WO2021089011A1 - Composé à structure bishydrazide, son procédé de préparation et son utilisation - Google Patents

Composé à structure bishydrazide, son procédé de préparation et son utilisation Download PDF

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WO2021089011A1
WO2021089011A1 PCT/CN2020/127252 CN2020127252W WO2021089011A1 WO 2021089011 A1 WO2021089011 A1 WO 2021089011A1 CN 2020127252 W CN2020127252 W CN 2020127252W WO 2021089011 A1 WO2021089011 A1 WO 2021089011A1
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hydrazine
carbonyl
carboxylic acid
substituted
cyclohexane
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PCT/CN2020/127252
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Chinese (zh)
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蒋华良
沈晓燕
郑明月
侯辉
鲍维廉
刘小红
张素林
杨瑞瑞
吴小龙
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中国科学院上海药物研究所
复旦大学
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    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C241/04—Preparation of hydrazides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a bishydrazide structure compound, a preparation method and application thereof.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • IL-12 family members especially IL-23
  • IL-23 can activate CD4+ memory cells, CD8+ cells, NK cells and a few mononuclear macrophages/dendritic cells.
  • IL-23R IL-23 receptor
  • the purpose of the present invention is to provide a class of bishydrazide structure compounds that can be used to treat IBD.
  • the first aspect of the present invention provides a compound represented by formula I, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof,
  • X 1 , X 2 , and X 3 are each independently selected from the following group: C(R 1 ) 2 , NR 1 , CR 1 or N;
  • G is selected from the following group: hydrogen, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino , Hydroxymethyl, C 1 -C 6 haloalkyl, or -L 1 -M;
  • Q is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino , Hydroxymethyl, C 1 -C 6 haloalkyl, or -L 1 -M;
  • Q can be located on X 1 or X 2 ;
  • G can be located on X 1 or X 2 ;
  • R 1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 Alkylamino, hydroxymethyl, or C 1 -C 6 haloalkyl;
  • M is independently selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 20 cycloalkyl, substituted or unsubstituted 3-20 heterocyclyl, substituted Or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted 6-14 membered heteroaryl; and -L 1 -M may optionally be further substituted by one or more halogens, 3-12 membered heterocyclic groups or C Substituted by 3-12 cycloalkyl;
  • substitution is selected from one or more of the following group: halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkylalkynyl, C 6 -C 14 aryl, 5-14 membered heterocyclic group, and the aryl and heteroaryl groups may optionally be further One or more substituents selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6
  • A is independently selected from the following group: substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclic group, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted 6 14-membered heteroaryl; wherein the substitution is selected from one or more of the following group: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkane Amino, hydroxymethyl or C 1 -C 6 haloalkyl;
  • the compound, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof have the following formula II Structure
  • X 1 , X 2 , and X 3 are each independently selected from: CR 1 or N;
  • R 1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, hydroxymethyl, halomethyl, or -L 1 -M;
  • M is independently selected from the group: C 2 -C 4 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene Group, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted 6-20 membered fused heterocyclic ring, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted 5-6 membered heteroaryl; said M may be further Is substituted by one or more halogen, 3-12 membered heterocyclic group or C 3-12 membered cycloalkyl; and the substitution is selected from one or more of the following group: halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 al
  • A is independently selected from the following group: substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, or substituted or unsubstituted 6-14 membered heteroaryl; wherein, the substituted One or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, hydroxymethyl or halomethyl;
  • the compound, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof have the following formula III The structure shown,
  • G, Q, A, and K are as described above.
  • the compound, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof have the following formula IV The structure shown,
  • G, Q, A, and K are as described above.
  • the compound, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof have the following formula V The structure shown,
  • G, Q, A, and K are as described above.
  • X 1 , X 2 , X 3 , G, Q, A, and K are the groups corresponding to the specific compounds in the embodiments.
  • the compound is selected from the following compounds:
  • the second aspect of the present invention provides the preparation of the compound of formula I described in the first aspect, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof
  • the method includes the following steps:
  • a 2 compound is reacted with compound b, and optionally further reacted to produce compound I;
  • X 1 , X 2 , X 3 , G, Q, A, and K are defined as described above.
  • the further reaction refers to substitution with halogenated alkane, or condensation reaction with alcohol or amine to obtain compound I;
  • the alcohol is C 1 -C 6 alkyl-OH, so
  • the amine mentioned is C 1 -C 6 alkyl-NH 2 or C 1 -C 6 alkyl-NC 1 -C 6 alkyl.
  • the first inert solvent is selected from: CH 3 CN, toluene, xylene, dichloromethane, DMF, or a combination thereof.
  • the method for preparing the salt includes making the compound of formula I and the free base or acid and the chemical equivalent or excess amount of acid (inorganic acid or organic acid) or base (inorganic base or organic base). Prepared by reaction in a suitable solvent or solvent composition.
  • the method for preparing the compound of formula I, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof further comprises the following steps :
  • compound a 1 reacts with hydrazine hydrate to form compound a 2 ;
  • X 1 , X 2 , X 3 , G, and Q are defined as described above.
  • the second inert solvent is an alcohol, preferably a C 1 -C 6 alkyl alcohol, more preferably methanol or ethanol.
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or Active metabolite; and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides the compound of the first aspect, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites, or the third aspect
  • the inflammatory bowel disease includes Crohn's disease or Behcet's disease accompanied by bowel disease, ulcerative colitis, hemorrhagic rectal ulcer and ileal bursitis.
  • the treatment includes: promoting mucosal healing, restoring intestinal epithelial structure, or a combination thereof.
  • the treatment includes: promoting the activity of intestinal stem cells, reducing the expression of pro-inflammatory cytokines, or a combination thereof.
  • the fifth aspect of the present invention provides a method for inhibiting IL-23 and up-regulating cyclinD1 in vitro, which includes the steps of combining the compound described in the first aspect of the present invention, its optical isomers or cis-trans isomers, and pharmaceutically acceptable
  • the salts, hydrates, solvates, prodrugs or active metabolites of serotonin can contact somatic cells (or tissues) to inhibit IL-23 and up-regulate cyclinD1.
  • said inhibiting IL-23 includes inhibiting the formation of IL-23 miRNA and inhibiting the expression of IL-23 protein.
  • said up-regulating cyclinD1 includes promoting the formation of cyclinD1 miRNA and promoting the expression of cyclinD1 protein.
  • the somatic cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells and intestinal epithelial cells), or a combination thereof.
  • the somatic cells are derived from rodents (such as mice, rats) or primates (such as humans).
  • the fifth aspect of the present invention provides a method for treating inflammatory bowel disease, including the steps of: administering the compound, optical isomer, or cis-trans isomer of the first aspect of the present invention to a subject in need of treatment , A pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite, or the pharmaceutical composition described in the third aspect.
  • the inflammatory bowel disease includes Crohn's disease or Behcet's disease accompanied by bowel disease, ulcerative colitis, hemorrhagic rectal ulcer and ileal bursitis.
  • the subject is a mammal, preferably a human.
  • Figure 1 shows the therapeutic effect of compound A 1 on a mouse colitis model.
  • Figure 2 shows at two concentrations, blood concentration of the compound orally administered to mice A 1.
  • Figure 3 shows the growth promoting effect of Compound A 1 pair of mouse origin Sausages organ.
  • the inventors unexpectedly developed a class of bishydrazide structure compounds that can inhibit IL-23 and up-regulate cyclinD1.
  • the compound of the present invention can not only inhibit the over-activated intestinal inflammatory response and immune response, thereby significantly reducing the inflammation of the colon of IBD mice, but also can effectively promote the healing of the intestinal mucosa and maintain the homeostasis, so it can be effectively and synergistically used to treat inflammatory Intestinal diseases.
  • the present invention has been completed on this basis.
  • alkyl refers to a straight or branched chain alkane group containing 1-18 carbon atoms, especially 1-6 carbon atoms.
  • Typical "alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, isopentyl, heptyl, 4,4-dimethylpentyl Alkyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc.
  • (C 1 -C 6 )alkyl refers to straight or branched chain alkyl, including from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, Tert-butyl, isobutyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkenyl refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon double bond.
  • (C 2 -C 6 )alkenyl refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, and 2-propenyl.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon triple bond substituent. Typical groups include ethynyl.
  • (C 2 -C 6 )alkynyl refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as ethynyl, 1-propynyl, 2 -Propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms, for example, containing 3-18 carbon atoms, especially 3 -14 carbon atoms, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornane.
  • Substituted cycloalkyl means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl ( Bridged cycloalkenyl substituted cycloalkyl groups include but are not limited to ), bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and hetero Cyclic aryl groups can be optionally substituted.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms, for example, containing 3-18 carbon atoms, especially 3-14 carbon atoms.
  • Typical cycloalkenyl groups are cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
  • Substituted cycloalkenyl means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include bridged ring, spiro ring or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (not including heteroaromatic ring), fused ring alkyl, fused cycloalkenyl, Condensed ring heterocyclic group or condensed ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic and heterocyclic aryl groups may be optionally substituted.
  • cycloalkylalkynyl refers to alkynyl substituted by cycloalkyl, including C3-C8 cycloalkyl-C ⁇ CR a
  • R a can independently represent none, hydrogen, deuterium, alkyl, cycloalkyl, alkenyl , Cycloalkenyl, alkynyl, heterocyclic or aromatic ring, for example: cyclopropylacetylene, cyclobutylacetylene, cyclopentylacetylene, cyclohexylacetylene.
  • the cycloalkyl group may be substituted, and the substituent may be as the substituent in the term "cycloalkyl".
  • aryl refers to an aromatic cyclic hydrocarbon compound group having 1-5 rings, for example, containing 6-18 carbon atoms, especially 6-14 carbon atoms. Especially refers to monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl) or condensed (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • heteroaryl refers to a heteroaromatic system containing 1-4 heteroatoms (preferably 1 or 2), 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably 5-membered or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole Group, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, purine, carbazole, indolyl, indazolyl, benzothienyl , Benzofuranyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazoly
  • Heteroaryl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, and alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • Haloalkyl refers to straight or branched chain haloalkyl, such as "C 1 -C 6 haloalkyl", which refers to a straight chain having 1 to 6 carbon atoms containing one or more identical or different halogen atoms Or branched chain haloalkyl, including without limitation -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Br, -CHBr 2 , -CBr 3 , CF 3 CH 2 , CCl 3 CH 2 , CBr 3 CH 2 .
  • alkoxy refers to a straight or branched chain alkoxy group, such as "C1-C6 alkoxy”, which refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, without limitation Ground includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preferably, it is a C1-C4 alkoxy group.
  • haloalkoxy refers to a halogen-substituted linear or branched alkoxy group, such as "C1-C6 haloalkoxy", which refers to a linear or branched haloalkoxy group having 1 to 6 carbon atoms, Including chloromethoxy, chloroethoxy, chloropropoxy, chloroisopropoxy, chlorobutoxy, bromomethoxy, bromoethoxy, bromo Propoxy, bromoisopropoxy and bromobutoxy, etc.
  • alkylamino refers to an amino-substituted linear or branched alkyl group, such as "C1-C6 alkylamino", which refers to an amino-substituted linear or branched alkyl group having 1 to 6 carbon atoms Groups, including without limitation H 2 N-CH 2 -, H 2 N-CH 2 CH 2 -, H 2 N-CH 2 CH 2 CH 2 -, H 2 N-CH(CH 3 )CH 2 -, etc. .
  • haloalkenyl refers to a substituent containing 2-18 carbon atoms and at least one carbon-carbon double bond.
  • haloalkynyl refers to a substituent containing 2-18 carbon atoms and at least one carbon-carbon triple bond.
  • (C 2 -C 6 )haloalkynyl refers to a straight or branched chain containing 2-6 carbon atoms, at least one carbon-carbon triple bond, and one or more identical or different halogen atom groups , Including -C ⁇ CCl, -C ⁇ CF, -C ⁇ CBr, -C ⁇ C-CH 2 F, -C ⁇ CCHF 2 , -C ⁇ C-CF 3 , -C ⁇ CCH 2 Br, -C ⁇ CCHBr 2 , -C ⁇ CCBr 3 and so on.
  • hydroxymethyl refers to -CH 2 OH.
  • condensation reaction means that the carboxylic acid compound obtained in the present invention reacts with alcohol or amine in the presence of a condensing agent; the condensing agent can use common condensing agents well known in the art, such as: DMAP, EDCI, HOBT, HOAT, HATU, HBTU, etc.
  • Salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts.
  • the term "salt” as used herein refers to a salt formed into an acid or basic form with an inorganic or organic acid and a base.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process.
  • the compound of the present invention may form a salt.
  • the compound I can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or by freeze-drying in an aqueous solution.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion.
  • the general formula including substituents in the formula of the present invention means that the substituents of the specified structure are substituted for hydrogen radicals.
  • each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • inflammatory bowel disease not only refers to inflammatory bowel disease in the strict sense such as Crohn’s disease and ulcerative colitis, but also refers to inflammatory bowel disease in a broad sense, including Behcet’s disease. Intestinal disease, hemorrhagic rectal ulcer, ileal bursitis, intestinal tuberculosis, ischemic enteritis, drug-induced colitis, radiation enteritis, infectious enteritis, etc.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable here refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, which is used herein for the above purpose.
  • the terms "compounds of the present invention” or “dihydrazide structure compounds of the present invention” are used interchangeably, and refer to compounds represented by formula I.
  • the term also includes the compound of formula I, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or active metabolites thereof.
  • the compound of formula I has the following structure:
  • X 1 , X 2 , X 3 , G, Q, A, and K are defined as described above.
  • the compound of formula I has the structure shown in formula II
  • X 1 , X 2 , X 3 , G, Q, A, and K are defined as described above.
  • the compound of formula I has the structure shown in formula III,
  • G, Q, A, and K are as described above.
  • the compound of formula I has the structure shown in formula IV,
  • G, Q, A, and K are as described above.
  • the compound of formula I has the structure shown in formula V,
  • G, Q, A, and K are as described above.
  • G is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, hydroxymethyl, C 1 -C 6 haloalkyl, or -L 1 -M;
  • Q is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino , Hydroxymethyl, C 1 -C 6 haloalkyl, or -L 1 -M;
  • M is independently selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-6 heterocyclyl, substituted Or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 6-10 membered heteroaryl; and -L 1 -M may optionally be further substituted by one or more (such as 2, 3 or 4) halogens, 3 -6 membered heterocyclic group or C 3-6 cycloalkyl substituted;
  • substitution is selected from one or more of the following groups (such as 2, 3 or 4): halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkylalkynyl, C 6 -C 14 aryl, 5-14 membered heterocyclic group, and the aryl, hetero
  • the aryl group may optionally be further substituted with one or more (such as 2, 3 or 4) substituents selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 al
  • A is selected from the following group: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6 -C 10 aryl, A substituted or unsubstituted 6-10 membered heteroaryl group; wherein the substitution is selected from one or more of the following group: halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, hydroxymethyl or C 1 -C 6 haloalkyl.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by the compound of the present invention and an acid or a base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • a base such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • alkali metal salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or calcium salt
  • ammonium salt such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts
  • methylamine salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or calcium
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination of the compound of the present invention with water.
  • the compounds of the present invention also include the prodrugs of the double hydrazide structure shown in Formula I.
  • prodrug includes biologically active or inactive itself, and when taken in an appropriate way, it undergoes metabolism or chemical reaction in the human body to convert it into a class of compounds of formula I, or formula I A salt or solution of a compound.
  • the prodrugs include (but are not limited to) carboxylic acid esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, and azo compounds of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
  • the preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out in an inert solvent at 0°C or room temperature to reflux temperature (such as 0°C to 160°C, preferably 0°C to 120°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • compound a 2 is reacted with compound b to prepare compound I.
  • the compound a2 can be prepared by the following steps:
  • the compound of the present invention has the effects of inhibiting IL-23 (e.g. inhibiting IL-23 mRNA) and up-regulating cyclinD1 (e.g. increasing cyclinD1 mRNA), the compound of the present invention, its optical isomers or cis-trans isomers are pharmaceutically acceptable
  • the salts, hydrates, solvates, prodrugs or active metabolites thereof, and pharmaceutical compositions containing the compound of the present invention as the main active ingredients can be used for the treatment, prevention and alleviation of IBD.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the bishydrazide structure compound of the present invention can enhance the activity of intestinal stem cells, promote the repair of intestinal epithelium, and reduce the expression of pro-inflammatory cytokines, thereby achieving the treatment of inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the bis-hydrazide structure compound of the present invention can not only inhibit IL-23 mRNA but also up-regulate cyclinD1 mRNA, so it can treat IBD synergistically and more efficiently.
  • Step 2 Dissolve compound 2 (400 mg) in CH 3 CH 2 OH (25 mL), add hydrazine hydrate (5 mL), and react under reflux for 4 h. After the completion of the reaction, it was concentrated under reduced pressure, and the solid was washed with ice water, and then recrystallized from ethanol to obtain compound 4 (120 mg, yield 40%).
  • the third step Dissolve compound 5 (352 mg) in CH 3 CN (15 mL), heat to reflux, then add compound 4 (500 mg), and keep refluxing for 30 min. After the completion of the reaction, the solid was obtained by suction filtration, and then washed with CH 3 CN, and dried under vacuum at 70° C. for 2 h to obtain compound A 1 (605 mg, yield 71%).
  • Example 1-2 Referring to the method of Example 1-2, the corresponding substrate was used to replace the substrate in Example 1 to synthesize compound A 3 -A 37 .
  • HCT116 cells and Raw264.7 cells were provided by the Cell Bank of the Chinese Academy of Sciences; the intestinal organoids were derived from intestinal crypt cultures isolated from Lgr5-EGFP mice; Lgr5-EGFP mice were donated by the Hua Guoqiang research group of the Fudan Institute of Radiation Medicine Yes, the genetic background is C57/BL6, and the mice are raised in the SPF animal room on the second floor of the Experimental Animal Center, School of Pharmacy, Fudan University.
  • test compounds were prepared into a stock solution with a concentration of 50 mM with DMSO, and stored in a refrigerator at -20 degrees.
  • Raw264.7 cells were seeded in a 12-well plate. After 24 hours, the cell density was about 70-80%. Compounds of different dilution ratios were added. After adding the drug, 20 ⁇ l (ie 0.5 ⁇ g/ml) of LPS was added to each well. Shake the culture plate to mix well. The blank group is not added.
  • RNA concentration of the sample After 6 hours, discard the culture medium, wash 3 times with ice-cold PBS buffer, add 1ml Trizol, let stand for 10 min, collect the lysate, centrifuge to obtain the supernatant, add 1/5 volume of chloroform, shake for 1 min, let stand for 3 min, 4 Centrifuge at 12000g at °C. Take the supernatant, add an equal volume of isopropanol and mix well, let it stand for 10 minutes, and centrifuge at 12000xg for 10 minutes. Remove the supernatant, wash the pellet with 70% ethanol, centrifuge at 7500g for 5 minutes, dry the pellet, and add 20 ⁇ L DEPC water. Detect the RNA concentration of the sample and adjust it to 100-1000ng/ ⁇ L, and use a commercially available reverse transcription kit and SYBR-qPCR kit to detect changes in IL-23 mRNA levels.
  • the reverse transcription kit prepare the following mixture in a RNase free centrifuge tube, and gently pipette to mix. Incubate at 42°C for 2 min.
  • the reverse transcription reaction procedure is as follows: Stage 1: 25°C, 5min; Stage 2: 42°C, 30min; Stage 3: 85°C, 5min; Stage 4: 4°C, keep, product -20°C, or directly used in RT- qPCR.
  • the primer sequences involved in Real-Time PCR are as follows:
  • the 2- ⁇ Ct method was used to analyze the data, and the value of 2- ⁇ Ct was calculated as the multiple of the target gene expression in the experimental group relative to the control group.
  • Colorectal cancer HCT 116 cell line was used for compound screening, and the medium used was McCOY's5A medium containing 10% FBS. Inoculate the cells in a 12-well plate so that the density of adherent cells on the next day is 70% to 80%. Take 1 ⁇ L of the stock solution (50 mM) in 1 ml of medium and prepare 50 ⁇ M of drug-containing medium (the control group is 0.1% DMSO medium). The original medium was discarded, the drug-containing medium was added, and cultured at 37°C for 6 hours.
  • RNA concentration of the sample and adjust it to 100-1000ng/ ⁇ L, and use a commercially available reverse transcription kit and SYBR-qPCR kit to detect changes in the level of cyclinD1 mRNA.
  • the reverse transcription kit prepare the following mixture in a RNase free centrifuge tube, and gently pipette to mix. Incubate at 42°C for 2 min.
  • the reverse transcription reaction procedure is as follows: Stage 1: 25°C, 5min; Stage 2: 42°C, 30min; Stage 3: 85°C, 5min; Stage 4: 4°C, keep, product -20°C, or directly used in RT- qPCR.
  • the primer sequences involved in Real-Time PCR are as follows:
  • Collect instrument data use the 2- ⁇ Ct method to analyze the data, and calculate the value of 2- ⁇ Ct as the multiple of the target gene expression in the experimental group relative to the control group.
  • the reaction program is set according to the instructions.
  • the experimental groups were set as the control group, the model group, the mesalazine administration group, the A 1 -10 mg/kg administration group and the compound A 1 -20 mg/kg administration group, a total of five groups, each with 8 8-week-old males C57/BL6 mice, except for the control group, were given 3% dextran sulfate sodium salt (DSS) water for free drinking, and they were reconstituted and replaced every other day for 7 days.
  • DSS dextran sulfate sodium salt
  • Compound A 1 was dissolved in DMSO to prepare mother liquor, and then separately dissolved in ultrapure water to prepare 4% DMSO aqueous solutions with final concentrations of 1 mg/ml and 2 mg/ml respectively, and mesalazine was prepared with 0.5% CMC-Na to prepare 50 mg/ml
  • the gavage was started at the same time as the model was made, and the gavage dose was 10 ⁇ L/g (corresponding to the administration dose of 10mg/kg, 20mg/kg and 50mg/kg) for 10 days.
  • mice The weight change of the mice was recorded every day, and the mice were sacrificed after 10 days for sampling.
  • mice After 10 days of the above-mentioned administration, the mice were taken to take the eyeballs to collect blood, and after the whole blood was collected, the blood was allowed to coagulate without interference for 15-30 minutes at room temperature. Serum was obtained by centrifugation in a centrifuge at 1,000 ⁇ g 4°C for 10 min. For serum samples, Daktronics' IL-1 ⁇ and IL-23 ELISA kits were used to detect the serum levels of IL-1 ⁇ and IL-23.
  • mice After taking blood from the above eyeballs, the mice were sacrificed, and the entire colon was taken for photographing and length measurement.
  • the qPCR primers of each inflammatory factor are as follows
  • Collect instrument data use the 2- ⁇ Ct method to analyze the data, and calculate the value of 2- ⁇ Ct as the multiple of the target gene expression in the experimental group relative to the control group.
  • a 0.5 cm colon of the mouse was taken from the middle section of the mouse, fixed with paraformaldehyde at 4°C for 16 hours, and entrusted to Wuhan Saiweier Biological Company for paraffin embedding, sectioning and hematoxylin-eosin (H&E) staining.
  • Wuhan Saiweier Biological Company for paraffin embedding, sectioning and hematoxylin-eosin (H&E) staining.
  • mice Eighteen mice (C57), male, weighing 18-22 g, were randomly divided into 6 groups, 3 in each group, and the test compound was given by gavage, fasting for 12 hours before the test, free drinking water, and uniform eating 2 hours after administration.
  • the experimental program is as follows:
  • blood was collected from the retroorbital venous plexus of mice, collected in EP tubes treated with sodium heparin, and centrifuged to obtain plasma.
  • Accurately draw 15 ⁇ L of plasma into the EP tube corresponding to the sample number add 300 ⁇ L of a methanol/acetonitrile equal volume mixed solution containing 50ng/mL tolbutamide as the internal standard, vortex the mixture for 1min, and centrifuge at 12000rpm for 10min at room temperature.
  • Ultra-high performance liquid chromatography Waters company for gradient separation, triple quadrupole mass spectrometry (API5000, SCIEX company) using an electrospray ion source, under negative ion conditions using multi-reaction monitoring mode (MRM, multi reaction monitoring) for detection.
  • MRM multi-reaction monitoring mode
  • Mass spectrometry conditions are as follows
  • composition of WNER medium is:
  • SPSS 13.0 was used to analyze the data, the comparison between the two groups was performed by paired t-test, and the comparison between multiple groups was performed by one-way analysis of variance, and P ⁇ 0.05 was regarded as a difference in the test results.
  • the data are expressed as mean ⁇ standard deviation (mean ⁇ SD).
  • GraphPad Prism 7.0 software makes bar graph and line graph.
  • Figure 1 shows the therapeutic effect of compound A 1 on a mouse colitis model.
  • C is the detection result of IBD-related protein mRNA expression in mouse colon tissue.
  • D is the ELISA test result of serum inflammatory factor levels in mice.
  • E is the result of H&E staining of a mouse colon specimen, showing the destruction of the crypts and inflammatory infiltration of the colon. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • Figure 2 shows the changes in the plasma concentration of the mouse within 24 hours after the oral route of administration of Compound A 1 at two concentrations of 3 mg/kg and 20 mg/kg.
  • the results showed that the peak plasma concentrations of compound A 1 after oral administration of 3 mg/kg and 20 mg/kg were 175 ng/mL and 700 ng/mL, respectively, and the peak time was about 1 hour; the half-life was about 1.72 hours; the drug-time curve
  • the lower areas were 410 (h*ng/mL) and 2363 (h*ng/mL), indicating a linear relationship between exposure and dose.
  • Figure 3 shows the growth promoting effect Sausages The mouse organs derived compound A.
  • A is the growth of mouse colonic crypts isolated and grown in Matrigel coated with WNER medium.
  • C is the organ under the action of intestinal type compound 50 ⁇ M of A 1, RT-qPCR show intestinal stem cell-associated genes Lgr5, Axin2 Ascl2 expression and significant upregulation compared to the control group.

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Abstract

L'invention concerne un composé ayant une structure bishydrazide représentée par la formule I, ainsi que son procédé de préparation et son utilisation. Le composé avec une structure bishydrazide peut améliorer l'activité de cellules souches intestinales, favoriser la réparation épithéliale intestinale et, en même temps, réduire l'expression de cytokines pro-inflammatoires, jouant ainsi un rôle dans le traitement de maladies intestinales inflammatoires.
PCT/CN2020/127252 2019-11-08 2020-11-06 Composé à structure bishydrazide, son procédé de préparation et son utilisation WO2021089011A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3964896A (en) * 1971-08-09 1976-06-22 Uniroyal, Inc. Oxadiazole benzoic acid derivatives as herbicides
US4210762A (en) * 1978-08-17 1980-07-01 Monsanto Company 2[5-(3-Trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl] benzoates
WO2000027835A1 (fr) * 1998-11-09 2000-05-18 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
RO116620B1 (ro) * 1997-12-22 2001-04-30 Ct De Cercetare Si Productie B N1-acil-n2-(o-carboxibenzoil)-hidrazine si procedeu pentru prepararea acestora
WO2005058832A1 (fr) * 2003-12-10 2005-06-30 Merck Patent Gmbh Derives de diacylhydrazine
RU2412160C1 (ru) * 2009-09-25 2011-02-20 Федеральное государственное учреждение науки "Государственный научный центр вирусологии и биотехнологии "Вектор" Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человека (ФГУН ГНЦ ВБ "Вектор" Роспотребнадзора) 7-[n'-(4-трифторметилбензоил)-гидразинокарбонил]-трицикло[3.2.2.02,4]нон-8-ен-6-карбоновая кислота, обладающая противовирусной активностью
CN102775381A (zh) * 2011-05-13 2012-11-14 中国科学院上海药物研究所 取代的酰肼类化合物及其制备方法、药物组合物和用途
CN104557691A (zh) * 2014-12-11 2015-04-29 中国农业大学 一种3-胺酰双酰肼衍生物及其制备方法和应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8283351B2 (en) * 2007-04-02 2012-10-09 Institute For Oneworld Health Cyclic and acyclic hydrazine derivatives compositions including them and uses thereof
CA2704562A1 (fr) * 2007-10-29 2009-05-07 Astellas Pharma Inc. Compose polypeptidique
AU2008345225A1 (en) * 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
WO2011006158A2 (fr) * 2009-07-10 2011-01-13 University Of Maryland, Baltimore Ciblage de la biosynthèse de la nad dans des bactéries pathogènes
WO2015125785A1 (fr) * 2014-02-18 2015-08-27 第一三共株式会社 Dérivé de pyrazolone portant de mulitples substituants
WO2018150755A1 (fr) * 2017-02-16 2018-08-23 株式会社Adeka Nouveau composé, agent de nucléation, composition de résine et article moulé

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3964896A (en) * 1971-08-09 1976-06-22 Uniroyal, Inc. Oxadiazole benzoic acid derivatives as herbicides
US4210762A (en) * 1978-08-17 1980-07-01 Monsanto Company 2[5-(3-Trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl] benzoates
RO116620B1 (ro) * 1997-12-22 2001-04-30 Ct De Cercetare Si Productie B N1-acil-n2-(o-carboxibenzoil)-hidrazine si procedeu pentru prepararea acestora
WO2000027835A1 (fr) * 1998-11-09 2000-05-18 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2005058832A1 (fr) * 2003-12-10 2005-06-30 Merck Patent Gmbh Derives de diacylhydrazine
RU2412160C1 (ru) * 2009-09-25 2011-02-20 Федеральное государственное учреждение науки "Государственный научный центр вирусологии и биотехнологии "Вектор" Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человека (ФГУН ГНЦ ВБ "Вектор" Роспотребнадзора) 7-[n'-(4-трифторметилбензоил)-гидразинокарбонил]-трицикло[3.2.2.02,4]нон-8-ен-6-карбоновая кислота, обладающая противовирусной активностью
CN102775381A (zh) * 2011-05-13 2012-11-14 中国科学院上海药物研究所 取代的酰肼类化合物及其制备方法、药物组合物和用途
CN104557691A (zh) * 2014-12-11 2015-04-29 中国农业大学 一种3-胺酰双酰肼衍生物及其制备方法和应用

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
A. V. DOLZHENKO, ET AL.: "Substituted amides and hydrazides of dicarboxylic acids. Part 13. Synthesis and hypoglycemic activity of some substituted amides and acylhydrazides of phthalic acid", PHARMACEUTICAL CHEMISTRY JOURNAL, SPRINGER NEW YORK LLC, US, vol. 37, no. 1, 1 January 2003 (2003-01-01), US, pages 19 - 21, XP055535741, ISSN: 0091-150X, DOI: 10.1023/A:1023642927375 *
BALLELL LLUÍS, BATES ROBERT H., YOUNG ROB J., ALVAREZ-GOMEZ DANIEL, ALVAREZ-RUIZ EMILIO, BARROSO VANESSA, BLANCO DELIA, CRESPO BEN: "Fueling Open-Source Drug Discovery: 177 Small-Molecule Leads against Tuberculosis", CHEMMEDCHEM COMMUNICATIONS, WILEY-VCH, DE, vol. 8, no. 2, 1 February 2013 (2013-02-01), DE, pages 313 - 321, XP055780298, ISSN: 1860-7179, DOI: 10.1002/cmdc.201200428 *
DATABASE REGISTRY External; ANONYMOUS: "7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid, 2-[2-(4-butoxybenzoyl)hydrazide], (2S)", XP055812618, retrieved from STN *
EL SADEK MOHAMED M., EL ESSAWI MOHYI M., ABDEL BAKY SAMY A.: "Synthesis and spectra of some phthalimido derivatives", JOURNAL OF CHEMICAL AND ENGINEERING DATA., AMERICAN CHEMICAL SOCIETY., US, vol. 34, no. 2, 1 April 1989 (1989-04-01), US, pages 257 - 259, XP055812602, ISSN: 0021-9568, DOI: 10.1021/je00056a031 *
KOLOTOVA N V, E. N. KOZ'MINYKH, V. É. KOLLA, B. YA. SYROPYATOV, E. V. VORONINA, V. O. KOZ'MINYKH: "SUBSTITUTED AMIDES AND HYDRAZIDES OF 1,4-DICARBOXYLIC ACIDS. PART 7.1 SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF SOME MALEIC, SUCCINIC, AND PHTHALIC ACID ACYLHYDRAZIDES", PHARMACEUTICAL CHEMISTRY JOURNAL, SPRINGER NEW YORK LLC, US, vol. 33, no. 5, 28 May 1999 (1999-05-28), US, pages 248 - 254, XP055812597, ISSN: 0091-150X *
TORRES EVA, DUQUE MARÍA D., CAMPS PELAYO, NAESENS LIEVE, CALVET TERESA, FONT-BARDIA MERCÈ, VÁZQUEZ SANTIAGO: "Polycyclic N-Benzamido Imides with Potent Activity against Vaccinia Virus", CHEMMEDCHEM COMMUNICATIONS, WILEY-VCH, DE, vol. 5, no. 12, 3 December 2010 (2010-12-03), DE, pages 2072 - 2078, XP055812606, ISSN: 1860-7179, DOI: 10.1002/cmdc.201000306 *
ZAVAREH, ELHAM REZAEE, MAHDI HEDAYATIB , LALEH HOGHOOGHI RADB , SORAYA SHAHHOSSEINIA , MEHRDAD FAIZIC AND SAYYED ABBAS TABATABAI: "Design, Synthesis and Biological Evaluation of 4-Benzamidobenzoic Acid Hydrazide Derivatives as Novel Soluble Epoxide Hydrolase Inhibitors", IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH, SHAHEED BEHESHTI MEDICAL UNIVERSITY - SCHOOL OF PHARMACY, IR, vol. 13, 1 January 2014 (2014-01-01), IR, pages 51 - 59, XP055812609, ISSN: 1735-0328 *

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