R 5 .
- R 5 in R 3 and R 18 each independently represents an alkyl group having 1 to 6 carbon atoms.
- Z represents any of the substituents represented by the following Z1 to Z7.
- R 6 -R 15 , Y and W are the same as defined in formula (I).
- 2-chloro-1- (thiophen-2-ylmethyl) -1H-pyrrole-5-carbaldehyde, ethyl 2-bromo-1- (4-methylbenzyl) -1H-pyrrole-5-carboxylate, and dimethyl Except 2-bromo-1- (2-chlorobenzyl) -1H-imidazole-4,5-dicarboxylate. ]
- R 3 is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (which may be substituted with one or more hydroxyl groups), a halogen atom, a trifluoromethyl group, or —CO 2 R 5 .
- R 3 is more preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, a chlorine atom, a bromine atom, or —CO 2 R 5 .
- R 17 is preferably a bromine atom or an iodine atom.
- R 18 is preferably a formyl group, —CO 2 CH 3 or —CO 2 C 2 H 5 .
- R 19 represents —CO 2 R 5 .
- R 5 in R 3 and R 19 each independently represents an alkyl group having 1 to 6 carbon atoms.
- Za is 2,5-dichlorobenzyl group, 3,5-dichlorobenzyl group, 2,5-dimethylbenzyl group, 2,5-bis (trifluoromethyl) benzyl group, 2-chloro-5-methylbenzyl group, Naphthalen-1-ylmethyl group, (2-methylnaphthalen-1-yl) methyl group, (4-methylnaphthalen-1-yl) methyl group, (8-methylnaphthalen-1-yl) methyl group, (8-bromo) Naphthalen-1-yl) methyl group, benzo [b] thiophen-3-ylmethyl group, (4-methylbenzo [b] thiophen-3-yl) methyl group, (4-chlorobenzo [b] thiophen-3-yl) methyl Group, (4-bromobenzo [b] thioph
- R 3 is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (which may be substituted with one or more hydroxyl groups), a halogen atom, a trifluoromethyl group, or —CO 2 R 5 .
- R 3 is more preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, a chlorine atom, a bromine atom, or —CO 2 R 5 .
- Preferred R 19 is —CO 2 CH 3 or —CO 2 C 2 H 5 .
- Preferred Za is 2,5-dichlorobenzyl group, 2,5-dimethylbenzyl group, naphthalen-1-ylmethyl group, (4-chlorobenzo [b] thiophen-3-yl) methyl group, or benzo [b] thiophene- 7-ylmethyl group.
- pyridine derivative represented by the formula (I) of the present invention include the following compounds.
- A1, A2, A7, A13, A14, A15, A19, A26, A81, A119, A121, A134, A135, A137, A139, A147, A156, A169, A233, B1 and B11 are more preferable.
- the pyridine derivative represented by the above formula (I) can be converted into a prodrug by a conventional method.
- a prodrug means a compound that is converted into a pyridine derivative represented by the formula (I) by an enzyme, gastric acid, or the like in a living body.
- a prodrug of the pyridine derivative represented by the formula (I) a compound in which a carboxyl group in the pyridine derivative is esterified or amidated (for example, alkyl esterification or phenyl esterification in which the carboxyl group has 1 to 6 carbon atoms) Carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl ) Compounds that are methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated), compounds in which the hydroxyl group in the pyridine derivative is acylated, alkylated, phosphorylated or borated (eg, hydroxyl group is acetylated, palmitoylated, Propanoylation, Compounds
- the prodrug of the pyridine derivative represented by the formula (I) is a physiological drug as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be a compound that is converted to a pyridine derivative represented by the formula (I) under conditions.
- R 3 and / or R 4 may be a prodrug that generates a compound having a carboxylic acid or a compound in which R 3 is an alkyl group substituted with a hydroxyl group and R 4 is a carboxyl group.
- Examples of the pyridine derivative represented by the formula (I) which can be a prodrug include A3, A221, A267, A268, A269, A270, A271, A272, A273, A274, A275, A276, A277, A278, A279. , A280, A281, and A282.
- the pyridine derivative represented by the formula (I) of the present invention or a prodrug thereof can be converted into a pharmaceutically acceptable salt as necessary.
- salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and carbonic acid; formic acid, acetic acid, propionic acid, trifluoroacetic acid, phthalic acid, Acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids
- Salt salt with amino acid such as lysine, arginine, ornithine, glutamic acid, aspartic acid; salt with alkali metal such as sodium, potassium, lithium; salt with alka
- the pyridine derivative represented by the above formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof can be converted into a solvate as necessary.
- solvents include water, methanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, Examples thereof include t-butyl methyl ether, benzene, toluene, DMF, DMSO and the like.
- Particularly preferred are water, methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, acetone, methyl ethyl ketone, and ethyl acetate.
- the pyridine derivative represented by the above formula (I) may be synthesized by any method, but A is a single bond, R 1 is a nitrogen atom, and R 3 is an alkyl group having 1 to 6 carbon atoms or a trifluoromethyl group. , R 4 is a carboxyl group, —CO 2 R 5 , or —CONHSO 2 R 5 , it can be synthesized as shown in Scheme A below. That is, after bromination of the imidazole derivative (IV) to obtain the compound (V), N-alkylation was performed by a reaction using a base and a halide compound or a Mitsunobu reaction using an alcohol to obtain a compound (II-1). Get.
- Compound (I-1) is obtained by Suzuki coupling reaction of compound (II-1) and a boronic acid derivative.
- Compound (I-2) can be obtained by hydrolyzing the ester group.
- an acylsulfonamide (I-3) can also be obtained by performing a condensation reaction with an alkylsulfonamide as necessary.
- Preferable reagents for bromination from compound (IV) to (V) in Scheme A include bromine, N-bromosuccinimide (NBS) and the like.
- the solvent used in this reaction is not particularly limited.
- ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, halogens such as dichloromethane and carbon tetrachloride.
- THF tetrahydrofuran
- 1,4-dioxane 1,2-dimethoxyethane
- 1,2-diethoxyethane 1,2-diethoxyethane
- halogens such as dichloromethane and carbon tetrachloride.
- halogens such as dichloromethane and carbon tetrachloride.
- This reaction is carried out at 0 ° C. to 100 ° C., preferably at room temperature to 50 ° C.
- N-alkylation of compound (V) to compound (II-1) proceeds by a reaction using a base and a halide compound or a Mitsunobu reaction using an alcohol.
- the base when a base and a halide compound are used include potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium hydride and the like.
- preferable bases are potassium carbonate, cesium carbonate, triethylamine, diisopropyl. Ethylamine.
- the halide compound include chloride, bromide, and iodide.
- Preferred halide compounds include chloride and bromide.
- the reaction temperature in the presence of a base and a halide compound is preferably room temperature to 150 ° C, more preferably 50 ° C to 120 ° C.
- the solvent in this reaction is not particularly limited, and examples thereof include ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, dimethylformamide, N-methylpyrrolidone and the like. Amides, dimethyl sulfoxide (DMSO), toluene, xylene, or a mixed solvent thereof. Further, N-alkylation from compound (V) to compound (II-1) proceeds also by Mitsunobu reaction with alcohol.
- a compound (II-1) is obtained by reacting a phosphine compound, a condensing agent, an alcohol, and the compound (V) in an inert solvent.
- phosphine include tributyl phosphine, triphenyl phosphine, tricyclohexyl phosphine, and the like, and triphenyl phosphine is preferable.
- a preferred condensing agent is diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).
- the reaction temperature of this Mitsunobu reaction may be any of 0 ° C.
- the solvent for Mitsunobu reaction is not particularly limited.
- ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, dimethylformamide, N-methylpyrrolidone, etc.
- Amides, halogen solvents such as dichloromethane, toluene, xylene, or a mixed solvent thereof.
- the Suzuki coupling reaction from compound (II-1) to compound (I-1) involves heating compound (II-1), a boronic acid derivative, a palladium catalyst, and a base in a solvent inert to the reaction. proceed. This reaction is preferably performed in an inert gas atmosphere.
- Preferred examples of the boronic acid derivative include boronic acid and boronic acid pinacol ester.
- the palladium catalyst include [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl 2 (dppf)), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ) and the like.
- the solvent used in this reaction is not particularly limited.
- ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, dimethylformamide, N-methylpyrrolidone, etc.
- THF tetrahydrofuran
- 1,4-dioxane 1,2-dimethoxyethane
- 1,2-diethoxyethane dimethylformamide
- N-methylpyrrolidone etc.
- These amides, alcohols such as ethanol, 2-propanol and butanol, toluene, xylene, water, or a mixed solvent thereof may be used.
- This reaction proceeds at 50 ° C. to 150 ° C., preferably 80 ° C. to 120 ° C.
- Hydrolysis reaction from compound (I-1) to compound (I-2) is performed by reacting compound (I-1) with an equal amount or a small excess of base in a mixed solvent inert to the reaction and water.
- bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide.
- the solvent is not particularly limited, but it is preferable to react in an organic solvent such as tetrahydrofuran (THF), alcohols such as methanol and ethanol and a mixed solvent of water. This reaction proceeds at 0 ° C. to 100 ° C., preferably room temperature to 60 ° C.
- the condensation reaction from compound (I-2) to compound (I-3) proceeds by reacting compound (I-2) with alkylsulfonamide in the presence of a base and a condensing agent in an inert solvent.
- the solvent include ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogen solvents such as dichloromethane and carbon tetrachloride, acetonitrile, and the like. A mixed solvent etc. are mentioned.
- Preferred solvents are tetrahydrofuran (THF), dimethylformamide, and dichloromethane.
- Examples of the base include potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium hydride and the like. Preferred bases are triethylamine and diisopropylethylamine.
- Condensation agents include dicyclohexylcarbodiimide (DCC), diphenylphosphoric azide (DPPA), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI or WSC), O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), O— (7-azabenzotriazol-1-yl) -N, N, N ′, N′— Examples thereof include tetramethyluronium tetrafluoroborate (TATU), and WSC is preferable.
- the reaction temperature may be 0 ° C. to 100
- R 1 is a nitrogen atom
- R 3 is an alkyl group having 1 to 6 carbon atoms
- R 4 is a carboxyl group, —CO 2 R 5 , or —CONHSO 2 R 5
- the following scheme B It can also be synthesized as follows. That is, after obtaining compound (VIII) by an imidazole ring formation reaction using compound (VI) and compound (VII), N-alkylation is performed by a reaction using a base and a halide compound or a Mitsunobu reaction using an alcohol. To obtain compound (I-1).
- Compound (I-2) can be obtained by hydrolyzing the ester group in the same manner as in Scheme A.
- the acylsulfonamide (I-3) can also be obtained by performing condensation with an alkylsulfonamide as necessary.
- the imidazole ring formation reaction using the compound (VI) and the compound (VII) is carried out, for example, in the presence of 2 equivalents or more, preferably 10 equivalents or more of ammonium acetate in a mixed solvent of toluene and water. It proceeds by heating VI) and compound (VII).
- the reaction temperature of this reaction is preferably from room temperature to 150 ° C, more preferably from 50 ° C to 120 ° C.
- the condensation reaction is preferably performed under the conditions described in Scheme A.
- compound (X) is obtained by N-alkylation reaction of compound (IX) that can be easily synthesized as another route, and then compound (XI) is obtained by bromination reaction.
- Compound (I-1) can also be obtained by CO insertion reaction in alcohol using.
- the conditions described in Scheme A are preferred for the N-alkylation reaction from Compound (IV) to Compound (III-1) in Scheme C.
- the bromination of compound (III-1) to compound (II-1) is preferably carried out under the conditions described in Scheme A. Further, a catalytic amount of 2,2′-azobis (isobutyronitrile) (AIBN) is reduced. The conditions to add are more preferable. Further, the Suzuki coupling reaction from compound (II-1) to compound (I-1) and the subsequent hydrolysis reaction are preferably carried out under the conditions described in Scheme A.
- the N-alkylation reaction from compound (IX) to compound (X) and the bromination from compound (X) to compound (XI) are preferably carried out under the conditions described in Scheme A.
- the CO insertion reaction from compound (XI) to compound (I-1) proceeds in a CO atmosphere using a palladium catalyst, a base, and compound (XI) in an alcohol solvent.
- a palladium catalyst As the alcohol solvent, methanol and ethanol are preferable.
- the palladium catalyst [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl 2 (dppf)), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ) and the like are preferable.
- the base is preferably triethylamine or diisopropylethylamine.
- the reaction temperature of this reaction is preferably room temperature to 150 ° C, more preferably 50 ° C to 90 ° C.
- the compound of the above formula (II) can be used as the compound (II-1) of the above scheme C, and the compound of the above formula (III) can be used as the compound (III-1) of the above scheme C.
- R 1 is a nitrogen atom
- R 3 is a chlorine atom
- R 4 is a carboxyl group
- an imidazole ring is formed using amidine hydrochloride (XII) and dihydroxyacetone dimer to obtain an alcohol form (XIII).
- XIII amidine hydrochloride
- XIV dihydroxyacetone dimer
- XV aldehyde form
- Compound (I-4) can be obtained by obtaining compound (XVI) by N-alkylation followed by further oxidation.
- compound (I-6) is obtained by chlorinating compound (I-5) in which R 3 is a hydrogen atom in compound (I-1) in the above-mentioned scheme C.
- Compound (I-4) can also be synthesized by decomposing.
- the imidazole ring formation reaction from the compound (XII) to the compound (XIII) is preferably carried out under conditions in which ammonium chloride is reacted with dihydroxyacetone dimer in aqueous ammonia. This reaction is carried out at 50 to 100 ° C., preferably 80 to 100 ° C.
- the chlorinating agent for compound (XIII) include N-chlorosuccinimide (NCS) and chlorine, and N-chlorosuccinimide (NCS) is preferred. This reaction is performed at room temperature to 50 ° C., but it is more preferable to react at room temperature in order to suppress side reactions.
- the oxidation from compound (XIV) to compound (XV) is preferably performed using manganese dioxide, and the reaction solvent is preferably a halogen solvent such as dichloromethane.
- N-alkylation of compound (XV) to compound (XVI) is preferably carried out under the conditions described in Scheme A.
- a pinic reaction is widely known, and conditions using sodium chlorite and sodium dihydrogen phosphate in the presence of 2-methyl-2-butene. Is preferred.
- a reaction solvent it is preferable to use a mixed solvent of alcohols such as tetrahydrofuran (THF), t-butanol, and propanol and water.
- the reaction temperature is preferably from room temperature to 50 ° C.
- N-chlorosuccinimide N-chlorosuccinimide
- This reaction is carried out at room temperature to 100 ° C, preferably 50 ° C to 80 ° C.
- Hydrolysis of compound (I-6) to compound (I-4) is preferably carried out under the conditions described in Scheme A.
- A is a single bond
- R 1 is a nitrogen atom
- R 3 is a C 1-6 alkyl group (hydroxyl group, amino group, C 1-6 dialkylamino group which may form a ring, imidazole ring, pyrazole Ring, pyrrolidine ring, piperidine ring, morpholine ring, and piperazine ring (which may be substituted with one or more of a C 1-6 alkyl group and a C 1-6 alkylsulfonyl group) When it is substituted with one or more), an acetyl group, a difluoromethyl group, or an ethynyl group, and R 4 is a carboxyl group, it can be synthesized as shown in Scheme E below.
- the diester form (XVII) is converted into the compound (XVIII) by bromination reaction, and the compound (II-2) is obtained by N-alkylation reaction.
- the compound (I-7) by Suzuki coupling reaction, hydroxymethyl compound (I-8) reduced only at the 4-position by selective reduction reaction using diisobutylaluminum hydride (DIBAL-H).
- DIBAL-H diisobutylaluminum hydride
- Compound (I-2) can be synthesized by converting this hydroxymethyl moiety to various R 3 by various general organic syntheses and then performing a hydrolysis reaction last.
- the alcohol moiety is converted to an aldehyde by oxidation with manganese dioxide, or the alcohol moiety is converted to a bromo group using tribromophosphine. Can be further converted into various R 3 .
- the hydrolysis is preferably performed under the conditions described in Scheme A.
- the compound of the above formula (II) can be used as the compound (II-2) of the above scheme E.
- A is a single bond
- R 1 is a nitrogen atom
- R 3 is an iodine atom, a phenyl group, a pyridyl group, a phenoxy group, a cyano group, an alkoxy group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms
- R 4 Can be synthesized as in Scheme F below. That is, the compound (X) obtained in the scheme (C) is iodinated to obtain the compound (XIX), and the compound (XX) is obtained by selective formylation.
- compound (I-I) is obtained by subjecting compound (I-) to pinic oxidation after obtaining compound (XXI) by Suzuki coupling, cyanation, or etherification by introduction of alcohol, thiol, phenol or the like under the conditions using palladium. 2) can be obtained.
- compound (I-2) can be obtained by directly oxidizing compound (XX).
- the iodination reaction from compound (X) to compound (XIX) in Scheme F is preferably performed using iodine and silver sulfate in methanol. This reaction is carried out at 0 ° C. to 100 ° C., preferably room temperature to 50 ° C.
- a Grignard reagent such as EtMgBr or a lithium reagent such as nBuLi in DMF or a mixed solvent of tetrahydrofuran (THF) and DMF.
- This reaction is carried out at ⁇ 50 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
- the Suzuki coupling reaction is preferably performed under the conditions described in Scheme A.
- This reaction is carried out at 50 to 150 ° C, preferably 80 to 100 ° C.
- reaction temperature is preferably 50 ° C to 100 ° C.
- the pinic oxidation reaction of compound (XX) or compound (XXI) is preferably performed under the conditions described in Scheme D.
- R 1 is a nitrogen atom
- R 3 is a hydrogen atom
- R 4 is a tetrazolyl group
- acrylic acid or thiomethylpropanoic acid they can be synthesized as shown in Scheme G below. That is, for the tetrazole compound, a cyano group is introduced into compound (XI) obtained in Scheme C above using palladium to form compound (XXII), and then the cyano group is converted to a tetrazolyl group using sodium azide. To obtain compound (I-9). In the case of acrylic acid, compound (XI) can be subjected to Heck reaction to form compound (XXIII), followed by hydrolysis reaction to obtain compound (I-10).
- the cyanation reaction from compound (XI) to compound (XXII) was carried out using [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl 2 (dppf)), tetrakis (triphenyl) in DMF. Conditions for heating a palladium catalyst such as phosphine) palladium (Pd (PPh 3 ) 4 ) and ZnCN 2 are preferred. This reaction is carried out at 50 to 150 ° C, preferably 80 to 100 ° C.
- the conversion from compound (XXII) to compound (I-9) is preferably carried out under the condition of reacting triethylamine hydrochloride and sodium azide in DMF.
- This reaction is carried out at 100 to 170 ° C, preferably 120 to 150 ° C.
- the Heck reaction from compound (XI) to compound (XXIII) is carried out by using [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (II) in acetonitrile or an amide solvent such as DMF or DMA.
- PdCl 2 (dppf)
- palladium catalysts such as tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4
- bases such as potassium carbonate, potassium acetate, triethylamine, diisopropylethylamine, compound (XI) and acrylic acid ester And proceed under heating conditions.
- This reaction proceeds from room temperature to 150 ° C, preferably from 80 ° C to 140 ° C.
- the hydrolysis is preferably performed under the conditions described in Scheme A.
- compound (XI) 2-ethylhexyl 3-mercaptopropionate, Pd 2 (dba) 3 , Xantphos, diisopropylethylamine was heated in 1,4-dioxane to heat the alkylthiol.
- Compound (XXIV) is obtained by carrying out a beta elimination reaction under basic conditions after introducing a part. For the beta elimination reaction, conditions using a small excess of KOtBu in DMF at room temperature are preferred.
- the S-alkylation from compound (XXIV) to compound (XXV) is preferably carried out under the same conditions as the N-alkylation in Scheme A, more preferably using a base and a halide compound.
- the hydrolysis is preferably performed under the conditions described in Scheme A.
- substitution reaction from compound (II-1) to compound (I-12) proceeds by reacting compound (II-1) with phenols in the presence of a base such as potassium carbonate or cesium carbonate in DMF. This reaction is carried out at 50 ° C to 150 ° C, preferably 90 ° C to 130 ° C.
- the hydrolysis of compound (I-12) to compound (I-13) is preferably performed under the conditions described in Scheme A.
- the compound of the above formula (II) can be used as the compound (II-1) of the above scheme H.
- R 1 is CH
- R 3 is a hydrogen atom
- R 4 is a carboxyl group
- they can be synthesized as shown in Scheme I below. That is, in the case of a carboxylic acid, compound (II-3) is obtained by N-alkylation of a known pyrrole derivative (XXVI), and then compound (XXVII) is obtained by Suzuki coupling reaction with a boronic acid derivative.
- the target compound (I-14) can be obtained by the subsequent oxidation reaction.
- acrylic acid a Horner-Emmons reaction is performed on compound (XXVII) to obtain compound (XXVIII), and then hydrolyzed to obtain compound (I-15).
- the N-alkylation reaction from compound (XXVI) to compound (II-3) in Scheme I and the subsequent Suzuki coupling reaction of compound (II-3) are preferably carried out under the conditions described in Scheme A.
- the oxidation reaction of the compound (XXVII) is preferably performed under the conditions described in Scheme D.
- the Horner-Emmons reaction from compound (XXVII) to compound (XXVIII) proceeds by reacting compound (XXVII) with ethyl diethylphosphonoacetate in THF in the presence of a base such as sodium hydride or nBuLi.
- the reaction temperature is preferably from 0 ° C. to room temperature.
- Subsequent hydrolysis is preferably performed under the conditions described in Scheme A.
- the compound of the above formula (II) can be used as the compound (II-3) of the above scheme I.
- the therapeutic or prophylactic agent for gout, hyperuricemia and the like containing the pyridine derivative of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is usually formulated. It is prepared using carriers, excipients, and other additives used in the above.
- 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. The usual thing is mentioned.
- 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.
- prevention refers to prevention of morbidity or onset in an individual who has not yet been affected or developed
- treatment refers to curing a disease or symptom in an already affected or afflicted individual. Means to suppress or improve.
- the effective amount of the active ingredient in the URAT1 inhibitor, therapeutic agent or prophylactic agent of the present invention varies depending on the administration route, patient age, sex, disease severity, etc., but is usually about 0.1 to 100 mg / day.
- the number of times is usually 1 to 3 times / day to 1 to 7 times / week, and it is preferable to prepare the preparation so as to satisfy such conditions.
- the structure of the isolated new compound was confirmed by 1 H-NMR and / or mass spectrometry using a single quadrupole instrument equipped with an electron spray source, and other appropriate analytical methods.
- HPLC high-performance liquid chromatography
- TOF-MS Time Of Flight-Mass Spectroscopy
- Ethyl 2- (triphenylphosphoranylidene) acetate (16.3 g, 47 mmol) is dissolved in dichloromethane (160 mL), and cyclopropanecarbonyl chloride (5.4 g, 51 mmol) and N, O are added under ice cooling.
- -Bis (trimethylsilyl) acetamide (BSA) (11.9 g, 58 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, water (100 mL) was added, and the aqueous layer was extracted twice with dichloromethane.
- Compound B35 was synthesized from compound B2 in the same manner as Example 267.
- Example 302 Uric acid transport inhibition test using human URAT1-expressing cells (1) Preparation of test compound After dissolving a test compound in DMSO (manufactured by Sigma) to a concentration of 20 mM, the desired concentration at the time of use Prepared and used.
- DMSO manufactured by Sigma
- Human URAT1 (hURAT1) full-length cDNA (Origine, NCBI Reference Sequence: NM — 144585) was subcloned into the expression vector pCMV6-Kan / Neo (Origene).
- the human URAT1 gene was introduced into human fetal kidney-derived cells (HEK293 cells) by a liposome method using Lipofectamine 2000 (manufactured by Invitrogen), and HEK293 cells that expressed the human URAT1 gene due to geneticin resistance were selected. In the same manner as described below, it was confirmed that the human URAT1 gene expressed its function, using as an index the transport of uric acid labeled with 14 C into cells.
- Human URAT1-expressing HEK293 cells were seeded in a 24-well cell culture dish at 3 ⁇ 10 5 cells / mL / well, and Dulbecco's modified Eagle medium (D-MEM medium) containing 10% fetal bovine serum at 37 ° C. After culturing for 2 days, the following uric acid transport inhibition test was performed.
- D-MEM medium Dulbecco's modified Eagle medium
- HBSS Hanks' Balanced Salt Solution
- HBSS / Na-gluconate Na-gluconate
- the HBSS / Na-gluconate was removed by aspiration and then preliminarily heated to 37 ° C., containing various concentrations of the example compounds and radioligands ( 14 C-labeled uric acid; final concentration 25 ⁇ M) described in (1) 14 C-uric acid solution was added, and the uptake reaction was carried out by incubation at 37 ° C. for 5 minutes.
- the radioactivity indicating URAT1 specific uric acid transport (radioactivity in human URAT1-expressing cells HEK293 cells in the absence of the Example compound (DMSO added)) is defined as 100%, and the uric acid transport rate (% of control) at each concentration of the Example compound. uptake) was calculated, and the concentration of the example compound (IC 50 ) at which the uric acid transport rate was inhibited by 50% was determined.
- the results are shown in the following table.
- symbols (*, **, ***) in the table represent the following inhibitory activity values.
- Capuchin capuchin monkey efficacy evaluation test A test compound suspended in a 0.5% methylcellulose solution (3 mg / kg to 30 mg / kg) was administered to the capuchin capuchin monkey through the nasal cavity into the stomach using a disposable catheter and syringe. . Blood before administration, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, 4 hours from immediately after administration, 4 to 8 hours after administration, 8 to 16 hours after administration Urine samples were collected between 16 and 24 hours after administration. The concentrations of uric acid and creatinine in the collected blood and urine samples were measured with an automatic analyzer (JEOL Ltd.).
- Uric acid was measured using L-type Wako UA ⁇ F (Wako Pure Chemical Industries), and creatinine was measured using L-type Wako Creatinine ⁇ F (Wako Pure Chemical Industries).
- the uric acid clearance was calculated from the uric acid concentration in blood and urine, and the creatinine clearance was calculated from the creatinine concentration in the same manner, and the uric acid excretion rate was determined by the following equation.
- the pyridine derivative of the present invention has an excellent uric acid excretion promoting action.
- the pyridine derivative of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof is used as a pharmaceutical product.
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Abstract
Description
また、本発明の別の目的は、前記URAT1阻害活性を有する新規化合物を有効成分として含有する痛風、高尿酸血症、高血圧症、間質性腎炎等の腎疾患、糖尿病、動脈硬化症、またはレッシュ・ナイハン症候群等、URAT1の関与する疾患の治療剤または予防剤を提供することである。
すなわち、本発明は、下記式(I)で表されるピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物である。
R1は、窒素原子またはCHを表す。
X1からX5のうち、1つは窒素原子を表し、残り4つはCR2を表す。
R2は、それぞれ独立に、水素原子、炭素数1-6のアルキル基、炭素数2-6のアルケニル基、炭素数2-6のアルキニル基、ハロゲン原子、トリフルオロメチル基、ジフルオロメチル基、シアノ基、炭素数2-7のアルキルカルボニル基、炭素数1-6のアルキルスルホニル基、ニトロ基、アミノ基、環を形成していてもよい炭素数1-6のジアルキルアミノ基、ホルミル基、水酸基、炭素数1-6のアルコキシ基(水酸基、フェニル基、シクロヘキシル基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、炭素数1-6のアルキルチオ基、フェニル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、またはフェノキシ基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)を表す。ただし、2つのCR2が隣り合う場合、R2どうしが結合して環を形成していてもよい。
R3は水素原子、炭素数1-6のアルキル基(水酸基、アミノ基、環を形成していてもよい炭素数1-6のジアルキルアミノ基、イミダゾール環、ピラゾール環、ピロリジン環、ピペリジン環、モルホリン環、およびピペラジン環(炭素数1-6のアルキル基、および炭素数1-6のアルキルスルホニル基のうちの1つ以上により置換されていてもよい)のうちの1つ以上により置換されていてもよい)、炭素数2-6のアルケニル基、炭素数2-6のアルキニル基、炭素数1-6のアルコキシ基(水酸基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、炭素数2-7のアルキルカルボニル基、炭素数1-6のアルキルチオ基、炭素数1-6のアルキルスルフィニル基、ハロゲン原子、トリフルオロメチル基、ジフルオロメチル基、シアノ基、フェニル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、ピリジル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、フェノキシ基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、カルボキシル基または-CO2R5を表す。
R4はカルボキシル基、テトラゾリル基、-CONHSO2R5、-CO2R5、または以下のいずれかの置換基を表す。
R3およびR4におけるR5は、それぞれ独立に、炭素数1-6のアルキル基を表す。
Zは、下記Z1からZ7で示される置換基のいずれかを表す。
R8は、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R9は、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R10は、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R11、R12は、それぞれ独立に、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R13、R14は、それぞれ独立に、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R15は、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
Yは水素原子または炭素数1-6のアルキル基を表す。
Wは硫黄原子、酸素原子またはNR16(R16は水素原子、炭素数1-6のアルキル基、もしくはベンジル基を表す)を表す。]
R17は塩素原子、臭素原子またはヨウ素原子を表す。
R18はホルミル基または-CO2R5を表す。
R3およびR18におけるR5は、それぞれ独立に、炭素数1-6のアルキル基を表す。
Zは、下記Z1からZ7で示される置換基のいずれかを表す。
R19は-CO2R5を表す。
R3およびR19におけるR5は、それぞれ独立に、炭素数1-6のアルキル基を表す。
Zaは、2,5-ジクロロベンジル基、3,5-ジクロロベンジル基、2,5-ジメチルベンジル基、2,5-ビス(トリフルオロメチル)ベンジル基、2-クロロ-5-メチルベンジル基、ナフタレン-1-イルメチル基、(2-メチルナフタレン-1-イル)メチル基、(4-メチルナフタレン-1-イル)メチル基、(8-メチルナフタレン-1-イル)メチル基、(8-ブロモナフタレン-1-イル)メチル基、ベンゾ[b]チオフェン-3-イルメチル基、(4-メチルベンゾ[b]チオフェン-3-イル)メチル基、(4-クロロベンゾ[b]チオフェン-3-イル)メチル基、(4-ブロモベンゾ[b]チオフェン-3-イル)メチル基、(4-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル基、(5-メチルベンゾ[b]チオフェン-3-イル)メチル基、(5-クロロベンゾ[b]チオフェン-3-イル)メチル基、(5-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル基、ベンゾ[b]チオフェン-7-イルメチル基、(5-フルオロベンゾ[b]チオフェン-7-イル)メチル基、(2,5-ジクロロチオフェン-3-イル)メチル基、(2,4-ジクロロチオフェン-5-イル)メチル基、キノリン-8-イルメチル基を表す。]
本発明におけるアルキル基とは、直鎖、分岐鎖、または環状の脂肪族飽和炭化水素基をいう。炭素数1-6のアルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、tert-ブチル基、ペンチル基、イソペンチル基、ヘキシル基、シクロプロピル基、シクロプロピルメチル基、シクロペンチル基、またはシクロヘキシル基を具体的な基として挙げることができる。
1)Aが単結合であり;R1が窒素原子であり;X1が窒素原子であり;X4がCR2かつX2とX3とX5はCHであり;R2が水素原子、炭素数1-6のアルキル基、ハロゲン原子、トリフルオロメチル基、ジフルオロメチル基、シアノ基、ニトロ基、環を形成していてもよい炭素数1-6のジアルキルアミノ基、水酸基、炭素数1-6のアルコキシ基(水酸基、フェニル基、シクロヘキシル基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、炭素数1-6のアルキルチオ基、フェニル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、またはフェノキシ基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)であり;R3が水素原子、炭素数1-6のアルキル基(水酸基、アミノ基、環を形成していてもよい炭素数1-6のジアルキルアミノ基、イミダゾール環、ピラゾール環、ピロリジン環、ピペリジン環、モルホリン環、およびピペラジン環(炭素数1-6のアルキル基、および炭素数1-6のアルキルスルホニル基のうちの1つ以上により置換されていてもよい)のうちの1つ以上により置換されていてもよい)、炭素数1-6のアルコキシ基、炭素数1-6のアルキルチオ基、ハロゲン原子、トリフルオロメチル基、ジフルオロメチル基、シアノ基、フェニル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、カルボキシル基、または-CO2R5であり;R4がカルボキシル基(R3が水酸基で置換された炭素数1-6のアルキル基である場合、R3と縮合してラクトン環を形成していてもよい)、テトラゾリル基、-CONHSO2CH3、-CONHSO2-シクロプロピル、または-CO2R5であり;Zは2,5-ジクロロベンジル基、3,5-ジクロロベンジル基、2,5-ジメチルベンジル基、2,5-ビス(トリフルオロメチル)ベンジル基、2-クロロ-5-メチルベンジル基、ナフタレン-1-イルメチル基、(2-メチルナフタレン-1-イル)メチル基、(4-メチルナフタレン-1-イル)メチル基、(8-メチルナフタレン-1-イル)メチル基、(8-ブロモナフタレン-1-イル)メチル基、ベンゾ[b]チオフェン-3-イルメチル基、(4-メチルベンゾ[b]チオフェン-3-イル)メチル基、(4-クロロベンゾ[b]チオフェン-3-イル)メチル基、(4-ブロモベンゾ[b]チオフェン-3-イル)メチル基、(4-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル基、(5-メチルベンゾ[b]チオフェン-3-イル)メチル基、(5-クロロベンゾ[b]チオフェン-3-イル)メチル基、(5-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル基、ベンゾ[b]チオフェン-7-イルメチル基、(5-フルオロベンゾ[b]チオフェン-7-イル)メチル基、(2,5-ジクロロチオフェン-3-イル)メチル基、(2,4-ジクロロチオフェン-5-イル)メチル基、キノリン-8-イルメチル基である。
R17は塩素原子、臭素原子またはヨウ素原子を表す。R18はホルミル基または-CO2R5を表す。
R3およびR18におけるR5は、それぞれ独立に、炭素数1-6のアルキル基を表す。
Zは、下記Z1からZ7で示される置換基のいずれかを表す。
R19は-CO2R5を表す。
R3およびR19におけるR5は、それぞれ独立に、炭素数1-6のアルキル基を表す。
Zaは、2,5-ジクロロベンジル基、3,5-ジクロロベンジル基、2,5-ジメチルベンジル基、2,5-ビス(トリフルオロメチル)ベンジル基、2-クロロ-5-メチルベンジル基、ナフタレン-1-イルメチル基、(2-メチルナフタレン-1-イル)メチル基、(4-メチルナフタレン-1-イル)メチル基、(8-メチルナフタレン-1-イル)メチル基、(8-ブロモナフタレン-1-イル)メチル基、ベンゾ[b]チオフェン-3-イルメチル基、(4-メチルベンゾ[b]チオフェン-3-イル)メチル基、(4-クロロベンゾ[b]チオフェン-3-イル)メチル基、(4-ブロモベンゾ[b]チオフェン-3-イル)メチル基、(4-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル基、(5-メチルベンゾ[b]チオフェン-3-イル)メチル基、(5-クロロベンゾ[b]チオフェン-3-イル)メチル基、(5-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル基、ベンゾ[b]チオフェン-7-イルメチル基、(5-フルオロベンゾ[b]チオフェン-7-イル)メチル基、(2,5-ジクロロチオフェン-3-イル)メチル基、(2,4-ジクロロチオフェン-5-イル)メチル基、キノリン-8-イルメチル基を表す。]
好ましいZaは、2,5-ジクロロベンジル基、2,5-ジメチルベンジル基、ナフタレン-1-イルメチル基、(4-クロロベンゾ[b]チオフェン-3-イル)メチル基 、またはベンゾ[b]チオフェン-7-イルメチル基である。
なお、上記式(II)の化合物は上記スキームAの化合物(II-1)として用いることができる。
DMF=N,N-ジメチルホルムアミド
THF=テトラヒドロフラン
NBS=N-ブロモスクシンイミド
NCS=N-クロロスクシンイミド
DEAD=アゾジカルボン酸ジエチル
DIAD=アゾジカルボン酸ジイソプロピル
PdCl2(dppf)=[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)
PdCl2(dppf)・CH2Cl2=[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)ジクロロメタン錯体
BSA=N,O-ビス( トリメチルシリル)アセトアミド
AIBN=2,2’-アゾビス(イソブチロニトリル)
HATU=O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロホスフェート
WSC=1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩
DMAP=N,N-ジメチル-4-アミノピリジン
DIBAL-H=水素化ジイソブチルアルミニウム
DAST=ジエチルアミノ硫黄トリフルオリド
s=singlet、d=doublet、t=triplet、q=quartet、brs=broad singlet、m=multiplet。
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%
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%HCO2H
B:H2O/アセトニトリル=5/95
0.1%HCO2H
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%
1H-NMR (CDCl3) δ: 4.35 (2H, q, J = 7.1 Hz), 2.51 (3H, s), 1.37 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 233 (M+ +H)
1H-NMR (CDCl3) δ: 8.01 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 7.8 Hz), 7.77 (1H, d, J = 8.3 Hz), 7.63-7.53 (2H, m), 7.33 (1H, t, J = 7.6 Hz), 6.43 (1H, dd, J = 7.3, 1.0 Hz), 6.07 (2H, s), 4.13 (2H, q, J = 7.1 Hz), 2.58 (3H, s), 1.11 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 373 (M+ +H)
1H-NMR (CDCl3) δ: 8.78 (1H, d, J = 2.0 Hz), 8.58 (1H, dd, J = 4.9, 1.5 Hz), 7.93-7.85 (2H, m), 7.82-7.77 (2H, m), 7.57-7.53 (2H, m), 7.38 (1H, t, J = 7.6 Hz), 7.24-7.20 (1H, m), 6.73 (1H, d, J = 6.3 Hz), 6.03 (2H, s), 4.13 (2H, q, J = 7.2 Hz), 2.67 (3H, s), 1.07 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 372 (M+ +H)
1H-NMR (DMSO-D6) δ: 8.69 (1H, d, J = 2.0 Hz), 8.60 (1H, dd, J = 4.9, 1.5 Hz), 8.05-8.01 (1H, m), 7.99-7.95 (1H, m), 7.93 (1H, dt, J = 8.0, 2.0 Hz), 7.84 (1H, d, J = 8.3 Hz), 7.60-7.57 (2H, m), 7.46-7.40 (2H, m), 6.59 (1H, d, J = 7.3 Hz), 6.09 (2H, s), 2.56 (3H, s).
HPLC保持時間 = 7.40 min
Pred. Mass = 344.1394 (M+ +H, C21H17N3O2)
Obs. Mass = 344.1391 (M+ +H)
1H-NMR (CDCl3) δ: 7.72 (1H, d, J = 8.3 Hz), 7.41-7.24 (3H, m), 6.15 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 2.57 (3H, s), 1.20 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 413 (M+ +H)
ESI-MS m/z = 412 (M+ +H)
1H-NMR (DMSO-D6) δ: 8.72 (1H, d, J = 2.0 Hz), 8.60 (1H, dd, J = 4.9, 2.0 Hz), 7.99-7.93 (2H, m), 7.47-7.44 (2H, m), 7.37 (1H, t, J = 8.0 Hz), 6.87 (1H, s), 6.05 (2H, s), 2.60 (3H, s).
HPLC保持時間 = 7.76 min
Pred. Mass = 384.0568 (M+ +H, C19H14ClN3O2S)
Obs. Mass = 384.0564 (M+ +H)
ESI-MS m/z = 176 (M+ +H)
1H-NMR (DMSO-d6) δ: 13.16 (1H, s), 9.09 (1H, d, J = 2.0 Hz), 8.54 (1H, dd, J = 4.9, 1.5 Hz), 8.24 (1H, dt, J = 8.1, 2.0 Hz), 7.47 (1H, dd, J = 7.8, 4.9 Hz), 5.31 (1H, t, J = 5.1 Hz), 4.45 (2H, d, J = 4.9 Hz).
ESI-MS m/z = 210 (M+ +H)
1H-NMR (DMSO-d6) δ: 14.22 (1H, s), 9.72 (1H, s), 9.24 (1H, s), 8.66 (1H, d, J = 4.4 Hz), 8.42 (1H, d, J = 7.3 Hz), 7.54 (1H, dd, J = 7.8, 4.9 Hz).
ESI-MS m/z = 208 (M+ +H)
ESI-MS m/z = 348 (M+ +H)
HPLC保持時間 = 8.52 min
Pred. Mass = 364.0847 (M+ +H, C20H14ClN3O2)
Obs. Mass = 364.0847 (M+ +H)
1H-NMR (CDCl3) δ: 7.67-7.40 (15H, m), 3.74 (2H, q, J = 7.2 Hz), 3.35-3.33 (1H, m), 0.85-0.81 (2H, m), 0.71-0.67 (2H, m), 0.65 (3H, t, J = 7.3 Hz).
ESI-MS m/z = 417 (M+ +H)
1H-NMR (CDCl3) δ: 4.34 (2H, q, J = 7.1 Hz), 2.16-2.11 (1H, m), 1.31 (3H, t, J = 7.1 Hz), 1.25-1.22 (2H, m), 1.15-1.10 (2H, m).
1H-NMR (DMSO-d6) δ: 13.07 (1H, brs), 9.16 (1H, brs), 8.56 (1H, d, J = 4.9 Hz), 8.33 (1H, brs), 7.46 (1H, dd, J = 7.8, 4.9 Hz), 4.30 (2H, brs), 2.59 (1H, brs), 1.32 (3H, t, J = 7.1 Hz), 0.97 (4H, brs).
ESI-MS m/z = 258 (M+ +H)
ESI-MS m/z = 398 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.62 (1H, d, J = 2.0 Hz), 8.56 (1H, dd, J = 4.9, 1.5 Hz), 8.05-7.95 (2H, m), 7.89-7.82 (2H, m), 7.60-7.56 (2H, m), 7.45-7.38 (2H, m), 6.55 (1H, d, J = 6.8 Hz), 6.05 (2H, s), 2.78-2.71 (1H, m), 1.04-0.96 (4H, m).
HPLC保持時間 = 8.28 min
Pred. Mass = 370.1550 (M+ +H, C23H19N3O2)
Obs. Mass = 370.1548 (M+ +H)
1H-NMR (CDCl3) δ: 7.34 (1H, d, J = 8.8 Hz), 7.20 (1H, dd, J = 8.8, 2.4 Hz), 6.40 (1H, d, J = 2.4 Hz), 5.60 (2H, s), 4.25 (2H, q, J = 7.2 Hz), 2.56 (3H, s), 1.27 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 391 (M+ +H)
1H-NMR (CDCl3) δ: 8.69-8.66 (2H, m), 7.82-7.78 (1H, m), 7.37-7.33 (2H, m), 7.26-7.22 (1H, m), 6.66 (1H, d, J = 2.4 Hz), 5.53 (2H, s), 4.25 (2H, q, J = 7.2 Hz), 2.65 (3H, s), 1.27 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 390 (M+ +H)
1H-NMR (DMSO-d6) δ: 13.01 (1H, s), 8.64-8.61 (2H, m), 7.84 (1H, d, J = 7.8 Hz), 7.52-7.44 (2H, m), 7.37 (1H, dd, J = 8.5, 2.2 Hz), 6.54 (1H, d, J = 2.0 Hz), 5.55 (2H, s), 2.49 (3H, s).
HPLC保持時間 = 7.33 min
Pred. Mass = 362.0458 (M+ +H, C17H13Cl2N3O2)
Obs. Mass = 362.0455 (M+ +H)
1H-NMR (CDCl3) δ: 4.44 (2H, q, J = 7.2 Hz), 1.40 (3H, t, J = 7.2 Hz).
ESI-MS m/z = 287 (M+ +H)
1H-NMR (CDCl3) δ: 7.38 (1H, d, J = 8.3 Hz), 7.26-7.23 (1H, m), 6.43 (1H, d, J = 2.4 Hz), 5.66 (2H, s), 4.32 (2H, q, J = 7.1 Hz), 1.32 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 445 (M+ +H)
1H-NMR (CDCl3) δ: 8.72 (1H, dd, J = 4.9, 1.5 Hz), 8.68 (1H, d, J = 1.2 Hz), 7.85-7.81 (1H, m), 7.41-7.35 (2H, m), 7.28-7.25 (1H, m), 6.64 (1H, d, J = 2.0 Hz), 5.60 (2H, s), 4.33 (2H, q, J = 7.1 Hz), 1.32 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 444 (M+ +H)
1H-NMR (DMSO-d6) δ: 14.13 (1H, s), 8.70-8.66 (2H, m), 7.92 (1H, dt, J = 7.8, 2.0 Hz), 7.53-7.47 (2H, m), 7.39 (1H, dd, J = 8.8, 2.4 Hz), 6.80 (1H, d, J = 2.4 Hz), 5.60 (2H, s).
HPLC保持時間 = 9.32 min
Pred. Mass = 416.0175 (M+ +H, C17H10Cl2F3N3O2)
Obs. Mass = 416.0175 (M+ +H)
1H-NMR (CDCl3) δ: 7.83 (1H, s), 7.67 (1H, s), 7.36 (1H, d, J = 8.8 Hz), 7.24 (1H, dd, J = 8.3, 2.4 Hz), 6.78 (1H, d, J = 2.4 Hz), 5.61 (2H, s), 3.83 (3H, s).
ESI-MS m/z = 285 (M+ +H)
1H-NMR (CDCl3) δ: 7.83 (1H, s), 7.36 (1H, d, J = 8.3 Hz), 7.21 (1H, dd, J = 8.8, 2.4 Hz), 6.34 (1H, d, J = 2.4 Hz), 5.66 (2H, s), 3.82 (3H, s).
ESI-MS m/z = 363 (M+ +H)
ESI-MS m/z = 362 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.71 (2H, s), 7.98 (1H, s), 7.94 (1H, d, J = 8.3 Hz), 7.57-7.49 (2H, m), 7.39 (1H, dd, J = 8.8, 2.4 Hz), 6.54 (1H, d, J = 2.4 Hz), 5.65 (2H, s).
HPLC保持時間 = 7.25 min
Pred. Mass = 348.0301 (M+ +H, C16H11Cl2N3O2)
Obs. Mass = 348.0296 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.71 (1H, d, J = 2.0 Hz), 8.58 (1H, dd, J = 4.9, 1.5 Hz), 7.92 (1H, dt, J = 8.1, 2.0 Hz), 7.52-7.36 (4H, m), 7.15 (1H, d, J = 1.5 Hz), 6.81 (1H, d, J = 2.4 Hz), 5.41 (2H, s).
ESI-MS m/z = 304 (M+ +H)
1H-NMR (CDCl3) δ: 8.67-8.63 (2H, m), 7.80 (1H, dt, J = 7.8, 2.0 Hz), 7.40-7.33 (3H, m), 7.30-7.26 (1H, m), 6.64 (1H, s), 5.28 (2H, s).
ESI-MS m/z = 382 (M+ +H)
1H-NMR (CDCl3) δ: 8.72-8.67 (2H, m), 8.03 (1H, s), 7.82 (1H, td, J = 5.0, 2.8 Hz), 7.39-7.34 (2H, m), 7.24 (1H, dd, J = 8.8, 2.4 Hz), 6.59 (1H, d, J = 2.4 Hz), 5.61 (2H, s), 4.28 (2H, q, J = 7.2 Hz), 1.31 (3H, t, J = 7.1 Hz).
ESI-MS m/z = 376 (M+ +H)
1H-NMR (CDCl3) δ: 8.72-8.67 (2H, m), 7.83 (1H, dt, J = 8.1, 2.0 Hz), 7.40-7.35 (2H, m), 7.26 (1H, dd, J = 8.8, 2.4 Hz), 6.70 (1H, d, J = 2.0 Hz), 5.58 (2H, s), 4.30 (2H, q, J = 7.2 Hz), 1.30 (3H, t, J = 7.3 Hz).
ESI-MS m/z = 410 (M+ +H)
1H-NMR (DMSO-d6) δ: 13.57 (1H, s), 8.69-8.64 (2H, m), 7.88 (1H, dt, J = 8.1, 2.0 Hz), 7.53-7.48 (2H, m), 7.39 (1H, dd, J = 8.5, 2.7 Hz), 6.79 (1H, d, J = 2.4 Hz), 5.57 (2H, s).
HPLC保持時間 = 8.74 min
Pred. Mass = 381.9911 (M+ +H, C16H10Cl3N3O2)
Obs. Mass = 381.9908 (M+ +H)
1H-NMR (CDCl3) δ: 8.67-8.62 (2H, m), 7.81 (1H, dt, J = 8.0, 2.0 Hz), 7.40-7.27 (3H, m), 6.66 (1H, d, J = 2.4 Hz), 5.32 (2H, s).
ESI-MS m/z = 556 (M+ +H)
1H-NMR (CDCl3) δ: 9.69 (1H, s), 8.74-8.68 (2H, m), 7.84 (1H, dt, J = 8.1, 1.7 Hz), 7.42-7.36 (2H, m), 7.27-7.25 (1H, m), 6.63 (1H, d, J = 2.0 Hz), 5.61 (2H, s).
ESI-MS m/z = 458 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.69-8.64 (2H, m), 7.90 (1H, dt, J = 7.8, 2.0 Hz), 7.54-7.48 (2H, m), 7.39 (1H, dd, J = 8.8, 2.4 Hz), 6.69 (1H, d, J = 2.4 Hz), 5.57 (2H, s).
HPLC保持時間 = 8.71 min
Pred. Mass = 473.9268 (M+ +H, C16H10Cl2IN3O2)
Obs. Mass = 473.9277 (M+ +H)
ESI-MS m/z = 408 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.73 (1H, s), 8.68 (1H, d, J = 3.9 Hz), 7.95 (1H, d, J = 8.0 Hz), 7.78-7.74 (2H, m), 7.54-7.50 (2H, m), 7.45-7.35 (4H, m), 6.73 (1H, d, J = 2.0 Hz), 5.61 (2H, s).
HPLC保持時間 = 9.08 min
Pred. Mass = 424.0614 (M+ +H, C22H15Cl2N3O2)
Obs. Mass = 424.0602 (M+ +H)
1H-NMR (CDCl3) δ: 10.56 (1H, s), 3.96 (6H, s).
ESI-MS m/z = 263 (M+ +H)
1H-NMR (CDCl3) δ: 9.78 (1H, s), 3.93 (3H, s), 1.68 (3H, s), 1.61 (3H, s).
ESI-MS m/z = 263 (M+ +H)
1H-NMR (CDCl3) δ: 7.37 (1H, d, J = 8.8 Hz), 7.24 (1H, d, J = 8.8 Hz), 6.46 (1H, s), 5.55 (2H, s), 3.77 (3H, s), 1.65 (6H, s).
ESI-MS m/z = 421 (M+ +H)
ESI-MS m/z = 420 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.71-8.65 (2H, m), 7.91 (1H, d, J = 7.8 Hz), 7.56-7.48 (2H, m), 7.39 (1H, dd, J = 8.5, 2.2 Hz), 6.56 (1H, d, J = 1.5 Hz), 5.59 (2H, s), 1.62 (6H, s).
HPLC保持時間 = 8.16 min
Pred. Mass = 406.0720 (M+ +H, C19H17Cl2N3O3)
Obs. Mass = 406.0725 (M+ +H)
1H-NMR (CDCl3) δ: 8.74-8.71 (2H, m), 7.92 (1H, s), 7.86 (1H, dt, J = 8.3, 2.0 Hz), 7.43-7.38 (2H, m), 7.31 (1H, dd, J = 8.3, 2.4 Hz), 6.67 (1H, d, J = 2.4 Hz), 5.41 (2H, s).
ESI-MS m/z = 329 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.75 (1H, d, J = 2.0 Hz), 8.69-8.65 (1H, m), 8.00-7.96 (2H, m), 7.56-7.48 (2H, m), 7.35 (1H, dd, J = 8.3, 2.4 Hz), 6.51 (1H, d, J = 2.4 Hz), 5.83 (2H, s).
HPLC保持時間 = 7.97 min
Pred. Mass = 372.0526 (M+ +H, C16H11Cl2N7)
Obs. Mass = 372.0527 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.74 (1H, d, J = 2.0 Hz), 8.69 (1H, dd, J = 4.9, 2.0 Hz), 7.99 (1H, dt, J = 8.0, 1.8 Hz), 7.58-7.53 (1H, m), 7.46 (1H, d, J = 8.3 Hz), 7.38 (1H, dd, J = 8.5, 2.7 Hz), 6.78 (1H, d, J = 2.4 Hz), 5.50 (2H, s), 3.13 (3H, s), 2.45 (3H, s).
HPLC保持時間 = 7.76 min
Pred. Mass = 439.0393 (M+ +H, C18H16Cl2N4O3S )
Obs. Mass = 439.0397 (M+ +H)
1H-NMR (CDCl3) δ: 8.53 (1H, s), 8.44 (1H, d, J = 2.9 Hz), 7.94-7.85 (2H, m), 7.80 (1H, d, J = 8.3 Hz), 7.63-7.53 (3H, m), 7.38 (1H, t, J = 7.8 Hz), 6.70 (1H, d, J = 6.8 Hz), 6.06 (2H, s), 4.14 (2H, q, J = 7.2 Hz), 2.67 (3H, s), 1.09 (3H, t, J = 7.2 Hz).
ESI-MS m/z = 390 (M+ +H)
1H-NMR (DMSO-d6) δ: 12.95 (1H, s), 8.58 (1H, d, J = 2.9 Hz), 8.48 (1H, s), 8.06-7.95 (2H, m), 7.85-7.80 (2H, m), 7.61-7.57 (2H, m), 7.40 (1H, t, J = 7.6 Hz), 6.52 (1H, d, J = 7.3 Hz), 6.12 (2H, s), 2.53 (3H, s).
HPLC保持時間 = 8.53 min
Pred. Mass = 362.1299 (M+ +H, C21H16FN3O2)
Obs. Mass = 362.1300 (M+ +H)
1H-NMR (CDCl3) δ: 7.36 (1H, d, J = 8.8 Hz), 7.24 (1H, dd, J = 8.8, 3.0 Hz), 6.52 (1H, d, J = 2.4 Hz), 5.54 (2H, s), 3.96 (3H, s), 3.85 (3H, s).
ESI-MS m/z = 421 (M+ +H)
1H-NMR (CDCl3) δ: 8.66 (1H, d, J = 2.0 Hz), 8.50 (1H, d, J = 2.0 Hz), 7.91 (1H, t, J = 2.0 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.29-7.26 (1H, m), 6.72 (1H, d, J = 2.4 Hz), 5.51 (2H, s), 3.99 (3H, s), 3.86 (3H, s).
ESI-MS m/z = 454 (M+ +H)
1H-NMR (CDCl3) δ: 8.65 (1H, d, J = 2.4 Hz), 8.50 (1H, d, J = 2.0 Hz), 7.91 (1H, t, J = 2.2 Hz), 7.39 (1H, d, J = 8.8 Hz), 7.27 (1H, dd, J = 8.3, 2.4 Hz), 6.63 (1H, d, J = 2.4 Hz), 5.59 (2H, s), 4.99-4.96 (2H, m), 3.85 (3H, s), 3.21 (1H, t, J = 5.6 Hz).
ESI-MS m/z = 426 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.72 (1H, d, J = 2.4 Hz), 8.56 (1H, d, J = 2.0 Hz), 8.04 (1H, t, J = 2.0 Hz), 7.51 (1H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.3, 2.4 Hz), 6.60 (1H, d, J = 2.4 Hz), 5.64 (2H, s), 4.71 (2H, s).
HPLC保持時間 = 8.81 min
Pred. Mass = 412.0017 (M+ +H, C17H12Cl3N3O3)
Obs. Mass = 412.0018 (M+ +H)
ESI-MS m/z = 481 (M+ +H)
1H-NMR (DMSO-d6) δ: 9.58 (1H, s), 8.76 (1H, d, J = 2.4 Hz), 8.61 (1H, d, J = 2.0 Hz), 8.10 (1H, t, J = 2.2 Hz), 7.51 (1H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.3, 2.4 Hz), 6.69 (1H, d, J = 2.4 Hz), 5.70 (2H, s), 4.60 (2H, d, J = 4.4 Hz), 3.35-3.19 (4H, m), 1.27 (6H, t, J = 7.3 Hz).
HPLC保持時間 = 8.55 min
Pred. Mass = 467.0803 (M+ +H, C21H21Cl3N4O2)
Obs. Mass = 467.0806 (M+ +H)
1H-NMR (CDCl3) δ: 8.74 (1H, d, J = 2.0 Hz), 8.53 (1H, d, J = 1.5 Hz), 8.05-8.01 (2H, m), 7.38 (1H, d, J = 8.8 Hz), 7.25 (1H, dd, J = 9.0, 2.2 Hz), 6.59 (1H, d, J = 2.0 Hz), 5.63 (2H, s), 4.29 (2H, q, J = 7.2 Hz), 1.32 (3H, t, J = 7.3 Hz).
ESI-MS m/z = 454 (M+ +H)
1H-NMR (DMSO-d6) δ: 13.23 (1H, s), 8.79 (1H, d, J = 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz), 8.15 (1H, t, J = 2.2 Hz), 7.93 (1H, s), 7.51 (1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 8.3, 2.4 Hz), 6.56 (1H, d, J = 2.4 Hz), 5.70 (2H, s).
HPLC保持時間 = 9.99 min
Pred. Mass = 425.9406 (M+ +H, C16H10BrCl2N3O2)
Obs. Mass = 425.9404 (M+ +H)
1H-NMR (CDCl3) δ: 10.51 (1H, s), 8.68 (1H, d, J = 2.4 Hz), 8.50 (1H, d, J = 2.0 Hz), 7.98 (1H, t, J = 2.2 Hz), 7.40 (1H, d, J = 8.3 Hz), 7.29 (1H, dd, J = 8.8, 2.4 Hz), 6.59 (1H, d, J = 2.4 Hz), 5.66 (2H, s), 3.97 (3H, s).
ESI-MS m/z = 424 (M+ +H)
1H-NMR (CDCl3) δ: 8.67 (1H, d, J = 2.4 Hz), 8.49 (1H, d, J = 2.0 Hz), 7.95 (1H, t, J = 2.2 Hz), 7.39 (1H, d, J = 8.8 Hz), 7.28 (1H, dd, J = 8.8, 2.2 Hz), 7.21 (1H, t, J = 54.1 Hz), 6.60 (1H, d, J = 2.4 Hz), 5.63 (2H, s), 3.91 (3H, s).
ESI-MS m/z = 446 (M+ +H)
1H-NMR (DMSO-d6) δ: 14.16 (1H, s), 8.75 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 2.0 Hz), 8.07 (1H, t, J = 2.2 Hz), 7.53-7.20 (3H, m), 6.75 (1H, d, J = 2.4 Hz), 5.66 (2H, s).
HPLC保持時間 = 11.04 min
Pred. Mass = 431.9879 (M+ +H, C17H10Cl3F2N3O2)
Obs. Mass = 431.9878 (M+ +H)
ESI-MS m/z = 420 (M+ +H)
1H-NMR (DMSO-d6) δ: 13.59 (1H, s), 8.73 (1H, d, J = 2.0 Hz), 8.57 (1H, d, J = 1.5 Hz), 8.06 (1H, t, J = 2.2 Hz), 7.48 (1H, d, J = 8.3 Hz), 7.38 (1H, d, J = 8.8 Hz), 6.73 (1H, s), 5.62 (2H, s), 4.44 (1H, s).
HPLC保持時間 = 10.67 min
Pred. Mass = 405.9911 (M+ +H, C18H10Cl3N3O2)
Obs. Mass = 405.9922 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.79 (1H, d, J = 2.2 Hz), 8.75 (1H, d, J = 2.0 Hz), 8.23 (1H, t, J = 2.2 Hz), 7.47-7.37 (2H, m), 7.30 (1H, d, J = 2.0 Hz), 5.51 (2H, s), 5.34 (2H, s).
HPLC保持時間 = 11.16 min
Pred. Mass = 393.9911 (M+ +H, C17H10Cl3N3O2)
Obs. Mass = 393.9911 (M+ +H)
ESI-MS m/z = 420 (M+ +H)
1H-NMR (DMSO-d6) δ: 8.43 (1H, dd, J = 4.9, 1.0 Hz), 7.95 (1H, d, J = 8.3 Hz), 7.58-7.40 (3H, m), 6.77 (1H, d, J = 2.4 Hz), 5.55 (2H, s), 2.33 (3H, s), 2.28 (3H, s).
HPLC保持時間 = 8.20 min
Pred. Mass = 392.0563 (M+ +H, C18H15Cl2N3O3)
Obs. Mass = 392.0570 (M+ +H)
1H-NMR (CDCl3) δ: 9.41 (1H, s), 8.04 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 7.8 Hz), 7.74 (1H, d, J = 8.3 Hz), 7.63-7.59 (1H, m), 7.57-7.52 (1H, m), 7.29 (1H, t, J = 7.8 Hz), 7.08 (1H, d, J = 4.4 Hz), 6.50 (1H, d, J = 3.9 Hz), 6.29 (1H, d, J = 7.3 Hz), 6.20 (2H, s).
ESI-MS m/z = 314 (M+ +H)
ESI-MS m/z = 313 (M+ +H)
1H-NMR (DMSO-d6) δ: 12.30 (1H, s), 8.52 (1H, d, J = 2.4 Hz), 8.44 (1H, dd, J = 4.9, 1.5 Hz), 8.05-7.92 (2H, m), 7.78 (1H, d, J = 8.3 Hz), 7.71 (1H, dt, J = 7.8, 2.0 Hz), 7.58-7.53 (2H, m), 7.37 (1H, t, J = 7.6 Hz), 7.31 (1H, dd, J = 8.3, 4.9 Hz), 7.15 (1H, d, J = 3.9 Hz), 6.54 (1H, d, J = 3.9 Hz), 6.31 (1H, d, J = 7.3 Hz), 6.10 (2H, s).
HPLC保持時間 = 8.04 min
Pred. Mass = 329.1285 (M+ +H, C21H16N2O2)
Obs. Mass = 329.1288 (M+ +H)
(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。
ヒトURAT1(hURAT1)完全長cDNA(Origene社製、NCBI Reference Sequence:NM_144585)を発現ベクターpCMV6-Kan/Neo(Origene社製)にサブクローニングし、リポフェクタミン2000(インビトロジェン社製)を用いたリポソーム法により、ヒトURAT1遺伝子をヒト胎児腎由来細胞(HEK293細胞)に導入し、Geneticin耐性によりヒトURAT1遺伝子を発現したHEK293細胞を選別した。下記方法と同様の方法で、14Cで標識された尿酸が細胞内に輸送されることを指標に、ヒトURAT1遺伝子が機能を発現していることを確認した。
IC50≦0.2μM:***
0.2μM<IC50≦2μM:**
2μM<IC50≦20μM:*
フサオマキザルに0.5%メチルセルロース液に縣濁した試験化合物(3mg/kg~30mg/kg)をディスポーザブルカテーテル及び注射筒を用いて鼻腔から胃内に投与した。投与前、投与後30分、1時間、2時間、4時間、8時間、12時間及び24時間に血液を、投与直後から4時間、投与後4時間から8時間、投与後8時間から16時間、投与後16時間から24時間の間の尿サンプルを採取した。採取した血液と尿サンプル中の尿酸及びクレアチニンの濃度を自動分析装置(日本電子株式会社)により測定した。尿酸はLタイプワコーUA・F(和光純薬工業)、クレアチニンはLタイプワコークレアチニン・F(和光純薬工業)を用いて測定した。血中及び尿中の尿酸濃度から尿酸クリアランスを、同様にクレアチニン濃度からクレアチニンクリアランスを算出し、尿酸排泄率を下式により求めた。
Claims (23)
- 下記式(I)で表されるピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
Aは単結合、酸素原子、硫黄原子、NHまたはCH2を表す。
R1は、窒素原子またはCHを表す。
X1からX5のうち、1つは窒素原子を表し、残り4つはCR2を表す。
R2は、それぞれ独立に、水素原子、炭素数1-6のアルキル基、炭素数2-6のアルケニル基、炭素数2-6のアルキニル基、ハロゲン原子、トリフルオロメチル基、ジフルオロメチル基、シアノ基、炭素数2-7のアルキルカルボニル基、炭素数1-6のアルキルスルホニル基、ニトロ基、アミノ基、環を形成していてもよい炭素数1-6のジアルキルアミノ基、ホルミル基、水酸基、炭素数1-6のアルコキシ基(水酸基、フェニル基、シクロヘキシル基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、炭素数1-6のアルキルチオ基、フェニル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、またはフェノキシ基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)を表す。ただし、2つのCR2が隣り合う場合、R2どうしが結合して環を形成していてもよい。
R3は水素原子、炭素数1-6のアルキル基(水酸基、アミノ基、環を形成していてもよい炭素数1-6のジアルキルアミノ基、イミダゾール環、ピラゾール環、ピロリジン環、ピペリジン環、モルホリン環、およびピペラジン環(炭素数1-6のアルキル基、および炭素数1-6のアルキルスルホニル基のうちの1つ以上により置換されていてもよい)のうちの1つ以上により置換されていてもよい)、炭素数2-6のアルケニル基、炭素数2-6のアルキニル基、炭素数1-6のアルコキシ基(水酸基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、炭素数2-7のアルキルカルボニル基、炭素数1-6のアルキルチオ基、炭素数1-6のアルキルスルフィニル基、ハロゲン原子、トリフルオロメチル基、ジフルオロメチル基、シアノ基、フェニル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、ピリジル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、フェノキシ基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、カルボキシル基または-CO2R5を表す。
R4はカルボキシル基、テトラゾリル基、-CONHSO2R5、-CO2R5、または以下のいずれかの置換基を表す。
R3およびR4におけるR5は、それぞれ独立に、炭素数1-6のアルキル基を表す。
Zは、下記Z1からZ7で示される置換基のいずれかを表す。
R8は、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R9は、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R10は、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R11、R12は、それぞれ独立に、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R13、R14は、それぞれ独立に、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
R15は、水素原子、ハロゲン原子、炭素数1-6のアルキル基、またはトリフルオロメチル基を表す。
Yは水素原子または炭素数1-6のアルキル基を表す。
Wは硫黄原子、酸素原子またはNR16(R16は水素原子、炭素数1-6のアルキル基、もしくはベンジル基を表す)を表す。)。] - Aが単結合である、請求項1に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- Aが酸素原子である、請求項1に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- R1が窒素原子である、請求項1から3のいずれか1項に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- R1がCHである、請求項1から3のいずれか1項に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- X1からX5のうち、X1またはX2が窒素原子である請求項1から5のいずれか1項に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- 4つのCR2のうち、3つがCHであり、残り1つのCR2のR2が、水素原子、炭素数1-6のアルキル基、ハロゲン原子、トリフルオロメチル基、ジフルオロメチル基、シアノ基、ニトロ基、環を形成していてもよい炭素数1-6のジアルキルアミノ基、水酸基、炭素数1-6のアルコキシ基(水酸基、フェニル基、シクロヘキシル基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、炭素数1-6のアルキルチオ基、フェニル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、またはフェノキシ基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)である、請求項1から6のいずれか1項に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- R2が水素原子、メチル基、エチル基、シクロプロピル基、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、イソブチロキシ基、ベンジロキシ基、メチルチオ基、フッ素原子、塩素原子、臭素原子、シアノ基、水酸基、ピロリジン-1-イル基、トリフルオロメチル基、ジフルオロメチル基、ニトロ基、フェニル基、またはフェノキシ基である、請求項7に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- 4つのCR2のうち、3つがCHであり、残り1つのCR2の位置がX4である、請求項1から8のいずれか1項に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- X2が窒素原子である、請求項9に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- R3が水素原子、炭素数1-6のアルキル基(水酸基、アミノ基、環を形成していてもよい炭素数1-6のジアルキルアミノ基、イミダゾール環、ピラゾール環、ピロリジン環、ピペリジン環、モルホリン環、およびピペラジン環(炭素数1-6のアルキル基、および炭素数1-6のアルキルスルホニル基のうちの1つ以上により置換されていてもよい)のうちの1つ以上により置換されていてもよい)、炭素数1-6のアルコキシ基、炭素数1-6のアルキルチオ基、ハロゲン原子、トリフルオロメチル基、ジフルオロメチル基、シアノ基、フェニル基(炭素数1-6のアルキル基、炭素数1-6のアルコキシ基、およびハロゲン原子のうちの1つ以上により置換されていてもよい)、カルボキシル基、または-CO2R5である、請求項1から10のいずれか1項に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- R3が水素原子、メチル基、エチル基、イソプロピル基、シクロプロピル基、塩素原子、臭素原子、ヨウ素原子、トリフルオロメチル基、ジフルオロメチル基、メトキシ基、フェニル基、シアノ基、アセチル基、カルボキシル基、-CO2R5、ヒドロキシメチル基、1-ヒドロキシエチル基、2-ヒドロキシプロパン-2-イル基、3-ヒドロキシペンタン-3-イル基、ジメチルアミノメチル基、ジエチルアミノメチル基、モルホリン-4-イルメチル基である、請求項11に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- R4がカルボキシル基(R3が水酸基で置換された炭素数1-6のアルキル基である場合、R3と縮合してラクトン環を形成していてもよい)、テトラゾリル基、-CONHSO2CH3、-CONHSO2-シクロプロピル、または-CO2R5である、請求項1から12のいずれか1項に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- ZがZ1、Z2、Z3、またはZ4である、請求項1から13のいずれか1項に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
- ZがZ1であり、R6およびR7が、ベンゼン環上において、2,5-ジクロロ置換、3,5-ジクロロ置換、2,5-ジメチル置換、2,5-ビス(トリフルオロメチル)置換、または2-クロロ-5-メチル置換であるか;
ZがZ2であり、R8が、ナフタレン環上において、水素原子、2-メチル基、4-メチル基、8-メチル基、または8-ブロモ基であるか;
ZがZ3であり、R9が、ベンゾチオフェン、ベンゾフラン、またはインドール環上において、水素原子、4-メチル基、4-クロロ基、4-ブロモ基、4-トリフルオロメチル基、5-メチル基、5-クロロ基、または5-トリフルオロメチル基であるか;または
ZがZ4であり、R10が、ベンゾチオフェン、ベンゾフラン、またはインドール環上において、水素原子、または5-フルオロ基である、請求項14に記載のピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。 - 以下の(1)ないし(193)の化合物より選択されるピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
(1)1-(2,5-ジメチルベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(2)4-メチル-1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(3)エチル 4-メチル-1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボキシレート
(4)4-メチル-2-(ピリジン-3-イル)-1-((4-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)-メチル)-1H-イミダゾール-5-カルボン酸
(5)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(6)1-((4-ブロモベンゾ[b]チオフェン-3-イル)メチル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(7)4-クロロ-1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(8)4-エチル-1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(9)4-シクロプロピル-1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(10)1-(2,5-ジクロロベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(11)1-(2,5-ジクロロベンジル)-4-エチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(12)4-シクロプロピル-1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(13)4-メチル-1-((4-メチルナフタレン-1-イル)メチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(14)4-シクロプロピル-1-((4-メチルナフタレン-1-イル)メチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(15)1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-4-(トリフルオロメチル)-1H-イミダゾール-5-カルボン酸
(16)1-(ベンゾ[b]チオフェン-3-イルメチル)-2-(ピリジン-3-イル)-4-(トリフルオロメチル)-1H-イミダゾール-5-カルボン酸
(17)4-クロロ-1-((4-メチルナフタレン-1-イル)メチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(18)4-イソプロピル-1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(19)4-イソプロピル-1-((4-メチルナフタレン-1-イル)メチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(20)1-(2,5-ジクロロベンジル)-4-イソプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(21)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-2-(ピリジン-3-イル)-4-(トリフルオロメチル)-1H-イミダゾール-5-カルボン酸
(22)1-((4-ブロモベンゾ[b]チオフェン-3-イル)メチル)-2-(ピリジン-3-イル)-4-(トリフルオロメチル)-1H-イミダゾール-5-カルボン酸
(23)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-4-シクロプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(24)1-((4-ブロモベンゾ[b]チオフェン-3-イル)メチル)-4-シクロプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(25)4-シクロプロピル-2-(ピリジン-3-イル)-1-((4-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル)-1H-イミダゾール-5-カルボン酸
(26)1-(ベンゾ[b]チオフェン-3-イルメチル)-4-シクロプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(27)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-4-イソプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(28)1-((4-ブロモベンゾ[b]チオフェン-3-イル)メチル)-4-イソプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(29)4-イソプロピル-2-(ピリジン-3-イル)-1-((4-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル)-1H-イミダゾール-5-カルボン酸
(30)1-(ベンゾ[b]チオフェン-3-イルメチル)-4-イソプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(31)1-(2-クロロ-5-フルオロベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(32)1-(5-クロロ-2-フルオロベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(33)1-(2-クロロ-5-(トリフルオロメチル)ベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(34)1-(5-クロロ-2-(トリフルオロメチル)ベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(35)1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(36)1-(2,5-ビス(トリフルオロメチル)ベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(37)1-(2-ブロモベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(38)1-(3-ブロモベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(39)1-(2,5-ジクロロベンジル)-4-メチル-2-(キノリン-3-イル)-1H-イミダゾール-5-カルボン酸
(40)1-(3,4-ジクロロベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(41)1-(2,3-ジクロロベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(42)1-(3,5-ジクロロベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(43)1-(3-クロロ-5-フルオロベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(44)1-(2,4-ジクロロベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(45)1-(2-クロロ-5-メチルベンジル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(46)1-((2,5-ジクロロチオフェン-3-イル)メチル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(47)1-((2,4-ジクロロチオフェン-5-イル)メチル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(48)1-(ベンゾ[b]チオフェン-7-イルメチル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(49)1-(ベンゾ[b]チオフェン-7-イルメチル)-4-シクロプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(50)1-(ベンゾ[b]チオフェン-7-イルメチル)-4-イソプロピル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(51)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(ピリジン-3-イル)-4-(トリフルオロメチル)-1H-イミダゾール-5-カルボン酸
(52)1-((5-フルオロベンゾ[b]チオフェン-7-イル)メチル)-4-メチル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(53)4-シクロプロピル-1-((5-フルオロベンゾ[b]チオフェン-7-イル)メチル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(54)4-クロロ-1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(55)4-ブロモ-1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(56)1-(2,5-ジクロロベンジル)-4-ヨード-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(57)1-(2,5-ジクロロベンジル)-4-フェニル-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(58)1-(2,5-ジクロロベンジル)-4-(3-フルオロフェニル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(59)1-(2,5-ジクロロベンジル)-4-(4-フルオロフェニル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(60)1-(2,5-ジクロロベンジル)-2,4-ジ(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(61)1-(2,5-ジクロロベンジル)-4-メトキシ-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(62)1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-4-(2,2,2-トリフルオロエトキシ)-1H-イミダゾール-5-カルボン酸
(63)1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-4-(p-トリロキシ)-1H-イミダゾール-5-カルボン酸
(64)1-(2,5-ジクロロベンジル)-4-(4-フルオロフェノキシ)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(65)4-シアノ-1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(66)1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-4-ビニル-1H-イミダゾール-5-カルボン酸
(67)4-(1-シクロペンテン-1-イル)-1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(68)1-(2,5-ジクロロベンジル)-4-(メチルチオ)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(69)1-(2,5-ジクロロベンジル)-4-(エチルチオ)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(70)1-(2,5-ジクロロベンジル)-4-(2-ヒドロキシプロパン-2-イル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(71)1-(2,5-ジクロロベンジル)-4-(3-ヒドロキシペンタン-3-イル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(72)3-(1-(2,5-ジクロロベンジル)-5-(1H-テトラゾール-5-イル)-1H-イミダゾール-2-イル)ピリジン
(73)1-(ベンゾ[b]チオフェン-7-イルメチル)-4-シクロプロピル-N-(メチルスルホニル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボキサミド
(74)1-(ベンゾ[b]チオフェン-7-イルメチル)-4-シクロプロピル-N-(シクロプロピルスルホニル)-2-(ピリジン-3-イル)-1H-イミダゾール-5-カルボキサミド
(75)2-(5-フルオロピリジン-3-イル)-4-メチル-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(76)2-(5-クロロピリジン-3-イル)-4-メチル-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(77)4-メチル-1-(ナフタレン-1-イルメチル)-2-(5-フェノキシピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(78)1-(ベンゾ[b]チオフェン-3-イルメチル)-2-(5-クロロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(79)1-(ベンゾ[b]チオフェン-3-イルメチル)-2-(5-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(80)1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(81)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(82)1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-4-(トリフルオロメチル)-1H-イミダゾール-5-カルボン酸
(83)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(トリフルオロメチル)-1H-イミダゾール-5-カルボン酸
(84)4-メチル-1-(ナフタレン-1-イルメチル)-2-(5-(トリフルオロメチル)ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(85)1-(2,5-ジクロロベンジル)-4-メチル-2-(5-(トリフルオロメチル)ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(86)1-(2,5-ジクロロベンジル)-4-(トリフルオロメチル)-2-(5-(トリフルオロメチル)ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(87)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-2-(5-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(88)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-2-(5-クロロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(89)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-4-メチル-2-(5-(トリフルオロメチル)ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(90)2-(5-クロロピリジン-3-イル)-4-イソプロピル-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(91)2-(5-クロロピリジン-3-イル)-4-シクロプロピル-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(92)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-イソプロピル-1H-イミダゾール-5-カルボン酸
(93)2-(5-クロロピリジン-3-イル)-4-シクロプロピル-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-カルボン酸
(94)4-エチル-2-(5-フルオロピリジン-3-イル)-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(95)2-(5-クロロピリジン-3-イル)-4-エチル-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(96)1-(2,5-ジクロロベンジル)-4-エチル-2-(5-フルオロピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(97)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-エチル-1H-イミダゾール-5-カルボン酸
(98)2-(5-フルオロピリジン-3-イル)-4-イソプロピル-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(99)4-シクロプロピル-2-(5-フルオロピリジン-3-イル)-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(100)1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-4-イソプロピル-1H-イミダゾール-5-カルボン酸
(101)4-シクロプロピル-1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(102)1-(2,5-ジクロロベンジル)-4-メチル-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(103)1-(2,5-ジクロロベンジル)-2-(5-メトキシピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(104)2-(5-シアノピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(105)1-(2,5-ジクロロベンジル)-4-メチル-2-(6-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(106)1-(2,5-ジクロロベンジル)-2-(2-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(107)1-(2,5-ジクロロベンジル)-2-(6-メトキシピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(108)1-(2,5-ジクロロベンジル)-2-(2-メトキシピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(109)2-(6-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(110)1-(2,5-ジクロロベンジル)-4-メチル-2-(5-(ピロリジン-1-イル)ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(111)1-(2,5-ジクロロベンジル)-4-メチル-2-(5-ニトロピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(112)2-(5-シクロプロピルピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(113)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-カルボン酸
(114)1-(2,5-ビス(トリフルオロメチル)ベンジル)-2-(5-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(115)1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(116)1-(2,5-ジクロロベンジル)-2-(5-ヒドロキシピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(117)1-(2,5-ビス(トリフルオロメチル)ベンジル)-2-(5-クロロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(118)1-(2,5-ジクロロベンジル)-2-(5-エトキシピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(119)1-(2,5-ジクロロベンジル)-2-(5-イソプロポキシピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(120)1-(2,5-ジクロロベンジル)-4-メチル-2-(5-フェニルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(121)2-(5-ブロモピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(122)1-(2,5-ジメチルベンジル)-2-(5-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(123)2-(5-クロロピリジン-3-イル)-1-(2,5-ジメチルベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(124)1-(2,5-ジメチルベンジル)-4-メチル-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(125)1-(2,5-ジクロロベンジル)-2-(5-エチルピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(126)1-(2,5-ジクロロベンジル)-4-メチル-2-(5-(メチルチオ)ピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(127)2-(5-アセチルピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(128)1-(2,5-ジクロロベンジル)-4-メチル-2-(5-プロポキシピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(129)1-(2,5-ジクロロベンジル)-2-(5-イソブトキシピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(130)2-(5-(シクロヘキシルメトキシ)ピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(131)2-(5-(ベンジロキシ)ピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(132)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(ヒドロキシメチル)-1H-イミダゾール-5-カルボン酸
(133)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-((ジメチルアミノ)メチル)-1H-イミダゾール-5-カルボン酸
(134)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-((ジエチルアミノ)メチル)-1H-イミダゾール-5-カルボン酸
(135)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(ピロリジン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(136)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(ピペリジン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(137)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(モルホリノメチル)-1H-イミダゾール-5-カルボン酸
(138)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-((4-メチルピペラジン-1-イル)メチル)-1H-イミダゾール-5-カルボン酸
(139)4-((1H-イミダゾール-1-イル)メチル)-2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-カルボン酸
(140)4-((1H-ピラゾール-1-イル)メチル)-2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-カルボン酸
(141)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-((4-プロピルピペラジン-1-イル)メチル)-1H-イミダゾール-5-カルボン酸
(142)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-1H-イミダゾール-5-カルボン酸
(143)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-((4-(エチルスルホニル)ピペラジン-1-イル)メチル)-1H-イミダゾール-5-カルボン酸
(144)2-(5-ブロモピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-カルボン酸
(145)1-(2,5-ジクロロベンジル)-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(146)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(ジフルオロメチル)-1H-イミダゾール-5-カルボン酸
(147)1-(2,5-ジクロロベンジル)-2-(5-(ジフルオロメチル)ピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(148)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-エチニル-1H-イミダゾール-5-カルボン酸
(149)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-4,5-ジカルボン酸
(150)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(1-ヒドロキシエチル)-1H-イミダゾール-5-カルボン酸
(151)1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-4-(2-ヒドロキシプロパン-2-イル)-1H-イミダゾール-5-カルボン酸
(152)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(2-ヒドロキシプロパン-2-イル)-1H-イミダゾール-5-カルボン酸
(153)1-(2,5-ジクロロベンジル)-4-(2-ヒドロキシプロパン-2-イル)-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(154)1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-4-(3-ヒドロキシペンタン-3-イル)-1H-イミダゾール-5-カルボン酸
(155)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-4-(3-ヒドロキシペンタン-3-イル)-1H-イミダゾール-5-カルボン酸
(156)1-(2,5-ジクロロベンジル)-4-(3-ヒドロキシペンタン-3-イル)-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(157)4-アセチル-2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-カルボン酸
(158)4-クロロ-1-(2,5-ジクロロベンジル)-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(159)4-クロロ-2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-カルボン酸
(160)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-フロ[3,4-d]イミダゾール-6(4H)-オン
(161)2-(5-クロロピリジン-3-イル)-1-(1-(2,5-ジクロロフェニル)エチル)-4-メチル-1H-イミダゾール-5-カルボン酸
(162)1-((2,5-ジクロロチオフェン-3-イル)メチル)-2-(5-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(163)2-(5-クロロピリジン-3-イル)-1-((2,5-ジクロロチオフェン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(164)1-((2,5-ジクロロチオフェン-3-イル)メチル)-4-メチル-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(165)1-((2,4-ジクロロチオフェン-5-イル)メチル)-2-(5-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(166)2-(5-クロロピリジン-3-イル)-1-((2,4-ジクロロチオフェン-5-イル)メチル)-4-メチル-1H-イミダゾール-5-カルボン酸
(167)1-((2,4-ジクロロチオフェン-5-イル)メチル)-4-メチル-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(168)1-(2-クロロ-5-メチルベンジル)-4-メチル-2-(5-メチルピリジン-3-イル)-1H-イミダゾール-5-カルボン酸
(169)1-(2-クロロ-5-メチルベンジル)-2-(5-クロロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(170)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(5-クロロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(171)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(5-フルオロピリジン-3-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(172)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(5-クロロピリジン-3-イル)-4-イソプロピル-1H-イミダゾール-5-カルボン酸
(173)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(5-クロロピリジン-3-イル)-4-シクロプロピル-1H-イミダゾール-5-カルボン酸
(174)3-クロロ-5-(1-(2,5-ジクロロベンジル)-5-(1H-テトラゾール-5-イル)-1H-イミダゾール-2-イル)ピリジン
(175)1-(2,5-ジメチルベンジル)-4-メチル-2-(ピリジン-4-イル)-1H-イミダゾール-5-カルボン酸
(176)2-(6-メトキシピリジン-2-イル)-4-メチル-1-(ナフタレン-1-イルメチル)-1H-イミダゾール-5-カルボン酸
(177)1-(2,5-ジクロロベンジル)-4-メチル-2-(ピリジン-4-イル)-1H-イミダゾール-5-カルボン酸
(178)1-(2,5-ジクロロベンジル)-4-メチル-2-(ピリジン-2-イル)-1H-イミダゾール-5-カルボン酸
(179)1-(2,5-ジクロロベンジル)-2-(6-メトキシピリジン-2-イル)-4-メチル-1H-イミダゾール-5-カルボン酸
(180)1-(2,5-ジクロロベンジル)-4-メチル-2-(ピリジン-2-イルオキシ)-1H-イミダゾール-5-カルボン酸
(181)1-(2,5-ジクロロベンジル)-4-メチル-2-(ピリジン-3-イルオキシ)-1H-イミダゾール-5-カルボン酸
(182)2-((5-クロロピリジン-3-イル)オキシ)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(183)2-((5-ブロモピリジン-3-イル)オキシ)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(184)1-(2,5-ジクロロベンジル)-4-メチル-2-((2-メチルピリジン-3-イル)オキシ)-1H-イミダゾール-5-カルボン酸
(185)2-((2-クロロピリジン-3-イル)オキシ)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(186)2-((2-ブロモピリジン-3-イル)オキシ)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(187)1-(2,5-ジクロロベンジル)-4-メチル-2-((5-メチルピリジン-3-イル)オキシ)-1H-イミダゾール-5-カルボン酸
(188)1-(2,5-ジクロロベンジル)-4-メチル-2-((4-メチルピリジン-3-イル)オキシ)-1H-イミダゾール-5-カルボン酸
(189)2-((4-クロロピリジン-3-イル)オキシ)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(190)2-((4-ブロモピリジン-3-イル)オキシ)-1-(2,5-ジクロロベンジル)-4-メチル-1H-イミダゾール-5-カルボン酸
(191)2-((2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-イル)チオ)-2-メチルプロパン酸
(192)1-((2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-5-イル)チオ)シクロブタンカルボン酸
(193)2-((5-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-イミダゾール-2-イル)チオ)-2-メチルプロパン酸 - 以下の(194)ないし(227)の化合物より選択されるピリジン誘導体もしくはその医薬上許容される塩、またはそれらの溶媒和物。
(194)1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(195)1-((4-メチルナフタレン-1-イル)メチル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(196)1-((4-ブロモベンゾ[b]チオフェン-3-イル)メチル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(197)1-((2-メチルナフタレン-1-イル)メチル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(198)1-((8-ブロモナフタレン-1-イル)メチル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(199)1-((4-メチルベンゾ[b]チオフェン-3-イル)メチル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(200)1-(ベンゾ[b]チオフェン-3-イルメチル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(201)2-(ピリジン-3-イル)-1-((4-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル)-1H-ピロ-ル-5-カルボン酸
(202)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(203)1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(204)1-(2,5-ジメチルベンジル)-2-(ピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(205)1-(2,5-ジクロロベンジル)-2-(5-メチルピリジン-3-イル)-1H-ピロール-5-カルボン酸
(206)1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-1H-ピロール-5-カルボン酸
(207)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-2-(5-メチルピリジン-3-イル)-1H-ピロ-ル-5-カルボン酸
(208)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-2-(5-フルオロピリジン-3-イル)-1H-ピロール-5-カルボン酸
(209)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-1H-ピロール-5-カルボン酸
(210)1-((4-クロロベンゾ[b]チオフェン-3-イル)メチル)-2-(5-クロロピリジン-3-イル)-1H-ピロール-5-カルボン酸
(211)2-(ピリジン-3-イル)-1-(キノリン-8-イルメチル)-1H-ピロール-5-カルボン酸
(212)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(ピリジン-3-イル)-1H-ピロール-5-カルボン酸
(213)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(5-メチルピリジン-3-イル)-1H-ピロール-5-カルボン酸
(214)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(5-フルオロピリジン-3-イル)-1H-ピロール-5-カルボン酸
(215)1-(ベンゾ[b]チオフェン-7-イルメチル)-2-(5-クロロピリジン-3-イル)-1H-ピロール-5-カルボン酸
(216)N-(メチルスルホニル)-1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-ピロール-5-カルボキサミド
(217)N-(シクロプロピルスルホニル)-1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-ピロール-5-カルボキサミド
(218)1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-N-(メチルスルホニル)-1H-ピロール-5-カルボキサミド
(219)N-(シクロプロピルスルホニル)-1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-1H-ピロール-5-カルボキサミド
(220)1-(2,5-ジクロロベンジル)-N-(メチルスルホニル)-2-(ピリジン-3-イル)-1H-ピロール-5-カルボキサミド
(221)2-(5-クロロピリジン-3-イル)-1-(2,5-ジクロロベンジル)-N-(メチルスルホニル)-1H-ピロール-5-カルボキサミド
(222)2-(5-クロロピリジン-3-イル)-N-(シクロプロピルスルホニル)-1-(2,5-ジクロロベンジル)-1H-ピロール-5-カルボキサミド
(223)N-(シクロプロピルスルホニル)-1-(2,5-ジクロロベンジル)-2-(ピリジン-3-イル)-1H-ピロール-5-カルボキサミド
(224)N-(シクロプロピルスルホニル)-1-(2,5-ジクロロベンジル)-2-(5-メチルピリジン-3-イル)-1H-ピロール-5-カルボキサミド
(225)(E)-3-(1-(ナフタレン-1-イルメチル)-2-(ピリジン-3-イル)-1H-ピロール-5-イル)アクリル酸
(226)(E)-3-(1-(2,5-ジクロロベンジル)-2-(5-メチルピリジン-3-イル)-1H-ピロール-5-イル)アクリル酸
(227)(E)-3-(1-(2,5-ジクロロベンジル)-2-(5-フルオロピリジン-3-イル)-1H-ピロール-5-イル)アクリル酸 - 請求項1から17のいずれか1項に記載のピリジン誘導体のプロドラッグ、もしくはそれらの医薬上許容される塩、またはそれらの溶媒和物。
- 請求項1から18のいずれか1項に記載のピリジン誘導体もしくはそのプロドラッグ、もしくはそれらの医薬上許容される塩、またはそれらの溶媒和物、および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から18のいずれか1項に記載のピリジン誘導体もしくはそのプロドラッグ、もしくはそれらの医薬上許容される塩、またはそれらの溶媒和物を有効成分として含有するURAT1阻害剤。
- 請求項1から18のいずれか1項に記載のピリジン誘導体もしくはそのプロドラッグ、もしくはそれらの医薬上許容される塩、またはそれらの溶媒和物を有効成分として含有する、痛風、高尿酸血症、高血圧症、腎疾患、糖尿病、動脈硬化症、およびレッシュ・ナイハン症候群からなる群より選ばれる一つ以上の疾患の治療剤または予防剤。
- 下記式(II)で表される化合物もしくはその医薬上許容される塩、またはそれらの溶媒和物。
R1およびR3は式(I)における定義と同じである。
R17は塩素原子、臭素原子またはヨウ素原子を表す。
R18はホルミル基または-CO2R5を表す。
R3およびR18におけるR5は、それぞれ独立に、炭素数1-6のアルキル基を表す。
Zは、下記Z1からZ7で示される置換基のいずれかを表す。
- 下記式(III)で表される化合物もしくはその医薬上許容される塩、またはそれらの溶媒和物。
R3は式(I)における定義と同じである。
R19は-CO2R5を表す。
R3およびR19におけるR5は、それぞれ独立に、炭素数1-6のアルキル基を表す。
Zaは、2,5-ジクロロベンジル基、3,5-ジクロロベンジル基、2,5-ジメチルベンジル基、2,5-ビス(トリフルオロメチル)ベンジル基、2-クロロ-5-メチルベンジル基、ナフタレン-1-イルメチル基、(2-メチルナフタレン-1-イル)メチル基、(4-メチルナフタレン-1-イル)メチル基、(8-メチルナフタレン-1-イル)メチル基、(8-ブロモナフタレン-1-イル)メチル基、ベンゾ[b]チオフェン-3-イルメチル基、(4-メチルベンゾ[b]チオフェン-3-イル)メチル基、(4-クロロベンゾ[b]チオフェン-3-イル)メチル基、(4-ブロモベンゾ[b]チオフェン-3-イル)メチル基、(4-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル基、(5-メチルベンゾ[b]チオフェン-3-イル)メチル基、(5-クロロベンゾ[b]チオフェン-3-イル)メチル基、(5-(トリフルオロメチル)ベンゾ[b]チオフェン-3-イル)メチル基、ベンゾ[b]チオフェン-7-イルメチル基、(5-フルオロベンゾ[b]チオフェン-7-イル)メチル基、(2,5-ジクロロチオフェン-3-イル)メチル基、(2,4-ジクロロチオフェン-5-イル)メチル基、キノリン-8-イルメチル基を表す。]
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RS20180390A RS57090B1 (sr) | 2012-11-14 | 2013-11-13 | Derivat piridina |
DK13854714.6T DK2944633T3 (en) | 2012-11-14 | 2013-11-13 | pyridine |
ES13854714T ES2662444T3 (es) | 2012-11-14 | 2013-11-13 | Derivado de piridina |
KR1020157008457A KR20150082194A (ko) | 2012-11-14 | 2013-11-13 | 피리딘 유도체 |
AU2013345894A AU2013345894B2 (en) | 2012-11-14 | 2013-11-13 | Pyridine derivative |
MEP-2018-91A ME03016B (me) | 2012-11-14 | 2013-11-13 | Derivat piridina |
BR112015010977A BR112015010977A2 (pt) | 2012-11-14 | 2013-11-13 | derivado de piridina, sal farmaceuticamente aceitável do mesmo ou solvato do mesmo, pró-droga, composição farmacêutica, inibidor do urat1, agente para o tratamento ou prevenção de uma ou mais doenças, e, composto |
MA38078A MA38078B1 (fr) | 2012-11-14 | 2013-11-13 | Dérivé de pyridine |
CN201380059519.0A CN104797570B (zh) | 2012-11-14 | 2013-11-13 | 吡啶衍生物 |
RU2015122698A RU2640588C2 (ru) | 2012-11-14 | 2013-11-13 | Производное пиридина |
MX2015003672A MX2015003672A (es) | 2012-11-14 | 2013-11-13 | Derivados de piridina. |
PL13854714T PL2944633T3 (pl) | 2012-11-14 | 2013-11-13 | Pochodna pirydyny |
LTEP13854714.6T LT2944633T (lt) | 2012-11-14 | 2013-11-13 | Piridino dariniai |
CA2891408A CA2891408A1 (en) | 2012-11-14 | 2013-11-13 | Pyridine derivative |
NZ708031A NZ708031A (en) | 2012-11-14 | 2013-11-13 | Pyridine derivative |
SI201330943T SI2944633T1 (en) | 2012-11-14 | 2013-11-13 | Derivate pyridine |
EP13854714.6A EP2944633B1 (en) | 2012-11-14 | 2013-11-13 | Pyridine derivative |
SG11201503770VA SG11201503770VA (en) | 2012-11-14 | 2013-11-13 | Pyridine derivative |
NO13854714A NO2944633T3 (ja) | 2012-11-14 | 2013-11-13 | |
US14/441,074 US9637469B2 (en) | 2012-11-14 | 2013-11-13 | Pyridine derivative |
UAA201505767A UA117359C2 (uk) | 2012-11-14 | 2013-11-13 | Похідне піридину |
JP2014547007A JP5774238B2 (ja) | 2012-11-14 | 2013-11-13 | ピリジン誘導体 |
IL238539A IL238539A (en) | 2012-11-14 | 2015-04-30 | Derivative of pyridine |
PH12015501037A PH12015501037A1 (en) | 2012-11-14 | 2015-05-08 | Pyridine derivative |
SA515360431A SA515360431B1 (ar) | 2012-11-14 | 2015-05-13 | مشتق بيريدين |
ZA2015/03322A ZA201503322B (en) | 2012-11-14 | 2015-05-13 | Pyridine derivative |
IL243193A IL243193A0 (en) | 2012-11-14 | 2015-12-17 | A pyridine derivative |
HK15112873.0A HK1211940A1 (en) | 2012-11-14 | 2015-12-31 | Pyridine derivative |
US15/466,088 US20170190694A1 (en) | 2012-11-14 | 2017-03-22 | Pyridine derivative |
AU2017204665A AU2017204665A1 (en) | 2012-11-14 | 2017-07-07 | Pyridine derivative |
HRP20180451TT HRP20180451T1 (hr) | 2012-11-14 | 2018-03-16 | Derivat piridina |
CY20181100389T CY1120127T1 (el) | 2012-11-14 | 2018-04-10 | Παραγωγο πυριδινης |
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2013
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WO2015174417A1 (ja) * | 2014-05-13 | 2015-11-19 | 帝人ファーマ株式会社 | ピラジン誘導体 |
CN106458970A (zh) * | 2014-05-13 | 2017-02-22 | 帝人制药株式会社 | 吡啶衍生物的新型多晶形体及其制造方法 |
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