WO2018159827A1 - Production d'un composé non stéroïdien ayant une activité de type hormone stéroïdienne végétale (brassinolide) - Google Patents

Production d'un composé non stéroïdien ayant une activité de type hormone stéroïdienne végétale (brassinolide) Download PDF

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WO2018159827A1
WO2018159827A1 PCT/JP2018/008083 JP2018008083W WO2018159827A1 WO 2018159827 A1 WO2018159827 A1 WO 2018159827A1 JP 2018008083 W JP2018008083 W JP 2018008083W WO 2018159827 A1 WO2018159827 A1 WO 2018159827A1
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compound
optionally substituted
group
salt
ring
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PCT/JP2018/008083
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Japanese (ja)
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好秋 中川
愛理 杉浦
征佑 瀧本
真理 幌岩
恒 宮川
美登理 松尾
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国立大学法人京都大学
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    • 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
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids

Definitions

  • This disclosure relates to novel non-steroidal compounds having brassinolide-like activity and uses thereof.
  • Non-patent Document 1 brassinolide (BL) was isolated from pollen of Brassica napus L. as an active substance that promotes plant growth, and its structure was determined (Non-patent Document 1). . After that, vigorous search for compounds having BL-like activity was carried out, and now more than 70 kinds of BL-like active compounds have been identified, and these compounds are collectively called brassinosteroid (BR). (Non-Patent Documents 2 to 5). At present, BR has been proved to be an indispensable substance for plant growth, and has been widely recognized as the sixth plant hormone (Non-patent Document 6).
  • BR is expected to be used as a growth promoter and biochemical tool because of its attractive activity.
  • One aspect described in the present disclosure has been made to solve the problems in the prior art as described above, and provides a novel non-steroidal compound having brassinosteroid (BR) -like activity or a salt thereof. It is.
  • the present disclosure also provides an agricultural composition comprising the compound or a salt thereof, and uses thereof.
  • a non-steroidal compound represented by formula (I) (hereinafter also referred to as compound (I)) or a salt thereof has BR-like agonist activity or antagonist activity.
  • the present invention has been found to have an aspect described in the present disclosure.
  • Ring A and Ring B are each independently selected from the group consisting of monocyclic non-aromatic carbocycles, monocyclic non-aromatic heterocycles, phenyl rings, and monocyclic aromatic heterocycles;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen, halogen, hydroxy, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, substituted
  • R 4 , R 5 , and R When any two groups selected from the group consisting of 6 are attached to adjacent atoms on ring B, the two groups are substituted together with the atoms on ring B to which they are
  • An optionally substituted monocyclic non-aromatic carbocycle, an optionally substituted monocyclic non-aromatic heterocycle, an optionally substituted phenyl ring, or an optionally substituted monocyclic aromatic heterocycle ring May form L 1 and L 2 are selected from the group consisting of a bond, alkylene, —NH—, —O—, —S—, —CO—, —CS—, —S (O) —, and —S (O) 2 —. Each selected independently; n is 0 or 1. Or a salt thereof. (However, the following compounds: Or its salts are excluded. ).
  • L 1 and L 2 are each independently selected from the group consisting of a bond, —CO—, —CS—, —S (O) —, and —S (O) 2 —, according to [1] above Compound or salt thereof.
  • Ring A and Ring B are each independently from the group consisting of a 6-membered monocyclic non-aromatic carbocycle, a 6-membered monocyclic non-aromatic heterocycle, a phenyl ring, and a 6-membered monocyclic aromatic heterocycle Or a salt thereof according to any one of [1] to [3] above.
  • [5] The compound or a salt thereof according to any one of [1] to [4] above, wherein both ring A and ring B are phenyl rings.
  • [6] The compound or a salt thereof according to any one of the above [1] to [5], wherein n is 1.
  • R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, carbamoyl optionally substituted with 1 alkyl, and amino optionally substituted with 1 alkanoyl Selected, R 2 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, halogen, and alkanoyl, or any two selected from the group consisting of R 4 , R 5 , and R 6 [1] wherein the group is attached to an adjacent atom on ring B and together with the atom on ring B to which they are attached forms an optionally substituted monocyclic aromatic heterocycle. ]-The compound or its salt as described in any one of [6].
  • the present disclosure also relates to the following [17] or [18].
  • [17] A method for regulating plant growth comprising the step of applying 1- (4- (4- (3,4-dihydroxybenzoyl) piperazin-1-yl) -3-fluorophenyl) butan-1-one or a salt thereof to a plant .
  • [18] The plant growth regulation method according to [17] above, wherein the plant is rice.
  • the compound (I) or a salt thereof of the present disclosure has BR-like agonist activity or antagonist activity, it is useful as a plant growth regulator, for example, a plant growth promoter or growth inhibitor.
  • FIG. 1 shows the results of a second leaf flexion test in rice of the compound of Example 1.
  • FIG. 2-1 shows the results of Brz's Arabidopsis hypocotyl measurement test.
  • FIG. 2-2 shows the result of the hypocotyl measurement test of the compound of Example 2 in Arabidopsis thaliana.
  • FIG. 2-3 shows the result of the hypocotyl measurement test of the compound of Example 3 in Arabidopsis thaliana.
  • FIG. 3-1 shows the results of gene expression analysis of CPD of the compound of Example 1.
  • FIG. 3-2 shows the results of gene expression analysis of BR-6-OX of the compound of Example 1.
  • FIG. 3-3 shows the results of gene expression analysis of BR-6-OX of the compounds of Examples 2 and 3.
  • FIG. 3-4 shows the results of BAS1 gene expression analysis of the compounds of Examples 2 and 3.
  • Fig. 3-5 shows the results of SAUR gene expression analysis of the compounds of Examples 2 and 3.
  • FIG. 3-6 shows the results of gene expression analysis of TCH4 of the compounds of Examples 2 and 3.
  • FIG. 3-7 shows the results of gene expression analysis of IAA19 for the compounds of Examples 2 and 3.
  • FIG. 3-8 shows the results of gene expression analysis of DWF4 of the compound of Example 5.
  • FIG. 3-9 shows the results of gene expression analysis of BR-6-OX2 of the compound of Example 5.
  • FIG. 3-10 shows the results of gene expression analysis of CPD of the compound of Example 5.
  • FIG. 3-11 shows the results of SAUR-AC1 gene expression analysis of the compound of Example 5.
  • FIG. 3-12 shows the results of gene expression analysis of BAS1 of the compound of Example 5.
  • FIG. 3-13 shows the result of gene expression analysis of IAA19 of the compound of Example 5.
  • FIG. 3-14 shows the results of gene expression analysis of DWF4 of the compound of Example 6.
  • FIG. 3-15 shows the results of gene expression analysis of BR-6-OX2 of the compound of Example 6.
  • FIG. 3-16 shows the results of CPD gene expression analysis of the compound of Example 6.
  • FIG. 3-17 shows the results of SAUR-AC1 gene expression analysis of the compound of Example 6.
  • FIG. 3-18 shows the results of gene expression analysis of BAS1 of the compound of Example 6.
  • FIG. 3-19 shows the result of gene expression analysis of IAA19 of the compound of Example 6.
  • alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms (C 1 -C 6 ). In one embodiment, “alkyl” may be a group having 1 to 4 carbon atoms (C 1 -C 4 alkyl). In another embodiment, it may be a group having 1 to 3 carbon atoms (C 1 -C 3 alkyl).
  • alkyl examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, i-amyl, n-pentyl, 1 , 2-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, and the like, but are not limited thereto.
  • “alkyl” can be, for example, methyl, ethyl, n-propyl, n-butyl, t-butyl, and the like.
  • alkylene refers to a divalent group obtained by removing one hydrogen atom from the above-mentioned linear or branched alkyl having 1 to 6 carbon atoms.
  • alkylene may be a group having 1 to 3 carbon atoms (C 1 -C 3 alkylene).
  • alkylene may be a group having 1 to 2 carbon atoms (C 1 -C 2 alkylene). More specifically, examples of “alkylene” include, but are not limited to, methylene, ethylene, propylene, and the like. In certain embodiments, “alkylene” can be methylene.
  • alkoxy refers to a monovalent group in which an oxygen atom is bonded to the above-mentioned linear or branched alkyl having 1 to 6 carbon atoms.
  • alkoxy can be a group having 1 to 4 carbon atoms (C 1 -C 4 alkoxy).
  • alkoxy may be a group having 1 to 3 carbon atoms (C 1 -C 3 alkoxy). More specifically, examples of “alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy and the like. In certain embodiments, “alkoxy” can be methoxy.
  • alkanoyl refers to a C 2-7 (C 2 -C 7 ) in which a carbonyl group is bonded to the above-mentioned linear or branched alkyl having 1 to 6 carbon atoms.
  • the monovalent group of may be a group having 2 to 5 carbon atoms (C 2 -C 5 alkanoyl).
  • alkanoyl may be a group having 2 to 4 carbon atoms (C 2 -C 4 alkanoyl).
  • alkanoyl includes, but is not limited to, acetyl, propionyl, pivaloyl, butanoyl, pentanoyl, hexanoyl, heptanoyl and the like.
  • alkanoyl can be acetyl, propionyl, butanoyl, and the like.
  • alkylsulfonyl refers to a monovalent group in which a sulfonyl group is bonded to the above-mentioned linear or branched alkyl having 1 to 6 carbon atoms.
  • alkylsulfonyl may be a group having 1 to 4 carbon atoms (C 1 -C 4 alkylsulfonyl).
  • alkylsulfonyl may be a group having 1 to 3 carbon atoms (C 1 -C 3 alkylsulfonyl).
  • alkylsulfonyl examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, and the like.
  • alkylsulfonyl can be ethylsulfonyl and propylsulfonyl.
  • the term “monocyclic non-aromatic carbocycle” as used herein refers to a 5-6 membered monocyclic non-aromatic carbocycle. More specifically, examples of the “monocyclic non-aromatic carbocycle” include 5-membered monocyclic non-aromatic carbocycles such as cyclopentane and cyclopentene, and 6-membered monocycles such as cyclohexane and cyclohexene. Non-aromatic carbocycles of the formula can be mentioned, but are not limited thereto. In certain embodiments, a “monocyclic non-aromatic carbocycle” can be a 6-membered monocyclic non-aromatic carbocycle.
  • monocyclic non-aromatic heterocycle refers to a 5- to 6-membered member containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom.
  • Monocyclic non-aromatic heterocycle as used herein refers to a 5- to 6-membered member containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom.
  • such monocyclic non-aromatic heterocycles include, for example, 5-membered monocyclic non-aromatic heterocycles such as pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, and oxazolidinyl, and piperidinyl 6-membered monocyclic non-aromatic heterocycles such as, but not limited to, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and thiomorpholinyl.
  • the “monocyclic non-aromatic heterocycle” can be a 6-membered monocyclic non-aromatic heterocycle.
  • the term “monocyclic aromatic heterocycle” refers to a 5- to 6-membered single atom containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom.
  • a cyclic aromatic heterocycle More specifically, such monocyclic aromatic heterocycles include, for example, 5-membered such as pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • Examples include, but are not limited to, monocyclic aromatic heterocycles and 6-membered monocyclic aromatic heterocycles such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, and triazinyl.
  • the “monocyclic aromatic heterocycle” can be a 5-membered monocyclic aromatic heterocycle.
  • the “monocyclic aromatic heterocycle” can be a 6-membered monocyclic aromatic heterocycle.
  • the “monocyclic aromatic heterocycle” may be pyrazolyl.
  • halogen means fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). In one embodiment, “halogen” can be fluorine, chlorine, or bromine. In another embodiment, “halogen” may be fluorine.
  • the number of substituents in the term “optionally substituted alkyl” may be 1 or more (eg, 1 to 5, 1 to 3, etc.). May be the same or different. Examples of such a substituent include halogen, hydroxy, cyano, nitro, 1-5 may be halogen substituted C 1 -C 3 alkoxy, and alkoxy may imino optionally substituted with like However, it is not limited to these.
  • the substituent of “optionally substituted alkyl” in R 1 , R 2 , and R 3 is independently selected from the group consisting of imino optionally substituted with hydroxy and alkoxy. 1 to 3 groups.
  • the “optionally substituted alkyl” substituent in R 4 , R 5 , and R 6 can be 1-3 hydroxy.
  • the number of substituents in the term “optionally substituted alkoxy” may be 1 or more (for example, 1 to 5, or 1 to 3, etc.).
  • the groups may be the same or different.
  • substituents can include, but are not limited to, halogen, hydroxy, cyano, nitro, and C 1 -C 3 alkoxy optionally substituted with 1 to 5 halogens.
  • the substituent of “optionally substituted alkoxy” in R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 can be 1 to 5 halogens.
  • such a substituent can be, for example, 1-5 fluoro.
  • the number of substituents in the term “optionally substituted alkanoyl” may be 1 or more (eg, 1 to 5, or 1 to 3).
  • the groups may be the same or different.
  • substituents can include, but are not limited to, halogen, hydroxy, cyano, nitro, and C 1 -C 3 alkoxy optionally substituted with 1 to 5 halogens.
  • the substituent of “optionally substituted alkanoyl” in R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 can be, for example, 1 to 5 halogens. .
  • such substituents can be 1 to 5 fluoro.
  • the number of substituents in the term “optionally substituted alkylsulfonyl” may be 1 or more (eg, 1 to 5, or 1 to 3, etc.)
  • the substituents may be the same or different.
  • substituents can include, but are not limited to, halogen, hydroxy, cyano, nitro, and C 1 -C 3 alkoxy optionally substituted with 1 to 5 halogens.
  • the substituent of “optionally substituted alkylsulfonyl” in R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 can be 1 to 5 halogens.
  • such substituents can be 1-5 fluoro.
  • the number of substituents in the term “optionally substituted carbamoyl” may be 1 to 2, and the substituents may be the same or different.
  • substituents can include, but are not limited to, halogen, hydroxy, alkyl optionally substituted with 1 to 5 halogens, and alkanoyl.
  • the substituent of “optionally substituted carbamoyl” in R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is substituted with 1 to 5 halogens.
  • 1 to 2 alkyls may be mentioned, and in another embodiment 1 to 2 methyls may be mentioned but are not limited thereto.
  • the number of substituents in the term “optionally substituted amino” may be 1 to 2, and the substituents may be the same or different. Examples of such a substituent include halogen, hydroxy, alkyl optionally substituted with 1 to 5 halogens, alkanoyl, and carbamoyl optionally substituted with 1 to 2 alkyls. However, it is not limited to these.
  • the substituent of “optionally substituted amino” in R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is substituted with alkanoyl and 1 to 2 alkyls. It may be 1 to 2 groups independently selected from the group consisting of optionally carbamoyl. In another embodiment, such substituents may be 1-2 groups independently selected from the group consisting of acetyl and carbamoyl optionally substituted with 1-2 methyl.
  • the terms “optionally substituted monocyclic non-aromatic carbocycle”, “optionally substituted monocyclic non-aromatic heterocycle”, “optionally substituted” The number of substituents in the “phenyl ring” or “optionally substituted monocyclic aromatic heterocycle” may be 1 to 4, and the substituents may be the same or different. Such substituents can be halogen, hydroxy, alkyl optionally substituted with 1 to 5 halogens, alkanoyl, carbamoyl optionally substituted with 1 to 2 alkyls, and the like.
  • optionally substituted monocyclic non-aromatic carbocycles optionally substituted monocyclic non-aromatic heterocycles, substituted in R 4 , R 5 , and R 6
  • the optionally substituted phenyl ring or optionally substituted monocyclic aromatic heterocyclic substituent may be 1 to 2 groups independently selected from the group consisting of halogen, hydroxy, and alkyl; In another embodiment, it can be alkyl.
  • ring A and ring B are cyclohexane ring, cyclohexene ring, piperidinyl ring, piperazinyl ring, tetrahydropyranyl ring, tetrahydrothiopyranyl ring, morpholinyl ring, thiomorpholinyl ring, phenyl ring, pyridyl ring, pyrimidinyl ring, Each may be independently selected from the group consisting of a pyrazinyl ring, a pyridazinyl ring, a thiazinyl ring, and a triazinyl ring. In one embodiment, both ring A and ring B can be phenyl rings.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen, halogen, hydroxy, cyano, nitro, optionally substituted alkyl, optionally substituted.
  • Each may be independently selected from the group consisting of alkoxy, optionally substituted alkanoyl, optionally substituted alkylsulfonyl, optionally substituted carbamoyl, and optionally substituted amino.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independent of the group consisting of hydrogen; halogen; hydroxy; nitro; imino and hydroxy optionally substituted with alkoxy.
  • any two groups are attached to adjacent atoms on ring B, the two groups are substituted with 1-2 alkyls, together with the atoms on ring B to which they are attached.
  • a monocyclic non-aromatic carbocycle which may be substituted a monocyclic non-aromatic heterocycle which may be substituted with 1 to 2 alkyls, a phenyl ring which may be substituted with 1 to 2 alkyls, Alternatively, it may form a monocyclic aromatic heterocycle which may be substituted with 1 to 2 alkyls.
  • R 1 , R 2 , and R 3 are 1 to 3 groups independently selected from the group consisting of hydrogen; halogen; hydroxy; imino and hydroxy optionally substituted with alkoxy Independently selected from the group consisting of optionally substituted alkyl; alkoxy; carbamoyl optionally substituted with 1 to 2 alkyls; and carbamoyl optionally substituted with alkanoyl and 1 to 2 alkyls
  • R 4 , R 5 , and R 6 are hydrogen; halogen; nitro; alkyl optionally substituted with 1 to 3 hydroxy; alkanoyl optionally substituted with 1 to 5 halogen; and 1 to 5
  • Any two groups independently selected from the group consisting of alkylsulfonyl optionally substituted with 1 halogen, or selected from the group consisting of R 4 , R 5 , and R 6 are ring B Bonded to the adjacent atoms above and together
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independent of the group consisting of hydrogen; halogen; hydroxy; nitro; imino and hydroxy optionally substituted with alkoxy.
  • R 1 , R 2 , and R 3 are hydrogen; fluoro; bromo; hydroxy; 1-3 independently selected from the group consisting of imino and hydroxy optionally substituted with methoxy C 1 -C 4 alkyl optionally substituted with a group; C 1 -C 4 alkoxy; carbamoyl optionally substituted with 1 to 2 C 1 -C 4 alkyl; and C 2 -C 5 alkanoyl and Each independently selected from the group consisting of amino optionally substituted with 1 to 2 groups independently selected from the group consisting of carbamoyl optionally substituted with 1 to 2 C 1 -C 4 alkyl. May be selected.
  • R 1 , R 2 , and R 3 may each be independently selected from the group consisting of hydrogen; fluoro; bromo; hydroxy; and amino. In one embodiment, R 1 , R 2 , and R 3 may each be independently selected from the group consisting of hydrogen and hydroxy, and in another embodiment, at least one of R 1 , R 2 , and R 3 is It can be hydroxy, and in yet another embodiment two of R 1 , R 2 , and R 3 can be hydroxy.
  • R 1, R 2, and R 3 is hydrogen; fluoro; bromo; C 1 -C 4 alkyl; C 1 -C 4 alkoxy; optionally substituted with and one methyl 1
  • Each may be independently selected from the group consisting of amino optionally substituted with carbamoyl.
  • R 1 , R 2 , and R 3 may each be independently selected from the group consisting of hydrogen; methoxy; and acetylamino; in another embodiment, R 1 , R 2 , and R 3 May be independently selected from the group consisting of hydrogen; methoxy; and acetylamino, and at least one may be hydrogen.
  • R 4 , R 5 , and R 6 are hydrogen; fluoro; nitro; C 1 -C 4 alkyl optionally substituted with 1 to 3 hydroxys; substituted with 1 to 5 fluoros Each independently selected from the group consisting of C 2 -C 5 alkanoyl which may be substituted; and C 1 -C 4 alkylsulfonyl optionally substituted with 1 to 5 fluoro, or R 4 , Any two groups selected from the group consisting of R 5 and R 6 are bonded to adjacent atoms on ring B, and together with the atoms on ring B to which they are bonded, 1-2 groups A pyrazolyl ring which may be substituted with alkyl may be formed.
  • R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, fluoro, and C 2 -C 5 alkanoyl, or R 4 , R 5 , and R 6 Any two groups selected from the group consisting of are bonded to adjacent atoms on ring B, and together with the atoms on ring B to which they are bonded, may be substituted with one alkyl A monocyclic aromatic heterocycle may be formed.
  • R 4 , R 5 , and R 6 are each independently selected from hydrogen, fluoro, and butanoyl, or selected from the group consisting of R 4 , R 5 , and R 6 Any two groups are attached to adjacent atoms on ring B and together with the atoms on ring B to which they are attached form a pyrazolyl ring optionally substituted with one isobutyl. Good.
  • R 4 , R 5 , and R 6 are hydrogen; fluoro; nitro; C 1 -C 4 alkyl optionally substituted with 1 to 3 hydroxys; substituted with 1 to 5 fluoros Each independently selected from the group consisting of C 2 -C 5 alkanoyl which may be substituted; and C 1 -C 4 alkylsulfonyl optionally substituted with 1 to 5 fluoro.
  • R 4 , R 5 , and R 6 may each be independently selected from the group consisting of hydrogen, fluoro, and C 2 -C 5 alkanoyl, and in yet another embodiment, hydrogen, fluoro, , And butanoyl may be independently selected.
  • L 1 and L 2 may each be independently selected from the group consisting of a bond, —CO—, —CS—, and —S (O) —.
  • L 1 may be independently selected from the group consisting of —CO—, —CS—, and —S (O) —, and L 2 may be a bond.
  • a compound of the present disclosure or a salt thereof has the formula (I ′), formula (I ′′), or formula (I ′ ′′): [Where: R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, and carbamoyl optionally substituted with 1 alkyl; R 4 is alkanoyl; R 5 is halogen; R 7 is alkyl] Or a salt thereof.
  • a compound of the present disclosure or a salt thereof has the formula (I ′): [Where: R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, and carbamoyl optionally substituted with 1 alkyl; R 4 is alkanoyl; R 5 is halogen] Or a salt thereof.
  • R 1 can be hydroxy
  • R 2 can be hydroxy
  • R 3 can be hydrogen
  • R 4 can be butanoyl
  • R 5 can be fluoro
  • R 6 can be hydrogen
  • R 7 can be isobutyl
  • the present disclosure provides 1- (4- (4- (3,4-dihydroxybenzoyl) piperazin-1-yl) -3-fluorophenyl) butan-1-one (Example 1); N- (5- (4- (4-butyryl-2-fluorophenyl) piperazine-1-carbonyl) -2-methoxyphenyl) acetamide (Example 2); 1- (4- (4-Benzoylpiperazin-1-yl) -3-fluorophenyl) butan-1-one (Example 3); 1- (4- (4- (3,4-dimethylbenzoyl) piperazin-1-yl) -3-fluorophenyl) butan-1-one (Example 4); 5- (4- (3,4-dihydroxybenzoyl) piperazin-1-yl) -1-isobutyl-1H-indazole (Example 5); and 5- (4- (3,4-dihydroxybenzoyl) piperazine-1 -Yl
  • the disclosure provides 1- (4- (4- (3,4-dihydroxybenzoyl) piperazin-1-yl) -3-fluorophenyl) butan-1-one (Example 1); N- (5- (4- (4-butyryl-2-fluorophenyl) piperazine-1-carbonyl) -2-methoxyphenyl) acetamide (Example 2); 1- (4- (4-benzoylpiperazin-1-yl) -3-fluorophenyl) butan-1-one (Example 3); and 1- (4- (4- (3,4-dimethylbenzoyl) piperazine -1-yl) -3-fluorophenyl) butan-1-one (Example 4); Or a salt thereof selected from the group consisting of:
  • the compound (I) of the present disclosure When the compound (I) of the present disclosure has an asymmetric carbon atom in the molecule, it can exist as a plurality of stereoisomers based on the asymmetric carbon atom (that is, diastereomeric isomer, optical isomer).
  • the compounds of the present disclosure include any one of these stereoisomers and mixtures thereof.
  • the compound (I) of the present disclosure includes a compound labeled with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 15 N, 18 F, 32 P, 35 S, 125 I, etc.) and a heavy compound. Includes hydrogen converter.
  • an isotope eg, 2 H, 3 H, 13 C, 14 C, 15 N, 18 F, 32 P, 35 S, 125 I, etc.
  • the compound (I) of the present disclosure can exist in a free form or a salt form.
  • the salt include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, formate, acetate, propionate, fumarate, oxalate, and malonic acid.
  • Acid addition salts such as salts, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, maleate, lactate, malate, tartrate, citrate, and trifluoroacetate; Metal salts such as lithium salt, potassium salt, calcium salt, magnesium salt, sodium salt, zinc salt, and aluminum salt; and base addition salts such as ammonium salt, diethanolamine salt, ethylenediamine salt, triethanolamine salt, and triethylamine salt However, it is not limited to these.
  • the compound (I) or a salt thereof of the present disclosure includes any of its internal salts and adducts, solvates or hydrates thereof.
  • the agricultural composition containing Compound (I) or a salt thereof of the present disclosure is added with an inert carrier, a surfactant, or other formulation adjuvants as appropriate, and oils, emulsions, flowables, wettable powders, granules It is formulated into a wettable powder, powder, granule or the like.
  • Inert carriers include, but are not limited to, solid carriers and liquid carriers. Examples of solid carriers include minerals such as kaolin clay, attapulgite clay, bentonite, montmorillonite, acid clay, pyrophyllite, talc, diatomaceous earth, calcite, natural organic substances such as corn cob powder, walnut shell powder, urea, etc.
  • Examples include, but are not limited to, synthetic organic materials, salts such as calcium carbonate and ammonium sulfate, and fine powders or granular materials made of synthetic inorganic materials such as synthetic hydrous silicon oxide.
  • the liquid carrier include aromatic hydrocarbons such as toluene, xylene, ethylbenzene, and methylnaphthalene, alcohols such as methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, and ethylene glycol monoethyl ether, acetone, methyl ethyl ketone,
  • Examples include, but are not limited to, ketones such as cyclohexanone, vegetable oils such as soybean oil and cottonseed oil, petroleum aliphatic hydrocarbons, esters, dimethyl sulfoxide, acetonitrile, and water.
  • surfactant examples include nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, and polyethylene glycol fatty acid ester, and anions such as alkyl sulfonate, alkyl benzene sulfonate, and alkyl sulfate. Surfactant etc. are mentioned, However, It is not limited to these.
  • formulation adjuvants examples include water-soluble polymers such as polyvinyl alcohol and polyvinylpyrrolidone, gum arabic, alginic acid and salts thereof, polysaccharides such as CMC (carboxymethyl cellulose) and xanthan gum, aluminum magnesium silicate, alumina sol Inorganic substances such as preservatives, colorants, and stabilizers such as PAP (isopropyl acid phosphate) and BHT, but are not limited thereto.
  • water-soluble polymers such as polyvinyl alcohol and polyvinylpyrrolidone, gum arabic, alginic acid and salts thereof, polysaccharides such as CMC (carboxymethyl cellulose) and xanthan gum, aluminum magnesium silicate, alumina sol Inorganic substances such as preservatives, colorants, and stabilizers such as PAP (isopropyl acid phosphate) and BHT, but are not limited thereto.
  • the agricultural composition of the present disclosure contains the compound (I) of the present disclosure or a salt thereof in an amount of usually 0.01 to 99% by weight, such as 0.1 to 95% by weight, or 0.5 to 90% by weight. Contained.
  • the compound (I) of the present disclosure or a salt thereof, or the agricultural composition of the present disclosure when applied to a plant, a part of the plant (stems, buds, flowers, fruits, ears, Seeds, roots, etc.) and the various growth stages of the plant (emergence stage before and after emergence, etc. after sowing, seedling transplanting, seedling transplanting, cuttings or cuttings, growth after planting, etc.) Vegetative growth period, reproductive growth period just before heading or heading period).
  • a method for regulating the growth of a plant of the present disclosure for example, a method for promoting plant growth or a method for inhibiting growth, comprises an effective amount of the disclosed compound (I) or a salt thereof, or the agricultural composition of the present disclosure. It is done by applying to the ground. When applied to a plant or a cultivation area thereof, the compound (I) of the present disclosure or a salt thereof, or the agricultural composition of the present disclosure is applied one or more times. For example, the number of spraying treatments is usually 1 to 3 times, but is not limited thereto.
  • treatment of plant foliage such as foliage spraying, treatment of vases or ears (that is, spraying treatment), treatment of plant seeds before seeding on soil or culture medium (that is, seeds) Treatment), treatment to soil (cultivation land) before planting or after planting (that is, soil treatment), treatment to seedling (eg seedling box processing, seedling tray processing), etc. It is not limited.
  • Examples of the spraying treatment on the foliage, flower vase, or ear of the plant in the present disclosure include, for example, the compound (I) or a salt thereof of the present disclosure on the surface of the plant such as spraying of the foliage, Examples include, but are not limited to, methods of applying an effective amount of the agricultural composition of the present disclosure.
  • One embodiment of the treatment for plants includes, but is not limited to, treatment for plants growing in paddy fields.
  • examples of the application time include, but are not limited to, flowering times including before flowering, during flowering, and after flowering.
  • the seed treatment of the plant in the present disclosure for example, the effectiveness of the compound (I) of the present disclosure or a salt thereof, or the agricultural composition of the present disclosure on the seed of the plant in a state before being sown in soil or a culture medium.
  • Examples include, but are not limited to, applying amounts.
  • Specific treatment methods include, but are not limited to, spraying treatment, smearing treatment, dipping treatment, impregnation treatment, coating treatment, film coating treatment, and pellet coating treatment.
  • a seed can be prepared which retains an effective amount of the disclosed compound (I) or a salt thereof, or the agricultural composition of the present disclosure on and / or inside.
  • the soil treatment in the present disclosure for example, a method of applying an effective amount of the compound (I) of the present disclosure or a salt thereof, or the agricultural composition of the present disclosure to a soil before or after planting a plant.
  • Specific treatment methods include, but are not limited to, application to soil, soil mixing, chemical irrigation to soil (chemical irrigation, soil injection, chemical drip).
  • the treatment time include, but are not limited to, the sowing time before sowing, at the time of sowing, immediately after sowing, the seedling season, before planting, at the time of planting, and after the planting.
  • a solid fertilizer such as a paste fertilizer containing the compound (I) of the present disclosure or a salt thereof or the agricultural composition of the present disclosure may be applied to the soil.
  • the disclosed compound (I) or a salt thereof, or the agricultural composition of the present disclosure may be mixed with an irrigation liquid, for example, injection into an irrigation facility (irrigation tube, irrigation pipe, sprinkler, etc.) Examples include, but are not limited to, mixing into intermittent water solution and mixing into hydroponic solution.
  • irrigation solution and the compound (I) of the present disclosure or a salt thereof, or the agricultural composition of the present disclosure are mixed in advance and, for example, the above irrigation method or other appropriate irrigation methods such as watering and flooding are used. Can be processed.
  • a diluted solution prepared by diluting the disclosed compound (I) or a salt thereof, or the agricultural composition of the present disclosure with water to an appropriate active ingredient concentration is sprayed over the entire seedlings.
  • Application treatment for adhering to the whole seedling the compound (I) of the present disclosure or a salt thereof, or the agricultural composition of the present disclosure prepared in a powder is not limited to these.
  • the treatment of the soil before or after planting the seedling includes, for example, the compound (I) of the present disclosure or a salt thereof, or the agricultural composition of the present disclosure to an appropriate active ingredient concentration with water.
  • the method of spraying the diluted diluted solution after seedling is planted on the seedling and surrounding soil, the compound (I) of the present disclosure or a salt thereof prepared into a solid preparation such as a granule or a granule, or the disclosed Examples include, but are not limited to, methods of spraying the agricultural composition on the surrounding soil after planting seedlings.
  • plants to which the compound (I) of the present disclosure or a salt thereof, or an agricultural composition can be applied include, but are not limited to, the following plants.
  • Crops such as corn, rice, wheat, barley, rye, oats, sorghum, cotton, soybeans, adzuki beans, kidney beans, peanuts, buckwheat, sugar beet, rapeseed, sunflower, sugarcane, tobacco, etc .
  • Vegetables such as eggplants (tomatoes, peppers, peppers, potatoes, etc.), cucumbers (cucumbers, pumpkins, zucchini, watermelon, melon, squash, etc.), cruciferous vegetables (radish, turnip, horseradish, Kohlrabi, Chinese cabbage, cabbage, mustard, broccoli, cauliflower, etc.), Asteraceae vegetables (burdock, shungiku, artichoke, lettuce, etc.), Liliaceae vegetables (such as leek, onion, garlic, and asparagus), celery family vegetables ( Carrot
  • the disclosed compound (I) or a salt thereof, or an agricultural composition is applied to rice, but is not limited thereto.
  • rice examples include Nihonbare, Hinohikari, Koshihikari, Akitakomachi, Haenuki, Sasanishiki, Hitomebore, Kinuhikari, Hoshino Yume, Kirara 397, Tsugaru Roman, Yume Akari, Hanaechizen, Yumetsushi, Hatsushimo, Yukihikari, Natsuka Asahi's dream, fragrant splash, Ai no Kaori, Aya no Kagayaki, Orozuki, and japonica species such as Yumehikari; Indica species; Javanica species; Sally Queen, Basmati, Kitakaori, Princess Sally, Khao Home Mari, Arborio, Carnaroli, Examples include, but are not limited to, Viarone Nano.
  • the compound (I) or a salt thereof of the present disclosure has BR-like agonist activity or antagonist activity, it is useful as a plant growth regulator, for example, a growth promoter or growth inhibitor.
  • the compound (I) of the present disclosure or a salt thereof can be used as a plant growth promoter.
  • ⁇ promoting plant growth '' means, for example, seed germination promotion, rooting promotion, establishment of growth, promotion of branch, leaf, and stem development and extension, promotion of flowering, promotion of fruiting, promotion of fruit maturation, Examples include, but are not limited to, promotion of fruit hypertrophy, disease resistance, and resistance to stress (eg, high salt concentration, drying, high temperature, low temperature, nutrient deficiency, etc.).
  • plant growth inhibition refers to, for example, seed germination inhibition, rooting inhibition, survival inhibition, branch and leaf and stem generation and elongation inhibition, flowering inhibition, fruiting inhibition, fruit maturation inhibition, In addition, examples include suppression of fruit enlargement and the like, and particularly include an action as a herbicide, but are not limited thereto.
  • plant growth inhibition include dicotyledonous plants such as Arabidopsis thaliana, but are not limited thereto.
  • each production step of compound (I) described below when protection of a functional group contained in the compound is necessary, it can be appropriately carried out by a method specifically described below or a conventional method. .
  • protecting groups For a general description of protecting groups and their uses, see T.W. W. Greene et al., “Protective Groups in Organic Synthesis”, John Wiley & Sons, New York, 2006. The protecting groups may be removed in subsequent steps using methods specifically described below or conventional methods.
  • the carboxylic acid compound or a salt thereof and the amine compound or a salt thereof can be converted into each other by a method specifically described below or a conventional salt formation treatment or desalting treatment. it can.
  • Compound (I) or a salt thereof of the present disclosure can be produced, for example, as follows.
  • R a represents a leaving group such as halogen (chlorine, bromine, or iodine), methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonate
  • R b represents halogen (chlorine, bromine, Or iodine) or hydroxy, and other symbols have the same meaning as described above.
  • Compound (II) and compound (III) may be commercially available materials, or may be produced from commercially available materials by known methods.
  • Compound (IV) can be obtained by coupling compound (II) and compound (III).
  • the coupling reaction of compound (II) and compound (III) is carried out according to a conventional method, in an appropriate solvent, in the presence or absence of a palladium catalyst, in the presence or absence of a base, in the presence or absence of a ligand. Can be implemented below. Any solvent may be used as long as it does not interfere with this reaction.
  • Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene, Aromatic hydrocarbons such as xylene, acetonitrile, or a mixture thereof may be mentioned, but not limited thereto.
  • the palladium catalyst include tris (dibenzylideneacetone) dipalladium (0) (Pd 2 dba 3 ), bis (triphenylphosphine) palladium dichloride (PdCl 2 (PPh 3 ) 2 ), and the like. It is not limited.
  • Examples of the base include, but are not limited to, metal alkoxides such as sodium tert-butoxide, amides such as sodium bis (trimethylsilyl) amide, and the like.
  • Examples of the ligand include 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene, 1,1′-bis (diphenylphosphino), 2,2′-bis (diphenylphosphine). Phino) -1,1′-binaphthyl (BINAP), phosphines such as triphenylphosphine (Ph 3 P), and the like, but are not limited thereto.
  • the amount of compound (III) to be used can be 1.0 to 2.0 equivalents, for example 1.0 to 1.5 equivalents, in molar ratio to compound (II).
  • the amount of the palladium catalyst used can be 0.01 to 0.1 equivalent, for example, 0.03 to 0.07 equivalent in terms of molar ratio to the compound (II).
  • the amount of the base used can be 1.0 to 3.0 equivalents, for example 1.3 to 2.0 equivalents, in molar ratio with respect to compound (II).
  • the amount of the ligand used can be 0.02 to 0.2 equivalent, for example 0.05 to 0.1 equivalent, in molar ratio with respect to compound (II). This reaction can be carried out at room temperature to 200 ° C., for example, 70 to 150 ° C.
  • any one of the two —NH— groups on the ring of the compound (III) may be protected by a protecting group.
  • the protecting group include, but are not limited to, a tert-butoxycarbonyl group (Boc group) and the like.
  • compound (IV) can be obtained by deprotecting the protecting group by a conventional method after coupling of compound (II) and compound (III).
  • compound (IV) can be obtained by deprotecting the coupling product of compound (II) and compound (III) by reacting with an acid in a solvent.
  • the solvent include, but are not limited to, dichloromethane and the like.
  • the acid include, but are not limited to, trifluoroacetic acid and the like.
  • the amount of the acid used can be 5.0 to 50.0 equivalents, for example 10.0 to 30.0 equivalents, in molar ratio to the coupling product.
  • This reaction can be carried out under cooling to heating, for example, from room temperature to heating.
  • Compound (IV) and compound (V) may be commercially available materials, or may be produced from commercially available materials by known methods.
  • Compound (I) can be obtained by condensing compound (IV) and compound (V).
  • the condensation of compound (IV) and compound (V) can be carried out in a suitable solvent in the presence or absence of a condensing agent and in the presence or absence of a base. Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like.
  • Aromatic hydrocarbons acetonitrile, or a mixture thereof, but not limited thereto.
  • the condensing agent include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3- Examples include (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), but are not limited thereto.
  • the base examples include triethylamine, alkylamines such as N, N-diisopropylethylamine; pyridine, pyridines such as 4-dimethylaminopyridine, and 1,8-diazabicyclo [5.4.0] -7.
  • -Organic bases such as undecene; and inorganic bases such as, but not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydride.
  • the amount of compound (V) to be used can be 0.8 to 3.0 equivalents, for example 0.8 to 2.2 equivalents, in molar ratio to compound (IV).
  • the amount of the condensing agent to be used can be 1.0 to 5.0 equivalents, for example 1.5 to 2.5 equivalents, relative to compound (IV).
  • the amount of the base used can be 1.0 to 5.0 equivalents, for example 2.0 to 4.0 equivalents, relative to compound (IV). This reaction can be carried out under cooling to heating, for example, from room temperature to heating.
  • R 1 , R 2 , or R 3 has a hydroxy group or an amino group
  • the hydroxy group or amino group may be protected by a protecting group.
  • the protecting group include, but are not limited to, an acetyl group (Ac group) and a tert-butoxycarbonyl group (Boc group).
  • R 1 , R 2 , or R 3 has a protective group
  • compound (IV) and compound (V) are condensed, and then the protective group is deprotected by a conventional method to obtain compound (I).
  • the condensation product of compound (IV) and compound (V) can be deprotected by reacting with a base in a solvent to obtain compound (I).
  • the solvent include methanol, but are not limited thereto.
  • the base include, but are not limited to, ammonium acetate.
  • the amount of the base used can be 1.0 to 20.0 equivalents, for example 1.0 to 10.0 equivalents, in molar ratio with respect to the condensation product.
  • This reaction can be carried out under cooling to heating, for example, from room temperature to heating.
  • a compound in which R 4 is alkanoyl can be produced, for example, by the following method. [Wherein R c is alkyl, M is MgX (where X is a halogen) or Li, and other symbols have the same meaning as described above. ]
  • Compound (VII) can be obtained by N-methoxy-N-methylamidation of compound (VI).
  • the N-methoxy-N-methylamidation reaction of compound (VI) can be carried out according to a conventional method by reacting with an amine in a suitable solvent in the presence or absence of an activating agent. Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene, Aromatic hydrocarbons such as xylene, acetonitrile, or a mixture thereof may be mentioned, but not limited thereto.
  • Examples of the activator include N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), tetrabromomethane / triphenylphosphine (CBr 4 / PPh 3 ) and the like.
  • Examples of amines include, but are not limited to, N, O-dimethylhydroxyamine hydrochloride and the like.
  • the amount of the activator used can be 1.0 to 1.5 equivalents, for example 1.0 to 1.2 equivalents, relative to compound (VI).
  • the amount of amine to be used can be 1.0 to 2.0 equivalents, for example 1.0 to 1.5 equivalents, relative to compound (VI). This reaction can be carried out under cooling to heating, for example, from room temperature to heating.
  • Compound (II) can be obtained by reacting compound (VII) with compound (VIII).
  • the reaction of compound (VII) and compound (VIII) can be carried out in a suitable solvent according to a conventional method. Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like. Aromatic hydrocarbons, acetonitrile, or a mixture thereof, but not limited thereto.
  • the amount of compound (VIII) to be used can be 0.9 to 3.0 equivalents, for example 0.95 to 2.0 equivalents, in molar ratio to compound (VII). This reaction can be carried out under cooling to heating, for example, from room temperature to heating.
  • the compound and intermediate compound of the present disclosure can be produced by the above production method, and can also be produced according to the methods described in Examples and Reference Examples described later. Further, the compounds and intermediate compounds of the present disclosure can be converted into other target compounds or intermediates by the methods described in the above production methods, examples described later, and reference examples and / or known methods or combinations thereof. it can. Examples of such methods include, but are not limited to, the methods described in the following (1) to (3).
  • a compound having a nitrogen-containing ring is reacted with an alkyl halide (eg, N, N-dimethylformamide, etc.) in the presence of a base (eg, sodium hydride, etc.).
  • an alkyl halide eg, N, N-dimethylformamide, etc.
  • a base eg, sodium hydride, etc.
  • the nitrogen atom of the nitrogen-containing ring can be alkylated (eg, isobutylated).
  • a hydroxy group can be converted to an acetoxy group by reacting a compound having a hydroxy group with acetic anhydride in the presence of an acid catalyst (such as sulfuric acid).
  • an acid catalyst such as sulfuric acid
  • Example 1 Preparation of 1- (4- (4- (3,4-dihydroxybenzoyl) piperazin-1-yl) -3-fluorophenyl) butan-1-one 3,4-dihydroxybenzoic acid (0.1 g, 0.64 mmol) and 1- (3-fluoro-4- (piperazin-1-yl) phenyl) butan-1-one (0.1 g, 0.40 mmol) After dissolving in anhydrous dichloromethane (5 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.2 g, 0.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • Example 3 Preparation of 1- (4- (4-benzoylpiperazin-1-yl) -3-fluorophenyl) butan-1-one Benzoic acid (0.1 g, 0.82 mmol) and 1- (3-fluoro-4- (piperazin-1-yl) phenyl) butan-1-one (0.1 g, 0.40 mmol) were added in anhydrous dichloromethane (5 mL). 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.2 g, 0.8 mmol) was added and stirred at room temperature for 2 hours. Thereafter, distilled water (10 mL) and chloroform (40 mL) were added to separate the layers.
  • Example 4 Preparation of 1- (4- (4- (3,4-dimethylbenzoyl) piperazin-1-yl) -3-fluorophenyl) butan-1-one 3,4-dimethylbenzoic acid (0.1 g, 0.67 mmol) and 1- (3-fluoro-4- (piperazin-1-yl) phenyl) butan-1-one (0.1 g, 0.40 mmol) After dissolving in anhydrous dichloromethane (5 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.2 g, 0.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • the brassinolide (BL) agonist activity and antagonist activity of the compound (I) of the present disclosure or a salt thereof were evaluated using rice and Arabidopsis as model organisms. Plants to which the salt can be applied are not limited to these.
  • Experimental example 1 Second leaf flexion test in rice (principle) When a compound having BL agonist activity is applied to rice, the second leaf blade of rice bends in a dose-dependent manner. Therefore, BL agonist activity was evaluated by measuring this angle.
  • SAUR-AC1 is also referred to as “SAUR”
  • BR-6-OX is also referred to as “BR-6-OX2”.
  • the expression levels of CPD and BR-6-OX which are genes whose expression is suppressed by BR, were examined.
  • RNA extraction Rneasy Plant Mini Kit (manufactured by Qiagen) was used for RNA extraction. About 50 mg of Arabidopsis thaliana grown in the same procedure as in Experimental Example 2 was weighed and stored in a falcon tube, and RLT buffer and mercaptoethanol were added (10 ⁇ L mercaptoethanol / 1 mL RLT buffer). The compound of Example 1 was cultured by adding 10 or 30 ⁇ M compound, cultured by adding DMSO, cultured by adding 100 ⁇ M BL, and cultured by adding 3 ⁇ M Brz. We compared what we did.
  • the compound of Example 2 or 3 was compared with the one cultured with 100 ⁇ M compound added, the one cultured with DMSO added, and the one cultured with 100 ⁇ M Brz added.
  • the compound of Example 5 was compared with the one cultured with addition of 10 ⁇ M or 30 ⁇ M compound, the one cultured with addition of DMSO, and the one cultured with addition of 100 nM BL.
  • As for the compound of Example 6, a sample cultured by adding 0.1 ⁇ M or 0.3 ⁇ M compound, a sample cultured by adding DMSO, and a sample cultured by adding 100 nM BL were compared. Samples frozen at ⁇ 80 ° C. were quickly ground using a pestle and mortar and transferred to a falcon tube.
  • RNA extracted above was diluted with RNase Free sterilized water so that the RNA amount was 1 ⁇ g / 20 ⁇ L, and dispensed into tubes.
  • a reaction solution was prepared using TaKaRa PrimeScript RT reagent Kit. The composition of the reaction solution is shown below. The reaction solution was incubated at 37 ° C. for 15 minutes and at 85 ° C. for 5 seconds to perform a reverse transcription reaction. After completion of the reaction, 80 ⁇ L of sterilized water was added.
  • the intercalator method is a technique for quantifying amplified DNA by detecting fluorescence intensity when a reagent emits fluorescence when an intercalator binds to double-stranded DNA synthesized by polymerase reaction.
  • the amplification curve begins to rise when the PCR amplification product reaches a concentration at which fluorescence can be detected. Therefore, the more DNA present first, the earlier the start of the rise.
  • Ct Total Cost (Threshold Cycle) value
  • the number of cycles until the Ct value is reached is proportional to the amount of DNA initially present.
  • the ⁇ Ct method was used as an analysis method. This is a method of converting a difference in Ct value with a calibrator into a relative amount without using a calibration curve.
  • actin which is considered to be constantly expressed, was used as a calibrator, and relative quantification was performed based on the expression level of actin.
  • SYBR registered trademark
  • Premix Ex Taq TM II Tli RNase H Plus
  • the composition of the reaction solution is shown below.
  • the thermal cycler used was Takara's Thermal cycler Dice.
  • the compound of Example 1 decreased the expression levels of CPD and BR-6-OX in a dose-dependent manner as compared with DMSO, and showed BL agonist activity (FIGS. 3-1 to 3-2).
  • the compounds of Examples 2 and 3 decreased the expression levels of BAS1, SAUR, TCH4, and IAA19, increased the expression levels of BR-6-OX, and exhibited BL antagonist activity compared to DMSO (FIG. 3-3 to Fig. 3-7).
  • the compounds of Examples 5 and 6 changed the expression levels of all genes in comparison with DMSO, and in particular, the compound of Example 5 showed the same action as BL in SAUR-AC1, BAS1, and IAA19 (FIG. 3-8 to 3-13), the compound of Example 6 showed the same action as BL in SAUR-AC1, IAA19, and CPD (FIGS. 3-14 to 3-19).
  • the compound (I) or a salt thereof of the present disclosure has BR-like agonist activity or antagonist activity, it is useful as a plant growth regulator, for example, a plant growth promoter or growth inhibitor.

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Abstract

La présente invention concerne un nouveau composé de type non stéroïdien ou un sel de celui-ci, ayant une activité de type BR qui est utile pour la régulation de la croissance végétale, une composition agricole contenant le composé ou son sel, et ses utilisations. La présente invention concerne particulièrement, le composé représenté par la formule (I), ou un sel de celui-ci. [Dans la formule, les symboles ont les significations définies dans les spécifications]
PCT/JP2018/008083 2017-03-03 2018-03-02 Production d'un composé non stéroïdien ayant une activité de type hormone stéroïdienne végétale (brassinolide) WO2018159827A1 (fr)

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JP2019503152A JPWO2018159827A1 (ja) 2017-03-03 2018-03-02 植物ステロイドホルモン（ブラシノライド）様活性をもつ非ステロイド化合物の創製

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Cited By (4)

* Cited by examiner, † Cited by third party
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JP2020147524A (ja) * 2019-03-13 2020-09-17 国立大学法人東海国立大学機構 花粉管成長調節剤
US10800757B2 (en) 2017-10-27 2020-10-13 Boehringer Ingelheim International Gmbh Inhibitors of TRPC6
US12059408B2 (en) 2020-08-13 2024-08-13 Boehringer Ingelheim International Gmbh Treatment of cognitive impairment associated with schizophrenia
WO2024172156A1 (fr) * 2023-02-16 2024-08-22 国立大学法人東海国立大学機構 Composé ayant une activité de type brassinostéroïde

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