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WO1998056785A1 - Derives de pyrazole - Google Patents

Derives de pyrazole Download PDF

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Publication number
WO1998056785A1
WO1998056785A1 PCT/JP1998/002552 JP9802552W WO9856785A1 WO 1998056785 A1 WO1998056785 A1 WO 1998056785A1 JP 9802552 W JP9802552 W JP 9802552W WO 9856785 A1 WO9856785 A1 WO 9856785A1
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Prior art keywords
group
substituted
optionally substituted
ring
formula
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PCT/JP1998/002552
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English (en)
Japanese (ja)
Inventor
Masashi Nakatsuka
Fumio Nishikaku
Takahiko Hashizuka
Shin-Ichiro Okada
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Sumitomo Pharmaceuticals Co., Ltd.
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Application filed by Sumitomo Pharmaceuticals Co., Ltd. filed Critical Sumitomo Pharmaceuticals Co., Ltd.
Priority to AU75531/98A priority Critical patent/AU7553198A/en
Publication of WO1998056785A1 publication Critical patent/WO1998056785A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to pyrazole derivatives useful as immunosuppressants.
  • an antimetabolite such as methotrexet, an imnophilin inhibitor such as cyclosporin, and the like have been conventionally used. These are said to contribute to the effect of inhibiting the proliferation and activation of lymphocyte-derived cells.
  • superantigen such as Staphylococcus enterotoxin, an exotoxin of Staphylococcus aureus, and autoimmune diseases.
  • Experimental allergic encephalomyelitis mouse an animal model of multiple sclerosis; collagen arthritis mouse, an animal model of rheumatoid arthritis; NOD mice spontaneously developing inulin-dependent type I diabetes; It has been reported that administration of superantigen to MRL / lpr mice exhibiting lupus erythematosus-like symptoms rapidly worsens the condition. It has also been suggested that Spar antigen is involved in the onset and exacerbation of Kawasaki disease and atopic dermatitis. Furthermore, superantigens are known to selectively induce the proliferation of autoreactive lymphocytes and the production of autoantibodies.
  • Pyrazole derivatives are known to be useful as nonsteroidal contraceptives or agents for treating hypertension (US 3816437, US 3816438, US 3842088, US 3843664, US 3843665, US 3843666, US 3932430). Disclosure of the invention
  • the present inventors have conducted intensive studies to provide a novel immunosuppressant, and as a result, The inventors have found that razol derivatives have an immunosuppressive action, and completed the present invention.
  • one of R 1 and R 2 represents an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group, and the other represents an optionally substituted aromatic heterocyclic group.
  • R 3 is a hydrogen atom, an alkyl group which may be substituted, an alkoxy group which may be substituted, an alkenyl group which may be substituted, an alkenyloxy group which may be substituted, an alkynyl group which may be substituted, An optionally substituted alkynyloxy group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, an optionally substituted rubamoyl group, an optionally substituted alkoxycarbonyl group, an acyl group, an acyloxy group, and an optionally substituted Represents a aryl group or an amino group which may be substituted.
  • R 3 combines with one of R 1 and R 2 to form one RR or one R 2 — R with the formula:
  • Ring A represents a monocyclic or bicyclic aromatic hydrocarbon ring which may be substituted, or a monocyclic or bicyclic aromatic heterocyclic ring which may be substituted.
  • X represents methylene, ethylene, trimethylene one CO_CH 2 -, one OCH 2 -, one SCH 2 - one N (R 5) CH 2 -., -CO-, oxygen atom, sulfur atom or a N represents a (R 5) one R 5 is It represents a hydrogen atom or an alkyl group.) It may represent a divalent group represented by
  • R 4 represents a hydrogen atom or an optionally substituted alkyl group.
  • An immunosuppressant comprising a pyrazole derivative represented by the formula or a pharmacologically acceptable salt thereof.
  • R 1 and R 2 is an optionally substituted phenyl group or an optionally substituted monocyclic aromatic heterocyclic group, and the other is an optionally substituted monocyclic or bicyclic ring
  • An immunosuppressant comprising a conductor or a pharmacologically acceptable salt thereof.
  • R 1 and R 2 are phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, phenyl, furyl or a substituted group, and the other is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl or substituted
  • R 3 represents a hydrogen atom, an optionally substituted alkyl group, a carboxy group, an optionally substituted alkoxycarbonyl group or an acyl group, or R 3 represents R 1 And one of R 2 and one R 1 — R 3 — or one R 2 — R 3 — are represented by the formula:
  • Ring A 1 represents a benzene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a thiophene ring, a furan ring, or a substituted ring thereof.
  • An immunosuppressant comprising the pyrazolyl derivative according to [1] or [2], which is a divalent group, or a pharmaceutically acceptable salt thereof.
  • X is methylene, ethylene, trimethylene, one CO—CH 2 —, one OCH 2—, one SCH 2 —, one N (R 5 ) CH 2 — (R 5 is as defined above) or —
  • An immunosuppressant comprising the pyrazolyl derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [4], which is CO—.
  • Y represents a halogen atom, an alkoxy group, a cyano group or an alkyl group.
  • ⁇ represents a hydrogen atom, a halogen atom, an alkoxy group, a cyano group, a nitro group, an amino group or an alkyl group.
  • R 6 , R 7 and R 8 are as defined in (1) or (2) below.
  • R 8 represents 3- or 4-monopyridyl which may be substituted.
  • R 6 and R 7 are taken together, and one R 6 —R 7 — represents methylene, ethylene, one OCH 2— or one SCH 2 —.
  • R 8 represents 3-pyridyl which may be substituted.
  • Zeta 1 is a hydrogen atom, a halogen atom, an alkoxy group, an Shiano group or a nitro group to the table.
  • Zeta 2 is a hydrogen atom, an alkyl group, Shiano group, a hydroxyl group or an alkoxy group to the table.
  • a medicament comprising the pyrazole derivative according to any one of [6] to [9] or a tautomer thereof, or a pharmacologically acceptable salt thereof.
  • An immunosuppressant comprising the pyrazole derivative according to any one of [6] to [9] or a tautomer thereof, or a pharmacologically acceptable salt thereof.
  • aryl group examples include groups having 6 to 14 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, and anthryl. Preferably, phenyl, 1-naphthyl and 2-naphthyl are mentioned.
  • monocyclic or bicyclic aromatic hydrocarbon ring examples include a hydrocarbon ring having 6 to 10 carbon atoms, and specific examples include benzene and naphthalene.
  • aromatic heterocyclic group a monocyclic or bicyclic aromatic heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms can be mentioned.
  • a 2- or 5-membered aromatic heterocyclic group such as a bicyclic 5-membered aromatic heterocyclic group and a pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl group; Can be
  • heterocyclic group examples include an aromatic heterocyclic group and a monocyclic or bicyclic aliphatic heterocyclic group containing 1 to 3 nitrogen, oxygen and / or sulfur atoms.
  • Specific examples of the aliphatic heterocyclic group include monocyclic or bicyclic 5-membered aliphatic heterocyclic groups such as tetrahydrofuryl, pyrrolidinyl, and birazolidinyl; and monocyclic rings such as piperidyl, morpholinyl, and piperazinyl. Or a bicyclic 6-membered aliphatic heterocyclic group.
  • the “monocyclic or bicyclic aromatic heterocycle” includes a monocyclic or bicyclic aromatic heterocycle containing 1 to 3 nitrogen atoms, oxygen atoms, and phosphorus or sulfur atoms.
  • Monocyclic or bicyclic 5-membered aromatic heterocycles such as dazols, benzothiazols and benzoxazols, and monocycles such as pyridine, pyrazine, pyrimidine, pyridazine, triazine, quinoline, isoquinoline, quinazoline and quinoxaline Or a bicyclic 6-membered aromatic heterocyclic ring.
  • Examples of the substituted aryl group, the substituted aromatic heterocyclic group, and the substituent of the monocyclic or bicyclic substituted aromatic hydrocarbon ring or the substituted aromatic heterocyclic ring include, for example, the following groups a) to g). Any group may be mentioned, and these may be arbitrarily substituted one or more times. Preferred numbers of substituents include 1, 2 or 3.
  • jj_halogen atom nitro group, cyano group, azide group, mercapto group, formyl group, hydroxyl group, hydroxyl group, optionally substituted amino group, optionally substituted hydroxyamino group, optionally substituted alkoxyamino Group, carboxyl group, optionally substituted rubamoyl group, optionally substituted rubamoyloxy group, sulfo group, optionally substituted sulfamoyl group, optionally substituted guanidino group, optionally substituted Amidino group, hydrazino group which may be substituted.
  • R 9 represents a phenyl group or a monocyclic heterocyclic group.
  • a phenyl group or a monocyclic heterocyclic group is, for example, a halogen atom, an alkyl group, a haloalkyl group, a cyano group, a nitro group, an azido group, a hydroxyl group, an alkoxy group, a haloalkoxy group, an amino group which may be substituted, It may be substituted with one or more groups arbitrarily selected from the group consisting of a rubamoyl group, a carboxy group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group. ]
  • Alkyl group Alkoxy group, alkoxycarbonyl group, alkoxy (thiothiol group), alkylthio group, (alkylthio) thiocarbonyl group, (alkylthio) carbonyl group, alkylcarbonyl group, alkylthioyl group, alkylsulfinyl group, alkyl Sulfonyl group, alkylcarbonyloxy group, alkylthioyloxy group, alkylsulfonyloxy group
  • each group in this group includes, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, an amino group which may be substituted, a hydroxyl group, an acyl group, an acyloxy group, and a carboxy group.
  • Cycloalkyl group (the cycloalkyl group is, for example, one or more groups selected from the group consisting of a halogen atom, an alkyl group, a non-alkyl group, an amino group which may be substituted, a hydroxyl group, an alkoxy group, and a haloalkoxy group; ),
  • An alkoxy group, an alkoxycarbonyl group and an alkylthio group are, for example, a halogen atom, a cycloalkyl group, a monocyclic heterocyclic group, a phenyl group, a cyano group) , Nitro group, hydroxyl group, alkoxy group, haloalkoxy group, amino group which may be substituted, force which may be substituted rubamoyl group, carboxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylthio group, alky
  • Alkenyl groups include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, formyl group, optionally substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, alkylthio group.
  • R 9 , -OR 9 , _SR 9 , —OCH 2 R 9 and —S CH 2 R 9 (R 9 is May be substituted with one or more groups arbitrarily selected from the group of e) alkynyl group
  • Alkynyl groups include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, formyl group, amino group which may be substituted, hydroxyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, alkylthio group.
  • R 10 represents a phenyl group, for example, a halogen atom, an alkyl group, a haloalkyl W 7
  • each group in this group may be substituted, for example, a halogen atom, an oxo group, an amino group which may be substituted, a hydroxyl group, an alkoxy group, a haloalkoxy group, an acyl group, an acyloxy group, an alkylthio group, a carboxy group. And may be substituted with one or more groups arbitrarily selected from the group consisting of a carbamoyl group, an alkoxycarbonyl group and a phenyl group.
  • each group in this group includes, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, an alkyl group, a haloalkyl group, a substituted or unsubstituted amino group, a hydroxyl group, an alkoxy group, It may be substituted with one or more groups arbitrarily selected from the group consisting of a haloalkoxy group, an acyl group, an acyloxy group, an alkylthio group, a carboxy group, an optionally substituted rubamoyl group and an alkoxycarbonyl group.
  • Preferred examples of the substituted aryl group, the substituted aromatic heterocyclic group, and the substituent of the monocyclic or bicyclic substituted aromatic hydrocarbon ring or the substituted aromatic heterocyclic ring include, for example, W 5
  • substituents include, for example, any of the following groups, which may be arbitrarily substituted one or more times.
  • halogen atom cyano group, nitro group, carboxyl group, amino group which may be substituted, hydrazino group which may be substituted, alkyl group which may be substituted, alkoxy group which may be substituted, substituted A good alkoxycarbonyl group.
  • substituted aryl group, the substituted aromatic heterocyclic group, and the substituent of the monocyclic or bicyclic substituted aromatic hydrocarbon ring or the substituted aromatic heterocyclic ring include methyl, hexyl, 2-methyl-1- _Propyl, 2-propyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 6,6,6-trifluorohexyl, Hydroxymethyl, methoxymethyl, hexoxymethyl, cyclopropylmethoxymethyl, acetomethyl, N, N-dimethyl
  • alkyl group includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2 _ Methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, 3,3-dimethylbutyl, etc.
  • substituent in the substituted alkyl group include, for example, any group included in each of the following groups a) to d), and these may be arbitrarily substituted one or more times.
  • Cycloalkyl group and cycloalkenyl group include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, formyl group, amino group which may be substituted, hydroxyl group, alkoxy, haloalkoxy, carboxy group, It may be substituted with a rubamoyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a phenyl group, a monocyclic heterocycle, or the like.
  • Alkoxy group, alkoxycarbonyl group and alkylthio group include, for example, halogen atom, cycloalkyl group, substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, carboxy group, optionally substituted rubamoyl group, alkyl group It may be substituted with a hydroxyl group, an alkoxycarbonyl group, a phenyl group, a monocyclic heterocycle, or the like.
  • R 9 is as defined above.
  • substituted alkyl group specifically, trifluoro Methyl, 2-nitroethyl, 2-cyanopropyl, 4-mercaptobutyl, 3-oxobutyl, 2-piridinoethyl, 2-hydroxyethyl, 3-methoxypropyl, ethoxycarbonylmethyl, cyclopropylmethyl, cyclohexylmethyl , 6-cyclohexylhexyl, 3-cyclohexenylbutyl, 2-phenylbutyl, benzyl, 2-na Examples include phthylmethyl, phenethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-quinolylmethyl, 3-phenylphenyl, and the like.
  • the haloalkyl group refers to an alkyl group substituted with 1 to 5 halogen atoms.
  • Alkoxy group refers to an oxy group to which an alkyl group is bonded. Specific examples include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like.
  • substituent of the substituted alkoxy group examples include the same substituents as those of the substituted alkyl group. Specific examples of the substituted alkoxy group include cyclopropyl methoxy, trifluoromethoxy, 2-pyrrolidinoethoxy, benzyloxy, 2-pyridylmethoxy and the like.
  • haloalkoxy group refers to an alkoxy group substituted with 1 to 5 halogen atoms.
  • Alkoxycarbonyl group refers to a carbonyl group to which an alkoxy group is bonded. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and the like.
  • the substituent in the substituted alkoxy group is the same as the substituent in the substituted alkyl group.
  • alkenyl group examples include a linear or branched alkenyl group having 2 to 6 carbon atoms and having 1 to 3 double bonds. Specifically, ethenyl, 1-probenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-pentenyl, 2— Pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl and the like.
  • Preferred alkenyl groups include, for example, ethenyl, 1-probenyl and 1-butenyl groups.
  • Examples of the substituent of the substituted alkenyl group include a halogen atom, a nitro group, and a cyano group.
  • an alkenyl group refers to an oxy group to which an alkenyl group is bonded.
  • alkynyl group examples include a linear or branched alkynyl group having 2 to 6 carbon atoms and having 1 to 3 triple bonds. Specific examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl and the like.
  • Preferred alkynyl groups include, for example, 1-propynyl, 1-butynyl and the like.
  • Examples of the substituent of the substituted alkynyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, a substituted amino group, a hydroxyl group, an alkoxy group, a haloalkoxy group, and an acyl group.
  • an alkynyloxy group refers to an oxy group to which an alkynyl group is bonded.
  • examples of the “cycloalkyl group” include a cycloalkyl group having 3 to 7 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • a cycloalkyloxy group refers to an oxy group to which a cycloalkyl group is bonded.
  • cycloalkenyl group examples include those having 5 to 7 carbon atoms, and specific examples include a cyclohexenyl group.
  • a cycloalkenyloxy group refers to an oxy group to which a cycloalkenyl group is bonded.
  • Examples of the substituent of the substituted cycloalkyl group and the substituted cycloalkenyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, Formyl group, alkyl group, haloalkyl group, substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, acyl group, acyloxy group, alkylthio group, carboxy group, carbamoyl group which may be substituted, alkoxycarbonyl group, etc. Are listed.
  • acyl group for example, a compound represented by the formula —Q—R 11 (wherein Q is one CO—, -CS
  • R 11 represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.
  • R 11 represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.
  • the acryl group include acetyl, propanol, 2-propanol, bivaloyl, trifluoroacetyl, benzoyl, nicotinyl, methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl.
  • Preferred acetyl groups include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as an acetyl group.
  • the term "acryloxy group” means an oxy group to which an acyl group is bonded.
  • substituents in the rubamoyl group include an alkyl group which may be substituted with an aryl group or a heterocyclic group, and an aryl group, a heterocyclic group, and the like.A plurality of the same or different groups are independently substituted. May be.
  • substituting rubamoyl group include ethylcarbamoyl, dimethylcarbamoyl, phenylcarbamoyl, 2-pyridylcarbamoyl, benzylcarbamoyl, and (3-pyridylmethyl) rubumoyl.
  • substituent in the substituted sulfamoyl group examples include an alkyl group, an aryl group and a heterocyclic group, and the same or different plural substituents may be independently substituted.
  • Specific examples of the substituted sulfamoyl group include ethylsulfamoyl, dimethylsulfamoyl, phenylsulfamoyl, and 2-pyridylsulfamoyl.
  • substituent in the substituted amino group examples include an acyl group and an alkyl group, and a plurality of same or different ones may be independently substituted.
  • Specific substituted amino groups include acetoamide, propionamide, butylamide, and 2-butylamine. Luamide, methylamino, 2-methylpropylamino, getylamino and the like.
  • the substituent in the substituted hydroxyamino group may be substituted with any of a nitrogen atom and an oxygen atom, and examples of the substituent include the same substituents as those in the substituted amino group.
  • Examples of the substituent in the substituted amidino group include an alkyl group, an aryl group and an arylalkyl group, and a plurality of the same or different groups may be independently replaced.
  • Specific examples of the substituted amidino group include methylamidino, phenylamidino, dimethylamidino, ethylamidino, and benzylamidino.
  • Examples of the substituent in the substituted guanidino group include, for example, an alkyl group, an aryl group and an arylalkyl group, and the same or different plural groups may be independently substituted.
  • Specific substituted guanidino groups include methyldanidino, phenyldanidino, dimethyldanidino, ethyldanidino, benzylguanidino and the like.
  • Examples of the substituent in the substituted hydrazino group include an alkyl group, an aryl group and an arylalkyl group, and the same or different plural substituents may be independently substituted.
  • Specific examples of the substituted hydrazino group include methylhydrazino, phenylhydrazino, dimethylhydrazino, ethylhydrazino, and benzylhydrazino groups.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • R 3 is bonded to one of R] and R 2 to form —R i—R 3 —or—R 2 —R 3 —force ⁇ formula: Five
  • ring A or ring A 1 is bonded to the carbon atom to which R 1 or R 2 is bonded, and X is bonded to the carbon atom to which R 3 is bonded.
  • the tautomer of a pyrazole derivative means an isomer formed by changing a bonding position of a hydrogen atom bonded to a pyrazole ring.
  • the present invention includes all tautomers of the pyrazol derivatives of the formula 1, and also includes a mixture of tautomers, even if not specified as tautomers.
  • the pyrazolyl derivative can be a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include acid addition salts and base addition salts.
  • acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, etc., citrate, oxalate, acetate, and formic acid.
  • Organic salts such as salts, propionates, benzoates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, and the like.
  • base addition salts are sodium salts and potassium salts.
  • inorganic base salts such as calcium salt, magnesium salt and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt.
  • the solvate such as a hydrate thereof is also included in the biazole derivative or a pharmacologically acceptable salt thereof in the present invention.
  • the pyrazole derivative of the formula 1 has a T cell proliferation induction inhibitory action.
  • the immunosuppressant of the present invention can treat, for example, the following diseases and the like.
  • Rheumatoid arthritis systemic lupus erythematosus, diabetes, multiple sclerosis, Hashimoto Disease, hemolytic anemia, myasthenia gravis, scleroderma, ulcerative colitis, autoimmune diseases such as idiopathic thrombocytopenic purpura
  • the pyrazole derivative of the formula 1 can be produced, for example, by the following two production methods.
  • RR 2 , R 3 and R 4 are as defined above.
  • R 12 and R 13 represents an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group, and the other represents an optionally substituted aromatic heterocyclic group.
  • R 14 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted An optionally substituted alkenyl group, an optionally substituted alkenyloxy group, an optionally substituted alkynyl group, an optionally substituted alkynyloxy group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, It represents an optionally substituted sorbamoyl group, an optionally substituted alkoxycarbonyl group, an acyl group, an acyloxy group, an optionally substituted aryl group or an optionally substituted amino group.
  • R 1 4 is combined with R 1 2 to form one R 1 2 —R 1 4 —force formula:
  • L represents a chlorine atom or a bromine atom.
  • the compound of formula 3 can be produced.
  • the halogenating agent to be used include bromine, chlorine, iodine chloride, sulfuryl chloride, copper compounds such as cuprous bromide, N-bromosuccinic acid imide, N-chlorosuccinic acid imide and the like.
  • the amount of the halogenating agent to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to the compound of the formula 2.
  • Examples of the solvent used for the halogenation reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; fatty acids such as acetic acid and propionic acid; and carbon disulfide.
  • the reaction temperature is, for example, a temperature in the range of 0 ° C. to the boiling point of the solvent, and the reaction is usually performed for about 5 minutes to 20 hours.
  • the compound of formula 5 By reacting the compound of formula 3 with the compound of formula 4 in the presence of a base, the compound of formula 5 can be produced.
  • the base used in the reaction include metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, butyllithium, lithium pistrimethylsilylamide, and the like.
  • Preferred bases are sodium methoxide, sodium Ethoxide and the like can be mentioned.
  • the solvent used in the reaction include alcohols such as ethanol and methanol.
  • hydrocarbons such as hexane, cyclohexane, benzene and toluene, and ethers such as tetrahydrofuran (THF) and getyl ether, and preferably alcohols.
  • ethers such as tetrahydrofuran (THF) and getyl ether, and preferably alcohols.
  • reaction temperature include a temperature in the range of 178 to 100 ° C.
  • the pyrazole derivative of the formula 1 By reacting the compound of the formula 5 with the compound of the formula 6, the pyrazole derivative of the formula 1 can be produced.
  • the amount of the compound of the formula 6 it is preferable to use an amount in the range of 1 to 1.2 equivalents to the compound of the formula 5.
  • the solvent used in the reaction include alcohols such as ethanol and methanol, hydrocarbons such as hexane, cyclohexane, benzene, and toluene, and ethers such as THF and methyl ether, and the like. May include alcohols.
  • the reaction can also be carried out without a solvent. In this reaction, the reaction proceeds even in the absence of an acid, but an acid may be added.
  • Examples of the acid used include mineral acids such as hydrochloric acid and hydrobromic acid, organic acids such as toluenesulfonic acid, and Lewis acids such as boron trifluoride. Preferably, toluene sulfonic acid and boron trifluoride are used. No.
  • the amount of the acid to be used is preferably 0.1 to 6 equivalents to the compound of the formula 5.
  • Examples of the reaction temperature include a temperature in the range of room temperature to the boiling point of the solvent used. Manufacturing method 2
  • the compound of formula 8 can be produced by reacting the compound of formula 2 with the compound of formula 7 in the presence of a base.
  • a base examples include lithium pistrimylsilyl amide, lithium disopropyl amide, potassium t-butoxide and the like. Is mentioned.
  • the reaction temperature is in the range of ⁇ 100 to 0 ° C., preferably in the range of 110 to 150 ° C.
  • the solvent used in the reaction include ethers such as THF and dimethyl ether, and hydrocarbons such as hexane, cyclohexane, benzene, and toluene.
  • the pyrazole derivative of the formula 1 By reacting the compound of the formula 8 with the compound of the formula 6, the pyrazole derivative of the formula 1 can be produced.
  • the amount of the compound of the formula 6 it is preferable to use a range of 1 to 1.2 equivalents to the compound of the formula 8.
  • the solvent used in the reaction include alcohols such as ethanol and methanol, hydrocarbons such as hexane, cyclohexane, benzene, and toluene, and ethers such as THF and methyl ether.
  • alcohols are used.
  • the reaction can also be carried out without a solvent. In this reaction, the reaction can be performed under neutral conditions, but can also be performed in the presence of an acid or a base.
  • examples of the acid used include mineral acids such as hydrochloric acid and hydrobromic acid, organic acids such as tosylic acid, and Lewis acids such as boron trifluoride. It is preferable to use 0.1 to 6 equivalents of the acid based on the compound.
  • examples of the base to be used include inorganic bases such as baking soda, sodium hydroxide and potassium hydroxide, and organic bases such as triethylamine and pyridine. Therefore, it is desirable to use 1 to 6 equivalents of the base.
  • examples of the reaction temperature include a temperature in the range of room temperature to the boiling point of the solvent used.
  • the pyrazole derivatives of Formula 1 produced by Production Methods 1 and 2 are formed as a mixture of two isomers in which R 4 has different substitution positions. Only the isomer can be obtained with high purity.
  • a highly reactive functional group such as an amino group or a hydroxyl group can be protected, deprotected, or converted with a suitable protecting group, if necessary.
  • This protection, deprotection, or conversion of the protecting group can be performed by a general method, for example, Protective Groups in Organic synthesis, 2nd Edition, T. Greene and PGM Wuts, John Wiley and Sons, Inc. (1991).
  • the substituent of the pyrazole derivative of the formula 1 may be subjected to various conversion reactions after the above reaction, if necessary.
  • conversion reactions include, for example, the conversion of sulfides to sulfoxides and sulfones by oxidation, the conversion of carbonyls to alcohols by reduction, the conversion of esters to alcohols or carboxyls by solvolysis, and the conversion of nitriles to carboxyls. Conversion, alkylation, acylation and the like.
  • the pyrazole derivative of Formula 1 or a pharmaceutically acceptable salt thereof can be administered orally or parenterally (eg, intravenously, subcutaneously, or intramuscularly, topically, rectally, transdermally, or nasally). ) Can be administered.
  • Formulations for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions, suspensions, and the like.
  • Formulations for parenteral administration include, for example, aqueous injections Or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like. These preparations are prepared using conventionally known techniques, and can contain nontoxic and inert carriers or excipients usually used in the field of preparation.
  • the dose varies depending on the patient's condition such as age and body weight, symptoms, and the administration route.
  • the amount of the active ingredient of the compound of the present invention per adult is from 0.05 to 5000 mg, preferably from 0.05 to 5000 mg.
  • a daily dose of 0.5 to 500 mg a continuous or intermittent dosing method, which can be administered once to three times a day, every day.
  • Example 2 The compound obtained in Example 2 was dissolved in 200 ml of methanol, and 10 ml of a 4N hydrogen chloride dioxane solution was added dropwise. After stirring the reaction solution for 2 hours, the solvent was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 1.80 g of the desired product.
  • Example 1 Example 1 1
  • Example 26 Data such as physical property values of these compounds are shown below.
  • Spleens were collected from BALB / c mice, and spleen cell suspensions were prepared according to a conventional method. So as to be a concentration of 10% ⁇ shea calf serum was added culture medium (RPMI1640; Nikken Biomedical Institute) in 1 X 1 0 7 cell / ml splenocytes were prepared at a concentration cell suspension 25 ⁇ 1 to 0.12 g / 25 ⁇ l of staphylococcal enterotoxin B solution and 50 ⁇ l of a pyrazolyl derivative at a concentration of 4, 12, 37, 111, 333, ⁇ were added thereto, and the cells were cultured under 5% CO 2 at 37 ° C. for 72 hours.
  • culture medium RPMI1640; Nikken Biomedical Institute
  • Hapten-induced ulcerative colitis was induced according to the method of El son et al. (J. Immunology, 157, 2174, 1996). Rectal infusion of trinitrobenzene sulfonic acid into BALB / c mice caused chronic inflammatory bowel disease.
  • the pyrazole derivative of Example 3 was suspended in a 0.5% methylcellulose solution, and orally administered at a dose of 50 mg / kg for two consecutive weeks from the day of sensitization of benzenesulfonic acid with trinitrate. During the test period, body weight and stool status were observed, and a score of 0 to 4 shown below was given according to the method of Murthy et al. (Digestive Disease and Science, 38, 1722, 1993).
  • the pyrazole derivative of the formula 1 or a pharmacologically acceptable salt thereof is useful as an immunosuppressant and can be used as a therapeutic agent for autoimmune diseases, allergic diseases and the like.

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Abstract

Cette invention se rapporte à des dérivés de pyrazole représentés par la formule générale (1), dans laquelle un des groupes que sont R1 et R2 représente un groupe aryle éventuellement substitué ou un groupe hétérocyclique aromatique éventuellement substitué, l'autre de ces groupes représentant un groupe hétérocyclique aromatique éventuellement substitué; R3 représente un atome d'hydrogène, un groupe alkyle éventuellement substitué ou analogue; et R4 représente un atome d'hydrogène ou un groupe alkyle éventuellement substitué. L'invention se rapporte également à des sels pharmacologiquement acceptables de ces dérivés qui s'avèrent utiles en tant qu'agents immunosuppresseurs et peuvent être utilisés en tant qu'agent thérapeutique de maladies auto-immunes, d'allergies et d'autres maladies.
PCT/JP1998/002552 1997-06-12 1998-06-09 Derives de pyrazole WO1998056785A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2000056719A1 (fr) * 1999-03-22 2000-09-28 Bristol-Myers Squibb Company Composes fusionnes de pyridopyridazine inhibiteurs de la cgmp phosphodiesterase
WO2001079187A3 (fr) * 2000-04-18 2002-02-21 Cytovia Inc Thiazepine-1,4 substituee et analogues de celle-ci activateurs de caspases et inducteurs d'apoptose, et utilisation
WO2002014314A3 (fr) * 2000-08-14 2002-06-06 Ortho Mcneil Pharm Inc Pyrazoles substitués
WO2002014315A3 (fr) * 2000-08-14 2002-06-13 Ortho Mcneil Pharm Inc Pyrazoles substitutes
WO2002020012A3 (fr) * 2000-09-06 2002-06-13 Ortho Mcneil Pharm Inc Methode de traitement d'allergies au moyen de pyrazoles substitues
WO2002020011A3 (fr) * 2000-09-06 2002-06-13 Ortho Mcneil Pharm Inc Methode de traitement des allergies a l'aide de pyrazoles substitues
WO2002020013A3 (fr) * 2000-09-06 2002-06-20 Ortho Mcneil Pharm Inc Methode de traitement d'allergies au moyen de pyrazoles substitues
WO2002014317A3 (fr) * 2000-08-14 2002-07-04 Ortho Mcneil Pharm Inc Pyrazoles substitues
US6562817B1 (en) 1998-01-28 2003-05-13 Shionogi & Co., Ltd. Tricyclic compound
US6579896B2 (en) 2000-09-06 2003-06-17 Ortho-Mcneil Pharmaceutical, Inc. Method for treating allergies using substituted pyrazoles
JP2004529154A (ja) * 2001-04-05 2004-09-24 トレント・ファーマシューティカルズ・リミテッド 老化−関連及び糖尿病性血管性合併症のための複素環式化合物
RU2277909C2 (ru) * 2001-08-10 2006-06-20 Орто-Макнейл Фармасьютикал, Инк. Способ лечения аллергии с использованием замещенных пиразолов
CN1294130C (zh) * 2000-08-10 2007-01-10 奥索-麦克尼尔药品公司 取代的吡唑
US7332494B2 (en) 2000-08-14 2008-02-19 Janssen Pharmaceutica, N.V. Method for treating allergies using substituted pyrazoles
EP1206935A4 (fr) * 1999-07-23 2008-07-30 Shionogi & Co Inhibiteurs de differenciation th2
WO2009028543A1 (fr) * 2007-08-30 2009-03-05 Takeda Pharmaceutical Company Limited Dérivé de pyrazole substitué
WO2011045224A1 (fr) 2009-10-12 2011-04-21 Bayer Cropscience Ag 1-(pyrid-3-yl)-pyrazole et 1-(pyrimid-5-yl)-pyrazole en tant qu'agents antiparasites
EP2583556A1 (fr) 2008-07-17 2013-04-24 Bayer CropScience AG Liaisons hétérocycliques en tant que moyen de lutte contre les parasites
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
JP2013544792A (ja) * 2010-10-22 2013-12-19 バイエル・インテレクチユアル・プロパテイー・ゲー・エム・ベー・ハー 殺害虫剤としての新規ヘテロ環式化合物
WO2014067962A1 (fr) * 2012-10-31 2014-05-08 Bayer Cropscience Ag Nouveaux composés hétérocycliques utilisés comme agents de lutte contre les nuisibles
US8748442B2 (en) 2010-06-30 2014-06-10 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9061030B2 (en) 2010-11-09 2015-06-23 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9139564B2 (en) 2011-12-27 2015-09-22 Ironwood Pharmaceuticals, Inc. 2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sGC stimulators
JP2016529234A (ja) * 2013-07-15 2016-09-23 ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ 殺有害生物化合物
CN110467601A (zh) * 2019-08-29 2019-11-19 杭州市西溪医院 一种吡唑联吡啶酮类化合物、中间体及其制备方法及应用

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DE2317716A1 (de) * 1971-10-13 1974-05-02 Sandoz Ag Neue organische verbindungen und verfahren zu deren herstellung
US3843665A (en) * 1973-04-11 1974-10-22 Sandoz Ag Process for preparing substituted indeno,naphtho and cyclohepta pyrazoles
JPH0873464A (ja) * 1994-06-30 1996-03-19 Eisai Co Ltd 複素環含有化合物
JPH0971566A (ja) * 1995-06-30 1997-03-18 Eisai Co Ltd ヘテロ環含有カルボン酸誘導体及びそれを含有する医薬

Cited By (62)

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US6562817B1 (en) 1998-01-28 2003-05-13 Shionogi & Co., Ltd. Tricyclic compound
US6316438B1 (en) 1999-03-22 2001-11-13 Bristol-Myers Squibb Co. Fused pyridopyridazine inhibitors of cGMP phosphodiesterase
WO2000056719A1 (fr) * 1999-03-22 2000-09-28 Bristol-Myers Squibb Company Composes fusionnes de pyridopyridazine inhibiteurs de la cgmp phosphodiesterase
EP1206935A4 (fr) * 1999-07-23 2008-07-30 Shionogi & Co Inhibiteurs de differenciation th2
WO2001079187A3 (fr) * 2000-04-18 2002-02-21 Cytovia Inc Thiazepine-1,4 substituee et analogues de celle-ci activateurs de caspases et inducteurs d'apoptose, et utilisation
US6861419B2 (en) 2000-04-18 2005-03-01 Cytovia, Inc. Substituted 1, 4-thiazepine and analogs as activators of caspases and inducers of apoptosis and the use thereof
CN1294130C (zh) * 2000-08-10 2007-01-10 奥索-麦克尼尔药品公司 取代的吡唑
US7388011B2 (en) 2000-08-14 2008-06-17 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
KR100837193B1 (ko) * 2000-08-14 2008-06-13 오르토-맥네일 파마슈티칼, 인코퍼레이티드 치환된 피라졸
CZ307185B6 (cs) * 2000-08-14 2018-03-07 Ortho Mcneil Pharmaceutical, Inc. Substituovaný pyrazol, farmaceutická kompozice s jeho obsahem a jejich lékařské aplikace
US7772236B2 (en) 2000-08-14 2010-08-10 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7589202B2 (en) 2000-08-14 2009-09-15 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US6635633B2 (en) 2000-08-14 2003-10-21 Ortho-Pharmaceutical, Inc. Substituted pyrazoles
JP2004512272A (ja) * 2000-08-14 2004-04-22 オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド 置換ピラゾール
US7452890B2 (en) 2000-08-14 2008-11-18 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7429591B2 (en) 2000-08-14 2008-09-30 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US6936603B2 (en) 2000-08-14 2005-08-30 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US6949540B2 (en) 2000-08-14 2005-09-27 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US6953793B2 (en) 2000-08-14 2005-10-11 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7417046B2 (en) 2000-08-14 2008-08-26 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
WO2002014314A3 (fr) * 2000-08-14 2002-06-06 Ortho Mcneil Pharm Inc Pyrazoles substitués
WO2002014317A3 (fr) * 2000-08-14 2002-07-04 Ortho Mcneil Pharm Inc Pyrazoles substitues
US7393850B2 (en) 2000-08-14 2008-07-01 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
CN1329392C (zh) * 2000-08-14 2007-08-01 奥索-麦克尼尔药品公司 取代的吡唑
US7265102B2 (en) 2000-08-14 2007-09-04 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7309703B2 (en) 2000-08-14 2007-12-18 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7332494B2 (en) 2000-08-14 2008-02-19 Janssen Pharmaceutica, N.V. Method for treating allergies using substituted pyrazoles
WO2002014315A3 (fr) * 2000-08-14 2002-06-13 Ortho Mcneil Pharm Inc Pyrazoles substitutes
WO2002020012A3 (fr) * 2000-09-06 2002-06-13 Ortho Mcneil Pharm Inc Methode de traitement d'allergies au moyen de pyrazoles substitues
US6583155B2 (en) 2000-09-06 2003-06-24 Ortho-Mcneil Pharmaceutical, Inc. Method for treating allergies using substituted pyrazoles
KR100818056B1 (ko) * 2000-09-06 2008-03-31 오르토-맥네일 파마슈티칼, 인코퍼레이티드 치환된 피라졸을 포함하는 알레르기 치료용 약제
CN1321641C (zh) * 2000-09-06 2007-06-20 奥索-麦克尼尔药品公司 取代的吡唑在制备用于治疗变态反应的药物中的应用
RU2290179C2 (ru) * 2000-09-06 2006-12-27 Орто-Макнейл Фармасьютикал, Инк. Способ лечения аллергий с использованием замещенных пиразолов
CN100384420C (zh) * 2000-09-06 2008-04-30 奥索-麦克尼尔药品公司 取代的吡唑在制备用于治疗变应性疾病的药物组合物中的应用
WO2002020011A3 (fr) * 2000-09-06 2002-06-13 Ortho Mcneil Pharm Inc Methode de traitement des allergies a l'aide de pyrazoles substitues
WO2002020013A3 (fr) * 2000-09-06 2002-06-20 Ortho Mcneil Pharm Inc Methode de traitement d'allergies au moyen de pyrazoles substitues
US6579896B2 (en) 2000-09-06 2003-06-17 Ortho-Mcneil Pharmaceutical, Inc. Method for treating allergies using substituted pyrazoles
JP2004529154A (ja) * 2001-04-05 2004-09-24 トレント・ファーマシューティカルズ・リミテッド 老化−関連及び糖尿病性血管性合併症のための複素環式化合物
JP2010100640A (ja) * 2001-04-05 2010-05-06 Torrent Pharmaceuticals Ltd 老化−関連及び糖尿病性血管性合併症のための複素環式化合物
RU2277909C2 (ru) * 2001-08-10 2006-06-20 Орто-Макнейл Фармасьютикал, Инк. Способ лечения аллергии с использованием замещенных пиразолов
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2009028543A1 (fr) * 2007-08-30 2009-03-05 Takeda Pharmaceutical Company Limited Dérivé de pyrazole substitué
EP2586311A1 (fr) 2008-07-17 2013-05-01 Bayer CropScience AG Liaisons hétérocycliques en tant que moyen de lutte contre les parasites
US9451775B2 (en) 2008-07-17 2016-09-27 Bayer Intellectual Property Gmbh Heterocyclic compounds as pesticides
EP2586312A1 (fr) 2008-07-17 2013-05-01 Bayer CropScience AG Liaisons hétérocycliques en tant que moyen de lutte contre les parasites
EP2583556A1 (fr) 2008-07-17 2013-04-24 Bayer CropScience AG Liaisons hétérocycliques en tant que moyen de lutte contre les parasites
EP2591674A1 (fr) 2008-07-17 2013-05-15 Bayer CropScience AG Liaisons hétérocycliques en tant que moyen de lutte contre les parasites
EP2583557A1 (fr) 2008-07-17 2013-04-24 Bayer CropScience AG Liaisons hétérocycliques en tant que moyen de lutte contre les parasites
US8809547B2 (en) 2008-07-17 2014-08-19 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US8685964B2 (en) 2009-10-12 2014-04-01 Bayer Cropscience Ag Heterocyclic compounds as pesticides
WO2011045224A1 (fr) 2009-10-12 2011-04-21 Bayer Cropscience Ag 1-(pyrid-3-yl)-pyrazole et 1-(pyrimid-5-yl)-pyrazole en tant qu'agents antiparasites
US9066518B2 (en) 2009-10-12 2015-06-30 Bayer Intellectual Property Gmbh Heterocyclic compounds as pesticides
US10189809B2 (en) 2010-06-30 2019-01-29 Ironwood Pharmaceuticals, Inc. SGC stimulators
US8748442B2 (en) 2010-06-30 2014-06-10 Ironwood Pharmaceuticals, Inc. sGC stimulators
JP2013544792A (ja) * 2010-10-22 2013-12-19 バイエル・インテレクチユアル・プロパテイー・ゲー・エム・ベー・ハー 殺害虫剤としての新規ヘテロ環式化合物
US9173396B2 (en) 2010-10-22 2015-11-03 Bayer Intellectual Property Gmbh Heterocyclic compounds as pesticides
US9061030B2 (en) 2010-11-09 2015-06-23 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9139564B2 (en) 2011-12-27 2015-09-22 Ironwood Pharmaceuticals, Inc. 2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sGC stimulators
CN104884449A (zh) * 2012-10-31 2015-09-02 拜尔农作物科学股份公司 作为害虫防治剂的新的杂环化合物
WO2014067962A1 (fr) * 2012-10-31 2014-05-08 Bayer Cropscience Ag Nouveaux composés hétérocycliques utilisés comme agents de lutte contre les nuisibles
JP2016529234A (ja) * 2013-07-15 2016-09-23 ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ 殺有害生物化合物
CN110467601A (zh) * 2019-08-29 2019-11-19 杭州市西溪医院 一种吡唑联吡啶酮类化合物、中间体及其制备方法及应用

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