WO2019044868A1 - Dérivé pyrimidine - Google Patents

Dérivé pyrimidine Download PDF

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Publication number
WO2019044868A1
WO2019044868A1 PCT/JP2018/031859 JP2018031859W WO2019044868A1 WO 2019044868 A1 WO2019044868 A1 WO 2019044868A1 JP 2018031859 W JP2018031859 W JP 2018031859W WO 2019044868 A1 WO2019044868 A1 WO 2019044868A1
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group
general formula
salt
alkyl group
ring
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PCT/JP2018/031859
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English (en)
Japanese (ja)
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亮 岡田
中野　洋一
卓 能勢
恭博 西本
前田　智史
友章 渡邊
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あすか製薬株式会社
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Priority to JP2019539556A priority Critical patent/JP7237002B2/ja
Publication of WO2019044868A1 publication Critical patent/WO2019044868A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel pyrimidine derivatives. More specifically, the present invention relates to a pyrimidine derivative having mPGES-1 inhibitory activity and useful as an active ingredient of a medicament for the prevention and / or treatment of diseases such as inflammation, pain and rheumatism.
  • Prostaglandin E2 is involved in inflammation, pain, fever and the like via PGE receptors, and can suppress inflammation by suppressing PGE2 production.
  • Non-steroidal anti-inflammatory drugs NSAIDs
  • COX cyclooxygenase
  • COX has two isozymes, COX-1 and COX-2.
  • COX-2 is induced in inflamed tissues by various proinflammatory stimuli (eg, cytokines such as interleukin-1 ⁇ ).
  • cytokines such as interleukin-1 ⁇
  • This drug that selectively inhibits COX-2 suppresses the production of PGI2 that has vasodilator activity and platelet aggregation activity, but on the other hand, thromboxane A2 (COX-1 catalyzes vasoconstriction and platelet aggregation) TXA2) is thought to increase the risk of thrombosis by not inhibiting production and to further increase cardiovascular events.
  • PGE2 is biosynthesized from PGH2 by prostaglandin E synthetase (PGES Synthase, PGES).
  • PGES Synthase PGES
  • mPGES-1 is a trimeric inducible enzyme whose expression is increased by inflammatory stimuli (Proc. Natl. Acad. Sci. USA, 96, 7220-7225, 1999), and it is characterized by cancer, inflammation, pain, fever, It is known to be involved in tissue repair and the like.
  • inhibitors of mPGES-1 can selectively suppress the final step of the biosynthetic pathway of PGE2 at the site of inflammation (Pharmacol. Rev., 59, pp. 207-224, 2007; J. Biol. Chem., 279 , pp. 33684-33695, 2004), which are expected as anti-inflammatory agents that do not cause gastric mucosal disorders such as non-steroidal anti-inflammatory agents.
  • mPGES-1 inhibitors include pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, large intestine Expected to be effective in the prevention and / or treatment of malignancies such as cancer or diseases in which suppression of PGE2 production is effective (PGE2, PGES, and mPGES-1, and use of mPGES-1 inhibitors, etc. See International Publication WO 2015/125842).
  • mPGES-1 inhibitors increase production of other prostanoids along with suppression of PGE2 production (J. Biol. Chem., 280, pp. 16579-16585, 2005).
  • mPGES-1 inhibitors known are heterocyclic derivatives disclosed in Patent No. 5601422, substituted pyrimidine compounds disclosed in International Publication WO2015 / 59618, and triazine compounds disclosed in International Publication WO2015 / 125842, etc. There is.
  • International Publication WO 2015/59618 discloses a pyrimidine compound (Example 2) substituted with p-trifluoromethylphenyl group and 2-chloro-5-isobutylamidobenzyl group
  • International Publication WO 2015/125842 discloses Disclosed are triazine compounds substituted with a p-trifluoromethylphenyl group and a 2-chloro-5-isobutyramidobenzyl group (Examples 1-28).
  • International Publication WO 2017/073709 discloses pyrimidine derivatives substituted with a phenyl group.
  • An object of the present invention is to provide a novel compound which has mPGES-1 inhibitory activity and is useful as an active ingredient of a medicine for the prevention and / or treatment of diseases such as inflammation, pain or rheumatism.
  • pyrimidine derivatives represented by the following general formula (1) have a strong inhibitory action on mPGES-1, inflammation,
  • the present invention has been found to be useful as an active ingredient of a medicine for the prevention and / or treatment of pain or a disease such as rheumatism.
  • X represents a carbonyl group or a sulfonyl group
  • R 1 represents a hydrogen atom, a halogen atom, an alkyl group, an alkanoyl group, a cyano group, or a carboxyl group
  • R 2 represents an alkyl group or a substituent group
  • R 3 represents a hydrogen atom, or 1 to 3 substituents to be substituted on ring A
  • the substituent is a halogen
  • R represents an atom, an alkyl group (the alkyl group may be substituted with a halogen atom), and an alkoxy group (the alkoxy group may be substituted with a halogen atom)
  • R 4 and R 5 each independently represent a hydrogen atom, a halogen atom, or an alkyl group
  • R 6 is an alkyl group (the alkyl group may be substituted with a hydroxy group, a halogen atom or an alk
  • X is the compound represented by the general formula (1) or a salt thereof is a carbonyl group
  • R 6 is a branched C 1-6 alkyl group (said alkyl group is C 1-
  • R 4 and R 5 are both hydrogen atoms Or a salt thereof
  • R 3 is a hydrogen atom, or an alkyl group (the alkyl group may be substituted with a halogen atom), and an alkoxy group (the alkoxy group may be substituted with a halogen atom)
  • R 1 is a hydrogen atom, an alkyl group or a cyano group the compound or a salt thereof
  • monocyclic 3-7 membered cyclic R 2 is saturated or may have a
  • an mPGES-1 inhibitor comprising the compound represented by the above general formula (1) or a salt thereof; and PGE2 comprising the compound represented by the above general formula (1) or a salt thereof Biosynthesis inhibitors are provided.
  • the present invention provides a medicament comprising the compound represented by the above general formula (1) or a physiologically acceptable salt thereof as an active ingredient.
  • the above-mentioned medicines include, for example, inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, large intestine It can be used for the prevention and / or treatment of malignancies such as cancer, or diseases in which PGE 2 production inhibition is effective.
  • mPGES-1 inhibitor use of the above mPGES-1 inhibitor, the above PGE2 biosynthesis inhibitor, or the compound represented by the above general formula (1) or a salt thereof for the production of the above medicament; mammalian animals including human
  • a method of inhibiting mPGES-1 in vivo comprising administering an effective amount of the compound represented by the above general formula (1) or a physiologically acceptable salt thereof to a mammal including human
  • a method comprising the step of administering to a mammal; and a method of promoting the production of another prostanoid by inhibiting the biosynthesis of PGE2 in vivo in a mammal including human, wherein Compound represented or physiologically acceptable Comprising administering an effective amount of the salt to a mammal including man.
  • the compound represented by the above general formula (1) provided by the present invention or a salt thereof exerts a strong inhibitory action on mPGES-1 and can inhibit the biosynthesis of PGE2, for example, inflammation Pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, malignant tumors such as colon cancer, or It is useful as an active ingredient of a medicine for the prevention and / or treatment of a disease for which PGE2 production suppression is effective.
  • X represents a carbonyl group or a sulfonyl group. It is preferred that X is a carbonyl group.
  • R 1 represents a hydrogen atom, a halogen atom, an alkyl group, an alkanoyl group, a cyano group or a carboxyl group.
  • halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.
  • a fluorine atom or a chlorine atom is preferable.
  • alkyl group includes alkyl groups consisting of linear, branched, cyclic, or a combination thereof, and the number of carbon atoms is not particularly limited, and it is, for example, 1 to 12, preferably Is 1 to 6, particularly preferably 1 to 4. The same applies to the alkyl part of other substituents having an alkyl part (for example, an alkoxy group).
  • R 1 a hydrogen atom, an alkyl group or a cyano group is preferable, a hydrogen atom, a methyl group or a cyano group is more preferable, and a hydrogen atom is particularly preferable.
  • R 2 represents an alkyl group, a carbocyclic group which may have a substituent, or a heterocyclic group which may have a substituent.
  • carbocyclic group for example, an aromatic hydrocarbon group or a saturated or partially saturated cyclic hydrocarbon group can be used.
  • aromatic hydrocarbon group for example, a phenyl group or a naphthyl group can be used, and as a saturated or partially saturated cyclic hydrocarbon group, for example, a saturated or partially saturated monocyclic or bicyclic 3 to 6
  • a 12-membered cyclic hydrocarbon group can be used.
  • a phenyl group can be used as the aromatic hydrocarbon group.
  • a saturated monocyclic 3- to 7-membered cyclic hydrocarbon group can be used as a cyclic hydrocarbon group, and a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or the like is more preferable. .
  • heterocyclic group a saturated or partially saturated heterocyclic group having one or more ring-constituting heteroatoms or an aromatic heterocyclic group having one or more ring-constituting heteroatoms can be used.
  • a ring-constituting hetero atom a nitrogen atom, an oxygen atom, or a sulfur atom can be used.
  • a saturated or partially saturated heterocyclic group having one or more ring-constituting heteroatoms for example, a saturated or partially saturated monocyclic 3- to 7-membered heterocyclic group or a bicyclic 8- to 12-membered heterocyclic group Can be used.
  • a saturated or partially saturated monocyclic 3- to 7-membered heterocyclic group for example, 1-aziridinyl group, 1-azetidinyl group, 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 2-tetrahydrofuryl group 3-tetrahydrofuryl group, thioranyl group, 1-imidazolidinyl group, 2-imidazolidinyl group, 4-imidazolidinyl group, 1-pyrazolidinyl group, 3-pyrazolidinyl group, 4-pyrazolidinyl group, 1- (2-pyrrolinyl) group, 1 -(2-Imidazolinyl) group, 2- (2-imidazolinyl) group, 1- (2-pyrazolinyl) group, 3- (2-pyrazolinyl) group, piperidino group, 2-piperidinyl group, 3-piperidinyl group, 4- Examples thereof include piperidinyl group, 1-homopiperidin
  • 2-membered heterocyclic group for example, 2-quinuclidinyl group, 2-chromanyl group, 3-chromanyl group, 4-chromanyl group, 5-chromanyl group, 6-chromanyl group, 7-chromanyl group, 8-chromanyl group, 1-isochromanyl group, 3-isochromanyl group, 4-isochromanyl group, 5-isochromanyl group, 6-isochromanyl group, 7-isochromanyl group, 8-isochromanyl group, 2-thiochromanyl group, 3-thiochromanyl group, 4-thiochromanyl group, 5-thiochromanyl group, 6-thiochromanyl group, 7-thiochromanyl group, 8-thiochromanyl group, 1-isothiochromanyl group, 3-isothiochromanyl group, 4-isothiochromanyl group, 5-isothiochromanyl group, 6-thiochromanyl group
  • aromatic heterocyclic group having one or more ring-constituting hetero atoms include, as a monocyclic aromatic heterocyclic group, for example, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group Group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group Group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 1-pyrazolyl Group, 3-pyrazolyl group, 4-pyrazolyl group, 5-pyrazolyl group, (1,2,3-oxazo
  • fused polycyclic aromatic heterocyclic group for example, 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl Group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzo [b] thienyl group, 3-benzo [b] thienyl group, 4-benzo [b] thienyl group, 5-benzo [b] Thienyl group, 6-benzo [b] thienyl group, 7-benzo [b] thienyl group, 1-benzo [c] thienyl group, 4-benzo [c] thienyl group, 5-benzo [c] thienyl group, 1 -Indolyl group, 2-indolyl group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-
  • a “functional group may be substituted” for a functional group the functional group is unsubstituted or in a chemically possible position, unless otherwise specified. It means that it may have one or more substituents.
  • the type of substituent present in the functional group, the number of substituents, and the substitution position are not particularly limited, and when two or more substituents are present, they may be the same or different.
  • a substituent present in a functional group for example, an alkyl group, a halogen atom, an oxo group, a thioxo group, a nitro group, a nitroso group, a cyano group, a isocyano group, a cyanato group, a thiocyanato group, an isocyanato group, an isothiocyanato group, a hydroxy group , Sulfanyl group, carboxy group, sulfanyl carbonyl group, oxalo group, meso oxalo group, thiocarboxy group, dithiocarboxy group, carbamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group, sulfino group, sulfinamoyl group, sulfeno group, sulfenamoyl group, Phosphono group, hydroxyphosphon
  • Such substituent may be substituted by another substituent at a chemically possible position on the substituent.
  • the type of substituent, the number of substituents, and the position of substitution are not particularly limited, and in the case of substitution with two or more substituents, they may be the same or different.
  • halogenated alkyl group eg, trifluoromethyl group etc.
  • hydroxyalkyl group eg, hydroxymethyl group etc.
  • halogenated alkyl-carbonyl group eg, trifluoroacetyl etc.
  • halogenated Alkyl-sulfonyl group eg, trifluoromethanesulfonyl etc.
  • acyl-oxy group e.g, acyl-sulfanyl group, N-hydrocarbon group-amino group, N, N-di (hydrocarbon) -amino group, N-heterocycle- Examples include, but are not limited to, groups such as amino group, N-hydrocarbon-N-heterocycle-amino group, acyl-amino group, di (acyl) -amino group and the like.
  • a saturated or partially saturated monocyclic 3- to 7-membered cyclic hydrocarbon group which may have a substituent, a phenyl group which may have a substituent, or a substituent A good saturated or partially saturated monocyclic 3- to 7-membered heterocyclic group (the heterocyclic group contains 1 to 3 ring-constituting hetero atoms), or a monocyclic aromatic ring which may have a substituent Heterocyclic groups, wherein the heterocyclic groups contain 1 to 3 ring-constituting heteroatoms, are preferred.
  • a saturated cyclic hydrocarbon group such as a cyclopentyl group or a cyclohexyl group, a phenyl group, a thienyl group, a pyridyl group, a pyrimidyl group, a thiazolyl group, a pyrazolyl group or a benzothiophene group, etc.
  • R 3 represents a hydrogen atom or 1 to 3 substituents substituted on ring A, and the substituent is a halogen atom or an alkyl group (the alkyl group may be substituted with a halogen atom) And an alkoxy group (the alkoxy group may be substituted with a halogen atom).
  • a halogen atom substituted to an alkyl group or an alkoxy group a fluorine atom is preferable.
  • R 3 represents one hydrogen atom or one substituent to be substituted on ring A, and the substituent is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy It is preferably a group, 2,2,2-trifluoroethoxy group, a fluorine atom or a chlorine atom.
  • substitution position of R 3 is not particularly limited, to indicate one substituent R 3 is substituted on ring A, the adjacent position relative to a pyrimidinyl group substituted on the ring A (ring A is a 6-membered In the case of a ring, it is preferably in the ortho position), and further, this substituent is adjacent to a pyrimidinyl group to be substituted on the ring A (ortho position when the ring A is a 6-membered ring) And it is more preferable that it is the farthest position to the aminomethyl group (para-position when ring A is a 6-membered ring).
  • R 4 and R 5 each independently represent a hydrogen atom, a halogen atom, or an alkyl group. Preferably both R 4 and R 5 are hydrogen atoms.
  • R 6 represents an alkyl group (the alkyl group may be substituted with a hydroxy group, a halogen atom or an alkoxy group), or an alkoxy group.
  • R 6 is a branched or cyclic C 1-6 alkyl group, and the branched C 1-6 alkyl group may be substituted by a C 1-6 alkoxy group.
  • R 6 preferably, an isopropyl group, 1-methyl-1-methoxyethyl group, cyclopropyl group, t-butyl group and the like can be used, and an isopropyl group can be particularly preferably used.
  • Ring A represents a heterocyclic diyl group.
  • a 4-oxo-pyrimidin-2-yl group substituted by R 1 and R 2 and an aminomethyl group substituted by R 4 , R 5 , and R 6 are bonded to the heterocyclic diyl group, and the ring R 3 is bonded to the top.
  • the heterocyclic diyl group it is possible to use a saturated or partially saturated heterocyclic diyl group having one or more ring-constituting heteroatoms, or an aromatic heterocyclic diyl group having one or more ring-constituting heteroatoms. it can.
  • a ring-constituting hetero atom a nitrogen atom, an oxygen atom, a sulfur atom or the like can be used.
  • heterocyclic structure constituting these heterocyclic diyl groups is not particularly limited, but may be, for example, the heterocyclic structure constituting the heterocyclic group described above, and any heterocyclic group described above may be exemplified.
  • a structure in which one hydrogen atom at the position is further removed can be exemplified. It is preferably a monocyclic aromatic heterocyclic diyl group, more preferably a monocyclic 5- or 6-membered aromatic complex containing 1 or 2 nitrogen atoms and / or sulfur atoms as ring-constituting hetero atoms.
  • a ring diyl group more preferably a pyridine diyl group, a pyrazine diyl group, a pyrimidine diyl group, a pyridazine diyl group, a pyrrol diyl group, an imidazole diyl group, a pyrazole diyl group, a thiazol diyl group, an isothiazole diyl group, etc. .
  • Particularly preferred is pyridine diyl group, pyrazine diyl group or thiazole diyl group.
  • Examples of the compound of the present invention included in the general formula (1) include N- ⁇ [6- (Difluoromethyl) -5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ pyridin-3-yl] methyl ⁇ Isobutyramide; N-[(6- ⁇ 4- [4- (cyclohexylmethoxy) phenyl] -6-oxo-1,6-dihydropyrimidin-2-yl ⁇ pyrazin-2-yl) methyl] isobutyramide; N-[(5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ pyridin-3-yl) methyl] isobutyramide; N-[(6-Ethoxy-5- ⁇ 6-oxo-4- [4- (tri
  • the compound represented by the general formula (1) may be in the form of a salt.
  • the salt is not particularly limited and may be appropriately selected according to the purpose. Examples thereof include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; methylamine, ethylamine, diethanolamine and the like Organic amine salts and the like, or mineral acid salts such as hydrochloride, sulfate and nitrate, and organic acid salts such as p-toluenesulfonate, maleate and tartrate are mentioned.
  • the compound represented by the general formula (1) or a salt thereof may exist in the form of a hydrate or a solvate.
  • the type of solvent that forms a solvate is not particularly limited, and examples thereof include ethanol, ethyl acetate, acetone and the like.
  • the compound represented by the general formula (1) may exist as an optical isomer, diastereoisomer or geometric isomer depending on the kind of substituent, but in addition to any isomer in pure form, Also, mixtures of any isomers are included in the scope of the present invention.
  • the compound represented by the general formula (1) or a salt thereof can be easily synthesized from the starting compounds readily available to those skilled in the art by conducting general chemical reactions widely used by those skilled in the art. Specific methods for producing the compounds of the present invention are shown in the examples of the present specification. Those skilled in the art can easily prepare the compounds of the present invention included in the general formula (1) by referring to their synthesis methods.
  • the compound of the present invention represented by the general formula (1) has an mPGES-1 inhibitory action, and can inhibit PGE2 biosynthesis based on the inhibitory action. Therefore, the medicament of the present invention containing the compound of the present invention represented by the general formula (1) or a physiologically acceptable salt thereof as an active ingredient is, for example, inflammation, pain, based on the mPGES-1 inhibitory action.
  • Rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, hypertension such as glaucoma, ischemic retinal disease, systemic scleroderma, malignant tumors such as colon cancer, or PGE2 production suppression Can be used for the prevention and / or treatment of a disease showing efficacy.
  • the medicament of the present invention includes, for example, inflammatory colitis, irritable bowel syndrome, migraine headache, backache, lumbar spinal canal stenosis, herniated disc, temporomandibular arthrosis, cervical shoulder arm syndrome, cervical spine Disease, endometriosis, uterine adenomyosis, preterm birth, preterm labor, dysmenorrhea, overactive bladder, voiding disorder associated with prostate hypertrophy, nocturia, urinary incontinence, neurogenic bladder, interstitial cystitis, Bladder pain syndrome, urinary calculus, prostatic hypertrophy, chronic prostatitis, pelvic pain syndrome, erectile dysfunction, cognitive disorder, neurodegenerative disease, Alzheimer's disease, pulmonary hypertension, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, Neuralgia, complex regional pain syndrome, myofascial disorder, ischemic heart disease, hypertension, an
  • a compound represented by the above general formula (1) which is an active ingredient or a physiologically acceptable salt thereof may be administered, but preferably, it is orally administered by a method known to those skilled in the art.
  • a pharmaceutical composition for parenteral or parenteral use can be prepared and administered.
  • pharmaceutical compositions suitable for oral administration include tablets, powders, capsules, fine granules, solutions, granules, syrups and the like
  • pharmaceutical compositions suitable for parenteral administration include For example, injections such as intravenous injections and intramuscular injections, drips, inhalants, eye drops, nasal drops, suppositories, transdermal absorption agents, transmucosal absorption agents and the like can be mentioned. It is not limited to
  • the above-mentioned pharmaceutical composition can be manufactured by methods well known to those skilled in the art using pharmaceutical additives widely used in the art for preparing pharmaceutical compositions.
  • the pharmaceutical additive is not particularly limited, and can be appropriately selected according to the form of the pharmaceutical composition and the purpose of imparting sustained release and the like. Examples include excipients, binders, fillers, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavors, fragrances, coatings, diluents, etc. There is no limitation to these.
  • the dosage of the medicament of the present invention is not particularly limited, and is appropriately selected according to the type of disease to be prevented or treated, the purpose of prevention or treatment, the type of active ingredient, body weight and age of the patient, symptoms, administration route and the like.
  • the dosage can be used in the range of about 0.01 to 500 mg as weight of active ingredient per adult per day.
  • the dose can be appropriately selected by those skilled in the art, and is not limited to the above range.
  • Reference example 25 2- [2-chloro-4- (trifluoromethyl) thiazol-5-yl] -6- [4- (trifluoromethyl) phenyl] pyrimidin-4 (3H) -one
  • Reference example 26 2- (5-chloro-2-methylpyridin-3-yl) -6- [4- (cyclopropylethynyl) phenyl] pyrimidin-4 (3H) -one
  • Example 1 N- ⁇ [6- (difluoromethyl) -5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ pyridine-3- [Illyl] methyl ⁇ isobutyramide N- ⁇ [5-carbamimidoyl-6- (difluoromethyl) pyridin-3-yl] methyl ⁇ isobutyramide hydrochloride 357 mg in 10 mL methanol solution of 301 mg ethyl phenylsulfonylacetate, 4- ( 230 mg of trifluoromethyl) benzaldehyde and 365 mg of potassium carbonate were added and stirred overnight at 55 ° C.
  • Example 2 N-[(6- ⁇ 4- [4- (cyclohexylmethoxy) phenyl] -6-oxo-1,6-dihydropyrimidin-2-yl ⁇ pyrazin-2-yl) methyl] isobutyramide
  • the same procedure as in Example 1 was carried out using cyclohexyl methoxy benzaldehyde to give the title compound.
  • Example 3 N-[(5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ pyridin-3-yl) methyl] isobutyramide -(5-chloropyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] pyrimidin-4 (3H) -one 211 mg in 25 mL of 1,4-dioxane in 5 mL water, potassium N- [ (Trifluoroborate) methyl] isobutyramide 248 mg, bis (dibenzylideneacetone) palladium (0) 17 mg, 2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl 28 mg, sodium carbonate 127 mg was added and stirred overnight at 100 ° C.
  • Example 4 N-[(6-Ethoxy-5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ pyridin-3-yl) methyl
  • 2- (2-chloro-2-ethoxypyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] pyrimidin-4 (3H) -one To give the title compound.
  • Example 5 N-[(4-Methyl-5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ thiazol-2-yl) methyl ] 2-Isobutylamide 2- (2-bromo-4-methylthiazol-5-yl) -6- [4- (trifluoromethyl) phenyl] pyrimidin-4 (3H) -one 296 mg of 1,4-dioxane 15 mL, water In a 3 mL solution, 294 mg of potassium N-[(trifluoroborate) methyl] isobutyramide, (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [2- (2 56 mg of '-amino-1,1'-biphenyl)] palladium (II) chloride and 294 mg of
  • Example 6 N-[(5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ -6- (2,2,2-tri) Fluoroethoxy) pyridin-3-yl) methyl] isobutyramide 2- [5-chloro-2- (2,2,2-trifluoroethoxy) pyridin-3-yl] -6- [4- (trifluoromethyl) The same procedure as in Example 5 was carried out using phenyl] pyrimidin-4 (3H) -one to give the title compound.
  • Example 7 N-[(6-Methyl-5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ pyridin-3-yl) methyl
  • 2- (2-chloro-2-methylpyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] pyrimidin-4 (3H) -one To give the title compound.
  • Example 8 N-[(5- ⁇ 4- [4- (cyclopropylethynyl) phenyl] -6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -4- ⁇ trifluoromethyl ⁇ thiazole-2 -Yl) methyl] isobutyramido 489 mg of 2- [2-bromo-4- (trifluoromethyl) thiazol-5-yl] -6- [4- (cyclopropylethynyl) phenyl] -3H-pyrimidin-4-one, Potassium N-[(trifluoroborate) methyl] isobutyramide 435 mg, (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [2- (2′-amino- A mixture of 165 mg of 1,1′-biphenyl)] palladium (II) chloride, 435
  • Example 9 N-[(5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ -4- ⁇ trifluoromethyl ⁇ thiazole-2 -Yl) methyl] isobutyramide Using 2- [2-chloro-4- (trifluoromethyl) thiazol-5-yl] -6- [4- (trifluoromethyl) phenyl] pyrimidin-4 (3H) -one The same procedure as in Example 8 was performed to give the title compound.
  • Example 10 N-[(5- ⁇ 4- [4- (cyclopropylethynyl) phenyl] -6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -6-methylpyridin-3-yl) methyl ] Isobutyramido 6- (5-chloro-2-methylpyridin-3-yl) -6- [4- (cyclopropylethynyl) phenyl] pyrimidin-4 (3H) -one 66.2 mg, potassium N-[(trifluoroboron) [Rate] methyl] isobutylamide 76 mg, (2-Dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1, 1'-biphenyl) [2- (2'-amino-1, 1'-biphenyl) 29 mg of palladium (II) chloride, 76 mg of potassium carbonate, 5 mL of 1,4-di
  • Example 11 N-[(5- ⁇ 6-oxo-4- [4- (trifluoromethyl) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ -6- (trifluoromethyl) pyridine-3 -Yl) methyl] isobutyramide
  • Example 12 N-[(5- ⁇ 4- [4- (cyclopropylethynyl) phenyl] -6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -6- (trifluoromethyl) pyridine-3 -Yl) methyl] isobutyramide
  • the same procedure as in Reference Example 24 was carried out using N- ⁇ [5-carbamimidoyl-6- (trifluoromethyl) pyridin-3-yl] methyl ⁇ isobutyramide hydrochloride, The compound is obtained.
  • Example 13 N-[(5- ⁇ 6-oxo-4- [4- (trifluoromethoxy) phenyl] -1,6-dihydropyrimidin-2-yl ⁇ -6- (trifluoromethyl) pyridine-3 -Yl) methyl] isobutyramide
  • Example 14 N-[(5- ⁇ 4- [4- (2-butoxyethoxy) phenyl] -6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -6- (trifluoromethyl) pyridine- 3-yl) methyl] isobutyramide Using 4- (2-butoxyethoxy) benzaldehyde and N- ⁇ [5-carbamimidoyl-6- (trifluoromethyl) pyridin-3-yl] methyl ⁇ isobutyramide hydrochloride, The same operation as in Reference Example 24 was performed to give the title compound.
  • Test Example 1 mPGES-1 inhibitory activity test Microsomes were prepared from COS-1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA, and used as mPGES-1 enzyme.
  • the mPGES-1 enzyme was diluted with sodium phosphate buffer (pH 7.2) containing reduced glutathione (2.5 mM) and EDTA (1 mM), and DMSO or a solution of test compound in DMSO (final concentration of DMSO 1%) was added and preincubated at 4 ° C. for 15 minutes.
  • a substrate PGH2 Prostaglandin H2

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Abstract

La présente invention concerne un composé ayant une activité inhibitrice de mPGES-1 et qui est utile en tant que principe actif d'un produit pharmaceutique pour le traitement d'une inflammation, d'une douleur ou de maladies telles que le rhumatisme. (Dans la formule, X représente un groupe carbonyle ou un groupe sulfonyle ; R1 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle, un groupe alcanoyle, un groupe cyano ou un groupe carboxyle ; R2 représente un groupe alkyle, un groupe carbocyclique ou un groupe hétérocyclique ; R3 représente un atome d'hydrogène ou un à trois substituants ; chacun de R4 et R5 représente un atome d'hydrogène, un atome d'halogène ou un groupe alkyle ; R6 représente un groupe alkyle ou un groupe alcoxy ; et l'anneau A représente un groupe diyle hétérocyclique.)
PCT/JP2018/031859 2017-08-30 2018-08-29 Dérivé pyrimidine WO2019044868A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022168808A1 (fr) 2021-02-02 2022-08-11 あすか製薬株式会社 Dérivé de pyrimidine
CN115043780A (zh) * 2022-07-11 2022-09-13 上海飞琰化工科技有限公司 一种4-羟基-5-氟-6-乙基嘧啶的合成方法及其应用
WO2024010015A1 (fr) * 2022-07-06 2024-01-11 あすか製薬株式会社 Dérivés de pyrimidine

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WO2001070726A1 (fr) * 2000-03-23 2001-09-27 Sanofi-Synthelabo Derives d'aminophenyl pyrimidone
WO2013186692A1 (fr) * 2012-06-15 2013-12-19 Glenmark Pharmaceuticals S.A. Composés triazolone utilisés comme inhibiteurs de la mpges-1
WO2015059618A1 (fr) * 2013-10-22 2015-04-30 Glenmark Pharmaceuticals S.A. Composés de pyrimidine substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2017073709A1 (fr) * 2015-10-29 2017-05-04 あすか製薬株式会社 Dérivé pyrimidine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070726A1 (fr) * 2000-03-23 2001-09-27 Sanofi-Synthelabo Derives d'aminophenyl pyrimidone
WO2013186692A1 (fr) * 2012-06-15 2013-12-19 Glenmark Pharmaceuticals S.A. Composés triazolone utilisés comme inhibiteurs de la mpges-1
WO2015059618A1 (fr) * 2013-10-22 2015-04-30 Glenmark Pharmaceuticals S.A. Composés de pyrimidine substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2017073709A1 (fr) * 2015-10-29 2017-05-04 あすか製薬株式会社 Dérivé pyrimidine

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DATABASE Database REGISTRY [o] 2014, retrieved from STN Database accession no. 1523307-89-2 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022168808A1 (fr) 2021-02-02 2022-08-11 あすか製薬株式会社 Dérivé de pyrimidine
KR20230142739A (ko) 2021-02-02 2023-10-11 아스카 세이야쿠 가부시키가이샤 피리미딘 유도체
WO2024010015A1 (fr) * 2022-07-06 2024-01-11 あすか製薬株式会社 Dérivés de pyrimidine
CN115043780A (zh) * 2022-07-11 2022-09-13 上海飞琰化工科技有限公司 一种4-羟基-5-氟-6-乙基嘧啶的合成方法及其应用
CN115043780B (zh) * 2022-07-11 2024-01-16 上海飞琰化工科技有限公司 一种4-羟基-5-氟-6-乙基嘧啶的合成方法及其应用

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