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WO2006043515A1 - Dérivé d’acide pyrimidine-5-carboxylique - Google Patents

Dérivé d’acide pyrimidine-5-carboxylique Download PDF

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Publication number
WO2006043515A1
WO2006043515A1 PCT/JP2005/019057 JP2005019057W WO2006043515A1 WO 2006043515 A1 WO2006043515 A1 WO 2006043515A1 JP 2005019057 W JP2005019057 W JP 2005019057W WO 2006043515 A1 WO2006043515 A1 WO 2006043515A1
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Prior art keywords
pyrimidine
methylthio
reference example
group
fab
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English (en)
Japanese (ja)
Inventor
Shigeki Seto
Kyoko Okada
Shigeki Isogai
Masahiro Suzuki
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Kyorin Pharmaceutical Co Ltd
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Kyorin Pharmaceutical Co Ltd
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Priority to JP2006542974A priority Critical patent/JPWO2006043515A1/ja
Publication of WO2006043515A1 publication Critical patent/WO2006043515A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/58—Two sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel pyrimidine-5_carboxylic acid derivative having PPARy modulator activity or a pharmacologically acceptable salt thereof and a pharmaceutical use thereof.
  • Peroxisome proliferator activated receptor is a member of the nuclear receptor family.
  • the nuclear receptor group includes a partial agonist or partial antagonist (these are collectively referred to as "modulators") in addition to the antagonist and antagonist.
  • modulators include raloxifene and tamoxifen, which are partial agonists or partial antagonists to the estrogen receptor.
  • Partial agonists have the property that transcriptional activity is small compared to agonists.
  • a partial antagonist is present at the same time as the antagonist, the transcriptional activation by the agonist is suppressed.
  • the degree of the suppression is smaller than that of the antagonist.
  • partial agonists often exhibit the properties of partial antagonists.
  • Non-patent Document 1 There is a strong correlation between the ability to activate PPAR y of these thiazolidinedione derivatives and the hypoglycemic effect in inherited obese mice.
  • PPAR y is considered to be a target molecule for the pharmacological action of thiazolidinedione derivatives (Non-patent Document 2).
  • PPAR y is considered to be a factor deeply involved in adipocyte differentiation (Non-patent Document 4).
  • PPAR 7 regulates cell differentiation and lipid metabolism at the transcriptional level (Non-Patent Documents 5 and 6), and PPRE (Peroxisomal
  • Is apolipoprotein A_1 (Non-patent Document 7) gene, lipiprotein lipase (Non-patent Document 8, Non-patent Document 9), etc., and is a gene promoter related to lipid metabolism that affects serum lipid profile.
  • PPAR is associated with diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, regressive osteoporosis, etc. It is thought to be deeply involved in the pathology. Therefore, development of novel compounds having excellent properties as pharmaceuticals, such as having excellent PPARy modulator activity and few side effects, is desired as preventive and therapeutic agents for various pathological conditions as described above.
  • Patent Document 1 includes the formula:
  • R 1 and R 2 are independently H, halogen, C 1 -C alkyl, C 1 -C alkenyl and
  • Ar 1 and Ar 2 are aryl and heteroaryl;
  • X, W 1 and W 2 are single bonds, Y or Y (CH) ⁇ ⁇ and ⁇ single bonds, ⁇ , S, SO, SO And NR;
  • R is H,
  • Patent Document 2 includes a formula:
  • B represents a substituted aryl group, a substituted cycloalkyl group or a substituted heterocyclic group, R a represents H or an alkyl group, and X represents a bond. , 0, S, CH,
  • n 0 or 1
  • Patent Document 3 includes the formula:
  • R 1 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
  • X and Y are the same or different and represent a bond, etc .;
  • Q is a divalent hydrocarbon residue having q to 20 carbon atoms;
  • ring A further has 1 to 3 substituents;
  • N represents a nitrogen-containing 5-membered heterocyclic ring;
  • W represents a divalent hydrocarbon residue having 1 to 20 carbon atoms;
  • V represents a bond, etc .;
  • R 2 represents an optionally substituted heterocyclic group, etc. . ) And the like are disclosed.
  • Patent Document 4 includes a formula:
  • Ar 1 Ar 2 and Ar 3 are 5- to 6-membered aryl groups and 1 to
  • Patent Document 1 WO01 / 30343 pamphlet
  • Patent Document 2 WO03 / 035602
  • Patent Document 3 WO03 / 000685 Pamphlet
  • Patent Document 4 Pamphlet of W ⁇ 99 / 08501
  • Patent Document 5 Pamphlet of W ⁇ 97 / 25321
  • Non-patent literature l Lehmann et al., Journal of Biological Chemistry, 1995, 270, pp. 12 953-12956.
  • Non-Patent Document 2 Willson et al., Journal of Medicinal Chemistry, 1996, Vol. 39, p. 665-6 68.
  • Non-Patent Document 3 Tontonoz et al., Genes and Development, 1994, VIII, p. 1224-1234
  • Non-Patent Document 4 Tontonoz et al., Cell, 1994, 79th, p. 1147-1156
  • Non-Patent Document 5 Spiegelman, Eur. J. Med. Res., 1997, Part 2, 457-464 ⁇
  • Non-Patent Document 6 Tontonoz & Nagy, Curr. Opin. Lipidol, 1999, Part 10. .485-490.
  • Non-Patent Document 7 Steal, Atherosclerosis, 1998, 137th (suppulo), S19-S23.
  • Non-patent document 8 Schhnjans, EMBO J., 1996, 15th suppulo, p.5536- 5548.
  • Non-patent document 9 Lefebvre, Arterio Thrombo Vase. Biol., 1997, 17th, p. 1756-176
  • the object of the present invention is to find a novel compound having PPAR 7 modulator activity, and various pathological conditions involving PPAR o / (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin (Tolerance, obesity, hyperlipidemia, arteriosclerosis, degenerative osteoporosis, etc.).
  • pyrimidine 5 strength rubonic acid derivatives have a PPARy modulator activity, and have found that various pathological conditions (glycuria, hypercholesterolemia) in which PPARy is involved.
  • pathological conditions glycuria, hypercholesterolemia
  • Y represents ⁇ , S, SO, SO or NH
  • Q 1 and Q 2 may be the same or different and may have a single bond or a substituent.
  • W represents ⁇ , S or NR 2
  • R 2 represents a hydrogen atom or C to C
  • a and B are the same or different and are aryl groups, cycloalkyl groups or heterocyclic groups (the A and B are the same or different and may be substituted with a halogen atom or a halogen atom).
  • the two substituents are bonded to each other to form a ring
  • R 1 represents ZR 3 (Z 0, S, SO or S 0; R 3 represents a hydrogen atom, C
  • a aryl group or an aralkyl group is shown.
  • NR 4 R 5 R 4 and R 5 are bonded to each other to form a ring, or the same or different, a hydrogen atom, C
  • R 4 and R 5 are the same or different and may be substituted with a halogen atom or a halogen atom.
  • Middle force of bonyl group and carboxyl group may have 1 to 3 substituents selected.
  • Pyrimidine mono-5-carboxylic acid derivative represented by
  • Q 1 and Q 2 may have a substituent.
  • Q 1 and Q 2 have a substituent, and may be C to C al
  • Q 1 and Q 2 may have a substituent.
  • Q 1 and Q 2 may have a substituent.
  • Q 1 and Q 2 may have a substituent.
  • R 1 is a mono- or di-substituted C-C anolenoquinamino group, 1 to 3 heteroatoms
  • Q 1 and Q 2 may have a substituent.
  • R 1 is mono- or di-substituted C to C canolequinolamino group, 1 to 3 heteroatoms
  • a therapeutic, prophylactic or inhibitory agent for obesity comprising as an active ingredient the pyrimidine 5 strength rubonic acid derivative or salt thereof according to any one of
  • a therapeutic, prophylactic or inhibitory agent for hyperglycemia comprising as an active ingredient the pyrimidine 5 strength rubonic acid derivative or a salt thereof according to any one of [10] to 14), ) To 10) A therapeutic, prophylactic or inhibitory agent for hyperlipidemia, comprising as an active ingredient the pyrimidine 5 strength rubonic acid derivative or a salt thereof according to any one of [10] to [10].
  • a therapeutic, prophylactic or inhibitory agent for hypercholesterolemia comprising as an active ingredient the pyrimidine 5 strength rubonic acid derivative or salt thereof according to any one of
  • a therapeutic, prophylactic or inhibitory agent for hypertriglyceridemia comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of the above :!) to 10) as an active ingredient ,
  • a therapeutic, prophylactic or inhibitory agent for insulin resistance comprising the pyrimidine-5-carboxylic acid derivative or salt thereof according to any one of the above :!) to 10) as an active ingredient,
  • a therapeutic, prophylactic or inhibitory agent for degenerative osteoporosis comprising as an active ingredient the pyrimidine-5-carboxylic acid derivative or salt thereof according to any one of the above :!) to 10) About.
  • the present invention has been found that a novel pyrimidine-5 carboxylic acid derivative or a salt thereof has an excellent PPAR y modulator action.
  • the compounds of the present invention and salts thereof are safe with low toxicity. Therefore, the compounds of the present invention and salts thereof are used in various pathological states involving PPAR y (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, It has high utility for treatment, prevention or suppression of regressive stage osteoporosis and the like.
  • PPAR y diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, It has high utility for treatment, prevention or suppression of regressive stage osteoporosis and the like.
  • X represents S, SO, SO or NH
  • Y represents O, S, SO, SO or NH
  • Preferred examples of X include S and NH.
  • Preferable Y includes 0, S, NH and the like.
  • Preferred combinations of X and Y include when X is S, Y is 0, S or NH.
  • Q 1 and Q 2 may be the same or different and each may have a single bond or a substituent.
  • W represents 0, S or NR 2
  • R 2 represents a hydrogen atom or C ⁇
  • C represents an alkyl group, and n represents 2-6.
  • Examples of "C to C canolylene” include methylene, ethylene, propylene, butylene and the like.
  • the substituents that they may have include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, sec butyl, and tert_butyl groups.
  • alkyl groups such as a cyclopentyl group and a cyclopentyl group.
  • Examples of the "ring formed by combining R 3 and R 4 with each other" include a cyclopropane ring, a cyclobutane ring, a cycloheptane ring, a cyclohexane ring, and the like.
  • C to C alkyl group examples include, for example, a methylol group, an ethyl group, a propyl group, an isop
  • W represents ⁇ , S or NR 2 .
  • R 2 represents a hydrogen atom or a C to C alkyl group.
  • C to C alkyl group a methylol group, an ethyl group, a propyl group, an isopropyl group
  • Cyclopropyl group butyl group, isobutyl group, cyclobutyl group, sec butyl group, tert butyl group, cyclopentyl group and the like.
  • n is preferably:! To 3.
  • a and B are the same or different and each represents an aryl group, a cycloalkyl group or a heterocyclic group.
  • a and B may be the same or different and may have a substituent.
  • the number of substituents may be substituted at any substitutable position in the ring, and may be about:! -3.
  • Two adjacent substituents may be bonded to each other to form a ring.
  • the substituent for A and B include, for example, a halogen atom, a C to C alkyl group optionally substituted by a halogen atom, an aryl group, a nitro group, one or two identical or
  • Examples thereof include c to c alkoxy groups.
  • aryl group includes, for example, an aromatic hydrocarbon group having 5 to 14 carbon atoms such as a phenyl group, an indur group, a naphthyl group, a phenanthrenyl group, and an anthracenyl group. Etc.
  • the "cycloalkyl group” may be condensed such as, for example, a cyclopropyl group, a cyclobutyl group, a cyclobenzoyl group, a cyclohexyl group, a norbornino group, an adamantyl group 3 to:
  • a 10-membered saturated hydrocarbon group can be exemplified.
  • Heterocyclic group refers to a 5- to 7-membered heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom.
  • Pyrrolyl group azepinyl group
  • pyrazolyl group imidazolyl group
  • oxazolyl group isoxazolyl group
  • thiazolyl group isothiazolyl group
  • 1,2,3_oxadiazolyl group triazolyl group, tetrazolyl group, thiadiazolyl group
  • pyranyl group pyridyl group , Pyridazinyl group, pyrimidinyl group, birazinyl group, etc.
  • heterocyclic group may be condensed with other cyclic groups, for example, isobenzazofuranyl group, benzoxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzoisothiazolyl group, chromenyl Group, chromanonyl group, xanthur group, phenoxathiinyl group, indolizinyl group, isoindolidinyl group, indolyl group, indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthaladuryl group, naphthyridinyl group, Examples thereof include a quinoxalinyl group, a quinazolinyl group, a carbazolyl group, a force-norbinolinole group, an atalidinyl group, and an isoindolinyl group.
  • Halogen atom includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
  • C-C alkyl group optionally substituted with a halogen atom examples include, for example, methyl
  • amino optionally substituted with one or two identical or different C to C alkyl groups examples include an aminosulfonyl group, a methylaminosulfonyl group, an ethylaminosulfonyl group, a dimethylaminosulfonyl group, and the like.
  • the "mono- or di-substituted C to C alkylamino group” includes a methylamino group and an ethylamino group.
  • C-C alkoxy group optionally substituted with a halogen atom examples include, for example,
  • Ring which two adjacent substituents may combine to form each other is, for example, when the two substituents forming the ring are both present on the same carbon,
  • Preferable A includes, for example, a phenyl group, a pyridinole group, a furyl group, a enyl group, a cyclohexyl group, and the like.
  • More preferable A includes a phenyl group and the like.
  • Preferred B includes, for example, a phenyl group, a pyridinole group, a furyl group, a enyl group, a cyclohexyl group, and the like.
  • Further preferable B includes a phenyl group and the like.
  • R 1 represents ZR 3 (Z represents O, S, SO or S O, R 3 represents a hydrogen atom, a C to C alkyl group,
  • NR 4 R 5 R 4 and R 5 may be bonded to each other to form a ring, or the same or different, a hydrogen atom, a C to C alkyl group, a cycloanol
  • R 3 , R 4 and R 5 are the same or different and may have a substituent. Substituents may be substituted at any substitutable position, and the number of substituents may be about 1 to 3. Two adjacent substituents may be bonded to each other to form a ring. Examples of the substituent for R 4 and R 5 include a halogen atom, a C to C alkoxy group optionally substituted with a halogen atom, a hydroxyl group,
  • aryl group "cycloalkyl group”, “halogen atom”, “C-C alkoxy group optionally substituted with a halogen atom” and "mono- or di-substituted C-C alkylamino".
  • the “group” is the same as described above.
  • the “C to C alkyl group” includes heptyl in addition to the above “C to C alkyl group”.
  • aralkyl group examples include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a trimethylbenzyleno group, and the like.
  • Examples of the "C to C alkylcarbonyl group” include a methylcarbonyl group, ethylca
  • Examples thereof include a norebonyl group, a propyl canoleboninole group, a butyl canoleboninole group, and a tert-butylcarboninole group.
  • Examples of the "C to C alkylsulfonyl group” include a methylsulfonyl group, ethyls
  • Examples thereof include a norephonyl group, a propylsulfonyl group, a butylsulfonyl group, and a trifluoromethylsulfonyl group.
  • arylsulfonyl group examples include a phenylsulfonyl group and a toluenesulfonyl group.
  • C-C alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxy group, and the like.
  • Examples thereof include a sicarbonyl group, a propyloxycarbonyl group, a butyloxycarbonyl group, and a tert-butyloxycarbonyl group.
  • Examples of the “C to C alkylthio group” include a methylthio group, an ethylthio group, a pro
  • Pyrthio group, butylthio group, pentylthio group, hexylthio group, heptylthio group, octylthio group, nonylthio group, decinoretio group and the like can be mentioned.
  • R methylthio group, ethylthio group, propylthio group, butylthio group,
  • Examples thereof include a pentylthio group, a hexylthio group, a heptylthio group, an octylthio group, a dimethylamino group, a pyrrolidino group, a piperidino group and a morpholino group.
  • Preferred compounds of the present invention include, for example,
  • salts derived from pharmaceutically acceptable non-toxic salt groups include inorganic bases such as anoleminium, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium.
  • Salts especially preferred are ammonium, calcium, manganese, potassium and sodium salts
  • primary, secondary, tertiary amines substituted amines (eg naturally occurring substituted amines), cyclic amines and Organic bases
  • basic ion exchange resins for example, anoleginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, jetylamine, 2-jetylaminoethanol, 2-dimethylaminoethanol
  • Ethanolamine ethylenediamine, N-ethylmorpholine, N-ethylbiperidine, Recamine, darcosamine, histidine, hydrabamine, isopropylamine, lysine, methyldanolecamine, monoleforin, piperazine, piperidine, polyamine resin, pro-in, purine, tebromine, triethinoreamine, trimethinoreamine, tripro With pinoleamine, t
  • Non-toxic acidity-derived salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citrate, Examples thereof include pharmaceutically acceptable salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or acetic acid
  • maleic acid fumaric acid
  • succinic acid lactic acid
  • malic acid tartaric acid
  • citrate examples thereof include pharmaceutically acceptable salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.
  • the compound of the present invention or a salt thereof may exist as a hydrate or a solvate.
  • Arbitrary hydrates and solvates formed by the pyrimidine mono-sulphonic acid derivative represented by the general formula (1) or a salt thereof, including the preferred compounds specifically described above. are included in the scope of the present invention.
  • Solvents that can form solvates include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, di-propyl ether, and the like.
  • the compound of the present invention or a salt thereof includes an optically active substance, a stereoisomer, and a rotational isomer in addition to a racemate.
  • the compound of the present invention can be produced by various synthetic methods. Next, typical production methods of the compound of the present invention and its salt will be described.
  • a hydroxycarbonyl group is introduced into compound (a) (R 1 is as defined above).
  • compound (b) (R 1 is as defined above) is produced.
  • the compound (b) can be produced by reacting the compound (a) with a base and then reacting the compound as a carbonyl source.
  • the base used in this step include lithium diisopropylamide and butyl lithium.
  • the reaction can be carried out at _100 ° C to 0 ° C, preferably at _100 ° C to -50 ° C.
  • the carbonyl source used in this step include carbon dioxide.
  • it can be carried out by treating with water and a suitable acid (hydrochloric acid, etc.).
  • This step is a step for producing a compound (c) (R 6 represents an alkyl group or an aryl group) from the compound (b) by an esterification reaction.
  • This reaction is a well-known method for forming an ester bond in synthetic organic chemistry, and is preferably performed in the presence of a normal solvent.
  • This reaction can be carried out by reacting with an alkyl halide or the like under basic conditions.
  • an alkali carbonate such as sodium hydrogen carbonate or potassium carbonate can be exemplified.
  • alkyl halide used in this reaction include methyl iodide, iodide til, benzylbutamide, benzyl chloride and the like.
  • the solvent used in this reaction is an inert solvent not involved in the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane. Ethyl acetate or the like is used.
  • This condensation reaction can be carried out at a temperature of -20 ° C to 100 ° C for 30 minutes to 48 hours.
  • This reaction can also be achieved by using sulfuric acid as a catalyst in an alcohol solvent such as methanol or ethanol.
  • this reaction can also be achieved by reacting a corresponding acyl halide such as carboxylic acid chloride with methanol, ethanol or the like.
  • This step is a step for producing a compound (e) by substituting the compound (d) for the black-atom of the compound (c) (R 1 and R 6 are the same as above).
  • This process consists of triethylamine, diisopropyle N, N-dimethylformamide, N in the presence or absence of organic bases such as tinoleamine, pyridine, 4-dimethylaminopyridine, DBU, or inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium acetate N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene, pyridine, quinoline, dichloromethane, etc. at -20 to 50 ° C for 30 minutes to 48 hours. It is possible to implement S.
  • This step is a step for producing the compound (g) by substituting the compound (f) for the black-atom of the compound) (R 1 and R 6 are the same as above).
  • This step can be performed according to the third step.
  • This step is a step of producing compound (h) by hydrolyzing the ester group of compound) (R 1 and R 6 are the same as described above).
  • This step is performed in the presence of a base in a solvent that does not affect the reaction according to a conventional method.
  • Examples of the base include alkali metal salts such as potassium hydroxide and sodium hydroxide.
  • Examples of the solvent that does not affect the reaction include tetrahydrofuran, dioxane, jetinoreethenole, methanolol, ethanol, propanol, isopropanol, butanol, water and the like.
  • the reaction temperature is usually about 0 to about 150 ° C.
  • the reaction time is usually about 0.5 to about 48 hours.
  • This step can be performed according to the first step of Method A.
  • This step is a step for producing the compound (i) by substituting the compound (f) for the open atom of the compound (b) (R 1 is the same as above) with the compound (f).
  • This step can be carried out according to the third step of Method A.
  • This step is a step for preparing the compound (h) by substituting the compound (d) for the open atom of the compound (i) (R 1 is the same as above).
  • This step can be carried out according to the third step of Method A.
  • This step is a step for producing a compound (b-1) by introducing a hydroxycarbonyl group into the compound (a-1).
  • This step can be performed according to the first step of Method A.
  • This step is the esterification reaction, the compound (b _ l) from the compound (c _ l) (R 6 is. Showing the alkyl group or Ariru group) is a step for preparing a.
  • This step can be performed according to the second method A.
  • This step can be carried out according to the third step of Method A.
  • This step is a step of producing compound (k) by oxidizing the methylthio group of compound (j) (R 6 is the same as above).
  • This step is performed in the presence of various oxidizing agents in a solvent that does not affect the reaction.
  • Examples of the oxidizing agent used in this step include organic peroxides such as m-peroxybenzoic acid, peracetic acid and magnesium monoperphthalate, and organic peroxides such as hydrogen peroxide and potassium permanganate. Thing etc. are mentioned.
  • This reaction is carried out at a temperature of about 20 to about 80 ° C, preferably about 0 to about 30 ° C, for 0.5 hours to 2 to 10 equivalents, preferably 2 to 3 equivalents. It can be implemented by processing for 72 hours.
  • Solvents used in this reaction include, for example, dichloromethane, toluene, ethyl acetate, dimethetetane, ethyl ether, dioxane, tetrahydrofuran, acetonitrile, N, N-dimethylenorenomamide, N, N-dimethylacetamide and the like. Can be illustrated.
  • This reaction is performed using 1 to 20 equivalents of compound (m) to compound (k) in the presence of a base. Or in the absence of about ⁇ 50 to about 100 ° C., preferably about ⁇ 20 to about 30 ° C. for 0.5 to 24 hours.
  • suitable bases include organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methyl monoleolin, pyridine, lutidine, collidine, N, N_dimethylaniline, sodium bicarbonate
  • inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, or tripotassium phosphate.
  • an inert solvent that does not participate in the reaction for example, N, N-dimethylformamide, N, N-dimethylacetamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, xylene, toluene, ethanol, water or the like is used. Used.
  • This step is a step for producing a compound (g-1) by substituting the compound (d) for the open atom of the compound) (R 6 is the same as above).
  • This step can be carried out according to the third step of Method A.
  • This step is a step for producing the compound (h-1) by hydrolyzing the ester group of the compound (g-1) (R 6 is the same as described above).
  • This step can be performed according to the fifth method A.
  • the compound (1) of the present invention can be isolated and purified by ordinary separation means (eg extraction, recrystallization, distillation, chromatography, etc.).
  • ordinary separation means eg extraction, recrystallization, distillation, chromatography, etc.
  • various salts can be produced by a usual method or a method equivalent thereto (for example, neutralization).
  • the compound (1) of the present invention or a salt thereof is singly or appropriately pharmacologically acceptable.
  • excipients and diluents for example, orally as a preparation such as a tablet, capsule, granule, chiral lj or syrup, or parenterally as a preparation such as an injection or suppository. It can be administered as a pharmaceutical composition.
  • compositions are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.
  • the excipient may be an organic excipient or an inorganic excipient.
  • the organic economy is, for example, Sugar derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; or pullulan, etc. It can be.
  • Inorganic excipients include, for example, light inorganic silicic acid, synthetic aluminum silicate, calcium silicate, silicate derivatives such as magnesium metasilicate magnesium phosphate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; Or it may be a sulfate such as calcium sulfate.
  • Lubricants include, for example, stearic acid, calcium stearate, metal stearate such as magnesium stearate; talc; colloidal silica; waxes such as bee gum; adipic acid; sulfuric acid such as sodium sulfate. Salt; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; possible.
  • the binder may be, for example, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, macrogol, or a compound similar to the above-described excipient.
  • the disintegrant is, for example, a cellulose derivative such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, internally crosslinked sodium carboxymethyl cellulose; or carboxymethyl starch, sodium carboxymethyl starch, crosslinked Chemically modified starches such as polyvinyl pyrrolidone. Can be celluloses.
  • Stabilizers include, for example, parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzalkonium chloride; and taresols such as phenol and talesol. Thimerosal; dehydroacetic acid; or sorbic acid.
  • the flavoring agent may be, for example, a commonly used sweetener, acidulant, and fragrance.
  • the dosage varies depending on the type of the compound (1) of the present invention or a salt thereof, the administration route, the age of the patient, symptoms, etc., but for example, the present compound (1) or a salt thereof is administered to mammals including humans. It is 0.001 to 500 mg / kg / day. Administration is, for example, once a day or divided into several times.

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Abstract

La présente invention a pour objet un nouveau dérivé d’acide pyrimidine-5-carboxylique présentant une activité régulatrice de PPARϜ, ainsi qu’un sel de qualité pharmacologique dudit dérivé. La présente invention a plus particulièrement pour objet un dérivé d’acide pyrimidine-5-carboxylique de formule générale (1) ci-dessous, et un sel dudit dérivé. [Exemple : acide 4-anillino-6-(benzylthio)-2-(méthylthio)pyrimidine-5-carboxylique]
PCT/JP2005/019057 2004-10-22 2005-10-17 Dérivé d’acide pyrimidine-5-carboxylique Ceased WO2006043515A1 (fr)

Priority Applications (1)

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JP2006542974A JPWO2006043515A1 (ja) 2004-10-22 2005-10-17 ピリミジン−５−カルボン酸誘導体

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116514782A (zh) * 2022-11-08 2023-08-01 江苏海悦康医药科技有限公司 巴瑞替尼有关物质的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025321A2 (fr) * 1996-01-05 1997-07-17 Texas Biotechnology Corporation Composes phenyle substitues et derives de ces composes modulant l'activite de l'endotheline
WO2000066595A1 (fr) * 1999-04-28 2000-11-09 Institute Of Medicinal Molecular Design. Inc. Derives d'acides carboxyliques heterocycliques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025321A2 (fr) * 1996-01-05 1997-07-17 Texas Biotechnology Corporation Composes phenyle substitues et derives de ces composes modulant l'activite de l'endotheline
WO2000066595A1 (fr) * 1999-04-28 2000-11-09 Institute Of Medicinal Molecular Design. Inc. Derives d'acides carboxyliques heterocycliques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DORIGO P. ET AL: "Synthesis and Cardiotonic Activity of Novel Pyrimidine Derivatives: Crystallographic and Quantum Chemical Studies", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 19, 1996, pages 3671 - 3683, XP002331359 *
ITO M. ET AL: "Medical Dictionary", 1 March 2003, IGAKU-SHOIN LTD., pages: 275, XP002999844 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116514782A (zh) * 2022-11-08 2023-08-01 江苏海悦康医药科技有限公司 巴瑞替尼有关物质的合成方法

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