WO2012046793A1 - Nouvel inhibiteur de jak3 contenant, à titre de principe actif, un dérivé de thiophène portant un groupe uréido et un groupe aminocarbonyle à titre de substituants - Google Patents

Nouvel inhibiteur de jak3 contenant, à titre de principe actif, un dérivé de thiophène portant un groupe uréido et un groupe aminocarbonyle à titre de substituants Download PDF

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WO2012046793A1
WO2012046793A1 PCT/JP2011/073050 JP2011073050W WO2012046793A1 WO 2012046793 A1 WO2012046793 A1 WO 2012046793A1 JP 2011073050 W JP2011073050 W JP 2011073050W WO 2012046793 A1 WO2012046793 A1 WO 2012046793A1
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thiophene
carboxamide
aminocarbonylamino
phenyl
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Japanese (ja)
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実 山本
幸史 藤澤
美絵 ▲高▼田
正和 伴
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参天製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—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
    • 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

Definitions

  • the present invention relates to a novel JAK3 inhibitor containing at least one of a thiophene derivative having a ureido group and an aminocarbonyl group as a substituent or a salt thereof as an active ingredient, and a novel thiophene derivative having a ureido group and an aminocarbonyl group as a substituent, or Relates to the salt.
  • the JAK3 inhibitor of the present invention is expected to be useful as a preventive and / or therapeutic agent for a disease in which JAK3 is involved.
  • the present invention also relates to a method for preventing and / or treating a disease that involves JAK3, using a thiophene derivative or a salt thereof.
  • the present invention further relates to the use of a thiophene derivative or a salt thereof for producing a JAK3 inhibitor.
  • JAK family (JAK1-3, TYK2) is a tyrosine kinase essential for cytokines to exert their biological activities. JAK is activated in the cell after the cytokine binds to the receptor, and activates the transcription factor Stat downstream thereof. JAK1 and JAK2 are widely expressed in vivo, while JAK3 is locally expressed in blood cells. This deficiency in JAK3 resulted in lymphocyte differentiation and proliferation failure in both humans and mice and exhibited severe combined immunodeficiency (SCID) (Japanese Journal of Clinical Immunology, 32, (2) 85. (2009) (Non-Patent Document 1)). This suggests that immunosuppression occurs by blocking signal pathways via JAK3. Therefore, a compound that inhibits JAK3 is expected to have an effect of controlling an immune response and is expected to be useful for the prevention and / or treatment of various autoimmune diseases.
  • SCID severe combined immunodeficiency
  • Non-patent Document 2 compounds having a pyrrolopyrimidine skeleton (Bioorganic & Medicinal Chemistry Letters, 16, 5633 (2006) (Non-patent Document 2)), compounds having a tetracyclic pyridone skeleton (Bioorganic & Medicinal Chemistry) Letters, 12, 1219 (2002) (non-patent document 3)), compounds having an oxindole skeleton (non-patent document 2), and the like are known.
  • thiophene derivatives having a ureido group and an aminocarbonyl group as substituents are known as IKK-2 inhibitors (The Journal of Pharmacology and Experimental Therapeutics, 312, 373 (2005) (Non-Patent Document 4)).
  • the present invention relates to a JAK3 inhibitor containing as an active ingredient at least one of a compound represented by the following general formula (1) or a salt thereof (hereinafter also referred to as “the present compound” unless otherwise specified).
  • A represents the following general formula (2a), (2b), (2c), (2d), (2e) or (2f);
  • R 1 is hydrogen atom, halogen atom, lower alkyl group, lower alkenyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, amino group, lower alkylamino group, morpholino group, amide of amino group An amino group sulfonamido, a mercapto group, a lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group or a cyano group;
  • R 2 represents a hydrogen atom or a lower alkyl group;
  • R 3 And R 4 are the same or different and each represents a hydrogen atom, a halogen atom or a lower alkyl group;
  • R 5 represents a hydroxy group or a lower alkoxy group; and when R 1 is a lower alkyl group, the lower alkyl group is a hydroxy group, From lower al
  • the present invention also provides a method for preventing and / or treating a disease associated with JAK3, which comprises administering to a patient a pharmacologically effective amount of at least one of the compounds of the present invention.
  • the present invention also provides a compound represented by the above general formula (1) or a salt thereof (the compound of the present invention) for use in the prevention and / or treatment of a disease in which JAK3 is involved.
  • the present invention further provides use of the compound of the present invention for producing a JAK3 inhibitor.
  • the compound of the present invention is preferably represented by the following general formula (2a) in the general formula (1).
  • the compound of the present invention preferably has the following general formula (2a) in the general formula (1):
  • R 1 is hydrogen atom, halogen atom, lower alkyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, lower alkylamino group, morpholino group, lower alkylcarbonylamino group, lower alkylsulfonylamino group , A lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylaminocarbonyl group, an N-methoxy-N-methylaminocarbonyl group or a cyano group; when R 1 is a lower alkyl group, The lower alkyl group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkylcarbonyloxy group and a morpholino group; when R 1 is a lower alkoxy group, the lower alkoxy group is a halogen atom.
  • Atom, lower alkylamino , Morpholino group, 4-fluorophenyl piperazino group may be substituted with 1 or more groups selected from the group consisting of carboxyl group and lower alkoxycarbonyl group; when R 1 is a lower alkylcarbonyl amino group
  • the lower alkylcarbonylamino group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkoxycarbonyl group and a cyano group; when R 1 is an aminocarbonyl group, the aminocarbonyl
  • the group may be substituted with one or more groups selected from the group consisting of a hydrogen atom, a lower alkyl group and a lower alkoxy group, and the lower alkyl group is selected from the group consisting of a carboxyl group and a lower alkoxycarbonyl group
  • p is 0, 1 It indicates 2 or 3; when p is 2 or 3, R 1 may be the same or different.
  • the present invention also provides 2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2,3,4-trimethoxyphenyl) thiophene-3-carboxamide; 2-aminocarbonylamino-5- (4-methoxypyridin-3-yl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-methylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-isopropylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-ethylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-methylthiophenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-ethoxyphenyl)
  • the compound of the present invention in the present invention is a disease in which JAK3 is involved, such as autoimmune disease, keratitis, conjunctivitis, blepharitis, dry eye syndrome (also called “dry eye”), allergic conjunctivitis, anterior grape Meningitis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular macular disease, proliferative vitreoretinopathy, retinitis pigmentosa, central retinal vein occlusion, branch retinal vein occlusion, uveitis It is expected to be useful as a preventive and / or therapeutic agent.
  • the present invention relates to 2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide for use in the prevention and / or treatment of diseases in which JAK3 is implicated, 2-aminocarbonylamino-5- (2,3,4-trimethoxyphenyl) thiophene-3-carboxamide; 2-aminocarbonylamino-5- (4-methoxypyridin-3-yl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-methylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-isopropylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-ethylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-methylthiophenyl) thiophene-3-carboxamide
  • the present invention also provides 2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2,3,4-trimethoxyphenyl) thiophene-3-carboxamide; 2-aminocarbonylamino-5- (4-methoxypyridin-3-yl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-methylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-isopropylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-ethylphenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-methylthiophenyl) thiophene-3-carboxamide, 2-aminocarbonylamino-5- (2-ethoxyphenyl)
  • the present invention further provides a pharmaceutical composition containing the compound or salt of the present invention described above.
  • the thiophene derivative having a ureido group and an aminocarbonyl group as a substituent, or a salt thereof, which is a compound of the present invention has excellent JAK3 inhibitory activity. Therefore, the compound of the present invention is used for diseases in which JAK3 is involved, such as autoimmune diseases, keratitis, conjunctivitis, blepharitis, dry eye syndrome (also called “dry eye”), allergic conjunctivitis, anterior uveitis Age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular macular disease, proliferative vitreoretinopathy, retinitis pigmentosa, central retinal vein occlusion, branch retinal vein occlusion, uveitis, etc.
  • diseases in which JAK3 is involved such as autoimmune diseases, keratitis, conjunctivitis, blepharitis, dry eye syndrome (also called “dry eye”), allergic conjunctiv
  • Derivatives or salts thereof, as well as the use of thiophene derivatives or salts thereof for preparing JAK3 inhibitors are also provided.
  • Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8, preferably 1 to 6 carbon atoms. Specific examples include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, isopropyl group, isobutyl group, sec-butyl group. , Tert-butyl group, isopentyl group and the like.
  • the “lower alkenyl group” refers to a straight or branched alkenyl group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms. Specific examples include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, an isopropenyl group, a 2-methyl-1-propenyl group, and a 2-methyl-2-butenyl group. .
  • lower alkynyl group refers to a straight chain or branched alkynyl group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms. Specific examples include ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group, isobutynyl group, isopentynyl group and the like.
  • the “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
  • aryl group is a residue obtained by removing one hydrogen atom from a monocyclic aromatic hydrocarbon having 6 to 14 carbon atoms or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon. Show. Specific examples include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and the like.
  • the “heterocyclic group” is a saturated or unsaturated monocyclic heterocycle having 1 or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring (preferably 1 or 2 A saturated or unsaturated monocyclic heterocyclic 5- or 6-membered ring having 3 to 5 carbon atoms and having a heteroatom in the ring) or a bicyclic or tricyclic condensed polycyclic heterocyclic ring (preferably 1 Or a residue obtained by removing one hydrogen atom from a bicyclic or tricyclic fused polycyclic heterocyclic ring having 7 to 13 carbon atoms and having 2 heteroatoms in the ring.
  • ⁇ saturated monocyclic heterocycle '' examples include a pyrrolidine ring having a nitrogen atom in the ring, a pyrazolidine ring, an imidazolidine ring, a triazolidine ring, a piperidine ring, a hexahydropyridazine ring, a hexahydropyrimidine ring, a piperazine ring, Homopiperidine ring, homopiperazine ring, etc. Tetrahydrothiophene ring, tetrahydrothiopyran ring, etc. that have sulfur atom in the ring, such as tetrahydrofuran ring, tetrahydropyran ring, etc.
  • oxygen atom in the ring in the ring examples thereof include thiazolidine rings, isothiazolidine rings, and thiomorpholine rings having nitrogen and sulfur atoms in the ring, such as oxazolidine ring, isoxazolidine ring, and morpholine ring.
  • the saturated monocyclic heterocycle is condensed with a benzene ring or the like to form a dihydroindole ring, a dihydroindazole ring, a dihydrobenzimidazole ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, a tetrahydrocinnoline ring, a tetrahydrophthalazine ring, Tetrahydroquinazoline ring, tetrahydroquinoxaline ring, dihydrobenzofuran ring, dihydroisobenzofuran ring, chroman ring, isochroman ring, dihydrobenzothiophene ring, dihydroisobenzothiophene ring, thiochroman ring, isothiochroman ring, dihydrobenzoxazole ring, dihydrobenzoiso Oxazole ring, dihydrobenzo
  • unsaturated monocyclic heterocycle examples include dihydropyrrole ring, pyrrole ring, dihydropyrazole ring, pyrazole ring, dihydroimidazole ring, imidazole ring, dihydrotriazole ring, triazole ring having a nitrogen atom in the ring, Oxygen atoms in the ring such as tetrahydropyridine ring, dihydropyridine ring, pyridine ring, tetrahydropyridazine ring, dihydropyridazine ring, pyridazine ring, tetrahydropyrimidine ring, dihydropyrimidine ring, pyrimidine ring, tetrahydropyrazine ring, dihydropyrazine ring, pyrazine ring Dihydrofuran ring, furan ring, dihydropyran ring, pyran ring, etc.
  • dihydrothiophene ring having a nitrogen atom and oxygen atom in the ring
  • dihydrothiophene ring having a nitrogen atom and oxygen atom in the ring
  • thiophene ring having a sulfur atom in the ring Droxazole ring
  • oxazole ring dihydroisoxazole ring
  • isoxazole ring dihydrooxazine ring, oxazine ring, etc.
  • dihydrothiazole ring, thiazole ring, dihydroisothiazole ring isothiazole ring having nitrogen and sulfur atoms in the ring
  • Examples include a dihydrothiazine ring and a thiazine ring.
  • these unsaturated monocyclic heterocycles are condensed with a benzene ring or the like to form indole, indazole, benzimidazole, benzotriazole, dihydroquinoline, quinoline, dihydroisoquinoline, isoquinoline, phenant.
  • Lysine ring dihydrocinnoline ring, cinnoline ring, dihydrophthalazine ring, phthalazine ring, dihydroquinazoline ring, quinazoline ring, dihydroquinoxaline ring, quinoxaline ring, benzofuran ring, isobenzofuran ring, chromene ring, isochromene ring, benzothiophene ring, Isobenzothiophene ring, thiochromene ring, isothiochromene ring, benzoxazole ring, benzoisoxazole ring, benzoxazine ring, benzothiazole ring, benzoisothiazole ring, benzothiazine ring, phenoxanthine , A carbazole ring, ⁇ -carboline ring, phenanthridine ring, acridine ring, phenanthroline ring, phena
  • “Lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkyl group. Specific examples include methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentoxy group, n-hexyloxy group, n-heptyloxy group, n-octyloxy group, isopropoxy group, isobutoxy group, Examples thereof include a sec-butoxy group, a tert-butoxy group, and an isopentoxy group.
  • “Lower alkenyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkenyl group. Specific examples include vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, isopropenyloxy, 2-methyl-1-propenyloxy, 2-methyl-2 -Butenyloxy group and the like.
  • the “lower cycloalkyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower cycloalkyl group. Specific examples include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group, and the like.
  • Aryloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryl group. Specific examples include phenoxy group, naphthoxy group, anthryloxy group, phenanthryloxy group and the like.
  • heterocyclic oxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a heterocyclic group.
  • lower alkylamino group refers to a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkyl group. Specific examples include a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group, a diethylamino group, and an ethyl (methyl) amino group.
  • the “lower cycloalkylamino group” is a group in which one or both hydrogen atoms of an amino group are substituted by a lower cycloalkyl group or one hydrogen atom of an amino group is a lower cycloalkyl group and the other hydrogen atom is lower A group substituted with an alkyl group, a lower alkenyl group or a lower alkynyl group is shown.
  • cyclopropylamino group examples include cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, cycloheptylamino group, cyclooctylamino group, dicyclohexylamino group, cyclohexyl (methyl) amino group, cyclohexyl (vinyl) amino group, Examples include cyclohexyl (ethynyl) amino group.
  • Arylamino group means a group in which one or both hydrogen atoms of an amino group are substituted with an aryl group, or one hydrogen atom of an amino group is an aryl group, and the other hydrogen atom is a lower alkyl group or a lower alkenyl group. And a group substituted with a lower alkynyl group or a lower cycloalkyl group.
  • phenylamino group examples include phenylamino group, naphthylamino group, anthrylamino group, phenanthrylamino group, diphenylamino group, methyl (phenyl) amino group, ethyl (phenyl) amino group, phenyl (vinyl) amino group, ethynyl ( A phenyl) amino group, a cyclohexyl (phenyl) amino group, and the like.
  • Heterocyclic amino group means a group in which one or both hydrogen atoms of an amino group are substituted with a heterocyclic group, or one hydrogen atom of an amino group is a heterocyclic group, and the other hydrogen atom is a lower alkyl group, A group substituted with a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group or an aryl group is shown.
  • “Amino group amide” refers to an amide formed from an amino group and a carboxylic acid.
  • the carboxylic acids are R a COOH (R a is a hydrogen atom, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an aryl which may have a substituent.
  • R a is a hydrogen atom, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an aryl which may have a substituent.
  • acid anhydrides [(R a CO) 2 O] of these carboxylic acids and acid halides are also included in the “carboxylic acids”.
  • Specific examples include saturated aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and vivalic acid; oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, etc.
  • Saturated aliphatic dicarboxylic acids unsaturated aliphatic carboxylic acids such as acrylic acid, propiolic acid, crotonic acid, and cinnamic acid; carbocyclic carboxylic acids such as benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, and toluic acid Acids: heterocyclic carboxylic acids such as furan carboxylic acid, thiophene carboxylic acid, nicotinic acid, and isonicotinic acid; acid anhydrides such as acetic anhydride.
  • the “lower alkylcarbonylamino group” is a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkylcarbonyl group or one hydrogen atom of an amino group is a lower alkylcarbonyl group and the other hydrogen atom is lower A group substituted with an alkyl group, a lower alkenyl group or a lower alkynyl group is shown.
  • Specific examples include methylcarbonylamino group, ethylcarbonylamino group, n-propylcarbonylamino group, n-butylcarbonylamino group, n-pentylcarbonylamino group, n-hexylcarbonylamino group, n-heptylcarbonylamino group, n -Octylcarbonylamino group, isopropylcarbonylamino group, isobutylcarbonylamino group, sec-butylcarbonylamino group, tert-butylcarbonylamino group, isopentylcarbonylamino group, dimethylcarbonylamino group, methylcarbonyl (methyl) amino group, methyl Examples thereof include a carbonyl (vinyl) amino group and a methylcarbonyl (ethynyl) amino group.
  • Amino group sulfonamide refers to a sulfonamide formed from an amino group and a sulfonic acid.
  • the sulfonic acids are R a SO 3 H (R a is a hydrogen atom, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent.
  • R a is a hydrogen atom, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent.
  • the sulfonic acid anhydrides [(R a SO 2 ) 2 O] and acid halides (R a SO 2 Hal, Hal represents a halogen atom) are also included in the “sulfonic acids”.
  • the sulfonic acids include p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, methanesulfonyl chloride, and the like.
  • the “lower alkylsulfonylamino group” is a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkylsulfonyl group or one hydrogen atom of an amino group is a lower alkylsulfonyl group and the other hydrogen atom is lower A group substituted with an alkyl group, a lower alkenyl group or a lower alkynyl group is shown.
  • methylsulfonylamino group examples include methylsulfonylamino group, ethylsulfonylamino group, n-propylsulfonylamino group, n-butylsulfonylamino group, n-pentylsulfonylamino group, n-hexylsulfonylamino group, n-heptylsulfonylamino group, n -Octylsulfonylamino group, isopropylsulfonylamino group, isobutylsulfonylamino group, sec-butylsulfonylamino group, tert-butylsulfonylamino group, isopentylsulfonylamino group, dimethylsulfonylamino group, methylsulfonyl (methyl) amino group, methyl A sulfony
  • “Lower alkylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with a lower alkyl group. Specific examples include methylthio group, ethylthio group, n-propylthio group, n-butylthio group, n-pentylthio group, n-hexylthio group, isopropylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, isopentyl group. And a ruthio group.
  • Arylthio group refers to a group in which a hydrogen atom of a mercapto group is substituted with an aryl group. Specific examples include a phenylthio group, a naphthylthio group, an anthrylthio group, a phenanthrylthio group, and the like.
  • “Lower alkylsulfonyl group” refers to a group in which a hydroxy group of a sulfonic acid group is substituted with a lower alkyl group. Specific examples include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, n-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group, isopropylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, Examples thereof include a tert-butylsulfonyl group and an isopentylsulfonyl group.
  • lower alkylcarbonyl group refers to a group in which the hydrogen atom of the formyl group is substituted with a lower alkyl group.
  • Specific examples include methylcarbonyl group, ethylcarbonyl group, n-propylcarbonyl group, n-butylcarbonyl group, n-pentylcarbonyl group, n-hexylcarbonyl group, isopropylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, Examples thereof include a tert-butylcarbonyl group and an isopentylcarbonyl group.
  • Arylcarbonyl group refers to a group in which a hydrogen atom of a formyl group is substituted with an aryl group. Specific examples include phenylcarbonyl group, naphthylcarbonyl group, anthrylcarbonyl group, phenanthrylcarbonyl group and the like.
  • the “lower alkoxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkoxy group. Specific examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl group, n-pentoxycarbonyl group, n-hexyloxycarbonyl group, n-heptyloxycarbonyl group, n-octyloxycarbonyl. Group, isopropoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, isopentoxycarbonyl group and the like.
  • Aryloxycarbonyl group refers to a group in which a hydrogen atom of a formyl group is substituted with an aryloxy group. Specific examples include a phenoxycarbonyl group, naphthoxycarbonyl group, anthryloxycarbonyl group, phenanthryloxycarbonyl group, and the like.
  • “Lower alkylcarbonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkylcarbonyl group. Specific examples include methylcarbonyloxy group, ethylcarbonyloxy group, n-propylcarbonyloxy group, n-butylcarbonyloxy group, n-pentylcarbonyloxy group, n-hexylcarbonyloxy group, n-heptylcarbonyloxy group, n -Octylcarbonyloxy group, isopropylcarbonyloxy group, isobutylcarbonyloxy group, sec-butylcarbonyloxy group, tert-butylcarbonyloxy group, isopentylcarbonyloxy group and the like.
  • Arylcarbonyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with an arylcarbonyl group. Specific examples include a phenylcarbonyloxy group, a naphthylcarbonyloxy group, an anthrylcarbonyloxy group, a phenanthrylcarbonyloxy group, and the like.
  • Aminocarbonyl group refers to a group in which a hydrogen atom of a formyl group is substituted with an amino group.
  • lower alkylaminocarbonyl group refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkylamino group.
  • Specific examples include a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, a dimethylaminocarbonyl group, a diethylaminocarbonyl group, and an ethylmethylaminocarbonyl group.
  • lower alkyl group optionally having substituent (s) or “lower alkenyl group optionally having substituent (s)” may have one or more substituents selected from the following ⁇ 1 group.
  • a preferable “lower alkyl group” or “lower alkenyl group” is shown.
  • aryl group optionally having substituent (s)” or “heterocyclic group optionally having substituent (s)” may have one or more substituents selected from the following ⁇ 1 group: An “aryl group” or a “heterocyclic group” is shown.
  • the “plural groups” as used in the present invention may be the same or different, and each group represents two or more groups at the substitution site, and the number of substitutions or less. The number is preferably two. Further, a hydrogen atom and a halogen atom are also included in the concept of “group”.
  • JK3 inhibitor means a pharmaceutical composition containing at least one of the compounds of the present invention as an active ingredient.
  • prevention and / or treatment agent means a drug for preventing and / or treating a disease.
  • “disease associated with JAK3” is, for example, autoimmune disease, rheumatoid arthritis, psoriasis, osteoarthritis, osteoporosis, spondyloarthritis, keratitis, keratoconjunctivitis, conjunctivitis, blepharitis, dry eyeball Syndrome (also called “dry eye”), allergic conjunctivitis, anterior uveitis, inflammation after anterior surgery of the anterior eye, ocular tissue transplant rejection, age-related macular degeneration (early age-related macular degeneration, atrophic addition) Age-related macular degeneration and / or wet age-related macular degeneration), diabetic retinopathy, diabetic macular edema, neovascular macular disease, idiopathic macular degeneration, proliferative vitreoretinopathy, retinitis pigmentosa, central retinal vein occlusion , Central retinal artery oc
  • the “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, glucone Acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, Salts with organic acids such as trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulf
  • halogen ions such as bromine ion, chlorine ion and iodine ion
  • alkali metals such as um
  • salts with alkaline earth metals such as calcium and magnesium, metals with iron and zinc
  • salts with ammonia triethylenediamine
  • the compounds of the present invention may take the form of hydrates or solvates.
  • the isomer is also included in the scope of the present invention.
  • the tautomer is also included in the present invention.
  • the crystal polymorph and crystal polymorph group are also included in the present invention.
  • the crystal polymorphism group means that the crystal form changes depending on the conditions and states (including the formulated state in this state) such as the production, crystallization, and storage of these crystals. Means the individual crystal forms at each stage and the whole process.
  • (A1) A represents the following general formula (2a), (2b), (2c), (2d), (2e) or (2f); and / or
  • R 1 is a hydrogen atom, halogen atom, lower alkyl group, lower alkenyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, amino group, lower alkylamino group, morpholino group, amino An amide of a group, a sulfonamido of an amino group, a mercapto group, a lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group or a cyano group; and / or (a3) R 2 is a hydrogen atom And / or (a4) R 3 and R 4 are the same or different and represent a hydrogen atom, a halogen atom or a lower alkyl group; and / or (a5) R 5 is a hydroxy group or a lower alkoxy group.
  • R 1 is lower alkyl
  • the lower alkyl group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkylcarbonyloxy group and a morpholino group; and / or (a7) R 1 is In the case of a lower alkoxy group, the lower alkoxy group is one or more groups selected from the group consisting of a halogen atom, a lower alkylamino group, a morpholino group, a 4-fluorophenylpiperazino group, a carboxyl group and a lower alkoxycarbonyl group.
  • R 1 when R 1 is an amide of an amino group, the amide of the amino group is one or more selected from the group consisting of a hydroxy group, a lower alkoxycarbonyl group and a cyano group may be substituted by the group; and / or (a9) when R 1 is an amino group,
  • the aminocarbonyl group may be substituted with one or more groups selected from the group consisting of a hydrogen atom, a lower alkyl group and a lower alkoxy group, and the lower alkyl group is a group consisting of a carboxyl group or a lower alkoxycarbonyl group.
  • p represents 0, 1, 2 or 3; and / or (a11) when p is 2 or 3, R1 May be the same or different.
  • the compound of the present invention is a compound represented by the general formula (1), wherein (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8) , (A9), (a10) and (a11), or a combination thereof, or a salt thereof.
  • a compound satisfying the combination of the condition (b) and the condition (a) or a salt thereof is preferable.
  • (C1) A represents the following general formula (2a); and / or
  • R 1 is hydrogen atom, halogen atom, lower alkyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, lower alkylamino group, morpholino group, lower alkylcarbonylamino group, lower alkyl Represents a sulfonylamino group, a lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylaminocarbonyl group, an N-methoxy-N-methylaminocarbonyl group or a cyano group; and / or (c3) R When 1 is a lower alkyl group, the lower alkyl group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkylcarbonyloxy group and a morpholino group; and / or (c4) when R 1 is a lower alkyl
  • R 1 when R 1 is a lower alkylcarbonylamino group, the lower alkylcarbonylamino group is substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkoxycarbonyl group and a cyano group
  • R 1 when R 1 is an aminocarbonyl group, the aminocarbonyl group is substituted with one or more groups selected from the group consisting of a hydrogen atom, a lower alkyl group, and a lower alkoxy group.
  • the lower alkyl group may be a carboxyl group and a lower group.
  • R 1 may be the same or different.
  • the compound of the present invention can be produced by the following method.
  • each specific manufacturing method is demonstrated in detail by the item of the below-mentioned Example [manufacturing example].
  • these illustrations are for understanding the present invention better and are not intended to limit the scope of the present invention.
  • R represents an arbitrary substituent
  • TFA represents trifluoroacetic acid
  • Hal represents a halogen atom
  • NaOH represents sodium hydroxide
  • Boc 2 O represents di-tert-dicarbonate.
  • the compound (I) of the present invention can be synthesized according to Synthesis Route 1. That is, compound (II) and trichloroacetyl isocyanate are reacted in an organic solvent such as acetonitrile at room temperature to 40 ° C. for 1 hour to 6 hours, and then an ammonia-methanol solution is further added, and 0 ° C. to room temperature for 1 hour.
  • the compound (I) of the present invention can be obtained by reacting for 24 hours.
  • This invention compound (I) is compoundable according to the synthetic pathway 2. That is, boronic acid ester (IV) such as boronic acid or boronic acid pinacol ester corresponding to compound (III) is mixed with cesium carbonate in an organic solvent such as N, N-dimethylformamide or a mixed solvent of organic solvent and water. In the presence of a base such as tetrakis (triphenylphosphine) palladium (0) and the like, the compound (I) of the present invention can be obtained by reacting at 70 to 100 ° C. for 1 to 6 hours.
  • a base such as tetrakis (triphenylphosphine) palladium (0) and the like
  • each of the compounds (I-2a-1) to (I-2a-4) sodium hydroxide or ammonia-methanol solution is added in an organic solvent such as methanol, and the temperature is from room temperature to 65 ° C. for 1 hour to 24 hours.
  • the compounds of the present invention (I-2a-5) to (I-2a-8) can be obtained by the reaction.
  • Compound (II) can be produced according to synthetic route 4. That is, boronic acid ester (IV) such as boronic acid or boronic acid pinacol ester corresponding to compound (V) in a mixed solvent of an organic solvent such as 1,4-dioxane and water, or a mixed solvent of ethanol and toluene.
  • Compound (VI) is obtained by reacting at 70 to 100 ° C. for 1 to 6 hours in the presence of a base such as cesium carbonate and a catalyst such as tetrakis (triphenylphosphine) palladium (0).
  • compound (II) can be obtained by adding trifluoroacetic acid to compound (VI) in an organic solvent such as dichloromethane and reacting at 0 ° C. to room temperature for 1 to 6 hours.
  • boronic acid esters (IV-a) to (IV-d) such as boronic acid or boronic acid pinacol ester corresponding to compound (V) are mixed with an organic solvent such as 1,4-dioxane and water or ethanol Compound (VI-) by reacting in a mixed solvent of toluene and toluene at 70 to 100 ° C. for 1 to 6 hours in the presence of a base such as cesium carbonate and a catalyst such as tetrakis (triphenylphosphine) palladium (0). 2a-1) to (VI-2a-4) are obtained.
  • a base such as cesium carbonate
  • a catalyst such as tetrakis (triphenylphosphine) palladium (0).
  • Compound (VI-2a-5) is a compound of compound (VI-2a-1) and various carboxylic acids in an organic solvent such as N, N-dimethylformamide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride It can be obtained by reacting in the presence of a salt and 1-hydroxybenzotriazole overnight at room temperature.
  • Compound (VI-2a-6) can be obtained by adding sodium hydroxide to compound (VI-2a-2) in an organic solvent such as methanol and reacting at room temperature to 65 ° C. for 1 to 24 hours. it can. Further, compound (VI-2a-6) and various amine compounds are present in an organic solvent such as N, N-dimethylformamide in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole. The compound (VI-2a-7) can be obtained by reacting at room temperature overnight.
  • Compound (VI-2a-8) is reacted by adding a base such as acetic anhydride and 4-dimethylaminopyridine to an N, N-dimethylformamide solution of compound (VI-2a-3) for 1 to 24 hours. Obtainable.
  • a base such as acetic anhydride and 4-dimethylaminopyridine
  • Compounds (VI-2a-9) and (VI-2a-10) are prepared by mixing compound (VI-2a-4) and various halogen compounds in a solvent such as tetrahydrofuran or N, N-dimethylformamide, potassium carbonate, cesium carbonate, etc. In the presence of a base at room temperature for 1 to 4 days. Further, compound (VI-2a-11) is obtained by reacting compound (VI-2a-10) with various amine compounds such as morpholine in an organic solvent such as N, N-dimethylformamide at room temperature to 100 ° C. for 1 day to 4 days. Can be obtained.
  • Compound (III) can be produced according to synthetic route 7. That is, compound (VIII) and trichloroacetyl isocyanate are reacted in an organic solvent such as acetonitrile at room temperature to 40 ° C. for 1 hour to 6 hours, and then an ammonia-methanol solution is further added, and 0 ° C. to room temperature for 1 hour. For 24 hours to give compound (X).
  • Compound (III) can be obtained by reacting compound (X) with N-bromosuccinimide in an organic solvent such as N, N-dimethylformamide at 0 ° C. to room temperature for 1 to 3 hours.
  • the compound of the present invention having JAK3 inhibitory activity is a disease in which JAK3 is involved, such as autoimmune disease, keratitis, conjunctivitis, blepharitis, dry eye syndrome (also called “dry eye”), allergic conjunctivitis, Anterior uveitis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular macular disease, proliferative vitreoretinopathy, retinitis pigmentosa, central retinal vein occlusion, branch retinal vein occlusion, It is expected to be useful as a preventive and / or therapeutic agent for uveitis and the like.
  • the present invention provides a novel JAK inhibitor using such a compound of the present invention, and a method for preventing and / or treating a disease associated with JAK3.
  • the present invention also provides a thiophene derivative or a salt thereof for use in the prevention and / or treatment of a disease associated with the above-mentioned JAK3, and a use of the thiophene derivative or a salt thereof for producing a JAK3 inhibitor. To do.
  • the compound of the present invention can be administered orally or parenterally.
  • dosage forms include oral administration, topical ocular administration (instillation administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, etc.
  • a pharmaceutically acceptable additive can be appropriately selected and used, and can be formulated into a dosage form suitable for the dosage form.
  • Examples of the dosage form include tablets, capsules, granules, powders, and the like in the case of oral preparations, and parenterals include injections, eye drops, eye ointments, insertion agents, preparations for intraocular implants, and the like. Can be mentioned.
  • excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium Disintegrants such as hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partially pregelatinized starch, polyvinyl pyrrolidone, polyvinyl alcohol; stearic acid Lubricants such as magnesium, calcium stearate, talc, hydrous silicon dioxide, hydrogenated oil; refined sucrose, hydroxypropyl methylcellulose, hydroxypropylcellulose, Chill cellulose, ethyl cellulose, a coating agent such as polyvinylpyrrolidone; citric acid, aspartame, ascorbic acid, and suitably selected depending on, for example, required a flavoring agent such as menthol, can be formulated.
  • excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen
  • the injection is appropriately selected according to need such as an isotonic agent such as sodium chloride; a buffering agent such as sodium phosphate; a surfactant such as polyoxyethylene sorbitan monooleate; a thickener such as methylcellulose.
  • an isotonic agent such as sodium chloride
  • a buffering agent such as sodium phosphate
  • a surfactant such as polyoxyethylene sorbitan monooleate
  • a thickener such as methylcellulose.
  • Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surface activity such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil Agents: Stabilizers such as sodium citrate and sodium edetate; preservatives such as benzalkonium chloride and paraben can be appropriately selected and used as necessary, and the pH is ophthalmic. There is no particular problem as long as it is within the range acceptable for the preparation, and a pH of 4 to 8 is desirable.
  • Ophthalmic ointment can be formulated using a widely used base such as white petrolatum or liquid paraffin.
  • the intercalator can be formulated using a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid, and if necessary, excipients, binders, stable An agent, a pH adjuster, and the like can be appropriately selected and used as necessary.
  • a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid, and if necessary, excipients, binders, stable
  • An agent, a pH adjuster, and the like can be appropriately selected and used as necessary.
  • Intraocular implant formulations can be formulated using biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, hydroxypropyl cellulose, and excipients as needed , Binders, stabilizers, pH adjusters and the like can be appropriately selected and used as necessary.
  • biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, hydroxypropyl cellulose, and excipients as needed , Binders, stabilizers, pH adjusters and the like can be appropriately selected and used as necessary.
  • the dosage of the compound of the present invention can be appropriately selected depending on the dosage form, patient's symptoms, age, weight and the like.
  • 0.01-5000 mg, preferably 0.1-2500 mg, particularly preferably 0.5-1000 mg can be administered in 1 to several times per day.
  • 0.00001 to 2000 mg, preferably 0.0001 to 1500 mg, particularly preferably 0.001 to 500 mg can be administered in 1 to several times per day.
  • 0.00001 to 10% (w / v), preferably 0.0001 to 5% (w / v), particularly preferably 0.001 to 1% is applied once to several times a day. can do.
  • an eye ointment one containing 0.0001 to 2000 mg can be applied.
  • an insert or an intraocular implant preparation one containing 0.0001 to 2000 mg can be inserted or implanted.
  • Reference Example 2 2- (tert-Butoxycarbonylamino) thiophene-3-carboxamide (Reference Compound 2)> 2-Aminothiophene-3-carboxamide (Reference compound 1, 10.8 g, 76 mmol) to di-tert-butyl dicarbonate (25 g, 115 mmol), N, N-diisopropylethylamine (29.4 g, 228 mmol), tetrahydrofuran (250 mL) ) was added and heated to reflux overnight under a nitrogen atmosphere. Di-tert-butyl dicarbonate (25 g, 115 mmol) was further added, and the mixture was heated to reflux for 2 days under a nitrogen atmosphere.
  • Reference Example 4 2- (tert-butoxycarbonylamino) -5- (2-isopropyloxyphenyl) thiophene-3-carboxamide (Reference compound 4-1)> 5-Bromo-2- (tert-butoxycarbonylamino) thiophene-3-carboxamide (Reference Compound 3, 0.20 g, 0.62 mmol) and 2-isopropyloxyphenylboronic acid (0.17 g, 0.93 mmol), carbonic acid Add cesium (0.30 g, 0.93 mmol), tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.09 mmol), ethanol (3 mL), toluene (3 mL) at 80 ° C.
  • reference compounds 4-2 to 4-34 were obtained in accordance with the production method of Reference Example 4 using the corresponding boronic acid or boronic acid ester commercially available.
  • Reference compound 5-2 was obtained according to the production method of Reference Example 5 using Reference compound 4-18 and malonic acid monoethyl ester.
  • the reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and then dried over magnesium sulfate.
  • the title compound (0.50 g) was obtained as a pale yellow solid by distilling off the solvent.
  • Reference Compound 6-2 was obtained according to the production method of Reference Example 6.
  • Reference Example 7 2- (tert-butoxycarbonylamino) -5- [3-[[(2-methoxy-2-oxoethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide (Reference Compound 7-1)> N, N-dimethylformamide (3 mL) was added to 2- (tert-butoxycarbonylamino) -5- (3-carboxyphenyl) thiophene-3-carboxamide (Reference compound 6-1, 0.10 g, 0.28 mmol).
  • reference compounds 7-2 to 7-5 were obtained according to the production method of Reference Example 7 using the amine corresponding to Reference Compound 6-2.
  • Reference Example 8 2- (tert-Butoxycarbonylamino) -5- (2-propoxyphenyl) thiophene-3-carboxamide (Reference Compound 8-1)> N, N-dimethylformamide (3 mL) was added to 2- (tert-butoxycarbonylamino) -5- (2-hydroxyphenyl) thiophene-3-carboxamide (Reference compound 4-31, 90 mg, 0.27 mmol), and carbonic acid was added. Cesium (130 mg, 0.40 mmol) and 2-iodopropane (70 mg, 0.40 mmol) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere.
  • the mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate.
  • reference compounds 8-2 to 8-3 were obtained according to the production method of Reference Example 8 using the halogen compound corresponding to Reference Compound 4-31.
  • Reference Compound 9-2 was obtained according to the production method of Reference Example 9.
  • Reference compound 10-2 was obtained in accordance with the production method of Reference Example 10 using a halogen compound corresponding to Reference Compound 4-31.
  • Reference Example 11 2- (tert-Butoxycarbonylamino) -5- [2- (3-bromopropoxy) phenyl] thiophene-3-carboxamide (Reference Compound 11)> N, N-dimethylformamide (5 mL) is added to 2- (tert-butoxycarbonylamino) -5- (2-hydroxyphenyl) thiophene-3-carboxamide (Reference compound 4-31, 50 mg, 0.15 mmol), and carbonic acid is added. Cesium (73 mg, 0.23 mmol) and 1,3-dibromopropane (46 ⁇ L, 0.45 mmol) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere.
  • the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate.
  • the residue obtained by distilling off the solvent was purified by silica gel column chromatography (mobile bed; ethyl acetate / n-hexane) to obtain the title compound (63 mg) as a white solid.
  • Reference compounds 12-2 to 12-3 were obtained in accordance with the production method of Reference Example 12 using the amine corresponding to Reference Compound 11.
  • Reference compounds 4-2 to 4-16, 4-20 to 4-32, 5-1, 5-2, 7-1 to 7-5, 8-1 to 8-3, 9-1, 9- Reference compounds 13-2 to 13-46 were obtained according to the production method of Reference Example 13 using 2, 10-1, 10-2, 12-1 to 12-3.
  • Reference Example 14 2-Amino-5- (3-methylphenyl) thiophene-3-carboxamide (Reference Compound 14-1)> 5-Bromo-2- (tert-butoxycarbonylamino) thiophene-3-carboxamide (Reference compound 3, 0.20 g, 0.62 mmol) and 3-methylphenylboronic acid (0.13 g, 0.93 mmol), cesium carbonate (0.30 g, 0.93 mmol), tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.09 mmol), ethanol (3 mL), toluene (3 mL) were added, and nitrogen was added at 80 ° C. to 90 ° C.
  • Reference compounds 14-2 to 14-18 were obtained according to the production method of Reference Example 14 using the corresponding boronic acid or boronate ester commercially available.
  • Reference Example 16 5-Bromo-2- (aminocarbonylamino) thiophene-3-carboxamide (Reference Compound 16)> N, N-dimethylformamide (15 mL) was added to 2- (aminocarbonylamino) thiophene-3-carboxamide (Reference compound 15, 560 mg, 3.1 mmol), and N-bromosuccinimide (600 mg, 3. 4 mmol) was added, and the mixture was stirred for 1 hour under ice-cooling in a nitrogen atmosphere and overnight at room temperature. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, and dried over magnesium sulfate. The title compound (537 mg) was obtained by distilling off the solvent.
  • Reference Example 17 2- (tert-Butoxycarbonylamino) -5- (2-propionylphenyl) thiophene-3-carboxamide (Reference Compound 17)> Dioxane (2.5 mL) and water (0.5 mL) were added to 1- (2-bromophenyl) propan-1-one (0.18 g, 0.82 mmol), and then potassium acetate (0.12 g, 1.2. 23 mmol), bis (pinacolato) diborane (0.31 g, 1.23 mmol), tetrakis (triphenylphosphine) palladium (0) (0.1 g, 0.082 mmol) were added, and the mixture was stirred at 90 ° C.
  • reference compounds 17-2 to 17-3 were obtained according to the production method of Reference Example 17 using various aryl halides, bis (pinacolato) diborane, and Reference Compound 3.
  • reference compounds 18-1 to 18-3 were obtained according to the production method of Reference Example 13 using reference compounds 17-1 to 17-3.
  • the organic layer was washed with water and saturated brine, and dried over magnesium sulfate.
  • Dioxane (2 mL) was added to the residue obtained by evaporating the solvent, 1N aqueous sodium hydroxide solution (78 ⁇ L) and methanol (1 mL) were added, and the mixture was stirred at 60 ° C. to 65 ° C. overnight.
  • the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and dried over magnesium sulfate.
  • the title compound (7 mg) was obtained by filtering off the yellow solid obtained by distilling off the solvent.
  • Examples 5-2 and 5-3 were obtained according to the production method of Example 5 using Reference Compound 16 and the corresponding boronic acid commercially available.
  • a tablet of the above formulation can be coated with 3 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the intended tablet.
  • a coating agent for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.
  • a desired tablet can also be obtained by changing suitably the kind and / or quantity of this invention compound and an additive.
  • Capsule (in 150mg) The compound of the present invention 5mg Lactose 135mg Carboxymethylcellulose calcium 4.5mg Hydroxypropylcellulose 4mg Magnesium stearate 1.5mg Desired capsules can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.
  • Eye drops (in 100 ml) Compound of the present invention 100mg Sodium chloride 900mg Polysorbate 80 500mg Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount
  • a desired eye drop can be obtained.
  • JAK3 inhibitory activity measurement test ⁇ JAK3 inhibitory activity measurement test> The JAK3 inhibitory activity was measured using QS SS Assist JAK3_TR-FRET Kit (Karna Biosciences, product number 08-046TX). The specific method is shown below.
  • test compound solution A test compound was dissolved in dimethyl sulfoxide, and then diluted with an assay buffer (Tween 20 and dithiothreitol-containing Tris buffer) to 40 ⁇ M.
  • assay buffer Teween 20 and dithiothreitol-containing Tris buffer
  • Test method and measurement method 1) 5 ⁇ L of the test compound solution, 5 ⁇ L of the JAK3 substrate solution (purchased from Carna Biosciences), and 10 ⁇ L of the JAK3 enzyme solution were added to each well of the 384-well plate.
  • TR-FRET signal was measured with a plate reader (ARVOsx; PerkinElmer).
  • JAK3 inhibition rate was calculated by the following formula.
  • JAK3 inhibition rate (%) 100 ⁇ ⁇ 1- (TR-FRET value of test substance ⁇ TR-FRET value of blank) / (TR-FRET value of control ⁇ TR-FRET value of blank) ⁇ (Evaluation results) Examples of evaluation results include test compounds (compounds 1-1, 1-2, 1-9, 1-12, 1-15, 1-19, 1-20, 1-21, 1-23, 1-25, 1-27, 1-33, 1-39, 1-42, 1-43, 1-47, 1-49, 1-50, 1-51, 1-53, 1-56, 1-57, 2, Table 91 shows the inhibition rate of JAK3 at 10 ⁇ M in 3-1, 3-2, 4, 5-1, and 5-2).
  • the inhibition rate of 100% or more was shown as 100%.
  • the compound of the present invention has excellent JAK3 inhibitory activity. Therefore, the compound of the present invention is expected to be useful as a prophylactic and / or therapeutic agent for diseases in which JAK3 is involved.

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Abstract

Inhibiteur de JAK3 contenant au moins un composé choisi parmi les composés représentés par la formule générale (1) et leurs sels, à titre de principe actif.
PCT/JP2011/073050 2010-10-07 2011-10-06 Nouvel inhibiteur de jak3 contenant, à titre de principe actif, un dérivé de thiophène portant un groupe uréido et un groupe aminocarbonyle à titre de substituants WO2012046793A1 (fr)

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WO2002030353A2 (fr) * 2000-10-12 2002-04-18 Smithkline Beecham Corporation INHIBITEURS DU NF-λB
WO2003010158A1 (fr) * 2001-07-25 2003-02-06 Astrazeneca Ab Nouveaux composes
WO2003029241A1 (fr) * 2001-10-04 2003-04-10 Smithkline Beecham Corporation Inhibiteurs de chk1 kinase
WO2008002246A1 (fr) * 2006-06-28 2008-01-03 Astrazeneca Ab Composition pharmaceutique comprenant un inhibiteur de la ikk2 et un second ingrédient actif
WO2008144011A1 (fr) * 2007-05-16 2008-11-27 Avalon Pharmaceuticals Compositions et procédés pour traiter ou empêcher des maladies auto-immunes
WO2009130475A1 (fr) * 2008-04-26 2009-10-29 Chroma Therapeutics Ltd., Thiophènecarboxamides substitués en tant qu’inhibiteurs de sérine-thréonine protéine kinase ikk-bêta

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