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WO2001023358A1 - Derives pyrazole, intermediaires pour la preparation de ces derives, procedes de preparation des derives et intermediaires, et herbicides dont ces derives sont le principe actif - Google Patents

Derives pyrazole, intermediaires pour la preparation de ces derives, procedes de preparation des derives et intermediaires, et herbicides dont ces derives sont le principe actif Download PDF

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Publication number
WO2001023358A1
WO2001023358A1 PCT/JP2000/006519 JP0006519W WO0123358A1 WO 2001023358 A1 WO2001023358 A1 WO 2001023358A1 JP 0006519 W JP0006519 W JP 0006519W WO 0123358 A1 WO0123358 A1 WO 0123358A1
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Prior art keywords
group
substituted
optionally substituted
general formula
pyrazole
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PCT/JP2000/006519
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English (en)
Japanese (ja)
Inventor
Kenji Hirai
Ryuta Ohno
Atsuko Yamada
Tomoko Matsukawa
Takuya Ueda
Original Assignee
Sagami Chemical Research Center
Kaken Pharmaceutical Co., Ltd.
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Application filed by Sagami Chemical Research Center, Kaken Pharmaceutical Co., Ltd. filed Critical Sagami Chemical Research Center
Publication of WO2001023358A1 publication Critical patent/WO2001023358A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/36—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< directly attached to at least one heterocyclic ring; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5

Definitions

  • the present invention relates to a novel pyrazole derivative, a production intermediate thereof, a production method thereof, and a herbicide containing them as an active ingredient.
  • pyrazole derivatives having physiological activity as a pesticide such as herbicidal activity and insecticidal activity have been known, but they are substituted at the 3-position of the pyrazole ring as shown by the general formula (1) of the present invention.
  • a pyrazole derivative having a hydroxy group and a substitutional rubamoyl group / substituted amino group at the 4-position and no report on their biological activity.
  • pyrazole derivatives having a structure similar to the pyrazole derivative # (1) of the present invention pyrazole derivatives described in WO99 / 33812 (FR 2773155) and WO99 / 33813 (FR 2773153) are known.
  • the present invention provides a novel pyrazole derivative having excellent herbicidal activity and high crop selectivity, an intermediate for producing the same, a method for producing the same, and a herbicide containing these derivatives as active ingredients.
  • the present inventors have conducted intensive studies in search of a herbicide having excellent herbicidal activity and crop selectivity.As a result, the pyrazole derivative represented by the general formula (1) of the present invention does not cause harm to crops. In addition, they have found excellent herbicidal activity when applied at a low dose, and have found these simple production methods, and have completed the present invention.
  • the present invention relates to the general formula (1)
  • R 1 a represents a Ararukiru group-CH but it may also be have an alkyl group or substituted substituted - may be 2
  • R 2 A represents a hydrogen atom, optionally substituted C
  • An alkyl group of 2 to 2 an optionally substituted C 3 to cycloalkyl group, an optionally substituted C 7 to C M aralkyl group, an optionally substituted C 3 to C 6 alkenyl group
  • R 3 is a hydrogen atom, an alkyl group of -C 6 R represents a optionally substituted rubamoyl group or an optionally substituted acylamino group.
  • R is formula - C0NR 4 R 5 (wherein, is hydrogen atom, substituted May be C, alkyl group having 1-2, a cycloalkyl group which substituted with optionally may ⁇ ⁇ C 8, Ararukiru groups substituted C 7 optionally ⁇ CM, substituted to have the or ⁇ C 6 also alkenyl group, a substituted and optionally alkynyl group - may be substituted with an optionally aromatic group, hydroxy group, substituted optionally C, ⁇ 2 alkoxy groups, substituted and optionally C 3 even though - C is a cycloalkyloxy group, optionally substituted to, an aralkyloxy group, optionally substituted C : I to C 6 alkenyloxy group or optionally
  • R 7 is a hydrogen atom, an optionally substituted C, an alkylyl group of ⁇ 2, an optionally substituted C 3 ((: a cycloalkyl group of 8 , optionally substituted good C 7 to CU of Ararukiru group, optionally substituted C 3 -C 6 alkenyl group, optionally substituted C 3 ⁇ alkynyl group, an optionally substituted aromatic group, substituted which may be C, -C 1 2 alkoxy group, optionally substituted C:, cycloalkyl O alkoxy group -C 8, Conversion and optionally C 7 ⁇ CM of Ararukiruokishi group, optionally substituted C:, Arukeniruokishi group ⁇ , Arukiniruokishi groups - which may be substituted, may be substituted aromatic group substituted Okishi group, Monoa Ruiwaji (optionally substituted C, ⁇ 2 alkyl) amino group, mono- or di (of ⁇ which may be substituted
  • the present invention provides an intermediate represented by the general formula (2)
  • R lb represents a hydrogen atom, substituted even if representing a good ⁇ C I 2 alkyl or substituted may be . ⁇ CM of Ararukiru group.
  • R 2 a and R 3 are as defined above
  • R 8 represents ( ⁇ to (; 6 alkoxy, hydroxy, halogen or azide group) Represent. However, when R 8 is a halogen atom or an azide group, 1 ⁇ and 1 ⁇ cannot be hydrogen atoms. Further, when R 8 is a hydroxy group, R 2 a is not become a good sulfonyl group which may optionally Ashiru or substituted be substituted. )).
  • R ′ b and 9 have the same meanings as described above; R : ia represents a halogen atom.).
  • R ′ b represents a hydrogen atom or a halogen atom;
  • R 2 b is an alkyl group and - may be 2-substituted, cycloalkyl group substituted with optionally 5 may be -C 8, Ararukiru group substituted ⁇ may be C u, substituted Represents an optionally substituted C 6 -alkenyl group, an optionally substituted C 3 -alkynyl group, an optionally substituted acyl group or an optionally substituted sulfonyl group, wherein Z is A compound represented by the general formula (2d):
  • R 1a and 1 R 9 represent the same meaning as described above.
  • R 2 e may be substituted (;, to (;, An alkyl group of which may be substituted, or a cycloalkyl group of up to C, which may be substituted.
  • the present invention relates to the general formula (2i) obtained as described above.
  • R la, R 3 and are as defined above.
  • R ′ a , R 2 e and 1 R 3 represent the same meaning as described above.
  • X represents a nodogen atom.
  • R 8 a represent the same meaning as above. Representing an alkoxy group, hydroxy group or eight androgenic atom ⁇ C 6) and pyrazole derivatives represented by the General Equation (8)
  • R is a hydrogen atom, an optionally substituted alkyl group of 2 to 2 , an optionally substituted cycloalkyl group of C 3 to C 8 , an optionally substituted C 7 to d 7 , Araru kill groups, substituted and may ⁇ ⁇ alkenyl group C 6, alkynyl group may ⁇ C 6 to be substituted, substituted an optionally aromatic group, hydroxy group, may be substituted
  • the present invention provides a compound represented by the general formula (lb) ′
  • R 5a is an optionally substituted alkyl group, an optionally substituted C 3 -cycloalkyl group, an optionally substituted, an aralkyl group of, or an optionally substituted
  • R la R 2 ⁇ RR "and 5a represent the same meaning as described above.
  • R is an alkyl group having 2 to which may be substituted ", which may be substituted are C: i cycloalkyl group-substituted and may have . ⁇
  • the Ararukiru groups, substituted good C 3 ⁇ also be an alkenyl group, or a substituted good C 3 ⁇ also represent alkynyl groups.
  • Z is by reacting a compound represented by the representative.) the leaving group in the presence of a base , General formula (le)
  • A may be substituted C:. Represents a polymethylene group of l -C s, these polymethylene group may contain an unsaturated bond and Z represents a leaving group.
  • R 7 a is a substituted ⁇ may be 2 alkyl group, Yo Le ⁇ be substituted (; 8 cycloalkyl group, ⁇ which may be substituted, the Ararukiru groups, substituted Optionally substituted C 3- (: 6 alkenyl groups, optionally substituted C 3- (: 6 alkynyl And represents an optionally substituted aromatic group.
  • Y is 0, S, represents NH or NR 7 b, R 7 is optionally substituted (:., ⁇ ⁇ 2 alkyl group or may be substituted, a ⁇ C 8 cyclo alkyl group, ?
  • the present invention provides a compound represented by the general formula (l i)
  • R 6B is an optionally substituted to C 12 alkyl group, an optionally substituted C 3 to cycloalkyl group, an optionally substituted C 7 to CH aralkyl group, It represents the also have good C 3 -C 6 alkenyl group or substituted optionally C 3 -C 6 alkynyl groups.
  • Z is reacted with a compound represented by the representative.) the leaving group By the general formula (11) ⁇ . (">
  • R ′ A , R 2T , R 3 , R 6B and R 7 have the same meanings as described above.).
  • R 7E is an optionally substituted alkyl group of C 12 , an optionally substituted C : cycloalkyl group of I to C 8 , an aralkyl group of Represents an optionally substituted alkenyl group to C 6 , an optionally substituted C 3 to (: an alkynyl group of 6 or an optionally substituted aromatic group.
  • W represents 0 or S. ;
  • R la , R 2e , R : i , R 7t ′, and R 7 have the same meanings as described above.
  • the present invention provides a compound represented by the general formula (In) «1 ⁇ ,
  • R 2e represents a benzyl group which may be substituted.
  • the present invention relates to a herbicide containing a pyrazole derivative represented by the following formula :
  • R, ⁇ ' ⁇ , ⁇ , X, ⁇ is described below by way of example the definition of location substituent represented by ⁇ and W.
  • alkyl groups eight androgenic atoms, a cycloalkyl group ⁇ C 8, Shiano group, a nitro group, an alkylthio group ⁇ C 6, ⁇ (: 6 alkoxy group, a ⁇ C 6 an alkoxy carbonyl group, It may be substituted by one or more carboxy, acyl, etc.More specifically, 2-chloroethyl, 3-chloropropyl, difluoromethyl, 3-fluoropropyl, cyclopropylmethyl, cyclopentylmethyl Group, cyclohexylmethyl group, cyanomethyl group, 2-cyanoethyl group, 3-cyanopropyl group, nitromethyl group, 2-methylthioethyl group, methoxymethyl group, ethoxymethyl group, 2-methoxyethylyl group, 2-methylethoxymethyl Group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, trimethoxycarbonylethyl group,
  • R: ', R:, ⁇ R 9 and R' as alkyl group ⁇ C 6 represented by °, linear be properly may be either branched, a methyl group, Echiru group, Propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isoamyl, neopentyl, neotylpropyl, trimethylbutyl, -methylbutyl, hexyl, iso Examples include a hexyl group, a 2-ethylbutyl group, a 4-methylpentyl group, and the like.
  • these cycloalkyl groups may be substituted with an octylogen atom, an alkyl group of, an alkoxycarbonyl group of C, to ⁇ , a cyano group, or the like. More specifically, a trimethylcyclopropyl group , 2,2-dimethylcyclopropyl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2-methoxycarbonylpropyl, 2-cyanocyclopropyl, 2-methylcyclopentyl, Examples thereof include a 3-methylcyclopentyl group.
  • R 7 a, R 7 h and, in R 7 e, and R 4, R '1 a or have in Ararukiruokishi group represented by R 7 is mono- or di (Ararukiru) amino group, the Ararukiru group, a benzyl group And aralkyl groups such as 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, trinaphthylmethyl group, 2-naphthylmethyl group, and the like.
  • the alkenyl group in the amino group may be linear, branched or cyclic, and may be a 1-propenyl group, an aryl group, a 2-methyl-2-propenyl group, -Butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, tricyclopentenyl group, 2-hexenyl group, 3-hexenyl group, 1-cyclohexenyl group, 2-heptenyl group, can be exemplified ⁇ ⁇ an alkenyl group of C 6 such Bok Shikurookuparu group.
  • alkenyl groups may be substituted with a nitrogen atom or the like, for example, a 2-chloro-2-propenyl group, a 3-chloropropenyl group, a 4-chloro-2-propyl group.
  • Butenyl groups and the like can be exemplified.
  • the alkynyl group may be linear or branched, and may be a propargyl group, a 1-butyn-3-yl group, or a 3-methyl group.
  • alkynyl groups such as -1-butyn-3-yl group, 2-butynyl group, 2-pentynyl group and 3-pentynyl group.
  • alkynyl groups may be substituted with a halogen atom or the like, for example, 3-fluoro-2-propynyl group, 3-chloro-2-propynyl group, 3-bromo-2-propynyl group, 4 -Bromo-2-butyl group, 4-bromo-3-butynyl group and the like.
  • the R 2 a ⁇ U3 ⁇ 4 which may be substituted Ashiru group represented by 2 b, a formyl group, Asechiru group, chloroacetyl group, triflate Ruo b acetyl group, a propionyl group, butenyl group, Pentanoiru group, pivaloyl group, Benzoyl, 4-methylbenzoyl, 2-chlorobenzoyl, 4-chlorobenzoyl, 2-fluorobenzoyl, 4-fluorobenzoyl, 2,4-difluoro Benzoyl group, 2,4-dichlorobenzoyl group, 3,5-dibromobenzoyl group, 3-methylbenzoyl group, 4- (trifluoromethyl) benzoyl group, 4-methoxybenzoylyl group, 3-phenoxybenzoyl group , 4-phenoxybenzoyl, 4-cyanobenzoyl, 4-nitrobenzoyl and the like.
  • Examples of the optionally substituted sulfonyl group represented by R 2 a and d include a methylsulfonyl group, a (trifluoromethyl) sulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a phenylsulfonyl group, and a p-sulfonyl group.
  • Examples of the optionally substituted benzyl group represented by R 2 e include a benzyl group, a 4-chlorobenzyl group, a 4-methylbenzyl group, a 3- (trifluoromethyl) benzyl group, and a 4-methoxy Examples thereof include a benzyl group, a 3,4-dimethoxybenzyl group, and a triphenylethyl group.
  • RR 4 a , R 5 , R 7 , R 7 a, and TT e and the aromatic group in the aromatic substituted oxy group or the aromatic amino group represented by R 7.
  • a group a halogen atom, - (: 1 2 Arukirire group, a haloalkyl group-C 6, (:, ⁇ (; 6 Ashiru groups, C substituted with Arukokishiimino group CI ⁇ , -C, 2 alkyl group, ⁇ C 6 alkoxycarbonyl group, carboxy group, cyano group, ⁇ alkoxy group, aryloxy group, ⁇ C 6 haloalkyloxy group, (:, ⁇ (: 6 alkylthio group, ( :, ⁇ (6 alkylsulfinyl group, C, ⁇ (; 6 alkylsulfonyl group, haloalkylthio group-C 6, C, haloalkylsulfinyl group -C 6,
  • Heterocycles formed integrally with the nitrogen atom to which ⁇ and R “'and R” and R 5 are bonded include pyrrole, pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, virazolidine, Lysine, piperazin, indole, indoline, isoindole, 1H-indazole, purine, oxazoline, oxazolidine, isoxazoline, isoxazolidine, thiazoline, thiazolidine, morpholine, thiomorpholine, aziridine, azocan, tetrahydro Oxazine and the like, which may be substituted one or more times with an octogen atom or a C 6 alkyl group.
  • the alkyl group in the alkoxy group represented by R 9 and R 8 and 8 a may be linear or branched, and may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group. And a C alkyl group such as an isobutyl group, an isobutyl group, a pentyl group, and a hexyl group.
  • Examples of the polymethylene group which may contain an unsaturated bond represented by A include a trimethylene group, a tetramethylene group, a 2-butylene group, a pentamethylene group, and a hexamethylene group. One or more of these may be substituted with a hydrogen atom, a logene atom or an alkyl group such as
  • R 3, R 3 a, R : ih, as the R 8, R 8 a and halogen atoms represented by can be exemplified fluorine atom, chlorine atom, bromine atom and the like.
  • Examples of the leaving group represented by Z include a chlorine atom, a bromine atom, a halogen atom such as an iodine atom, a methylsulfonyloxy group, a (trifluoromethyl) sulfonyloxy group, a phenylsulfonyloxy group, a p- Examples thereof include an alkyl group such as a tolylsulfonyloxy group or an arylsulfonyl group, and an acsyloxy group such as an acetoxy group and a bivaloyloxy group.
  • Production method 1 (steps 1 and 2) is a reaction between a substituted hydrazine (3) and an alkoxymethyl acid ester derivative (4) to produce the 3-hydroxypyra of the present invention.
  • the method for producing the pyrazole derivative (2b) of the present invention will be described.
  • Step 11 is a step of producing a pyrazole derivative (2a) of the present invention by cyclocondensation of a substituted hydrazine (3) with an alkoxymethylidenemalonate ester derivative (4).
  • the reaction can be carried out without using a base because the hydrazines as the raw materials are basic, but can also be carried out under a base.
  • Bases include sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium-1-butoxide, 7] ⁇ sodium oxide, alkali metal base such as 7K potassium oxide, triethylamine, Organic amines such as triptylamine, N-methylmorpholine, pyridine and dimethylaniline can be used.
  • the amount of the base used is not particularly limited, but it is preferable to use the base in an amount of 0.1 equivalent or more based on the reaction substrate in terms of good yield.
  • the reaction is preferably carried out in a solvent, and any solvent that does not harm the reaction can be used.
  • solvent examples include aromatic hydrocarbon solvents such as benzene, toluene, xylene, and benzene, and dimethyl ether.
  • the reaction temperature varies depending on the base used and is selected from the range of -30 ° C to the reflux temperature of the reaction solvent, but the reaction should be performed at a temperature selected from the range of 0 ° C to 100 ° C. Is preferred in that the yield is good.
  • the desired product can be obtained by ordinary post-treatment operations, but if necessary, it can be purified by column chromatography or recrystallization.
  • the present inventors have now succeeded in carrying out the reaction at a temperature selected from a low to medium temperature range of 0 to 100 ° C, so that the route ⁇ ⁇ ⁇ reaction can proceed preferentially, and the adduct (A ), It has been found that the 3-hydroxyvirazole derivative (2a) of the present invention can be synthesized with high selectivity.
  • N- (2,2) was obtained by benzylating 3-ethyl-1-methylpyrazole-4-carboxylate obtained by this reaction and converting the ester to an amide.
  • 4-difluoro-5-ditophenyl) -3- [3,5-bis (trifluoromethyl) benzyloxy] -1-methylpyrazole-4-carboxamide (see Examples-6, 34, 86, 302) ) was confirmed by X-ray crystal structure analysis.
  • Step 12 is a step of producing the pyrazole derivative (2b) of the present invention by halogenating the 5-position of the 3-hydroxypyrazole derivative (2a).
  • the halogenation can be performed using a halogenating agent.
  • a halogenating agent sulfuryl chloride, N-chlorosuccinimide, N-bromosuccinimide and the like can be used.
  • the reaction is preferably carried out in a solvent, and any solvent that does not harm the reaction can be used.
  • aliphatic carbon dioxide solvents such as pentane, hexane, and octane; , Tetrahydrofuran, dioxane, DME, etc., ether solvents, dichloromethane, chloroform, carbon tetrachloride, etc., aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene, etc., acetic acid, propylion
  • organic acid-based solvent such as an acid, water, and a mixed solvent thereof.
  • the reaction temperature varies depending on the halogenating agent used, and is selected from the range of -10 ° C to 150, but the reaction can be carried out at a temperature selected from the range of 0 ° C to the reflux temperature of the reaction solvent. It is preferable because the yield is good.
  • the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • Production method 1-2 shows a method for producing the pyrazole derivative (2d) of the present invention by reacting the 3-hydroxypyrazole derivative (2c) with the compound (5).
  • R ′ b , R 2 , R 3b , R 9 and Z represent the same meaning as described above.
  • Step 13 is a step of producing the pyrazodyl derivative (2d) of the present invention by reacting the 3-hydroxypyrazole derivative (2c) with the compound (5) in the presence of a base.
  • This reaction must be performed in the presence of a base.
  • the base include sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium-1-butoxide, and 7K sodium oxide.
  • alkali metal bases such as potassium hydroxide and the like, and organic amines such as triethylamine, triptylamine, N-methylmorpholine, pyridine and dimethylaniline.
  • the amount of the base to be used is not particularly limited, but the target compound can be obtained in good yield by carrying out the reaction using an equivalent amount or more of the reaction substrate.
  • the reaction is preferably performed in a solvent, and any solvent that does not harm the reaction can be used.
  • ether solvents such as getyl ether, THF, DME, and dioxane, acetone, and ethyl.
  • Ketone solvents such as methyl ketone; ester solvents such as ethyl acetate and butyl acetate; nitriles such as acetonitrile and propionitrile; aromatic hydrocarbon solvents such as benzene, toluene, xylene, and benzene; DMF And amides such as N-methylpyrrolidone, DMS0, water or a mixed solvent thereof.
  • the reaction temperature is not particularly limited, but the desired product can be obtained in good yield by reacting with fi3 ⁇ 4 selected from the range of 0 to 150 ° C. After completion of the reaction, the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • a certain 3-hydroxypyrazole-induced body substituent 11 1 13 is a hydrogen atom when used as the raw material, in addition to the intended 3- (substituted Okishi) pyrazole derivative (2d), 1-position nitrogen atom
  • a product with a substituent introduced on the top (see Step 4) and a product with a substituent introduced on the 1-nitrogen atom and the 3-position oxygen atom are also produced as by-products. It can be easily separated and purified by column chromatography.
  • Production method 13 (step 14) is a reaction between a pyrazole derivative (2e) in which the substituent R lb is a hydrogen atom and a compound (6) in a pyrazole derivative represented by the general formula (2c) or (2d). Shows the method for producing the pyrazole derivative (20) of the present invention. [ss method 1 3]
  • R la , R 2a , R : ib , R 3 and Z represent the same meaning as described above.
  • Step _4 must be performed in the presence of a base.
  • the base include sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium-1-butoxide, and sodium heptaoxide.
  • alkali metal bases such as potassium hydroxide and the like, and organic amines such as triethyleamine, triptylamine, N-methylmorpholine, pyridine and dimethylaniline.
  • the amount of the base to be used is not particularly limited, but the target compound can be obtained by using at least an equivalent amount to the reaction substrate.
  • the reaction is preferably performed in a solvent, and any solvent that does not harm the reaction can be used.
  • ether solvents such as getyl ether, THF, DME, and dioxane
  • acetone and ethyl.
  • Ketone solvents such as methyl ketone
  • ester solvents such as ethyl acetate and butyl acetate
  • nitriles such as acetonitrile and propionitrile
  • aromatic hydrocarbon solvents such as benzene, toluene, xylene, and benzene
  • Amides such as N-methylpyrrolidone, DMS0, water or a mixed solvent thereof can be used.
  • the reaction temperature is not particularly limited, but the desired product can be obtained by reacting at a temperature selected from the range of 0 to 150 ° C.
  • Production method 1 (step 1 5) alkylates the 5-position of the pyrazole derivative (2g), 4 shows a method for producing the pyrazole derivative (2h) of the present invention.
  • step 15 be performed in the presence of a base, and as the base, a strong base such as butyllithium, s_butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide can be used.
  • a strong base such as butyllithium, s_butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide.
  • the amount of the base used is at least 1 equivalent to the amount of the reaction substrate, so that the desired product can be obtained.
  • the reaction is preferably performed in a solvent, and any solvent that does not harm the reaction can be used.
  • ether solvents such as getyl ether, THF, DME, and dioxane, DMF, and N- Amides such as methylpyrrolidone, DMS0, or a mixed solvent thereof can be used.
  • the reaction temperature is not particularly limited, but the desired product can be obtained by performing the reaction at a temperature selected from the range of -78 ° C to 50 ° C.
  • Step-6 shows a method of hydrolyzing the ester of the pyrazole derivative (2i) to produce the pyrazole-4-carboxylic acid derivative (2j) of the present invention.
  • the target product can be easily obtained by using a method usually used for the power of the ester and the water splitting reaction.
  • an alkali metal such as sodium hydroxide, potassium heptaoxide and the like can be obtained.
  • the reaction can be carried out in an aqueous hydroxide solution as a base, in water, or in a mixed solvent of water and an organic solvent such as acetonitrile, THF, dioxane, methanol, ethanol, etc., which is uniformly mixed with water. Wear.
  • the reaction can be performed at a temperature ⁇ selected from the range of 0 ° C to 150 ° C.
  • the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by recrystallization or the like.
  • Production method 16 shows a method for producing the acid halide derivative (21) from the pyrazole-4-carboxylic acid derivative (2k).
  • the target compound can be easily obtained by using a method usually used for a conversion reaction from carboxylic acid to acid octylide.
  • a method usually used for a conversion reaction from carboxylic acid to acid octylide For example, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxychloride
  • Use reagents such as phosphorus, phosphorus tribromide, and fluorosulfuric acid in equal amounts or more, in the absence of a solvent or in a solvent such as benzene, toluene, xylene, chlorobenzene, chloroform, or dichloromethane that does not harm the reaction.
  • the reaction can be carried out at a temperature appropriately selected from the range of 0 ° C to 180 ° C.
  • metal fluorides such as potassium fluoride, cesium fluoride, ammonium fluoride, triphenylmethylphosphonium fluoride and the like, and fluorides such as ammonium fluoride and phosphonium fluoride are used. It can also be converted to an acid fluoride derivative [Japan Kokai Tokkyo Koho JP 09/1 76126 (EP 776889, CN 1161329, DE 19544800, US 5675016, US 5750721)]. After completion of the reaction, the intended pyrazole-4-carboxylic acid halide (21) can be easily obtained by removing the solvent and excess halogenating reagent, for example, under reduced pressure by heating.
  • the production method 17 comprises reacting the pyrazole derivative (2m) with an amine (8) in the presence of a base or a dehydrating agent, as the case may be, to obtain the pyrazole-4-caprolamide of the present invention.
  • the method for producing the derivative (la) will be described. [K construction method 1 7]
  • R la , R 2c , R 3 , R 4a , R 5 and 8a represent the same meaning as described above.
  • step one 8 if the R 8 a is an alkoxy group in the pyrazole derivative (2m), i.e. pyrazole - Te reaction smell of 4-carboxylic acid esters with amines and (8), the reaction, Toryechiruamin, Toripuchiruamin, dimethyl It is preferable to carry out the reaction in the presence of an organic amine base such as aniline, N-methylmorpholine, pyridine or the like in terms of good yield.
  • the amount of the base used is not particularly limited, and it is more preferable to use the base in an amount of about 1 to 5 equivalents in that the desired product can be obtained in good yield.
  • the reaction is preferably performed in an organic solvent, such as benzene, toluene, xylene, THF, dimethyl ether, chloroform, dichloromethane, acetone, ethyl methyl ketone, methanol, ethanol, propyl alcohol, isopropyl alcohol, t-butyl alcohol, and acetic acid.
  • organic solvent such as benzene, toluene, xylene, THF, dimethyl ether, chloroform, dichloromethane, acetone, ethyl methyl ketone, methanol, ethanol, propyl alcohol, isopropyl alcohol, t-butyl alcohol, and acetic acid.
  • Ethyl, butyl acetate, DMF, DMS0, etc. can be used.
  • the reaction can be carried out at a temperature selected from room temperature to solvent reflux ⁇ JS.
  • step 18 when R 8a in the pyrazole derivative (2m) is a hydroxy group, that is, in the reaction of pyrazole-4-carboxylic acid with an amine (8), an amide bond using a de-sizing agent is used.
  • the target compound can be obtained in high yield by using a method generally used for the formation reaction (Synthetic Chemistry Series "Peptide Synthesis”; pp. 117-150: Nobuo Izumiya, 1975, Maruzen).
  • DEC ⁇ , ⁇ '-dicyclohexylcarpoimide
  • DIPC N'-diisopropylpropylcarpoimide
  • ⁇ -ethyl-N '-(3-dimethylaminopropyl) It is possible to use carbodimids such as carbodimid hydrochloride, such as carboediimidazole.
  • the reaction is preferably performed in an organic solvent, such as benzene, toluene, xylene,
  • THF THF
  • getyl ether black form, dichloromethane, ethyl acetate and the like
  • the reaction temperature is (low to medium temperature selected from TC to 80 ° C) It is preferable to carry out the reaction at a lower temperature in terms of good yield.
  • Step 18 when R 8a in the pyrazole derivative (2m) is a halogen atom, that is, in the reaction of the pyrazole-4-carboxylic acid halide with the amines (8), the reaction is carried out in the presence of a base.
  • a base include alkali metal bases such as sodium hydrogen hydride, sodium amide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium-1-butoxide, sodium 7-acid, sodium hydroxide, potassium hydroxide and the like, triethylamine, triptylamine.
  • organic amines such as N-methylmorpholine, pyridine and dimethylaniline.
  • the target product can be obtained in good yield by carrying out the reaction using an equivalent amount or more of the base to the reaction substrate.
  • the reaction is preferably carried out in an organic solvent, and benzene, toluene, xylene, THF, getyl ether, chloroform, dichloromethane, acetone, ethyl methyl ketone, ethyl acetate, butyl acetate, DMF and the like can be used.
  • the reaction can be carried out at a low temperature selected from the range of -30 ° C to 60 ° C.
  • the target compound in the above reaction of this step-8, after completion of the reaction, the target compound can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • a pyrazole-4-carboxamide derivative (lb) is reacted with compound (9) in the presence of a base to introduce a substituent onto the amide nitrogen atom,
  • the method for producing the pyrazole derivative (lc) of the present invention is described.
  • the production method 19 (step-10) is a pyrazole-4-carboxamide derivative (Id) having a hydroxy group on the amide nitrogen atom and the compound (10).
  • a method for producing a pyrazole-4-carboxylic acid amide derivative (le) and a pyrazole-4-carboxylic acid amide derivative (1f) of the present invention is a pyrazole-4-carboxamide derivative (Id) having a hydroxy group on the amide nitrogen atom and the compound (10).
  • the base may be sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium- Alkali metal bases such as 1-butoxide, sodium hydroxide, and potassium heptaoxide, and organic amines such as tritylamine, triptylamine, N-methylmorpholine, pyridine, and dimethylaniline can be used.
  • the amount of the base to be used is not particularly limited, but the target compound can be obtained in good yield by carrying out the reaction using an equivalent amount or more of the reaction substrate.
  • the reaction is preferably performed in a solvent, and any solvent that does not harm the reaction can be used.
  • ether solvents such as getyl ether, THF DME, and dioxane
  • acetone such as acetone
  • ethyl methyl Ketone solvents such as ketones
  • ester solvents such as ethyl acetate and butyl acetate
  • nitriles such as acetonitrile and propionitol
  • aromatic hydrocarbon solvents such as benzene, toluene, xylene, and benzene
  • DMF Amides such as N-methylpyrrolidone, DMS0, water or a mixed solvent thereof can be used.
  • the reaction temperature is not particularly limited, but the reaction can be performed at a temperature selected from the range of 0 to 100 ° C. and the desired product can be obtained in good yield.
  • the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • the production method 10 (step 11) is a method for preparing a pyrazole-4-carboxylic acid amide derivative (Id) having a hydroxy group on an amide nitrogen atom and a compound (11) having two leaving groups.
  • a pyrazole-4-carboxylic acid amide derivative (lg) of the present invention Here's how to do it.
  • This reaction must be carried out in the presence of a base.
  • the base include sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium-1-butoxide, and hydroxylamine.
  • Metal salts such as sodium and zirconium oxide and organic amines such as triethylamine, triptylamine, m-methylmorpholine, pyridine and dimethylaniline can be used.
  • the amount of the base used is not particularly limited, but the target compound can be obtained in good yield by performing the reaction using at least two equivalents of the reaction substrate.
  • the reaction is preferably carried out in a solvent, and any solvent that does not harm the reaction can be used.
  • ether solvents such as getyl ether, THF, DME, and dioxane, acetone, and ethyl.
  • Ketone solvents such as methyl ketone, ester solvents such as ethyl acetate and butyl acetate 3 ⁇ 4
  • nitriles such as acetonitrile, propionitrile, and aromatic hydrocarbon solvents such as benzene, toluene, xylene, and benzene
  • amides such as DMF, N-methylpyrrolidone, DMS0, water or a mixed solvent thereof.
  • the reaction temperature is not particularly limited, but the desired product can be obtained in good yield by performing the reaction at a temperature selected from the range of 0 ° C to 100 ii ⁇ !. After completion of the reaction, the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be made into armor by column chromatography or recrystallization.
  • Production method 11 shows a method for producing a pyrazole derivative (2n) of the present invention by reacting a pyrazole-4-carboxylic acid halide derivative (21) with sodium azide.
  • This reaction is preferably performed in an organic solvent, and benzene, toluene, xylene, THF, getyl ether, chloroform, dichloromethane, ethyl acetate, DMF and the like can be used.
  • the reaction can be carried out at a medium to low temperature appropriately selected from the range of -30 ° C to 60 ° C.
  • the desired product can be obtained by a usual post-treatment operation. If necessary, it can be purified by column chromatography or recrystallization, but can be used in the next step without purification.
  • Step 13 is a Curtius rearrangement reaction of a 4-azidocarborvirazole derivative (2n) in the presence of an alcohol, thioalcohol or amine represented by the general formula (12), 1 shows a method for producing the 4-substituted aminopyrazole derivative (1 h) of the present invention.
  • This reaction is preferably performed in a solvent, and any solvent that does not harm the reaction can be used.
  • solvent solvents such as getyl ether, THF, DME, and dioxane, acetonitrile, and propionitrile.
  • Aromatic solvents such as benzene, toluene, xylene, and benzene, amides such as DMF and N-methylpyrrolidone, DMS0, and a mixed solvent thereof.
  • the reaction can be carried out at a temperature selected from the range of 50 ° C. to the reflux temperature of the solvent i I: the desired product can be obtained in good yield. After completion of the reaction, the desired product can be obtained by usual post-treatment operations. It can also be made blue by means of matography or recrystallization.
  • Production method 13 (steps-14, 15, 16) is based on the pyrazole derivative (lh) obtained in production method-12, in which the pyrazole derivative (1 i) in which Y is a nitrogen atom is decomposed 7K, After producing the 4_aminovirazole derivative (lj) of the present invention, the pyrazolecarboxylic acid derivative (lk) of the present invention is produced by reaction with the acylating agent 5 (13), A method for producing the pyrazole derivative (11) of the present invention by reacting with the agent (14) will be described.
  • Step 14 is to hydrolyze the pyrazole derivative (1 i), This is a step for producing a 4-aminopyrazole derivative (lj).
  • the reaction is usually carried out by using the method used for J
  • the desired product can be obtained easily by using, for example, an aqueous solution of an alkali metal hydroxide such as sodium ⁇ -oxide or potassium hydroxide as a base, with water or acetonitrile, THF, dioxane.
  • the reaction can be carried out in a mixed solvent of water and an organic solvent that is uniformly mixed with water.
  • the reaction can be carried out at a temperature selected from the range of 0 ° C to 150 and ii! C.
  • the desired product can be obtained by a usual post-treatment operation. However, if necessary, it can be purified by column chromatography, recrystallization or the like.
  • step 15 the 4-aminovirazole derivative (lj) is reacted with the acylating agent (13) in the presence of a base, and the pyrazole derivative (lk) of the present invention in which an acyl group has been introduced on the amino group. This is the step of manufacturing.
  • This reaction must be carried out in the presence of a base.
  • bases include sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium-1-butoxide, and sodium tau oxide.
  • Alkali metal bases such as potassium hydroxide, and organic amines such as triethylamine, triptylamine, N-methylmorpholine, pyridine, and dimethylaniline can be used.
  • the amount of the base to be used is not particularly limited, but the target compound can be obtained in good yield by carrying out the reaction using an equivalent amount or more of the reaction substrate.
  • the reaction is preferably performed in a solvent, and any solvent that does not harm the reaction can be used.
  • ether solvents such as getyl ether, THF, DME, and dioxane, acetonitrile, and propionyl
  • nitriles such as tolyl
  • aromatic hydrocarbon solvents such as benzene, toluene, xylene, and benzene
  • amides such as DMF and N-methylpyrrolidone, DMS0, or a mixed solvent thereof.
  • DMS0 N-methylpyrrolidone
  • the desired product By reacting at the selected temperature, the desired product can be obtained in high yield. After completion of the reaction, the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • R 7 is a hydrogen atom, that is, when a formyl group is introduced on a nitrogen atom, for example, the target compound can be easily obtained by treating with formic acid and acetic anhydride at a low temperature.
  • step 16 a pyrazole derivative (lk) is reacted with an alkylating agent (14) in the presence of a base, and a substituent is further introduced on the amide nitrogen atom to form a pyrazole derivative (11) of the present invention. This is the manufacturing process.
  • This reaction must be performed in the presence of a base.
  • a base examples include sodium hydride, sodium amide, methyllithium, butyllithium, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium-1- Alkali metal bases such as butoxide, sodium acid sodium and potassium potassium hydroxide can be used.
  • the amount of the base used is not particularly limited, but the target compound can be obtained in good yield by carrying out the reaction using an equivalent amount or more of the reaction substrate.
  • the reaction is preferably performed in a solvent, and any solvent that does not harm the reaction may be used.
  • ether solvents such as getyl ether, THF, DME, and dioxane
  • ketone solvents such as acetone and ethyl methyl ketone
  • ester solvents such as ethyl acetate and butyl acetate.
  • Nitrils such as acetonitrile and propionitrile
  • aromatic hydrocarbon solvents such as benzene, toluene, xylene, and benzene
  • amides such as DMF and N-methylpyrrolidone
  • DMS0 water
  • water or a mixture thereof
  • a solvent or the like can be used.
  • the reaction temperature is not particularly limited, but the reaction can be carried out at a temperature selected from iffi in the range of -78 ° C to 100 ° C to obtain the desired product in good yield.
  • the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • Production method 14 (step 17) is carried out by reacting the 3-aminopyrazole derivative (1 j) obtained in production method 13 with isocyanate or isothiocyanates (15).
  • 1 shows a method for producing the pyrazole derivative (lm) of the present invention.
  • This reaction can be promoted by performing it in the presence of a base.
  • a base examples include alkali metal bases such as sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium-1-butoxide, sodium hydroxide, and potassium hydroxide, triethylamine, Organic amines such as triptylamine, N-methylmorpholine, pyridine and dimethylaniline can be used.
  • the amount of the base to be used is not particularly limited, but the target compound can be obtained in good yield by performing the reaction on the reaction substrate using a so-called catalytic amount of the base.
  • the reaction can be performed in the absence of a solvent, but any solvent that does not harm the reaction can be used, for example, dimethyl ether, THF, DME, dioxane.
  • Ether solvents such as methyl acetate, ethyl acetate, etc.
  • ketone solvents such as ethyl methyl ketone
  • nitriles such as acetonitrile, propionitrile
  • fragrances such as benzene, toluene, xylene, and benzene.
  • Aromatic hydrocarbon solvents, amides such as DMF and N-methylpyrrolidone, DMS0 or a mixed solvent thereof can be used.
  • the reaction temperature is not particularly limited, but the reaction can be carried out at a temperature selected from the range of 0 ° C to 100, and the desired product can be obtained in good yield.
  • the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • Step-18 is a step of hydrogenating the benzyl group of the pyrazole derivative (In) to produce the 3-hydroxypyrazole-derivative (lo) of the present invention.
  • reaction a method of hydrogenolysis of a benzyl group commonly used (see, for example, Protective Groups in Organic Synthes is, TW Greene, John Wiley & Sons, p. 97, 1981) can be used. .
  • the reaction should be carried out in a (mixed) solvent such as benzene, toluene, xylene, methanol, ethanol, acetic acid, or water, using palladium carbon as a catalyst and in the presence of hydrogen gas or a hydrogen donor such as hexahexene.
  • a hydrogen gas or a hydrogen donor such as hexahexene.
  • the reaction can be carried out at a temperature selected from room temperature to loot: M: selected temperature.
  • the reaction is carried out at a low pressure of about 10 atm from normal pressure. be able to.
  • the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • Step 19 is a step of reacting the 3-hydroxypyrazole derivative (lo) with the compound (16) in the presence of a base to produce the pyrazole derivative (lp) of the present invention.
  • the reaction can be carried out in the same manner as in the method described in Production Method_2 (Step-3).
  • the desired product can be obtained by a usual post-treatment operation, but if necessary, it can be purified by column chromatography or recrystallization.
  • the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
  • the organic layer was washed with 1 ⁇ - «(200 mL) and water (50 mL), dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure.
  • a yellow oil (1.05 g, yield: 27.4%) was obtained.
  • Example 1 13-Hydroxy-trimethylvirazole-4-carboxylate was reacted with 3-chloropentyl chloride in the same manner as 13 to give 3- (3-chlorobenzyloxy) -trimethylpyrazole-4- A white solid of ethyl carboxylate was obtained.
  • Example—17 13-Hydroxy-trimethylvirazole-4-carboxylate was reacted with 3-chloropentyl chloride in the same manner as 13 to give 3- (3-chlorobenzyloxy) -trimethylpyrazole-4- A white solid of ethy
  • Example 1 13-Ethyl 3-hydroxy-1-methylpyrazole-4-carboxylate was reacted with 3,5-dibromobenzyl chloride in the same manner as in 13 to give 3- (3,5_dibromobenzyloxy) -1-methyl A pale yellow solid of ethyl virazole-4-carboxylate was obtained.
  • Example—32 Ethyl 3-hydroxy-1-methylpyrazole-4-carboxylate and 4- (trifluoromethyl) were prepared in the same manner as in Example 13. methyl) reacting the benzyl chloride, 1-methyl-3 - was obtained [4- (triflate Ruo ii methyl) Benjiruokishi] pyrazole-4-carboxylic acid Echiru a white solid mp:.
  • reaction mixture was poured into 1N solution (30 mL), and the precipitated solid was filtered, washed with water and sufficiently dried to obtain 5-methyl-1-methyl-3- [3- ( A white solid (1.44 g, yield: 61.5%) of trifluoromethyl) benzyloxy] pyrazole-4-carboxylate was obtained.
  • Example 1 In the same manner as in 13, ethyl 3-hydroxy-1-methylpyrazole-4-carboxylate was reacted with phenacyl chloride to give 1-methyl-3- (phenacyloxy) pyrazole-4-ethyl carboxylate in white. A solid was obtained. Soku: 83 ⁇ 85; 'H- MR (CDC1 3, TMS, ppm): ⁇ 5 8. 00 (s, 2H), 7. 65 (s, IH), 7. 60 (m, IH), 7. 48 (m, 2H), 5.52 (s, 2H), 4.2
  • Example 1 In the same manner as in Example 51, 3_ (3-cloral benzyloxy) pyrazole-4-force was reacted with ethyl ribonate and benzoyl thiol, to give 3- (3-cloral benzyloxy) -pyrazole- A white solid of ethyl 4-carboxylate was obtained.
  • Example 1 In the same manner as in Example 51, 3- (3-bromobenzyloxy) pyrazole-4-force was allowed to react with ethyl ribonate and acetyl chloride to give 3- (3-bromobenzyloxy) -1-ethylpyrazo. A white solid of ethyl 4-carboxylate was obtained.
  • Example 51 In the same manner as in 51, 3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-ethyl carboxylate was reacted with propyl iodide to give 3- [3- (trifluoromethyl) benzyloxy] A white solid of 1-propylpyrazole-4-ethyl carboxylate was obtained. m: 64-66 ° C; 'H -NMR (CDC 1 3, TMS, ppm): ⁇ 7. 78 (s, 1H), 7. 71 (s, IH)
  • Example 1 (tert-butyl) -3-hydroxypyrazole-4-carboxylate was allowed to react with 4-chloropentyl chloride in the same manner as in 13 to give 3_ (4-chlorobenzyloxy) -trityl. A white solid of (tert-butyl) pyrazole-4-ethyl ethyl ester was obtained.
  • Example 1 3-Bromobenzyl) -3-hydroxypyrazole-4-carboxylate was reacted with 3- (trifluoromethyl) benzyl chloride in the same manner as 11 to give A white solid of -bromobenzyl) -3- [3- (trifluoromethyl) benzyloxy] virazole-4-carboxylate was obtained.
  • Example 1 In the same manner as in Example 65, ethyl 3- (3-fluorobenzyloxy) -1-methylvirazole-4-carboxylate was hydrolyzed with carohydrate to give 3- (3-fluorobenzyloxy) A white solid of -1-methylvirazole-4-carboxylic acid was obtained. Immediately: ⁇ ⁇ ⁇ :; 1 !!-MR (DMS)
  • Example 1 In the same manner as in Example 65, 3- (3-bromobenzyloxy) -1-methylpyrazole-4-carboxylate was hydrolyzed to give 3- (3-bromobenzyloxy) -trimethylpyrazole. -A white solid of 4-carboxylic acid was obtained. Immediately: 174 ⁇ 176 ° C; MR (DMS0-d 6 , pm): ⁇ ⁇ .
  • Example 1 In the same manner as in Example 65, 3- (3,5-difluorobenzyloxy) -trimethylpyrazole-4-ethyl ethylate was decomposed by carohydrolysis to give 3- (3,5-difluorobenzene). A white solid of benzyloxy) -1-methylvirazole-4-carboxylic acid was obtained. Immediately: 180 82 ° C; ' ⁇ -NMR (DMS0-d 6 , ppm): 511.90-12.20 (br s, 1H), 8.06 (s, IH), 7.12-7.25 (m, 3H), 5.26 ( s, 2H), 3.72 (s, 3H).
  • Example 1 In the same manner as in Example 65, 3- (2,4-dichlorobenzyloxy) -1-methylbiazole-4-carboxylate was hydrolyzed to give 3 (2,4-dichlorobenzyloxy) -trimethyl. A white solid of pyrazole-4-carboxylic acid was obtained. Immediately: S ZSiTC 'H-NMR
  • Example 1 65-Ethyl 3- (3,5-dibromobenzyloxy) -1-methylbiazole-4-carboxylate was hydrolyzed in the same manner as in 65 to give 3- (3,5-dibromobenzyloxymethyl) methyl.
  • Virazol-4-carboxylic acid was obtained as a white solid Immediately: 202 ⁇ 205 ° C: 'H-NMR (DMSO-de, ppm): ⁇ 11.84-12.10 (brs, IH), 7.98 (s, IH), 7.72 (br s, IH), 7.61 (br s, 2H), 5.16 (s, 2H), 3.64 (s, 3H). 7 4
  • Example 1 65-Ethyl 3- [2-fluoro-3- (trifluoromethyl) benzyloxy] -1-methylvirazole-4-carboxylate was hydrolyzed to give 3- [2- Fluoro-3- (trifluoromethyl) benzyloxy] -l-methylvirazole-4-forcerileponic acid was obtained as a white solid. mp: 182 to 184; 'H-NMR (CDC1: ,, TMS, ppm): ⁇ 7.83 (dd, J HF
  • Example 1 65-Ethyl 3- [5-fluoro-3- (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-carboxylate was hydrolyzed in the same manner as in 65 to give 3- [5-fluoro 2- (Trifluoromethyl) benzyloxy] -1-methylvirazole-4-carboxylic acid was obtained as a white solid. mp: 146-148 ° C; 'H -NMR (CDC1 3, TMS, ppm): ⁇ 7. 76 (s, IH),
  • Example 1 3- (4-Isopropylbenzyloxy) -trimethylpyrazole-4-ethyl carboxylate was hydrolyzed in the same manner as in Example 65 to give 3- (4-isopropylbenzyloxy) -1- A white solid of methylvirazole-4-carboxylic acid was obtained.
  • Example-80 4-Isopropylbenzyloxy) -trimethylpyrazole-4-ethyl carboxylate was hydrolyzed in the same manner as in Example 65 to
  • Example 1 In the same manner as in Example 65, 3- (2,4-dimethylpentyloxy) -trimethyl virazole-4-ethyl hydrocarbylate was hydrolyzed to give 3- (2,4-dimethylpentyloxy) A white solid of trimethylpyrazole-4-carboxylic acid was obtained.
  • Example 1 Trimethyl-3- [2- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylate was hydrolyzed in the same manner as in Example 65, and trimethyl-3- [2- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylate was hydrolyzed in the same manner as in Example 65, and trimethyl-3- [2- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylate was hydrolyzed in the same manner as in Example 65, and trimethyl-3- [2- (trifluoromethyl) pyrazole-4-carboxylate was hydrolyzed in the same manner as in Example 65, and trimethyl-3- [2- (trifluoromethyl) pyrazole-4-carboxylate was hydrolyzed in the same manner as in Example 65, and trimethyl-3- [2- (trifluoromethyl) pyrazole-4-carboxylate was hydrolyzed in the same manner as in Example 65, and trimethyl-3- [2-
  • Example 3- [4- (Trifluoromethyl) benzyloxy] -1-ethylmethylazole-4-carboxylate was hydrolyzed in the same manner as in Example 65 to give 3- [4- (trifluoromethyl) benzyloxy]
  • a white solid of trimethylpyrazole-4-carboxylic acid was obtained.
  • Example 1 In the same manner as in Example 65, 3- [2,4-bis (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-hydrocarboxylate was hydrolyzed to give 3- [2,4-bis ( A white solid of [trifluoromethyl) benzyloxy] -trimethylpyrazol-4-carboxylic acid was obtained. mp: 181 ⁇ 183 ° C; 1 H-NMR (DMSO-d 6 , DPm): 6U.00-13.00 (br s, 1H),
  • Example 1 In the same manner as in Example 65, 3- [tri (3-bromophenyl) ethyloxy] -tomethylyllevirazole-4-hydrocarbylate was hydrolyzed to give 3- [tri (3-bromophenyl) ethyloxy] -trimethylvilla. A white solid of sol-4-carboxylic acid was obtained.
  • Example 1 In the same manner as in Example 65, 3- (3-bromobenzyloxy) -tolylpyrazole-4 was hydrolyzed to form ethyl 3- (3-bromobenzyloxy) -tolylpyrazole. A white solid of -4-carboxylic acid was obtained. mp: 146-147:; 1 H-NMR (CDC ⁇ .
  • Example 1 In a manner similar to 65, triisopropyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylate was hydrolyzed to give triisopropyl-3- [3- (trifluoromethyl). ) Benzoxy] pyrazolyl-4-carboxylic acid was obtained as a white solid. mp: 146- 148 ° C; 1 H-NMR (CDC 1 3, TMS, ppm): (5 7. 81 (s, 1H), 7. 77 (s, IH), 7.
  • Example 1 In the same manner as in 65, 3- (3-bromobenzyloxy) -tri (tert-butyl) pyrazole-4-carboxylate was hydrolyzed to give 3- (3-bromobenzyloxy)- A white solid of tri (tert-butyl) pyrazole-4-carboxylic acid was obtained.
  • Example 1 In the same manner as in Example 65, ethyl (tert-butyl) -3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylate was hydrolyzed with carohydrate to give l- (tert-butyl) -A white solid of 3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was obtained.
  • Example 1 In the same manner as in Example 65, 3-ethoxy-1- [3- (trifluoromethyl) benzyl] pyrazole-4-carboxylate was decomposed by caro 7K to give 3-ethoxy-1- [3- ( A white solid of trifluoromethyl) benzyl] pyrazole-4-carboxylic acid was obtained.
  • Example 1 In the same manner as in 104, 3-isopropyloxy-trimethylvirazole-4-carboxylic acid was reacted with 2,4-difluoroaniline to obtain N- (2,4-difluorophenyl). Colorless needle-like crystals of -3-isopropyloxy-1-methylpyrazole-4-hexanoloxamide were obtained (yield: 49.4%). m: 120-12:;.. 1 HN R (CDC 1 :,, TMS, ppm): 5 9. 08 (br s, 1H), 8.
  • Example 1 In the same manner as in 104, 3-propargyloxy-1-methylvirazole-4-carboxylic acid was reacted with ethylpropylpropylamine to give N-ethyl-N-propyl-3-propargylol. A colorless transparent oily product of xy-1-methylpyrazole-4-carboxamide (yield: 51.7%) was obtained.
  • Example 1 In a manner similar to that of 108, 3- (3-fluorobenzyloxy) -1-methylbiazole-4-carboxylic acid was reacted with ethylpropylamine to give N-ethyl-N-propyl propyl. A white-orange solid of 3- (3-fluorobenzyloxy) -1-methylpyrazol-4-carboxamide was obtained (yield: 92.3%).
  • Example 1 In a manner similar to that of 108, 3- (3-fluorobenzyloxy) -1-methylbiazole-4-potassium sulfonic acid was reacted with piperidine to give N, N-pentamethylene-3-. There was obtained a white-orange solid (yield: 86.4%) of (3-fluorobenzyloxy) -1-methylvirazole-4-hexanoloxamide.
  • Example 1 In the same manner as in 108, 3- [2-fluoro-3- (trifluoromethyl) benzoyloxy] -1-methylpyrazole-4-carboxylic acid and 0-ethylhydroxylamine hydrochloride were used. Was reacted to obtain N-ethoxy-3- [2-fluoro-3- (trifluoromethyl) benzyloxy] -1-methylvirazole-4-carboxamide as a white solid (yield: 96.6.). m: 136-137T; 1 H-NMR (CDC 1 3, TMS, ppm): (5 8. 96 (s, 1H), 7. 78 (s, IH), 7.
  • Example 1 In the same manner as in Example 108, 3- [4-fluoro-3- (trifluoromethyl) benzoyloxy] -trimethylpyrazole-4-carboxylic acid was reacted with hydroxylamine hydrochloride. A white solid of 3- [4-fluoro-3- (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-carbohydroxamic acid was obtained (yield: 63.6.). mp: 146-1481 :; 1 H-NMR (CDC 1 3, TMS, ppm):. ⁇ 8. 97 (s, IH), 8. 00-8 80 (br, IH), 7. 75 (s, 1 H), 7.60-7.75 (m, 2H), 7.20-7.30 (m, IH), 5.31 (s, 2H), 3.76 (s, 3H). — 1 1 5
  • Example 1 In the same manner as in 108, 3- [4-fluoro-3- (trifluoromethyl) benzoyloxy] -1-methylpyrazole-4-carboxylic acid and 0-ethylhydroxylamine hydrochloride was reacted to obtain N-ethoxy-3- [4-fluoro-3- (trifluoromethyl) benzyloxy] -trimethylvirazole-4-carboxamide as a white solid (yield: 74.13 ⁇ 4).
  • Example 1 Reaction of 3- [4-fluoro-3- (trifluoromethyl) benzoyloxy] -trimethylpyrazole-4-carbohydroxamic acid with tribromo-2-fluoroethane in the same manner as in Example 24 N- (2-Fluoroethyloxy) -3- [4-fluoro-3- (trifluoromethyl) benzyloxy] -trimethylvirazole-4- white lipoxamide as a white solid (yield: 52. resulting m:. 128-1301 :; 1 HN R (CDC 1 3, TMS, ppm):. ⁇ 9. 15 (s, IH), 7. 79 (s, IH), 7.
  • Example 1 3- [5-Fluoro-3- (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-hydroxysulfonic acid and 0-ethylhydroxylamin hydrochloride in the same manner as in 108 To give N-ethoxy-3- [5-fluoro-3- (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-carboxamide as a white solid (yield: 88.23 ⁇ 4). mp: 125-127T; 1 H-NMR (CDC 1 3, TMS, ppm): 5 8. 93 (s, 1H), 7. 79 (s, 1H),
  • Example 1 In the same manner as in 108, 3- (2-chlorobenzyloxy) -trimethylpyrazole-4-carboxylic acid was allowed to react with isopro, pyramine to give N-isopropyl-2- 2-chlorobenzyloxy-1-. Methylvirazole-4-carboxamide white solid
  • Example 1 In the same manner as in 108, 5-chloro-3- (3-chlorobenzyloxy) -methylpyrazole-4-carboxylic acid was reacted with ethylpropylamine to give N-ethyl. -A pale yellow-white solid of N-propyl-5-oct-3- (3- (octylbenzyloxy) -trimethylpyrazol-4-hexanol ⁇ (yield: 67.1%) was obtained.
  • Example 1 In the same manner as in 108, 3- (3-chlorobenzyloxy) -1-methylvirazole-4-carboxylic acid was reacted with 2-methoxyethylamine to give N- (2-methoxyethyl). A pale orange-white solid (yield: 99.6%) of -3- (3-c-hydroxybenzyloxy) -1-methylvirazole-4-carboxamide was obtained. Soku:. 50 ⁇ 52; 'H- NMR ( CDC1 3, TMS, ppm): ⁇ 7 • 74 (s, IH), 7. 45 (br s, IH), 7.
  • Example 1 In the same manner as in Example 108, 3- (3-chlorobenzyloxy) -1-methylvirazole-4-carboxylic acid was reacted with piperidine to give N, N-pentamethylene-3- (3-chlorobenzyloxy. ) -Trimethylpyrazole-4-carboxamide was obtained as a white solid (yield: 49.53 ⁇ 4).
  • Example 1 In the same manner as in 108, 3_ (3-chlorobenzyloxy) -trimethylvirazole-4-carboxylic acid was reacted with N-methylaniline to give N-methyl-N-phenyl. A white solid (yield: 74.0%) of -3- (3-chlorobenzyloxy) -1-methylvirazosole-4-carboxamide was obtained. mp: 92-94 ° C; 'H-NMR (CDCl 3 , TMS, ppm): ⁇ 7.28 (br s, 1H), 7.26 (s, 1H), 7.15-7.27 (m, 5H), 7.05-7.14 (m, 2H), 6.89 ( s, 1H), 4.95 (s, 2H), 3. 59 (s, 3H), 3.39 (s, 3H) example -. 129 c i -Q 3 ⁇ 4
  • Example 1 In the same manner as in 1 O 8, 3- (3-chlorobenzyloxy) -trimethylvirazole-4-carboxylic acid was allowed to react with 3-chloro-2,4-difluoroaniline, and N- ( There was obtained a white solid of 3-mouth-2, 4-difluorophenyl)-3-(3-mouth benzyloxy)-trimethylvirazole-4-lipoxamide (yield: 81.0%).
  • N- (3-chloro-2,4-difluorophenyl) -3- (3-cyclobenzyloxy) -trimethylvirazole-4-carpoxamide was mixed with methyl iodide. Reaction, N_ (3-chloro-2,4-difluorophenyl) -N-methyl-3- (3-chlorobenzyloxy) -1-methylbirazol-4-cearliestpoxamide pale purple solid (yield: 69.7 %).
  • N- (4-Acetylphenyl) -3- (3-chlorobenzyloxy) -1-methylpyrazole-4-carboxamide (0.51 ⁇ 2, 1.35 ⁇ 01) in methanol (20110 solution with sodium methoxide (0.11 lg, 2.03 bandol) and 0-methylhydroxylamine assalt (0.19 g, 2.29IMO1) were added at 0 ° C, and the solution was heated and stirred at 80 ° C for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water (lOmL), and the precipitated solid was filtered and sufficiently dried.
  • Thionyl chloride (1.5 mL) was added to a toluene (25 mL) solution of 3- (3-cyclohexylbenzyloxy) -trimethylpyrazole-4-carboxylic acid (0.35 g, 1.30 t) at room temperature. This solution was heated and stirred at 120 ° C. for 2 hours. The temperature was then raised to 140: and toluene and excess thionyl chloride were removed using Dean 'Stark.
  • Example 1 In the same manner as in Example 108, 3- (3-chlorobenzyl) -thretylvirazole-4-potassoleic acid was reacted with 0-ethylhydroxylamine hydrochloride to give N-ethoxy_3- ( A white solid (yield: 63 ⁇ 33 ⁇ 4) of 3-cycloethyl benzyl) -1-ethylpyrazole-4-carboxamide was obtained.
  • m 75 ⁇ 77:; 1 H-NMR (CDC 1 3, TMS, ppm): ⁇ 9. 01 (s, 1H), 7. 83 (s, IH), 7. 45 (s, IH), 7 30-7.
  • Example 1 1- (tert-butyl) -3- (3-chlorobenzyloxy) pyrazole-4-carboxylic acid was reacted with ethylpropylamine in the same manner as in 108, and N- Ethyl-N-propyl- (tert-butyl) -3- (3-tert-butylbenzyloxy) pyrazole-4-force A lipoxamide free ⁇ -clear oil (yield: 45.0%) was obtained.
  • Example 155-Example 1 In the same manner as in Example 108, 3- (3-bromobenzyloxy) -trimethylvirazole-4-carboxylic acid was used. Reaction with piperidine yielded N, N-pentamethylene-3- (3-bromobenzyloxy) -1-methylvirazole-4-carboxamide as a white-orange solid (yield: 85.63 ⁇ 4).
  • hydroxylamine salt 2.0 g, 28.9 ol
  • carbonic acid rim 3.99 g, 28.9 ol
  • the temperature was gradually raised to room temperature, followed by stirring at the same temperature for 2 hours.
  • the reaction mixture was poured into a 1N experiment (50 mL), and extracted with ethyl acetate (80 IDL X 2.)
  • the organic layer was water (100 mL), and a 0.5% aqueous sodium hydroxide solution (70 mL).
  • Example 1 3- (3-bromobenzyloxy) -1-methylpyrazole-4-carpohydroxamic acid was reacted with 1-bromopropane to give N-propoxy-3- ( A white solid (3-bromobenzyloxy) -trimethylpyrazole-4-force lpoxamide was obtained (yield: 55.2%). mp: 91-93 0 C; 'H-MR (CDCl 3, TMS, ppm): ⁇ 8.98 (s,
  • -White solid of carboxamide (0.09 g, yield: 26.3) mp: 115-117 X: 1 HNR (CDC 1:,, TMS, ppm): 58.90 (s, IH)
  • Example 2 In the same manner as in Example 24, 3- (3-bromobenzyloxy) -1-methylpyrazole-4-carpohydroxamic acid was reacted with 3-butenyl bromide to give N- (3-butenyl (Roxy) -3- (3-bromobenzyloxy) -trimethylvirazole-4-carboxamide was obtained as a white solid (yield: 32.6%).
  • Example 1 In the same manner as in 108, 3- (3-bromobenzyloxy) -1-ethylvinylazole-4-carboxylic acid was reacted with 0-ethylhydroxylamine hydrochloride to give N-ethoxy- A white solid (yield: 78.33 ⁇ 4) of 3- (3-bromobenzyloxy) -tethylvirazole-4-hexanoloxamide was obtained. Soku: 82 ⁇ 84; 1 H - thigh (CDC 1 3, TMS, ppm ): 6 9. 0 0 (s, IH), 7. 83 (s, IH), 7.
  • Example 1 In the same manner as in 108, 3- (3-bromobenzyloxy) -1- (tert-butyl) pyrazole-4_carboxylic acid was reacted with ethylpropylamine to give N-ethyl. A pale yellow oil of -N-propyl-3- (3-bromobenzyloxy) -tri (tert-butyl) pyrazole-4-potanol was obtained (yield: 69.9%).
  • Example 1 In the same manner as in 108, 3- (2,4-dichlorobenzyloxy) -trimethylpyrazole-4-carboxylic acid was reacted with propargylamine to give N-propargyl-3- (2, 4-Dichlorobenzyloxy) -1-methylvirazole-4-carboxamide was obtained as a white solid (yield: 49.03 ⁇ 4).
  • Example 1 In the same manner as in 108, 3- (2,6-dichlorobenzyloxy) -trimethylpyrazole-4-carboxylic acid was reacted with ethylpropylamine to give N-ethyl-N-propyl- 3- (2,6-dichlorobenzyloxy) -1-methylvirazole-4-carboxamide orange-white solid (Yield: 92.63 ⁇ 4.
  • Example 1 In the same manner as in 108, 3- (2,6-dichlorobenzyloxy) -1-methylpyrazole-4-carboxylic acid was reacted with 3-chloro-2,4-difluoroaniline. , N- (3-Chloro-2,4-difluorophenyl) -3- (2,6-dicyclohexylbenzyloxy) -trimethylvirazole-4-white sulfoxamide (yield: 63.3) I got Immediately: 176 ⁇ ns i 'H-NMRCCDCh.
  • Example 1 In the same manner as in 108, 3- (3,5-dibromobenzyloxy) -1-methylpyrazole-4-carboxylic acid was reacted with ethylpropylamine to give N-ethyl-N-propyl. - 3- (3, 5-dibromo-benzyl O carboxymethyl) -1-methyl Villa tetrazole - 4 carboxyl Samido orange white solid (yield: 79. give a 23 ⁇ 4 m:. 73 ⁇ 75 ° C; 1 H- NMR (CDC 1 3, TMS, ppm): ⁇ 7. 60 (br s, 1H), 7. 50 (m, 2H), 7. 45 (s, 1H), 5. 19 (s, 2H), 3 . 74 (s, 3H), 3.30-3.50
  • Example 1 In the same manner as in Example 108, to-methyl-3- (3-methylbenzyloxy) virazole-4-carboxylic acid was reacted with ethylpropylpropylamine to give N-ethyl-N-propyl-tomethyl-. A colorless, transparent oil of 3- (3-methylbenzyloxy) pyrazole-4-carboxamide was obtained (yield: 84.5%).
  • Example 1 In the same manner as in 108, 3- (2,4-dimethylbenzyloxy) -1-methylpyrazole-4-carboxylic acid was reacted with ethylpropylpropylamine to give N-ethyl-N- A white solid of propyl-3- (2,4-dimethylbenzyloxy) -1-methylpyrazole-4-carboxamide was obtained (yield: 46.8%).
  • Example 1 In the same manner as in Example 108, 3- (2,4-dimethylpentyloxy) -trimethylpyrazole-4-carboxylic acid was reacted with 4-methylthioaniline to give N- (4-methyl Thiophenyl) -3- (2,4-dimethylbenzyloxy) -1-methylvirazole-4-carpoxamide was obtained as a white solid (yield: 63.4%).
  • m 128-130 ° C; 1 H -NMR (CDC 1 3, TMS, ppm): ⁇ 8. 57 (br s, IH), 7. 80 (s, IH), 7.
  • Example 1 N- (4-methylthiophenyl) -3- (2,4-dimethylbenzyloxy) -1-methylvirazole-4-carboxamide was converted to m-chloroperbenzoic acid in the same manner as in 108. Oxidation with N- (4-methylsulfonylphenyl) -3- (2,4-dimethylbenzyloxy) -trimethylpyrazole-4-carboxamide as a white solid (yield: 94. 53 ⁇ 4) was obtained.
  • Example 1 Trimethyl-3- [2_ (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with ethylpropylamine in the same manner as in 108, to give N-ethyl-N-propyl. A white solid (yield: 63.9) of -trimethyl-3- [2- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained.
  • Example 1 In the same manner as in 108, 1-methyl-3- [2- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was mixed with 3-chloro-2,4-difluoroaline. The reaction was allowed to proceed, and a white solid of N- (3- ⁇ ⁇ ⁇ -2,4-difluorophenyl) -trimethyl-3- [2- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 54.2). %).
  • Example 1 In the same manner as in 108, 1-methyl-3_ [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with ethylpropylamine to obtain -ethyl-N-propyl. A pale orange oil of 1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 92.3%).
  • Example 1 In the same manner as in 108, 5-chloro-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with ethyl (cyclohexyl) amine. N-ethyl-N-cyclohexyl-5-coguchi-1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide as a white solid (yield: 75.93 ⁇ 4) Obtained. mp: 92 ⁇ 94 ° C; ' ⁇ -certification (CDC1: ,, TMS, ppm): ⁇ 7.67 (s, IH), 7.58 (br d, J-7.
  • Example 1 In the same manner as in Example 108, 5_chloro-1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with pyrrolidine to give N, N-tetramethylene. A white solid (yield: 85.5%) of 5-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazol-4-carboxamide was obtained.
  • thionyl chloride 1.2 mL
  • arylamine (0.07 g, 1.30 mmol) and triethylamine (0.12 g, 1.20 mmol) were added, and the temperature was gradually raised to room temperature, followed by stirring at the same temperature for 5 hours.
  • the reaction mixture was poured into 1N-medullary (20 mL), and extracted with ethyl acetate (20 mL ⁇ 2).
  • the organic layer was washed with 1N-don (20 mL ⁇ 3) and water (50 mL), dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure.
  • Example 1 Trimethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was allowed to react with propargylamine in the same manner as in Example 108, and N-propargyl-1-methyl was reacted. A white solid of 3_ [3_ (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 73.5%).
  • Example 3 In the same manner as in 108, 3- [3- (trifluoromethyl) benzyloxy] -trimethylvirazole-4-carboxylic acid was reacted with aniline to give N-phenyl .-Methyl-3- [3- (triflate Ruo ii methyl) Benjiruokishi] pyrazole - 4- Karubokisa bromide as a white solid (yield: 84.
  • Example 1 In a manner similar to that of 279, N-phenyl-3- [3- (trifluoromethyl) benzyloxy] -trimethylvirazole-4-carboxamide was allowed to react with N-butyl chloride to give N-phenyl. A colorless transparent oil (yield: 56.6%) of ethyl-N-phenyl-3- [3- (trifluoromethyl) benzyloxy] -1-methylvirazole-4-carboxamide was obtained.
  • Example 1 1-methyl-3- [3- (trifluoromethyl) benzyl Reaction of 2,4-dichloroaniline with 2,4-dichloroaniline and N- (2,4-dichlorophenyl) -trimethyl-3- [3- (trifluoromethyl) A white solid (benzyloxy) pyrazole-4-carboxamide was obtained (yield: 54.7%).
  • Example 1 In the same manner as in 108, 1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with 3,5-dichloroaniline, and N- ( A white solid of 3,5-dichlorophenyl) -trimethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 56.33 ⁇ 4).
  • Example 1 In the same manner as in 108, 5-chloro-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid and 3-chloro-2,4-difluoroaniline were used. To give N- (3-chloro-2,4-difluorophenyl) -5-chloro-trimethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide white A solid (yield: 69.83 ⁇ 4) was obtained.
  • Example 1 In the same manner as in 108, 1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carbonic acid and 4-chloro-2-fluoro-5- (tobutyne -3-yloxy) aniline to react with ⁇ - [4-ku-guchi-2-fluoro-5- (1-butyne-3-yloxy) phenyl] -trimethyl-3- [3- (trifur (Oromethyl) benzyloxy] pyrazole_4_carboxamide orange white solid (Yield: 40.8. Mp: 161-163 ° C: 1 H-NMR (CDC 13, TMS, ppm): 58.
  • Example 1 1-Methyl-3- [3- (trifluoromethylyl) benzyl [Roxy] pyrazole-4-carboxylic acid is reacted with 2,4-difluoro-5-nitroaniline to give N- (2,4-difluoro-5-ditrophenyl) -1-methyl-3- [3- (triflur (Oromethyl) benzyloxy] pyrazole-4-carboxamide was obtained as a white solid (yield: 49.93 ⁇ 4).
  • Example 1 Trimethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with 4-cyanoaniline in the same manner as in 108 to obtain N- (4-cyanophenyl). A white solid of 1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 84.93 ⁇ 4).
  • Example 1 In the same manner as in 108, 1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with 4-methylthioaniline to obtain N- (4 -Methylthiophenyl)-1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4- white sulfoxamide as a white solid (yield: 95.5.
  • Example 1 N- (4-methylthiophenyl) -1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-caprolepoxamide was prepared in the same manner as in 108. Oxidation with perbenzoic acid gives a white solid of N- (4-methylsulfenylphenyl) -1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide ( yield: 45. 2%) [mp: 132-134:; 1 H-NMR (CDC 1 3, TMS, ppm): (5 8. 67 (br s, 1H), 7.
  • N-methylhydroxylamine hydrochloride (0.25 g, 3.00 marl) and carbonic acid rim (0.55 g, 4 mL) were added.
  • pour the reaction mixture into 1N-don (20 mL) and add ethyl acetate (20 mL x 2).
  • the organic layer was washed with IN- ⁇ (20 mL), 2N-7j ⁇ sodium oxide (20 mU, then with water (20 mL x 2), and dried over anhydrous magnesium sulfate.
  • Example 1 The reaction of 3- [3- (trifluoromethyl) benzyloxy] -1-methylvirazole-4-carbohydroxamic acid and sec-butyl iodide in the same manner as in Example 2 A white solid of sec-butoxy-3- [3- (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-carboxamide was obtained (yield: 12.5%). Soku: ⁇ ⁇ ⁇ :; 1 !! - N MR (CDC1 3, TMS, pm): ⁇ 8. 85 (s, 1H), 7. 78 (s, 1H), 7.
  • Example 1 3- [3- (Trifluoromethyl) benzyloxy] -trimethylpyrazole-4-carbohydroxamic acid was reacted with octane iodide in the same manner as in Example 2 to give N-butyroxy-3. -[3- (Trifluoromethyl) benzyloxy] -1-methylvirazole-4-carboxamide was obtained as a white solid (yield: 38.3%).
  • Example 1 Trimethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carbohydroxamic acid was reacted with methyl chloroacetate in the same manner as in Example 24 to obtain N- (methoxy). A pale orange solid of carbonylmethyloxy) -1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 75.83 ⁇ 4).
  • Example 1 1-Methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carbohydroxamic acid was reacted with ⁇ -bromopropionate in the same manner as in 24 A white solid of ⁇ - [1- (ethoxycarponyl) ethyloxy] -1-methyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 63.33 ⁇ 4). .
  • Triethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid (0.23 g, 0.73 recited ol) in a solution of toluene (20 mL) in thionyl chloride (1. OmL) was added at room temperature, and the solution was heated and stirred at 120 ° C. for 2 hours. Then raise the temperature to 140 ° C Then, toluene and excess thionyl chloride were removed using Din-Stark.
  • reaction mixture was poured into a 1N experiment (50 mL) and extracted with ethyl acetate (80 mL ⁇ 2).
  • the organic layer was washed with water (1 OOmL), 0.5% sodium hydroxide aqueous solution (70mL) and water (1 OOmL), and dried over anhydrous magnesium sulfate.
  • the drying agent was removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure.
  • the obtained crude product was washed with hexane dimethyl ether to obtain a white solid of triethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carbohydroxamic acid (0.
  • Toluyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid (0.5 g, 1.59 mmol) in toluene (20 mL) was treated with thionyl chloride (1. OmL) at room temperature. The solution was stirred at 12 (TC for 2 hours. The temperature was then raised to 140 ° C, and toluene and excess thionyl chloride were removed using Dean-Stark. The reaction mixture was brought to room temperature.
  • Example 1-Ethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carbohydroxamic acid and isopropyl iodide were reacted in the same manner as in 245 to give N-isopropoxy-1- A light brown solid (yield: 26.53 ⁇ 4) of ethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained.
  • 87-89 ° C; ' ⁇ -thigh (CDC13, TMS, ppm): ⁇ 8.90 (s, IH), 7.83 (s, IH), 7.74 (s, IH), 7.63 (d, J 7
  • Example 1-Ethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carpohydroxamic acid was reacted with getylcarbamoyl oxalate in the same manner as in Example 2
  • a white solid (yield: 45.5%) of -Jetylcarbamoy xy-ethoxyl-3- [3- (trifluoromethyl) benzyloxy] pyrazol-4-carboxamide was obtained.
  • Example 1 108- (tert-butyl) -3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with ethylpropylamine in the same manner as in Example 108 to give N-ethyl- A colorless and transparent viscous product of N-propyl-1- (tert-butyl) -3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 53.9%).
  • Example 1 In the same manner as in 108, triisopropyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxylic acid was reacted with 2,4-difluoroaniline, and N- (2,4 A white solid (-difluorophenyl) -triisopropyl-3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-carboxamide was obtained (yield: 76.3%).
  • N-propargyl-1- (tert-butyl) -3- [3- (trifluoromethyl) benzyloxy] pyrazole-4-potency lipoxamide (0.53 g, 1.40 mmol) and stir at room temperature for 10 minutes, then cool to 0 ° C Rejected. Then, methyl iodide (0.24 g, 1.68 bandol) was added, the temperature was gradually raised to room temperature, and the mixture was stirred at that temperature for 20 hours.
  • reaction mixture was poured into 1N-volume (100 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • the organic layer was washed with 1N hydrochloric acid (100 mL) and water (50 mL), dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure.
  • Tridifluoromethyl-3- [3- (trifluoromethyl) benzyloxy] pyrazo Thionyl chloride (5 mL) was added at room temperature to a toluene (10 mL) solution of ru-4-carbonic acid (0.50 g, 1.49 ol), and the solution was heated and stirred at 120 ° C. for 8 hours. The temperature was then raised to 140 ° C and toluene and excess thionyl chloride were removed using Dean-Stark. After cooling the reaction mixture to room temperature, DMF (10 mL) was added and further cooled to 0 ° C.
  • Example 1 In the same manner as in 108, 3- [2,4_bis (trifluoromethyl) benzyloxy] -1-methylvirazole-4-caproluconic acid was reacted with piperidine to give N, N-pentane. Methylene-3- [2,4-bis (trifluoromethyl) benzyloxy] -1-methylpyrazole-4-carboxamide was obtained as a white solid (yield: 79.1%).
  • Example 1 In the same manner as in 108, 3- [3,5-bis (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-carboxylic acid was reacted with ethylpropylamine to give N- A white viscous substance of ethyl-N-propyl-3- [3,5-bis (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-carboxamide was obtained (yield: 54.1%).
  • ' ⁇ -hidden (CDC1 TMS, ppm): ⁇ 7.89 (s, 2H), 7.83 (s, IH), 7.46 (s, IH), 5.37 (s, 2H), 3.
  • Example 1 3- [3,5-bis (trifluoromethyl) benzyloxy] -1-methylpyrazole-4-carboxylic acid and morpholine were reacted in the same manner as in 108 to obtain ⁇ , ⁇ -methylenoxy.
  • Example 1 In the same manner as in 108, 3- [3,5-bis (trifluoromethyl) benzyloxy] -trimethylvirazole-4-carboxylic acid and 3-chloro-2,4-difluoroacetic acid And N- (3-chloro-2,4-difluorophenylyl) -3- [3,5-bis (trifluoromethyl) benzyloxy] -trimethylpyrazole-4-carboxamide as a white solid ( Yield: 36.8%).
  • Example 1 In the same manner as in 108, 3- [3,5-bis (trifluoromethyl) benzyloxy] -1-methylbiazole-4-carboxylic acid and 2,4,5-trichloroaniline To give a white solid of N- (2,4,5-trichlorophenyl) -3- [3,5-bis (trifluoromethyl) benzyloxy] -1-methylvirazole-4-carboxamide (yield: 27. Got 2tt.

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Abstract

La présente invention concerne des dérivés pyrazole représentés par la formule générale (I) et faisant preuve d'un excellent effet comme principe actif d'herbicides. L'invention concerne également, d'une part des intermédiaires pour la préparation de ces dérivés, d'autre part des procédés de préparation de ces dérivés et intermédiaires, et enfin des herbicides dont ces dérivés sont le principe actif. Dans cette formule, R1a est C¿1-12? alkyle éventuellement substitué ou C7-11 aralkyle éventuellement substitué; R?2a¿ est hydrogène, C¿1-12? alkyle éventuellement substitué, C3-8 cycloalkyle éventuellement substitué, C7-11 aralkyle éventuellement substitué, C3-6 alcényle éventuellement substitué, C3-6 alkynyle éventuellement substitué, acyle éventuellement substitué, ou sulfonyle éventuellement substitué; R?3¿ est hydrogène, C¿1-6? alkyle, ou halogéno; et R est carbamoyle éventuellement substitué ou acylamino éventuellement substitué.
PCT/JP2000/006519 1999-09-27 2000-09-22 Derives pyrazole, intermediaires pour la preparation de ces derives, procedes de preparation des derives et intermediaires, et herbicides dont ces derives sont le principe actif WO2001023358A1 (fr)

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JP27269999 1999-09-27
JP11/272700 1999-09-27
JP11/272699 1999-09-27
JP27270099 1999-09-27

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002348280A (ja) * 2001-03-23 2002-12-04 Sagami Chem Res Center ピラゾール誘導体とその製造中間体及びそれらの製造方法、並びにそれらを有効成分とする除草剤
WO2005113511A1 (fr) * 2004-05-12 2005-12-01 Bristol-Myers Squibb Company Antagonistes uréiques du récepteur p2y1 pour le traitement des syndromes thrombotiques
WO2007058346A1 (fr) * 2005-11-21 2007-05-24 Shionogi & Co., Ltd. COMPOSE HETEROCYCLIQUE PRESENTANT UNE ACTIVITE INHIBITRICE DE LA 11-β-HYDROXYSTEROIDE DESHYDROGENASE DE TYPE I
WO2008142986A1 (fr) 2007-05-18 2008-11-27 Shionogi & Co., Ltd. DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DE L'AZOTE POSSÉDANT UNE ACTIVITÉ INHIBITRICE SUR LA 11 β-HYDROXYSTÉROÏDE DÉSHYDROGÉNASE DE TYPE I
US7550499B2 (en) 2004-05-12 2009-06-23 Bristol-Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7645778B2 (en) 2005-01-19 2010-01-12 Bristol-Myers Squibb Company Heteroaryl compounds as P2Y1 receptor inhibitors
US7700620B2 (en) 2005-06-27 2010-04-20 Bristol-Myers Squibb Company C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
CN1917763B (zh) * 2004-02-06 2010-05-05 拜尔农作物科学股份公司 作为用于植物保护及材料保护的杀微生物活性成分的n-(2-羟甲基)苯基-1h-吡唑-4-甲酰胺衍生物及相关化合物
US7714002B2 (en) 2005-06-27 2010-05-11 Bristol-Myers Squibb Company Carbocycle and heterocycle antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7728008B2 (en) 2005-06-27 2010-06-01 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7816382B2 (en) 2005-06-27 2010-10-19 Bristol-Myers Squibb Company Linear urea mimics antagonists of P2Y1 receptor useful in the treatment of thrombotic condition
JP2011502133A (ja) * 2007-11-02 2011-01-20 メシルジーン インコーポレイテッド ヒストンデアセチラーゼの阻害剤
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
WO2015200650A1 (fr) * 2014-06-25 2015-12-30 Epizyme, Inc. Composés hétéroaryles bicycliques fusionnés en 6,5 ou benzènes substitués

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US4666502A (en) * 1982-02-09 1987-05-19 Sandoz Ltd. Herbicidal N-thienyl-chloroacetamides
US4792565A (en) * 1986-04-24 1988-12-20 Mitsui Toatsu Chemicals, Inc. Pyrazolecarbonylamine derivatives and agricultural and horticultural fungicides containing said compounds
JPH01207289A (ja) * 1987-10-19 1989-08-21 Mitsui Toatsu Chem Inc アシルアミノアセトニトリル誘導体の製造法
US5223526A (en) * 1991-12-06 1993-06-29 Monsanto Company Pyrazole carboxanilide fungicides and use
WO1999012911A1 (fr) * 1997-09-05 1999-03-18 Basf Aktiengesellschaft Procede de preparation d'hydroxylamines (hetero)aromatiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4666502A (en) * 1982-02-09 1987-05-19 Sandoz Ltd. Herbicidal N-thienyl-chloroacetamides
US4792565A (en) * 1986-04-24 1988-12-20 Mitsui Toatsu Chemicals, Inc. Pyrazolecarbonylamine derivatives and agricultural and horticultural fungicides containing said compounds
JPH01207289A (ja) * 1987-10-19 1989-08-21 Mitsui Toatsu Chem Inc アシルアミノアセトニトリル誘導体の製造法
US5223526A (en) * 1991-12-06 1993-06-29 Monsanto Company Pyrazole carboxanilide fungicides and use
WO1999012911A1 (fr) * 1997-09-05 1999-03-18 Basf Aktiengesellschaft Procede de preparation d'hydroxylamines (hetero)aromatiques

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4559690B2 (ja) * 2001-03-23 2010-10-13 公益財団法人相模中央化学研究所 ピラゾール誘導体とその製造中間体及びそれらの製造方法、並びにそれらを有効成分とする除草剤
JP2002348280A (ja) * 2001-03-23 2002-12-04 Sagami Chem Res Center ピラゾール誘導体とその製造中間体及びそれらの製造方法、並びにそれらを有効成分とする除草剤
CN1917763B (zh) * 2004-02-06 2010-05-05 拜尔农作物科学股份公司 作为用于植物保护及材料保护的杀微生物活性成分的n-(2-羟甲基)苯基-1h-吡唑-4-甲酰胺衍生物及相关化合物
WO2005113511A1 (fr) * 2004-05-12 2005-12-01 Bristol-Myers Squibb Company Antagonistes uréiques du récepteur p2y1 pour le traitement des syndromes thrombotiques
US7388021B2 (en) 2004-05-12 2008-06-17 Bristol Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7550499B2 (en) 2004-05-12 2009-06-23 Bristol-Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7674828B2 (en) 2004-05-12 2010-03-09 Bristol-Myers Squibb Company Urea antagonists of P2Y1receptor useful in the treatment of thrombotic conditions
US7645778B2 (en) 2005-01-19 2010-01-12 Bristol-Myers Squibb Company Heteroaryl compounds as P2Y1 receptor inhibitors
US7714002B2 (en) 2005-06-27 2010-05-11 Bristol-Myers Squibb Company Carbocycle and heterocycle antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7700620B2 (en) 2005-06-27 2010-04-20 Bristol-Myers Squibb Company C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7728008B2 (en) 2005-06-27 2010-06-01 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7816382B2 (en) 2005-06-27 2010-10-19 Bristol-Myers Squibb Company Linear urea mimics antagonists of P2Y1 receptor useful in the treatment of thrombotic condition
US8329718B2 (en) 2005-06-27 2012-12-11 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
WO2007058346A1 (fr) * 2005-11-21 2007-05-24 Shionogi & Co., Ltd. COMPOSE HETEROCYCLIQUE PRESENTANT UNE ACTIVITE INHIBITRICE DE LA 11-β-HYDROXYSTEROIDE DESHYDROGENASE DE TYPE I
AU2006316087B2 (en) * 2005-11-21 2011-03-10 Shionogi & Co., Ltd. Heterocyclic compound having inhibitory activity on 11-beta-hydroxysteroid dehydrogenase type I
US8324265B2 (en) 2005-11-21 2012-12-04 Shionogi & Co., Ltd. Heterocyclic compounds having type I 11β hydroxysteroid dehydrogenase inhibitory activity
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
WO2008142986A1 (fr) 2007-05-18 2008-11-27 Shionogi & Co., Ltd. DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DE L'AZOTE POSSÉDANT UNE ACTIVITÉ INHIBITRICE SUR LA 11 β-HYDROXYSTÉROÏDE DÉSHYDROGÉNASE DE TYPE I
US8383622B2 (en) 2007-05-18 2013-02-26 Shionogi & Co., Ltd. Nitrogen-containing heterocyclic derivative having 11β-hydroxysteroid dehydrogenase type I inhibitory activity
JP2011502133A (ja) * 2007-11-02 2011-01-20 メシルジーン インコーポレイテッド ヒストンデアセチラーゼの阻害剤
WO2015200650A1 (fr) * 2014-06-25 2015-12-30 Epizyme, Inc. Composés hétéroaryles bicycliques fusionnés en 6,5 ou benzènes substitués

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