WO2012128530A2 - Dérivés de 2-méthyl-2-alkyl-6-amido-2h-benzopyrane ayant une activité anticancéreuse - Google Patents

Dérivés de 2-méthyl-2-alkyl-6-amido-2h-benzopyrane ayant une activité anticancéreuse Download PDF

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WO2012128530A2
WO2012128530A2 PCT/KR2012/001971 KR2012001971W WO2012128530A2 WO 2012128530 A2 WO2012128530 A2 WO 2012128530A2 KR 2012001971 W KR2012001971 W KR 2012001971W WO 2012128530 A2 WO2012128530 A2 WO 2012128530A2
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methyl
benzopyran
group
amido
propyl
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WO2012128530A3 (fr
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공영대
김정엽
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Industry Academic Cooperation Foundation of Dongguk University
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Industry Academic Cooperation Foundation of Dongguk University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides novel 2-methyl-2-alkyl-6-amido-2 H -benzopyran derivatives having a good NF- ⁇ B target gene expression inhibitory activity, pharmaceutically acceptable salts thereof, methods for preparing the compounds, and An anticancer agent comprising the compound as an active ingredient.
  • anticancer agent refers to chemotherapeutic agents other than surgery or radiation therapy among the methods used to treat malignant tumors, and most of them show anticancer activity by inhibiting the synthesis of nucleic acids.
  • Chemotherapeutic agents are broadly classified into antimetabolites, alkylating agents, antimitotic drugs, and hormones.
  • Metabolic antagonists that inhibit metabolic processes necessary for the proliferation of cancer cells include folate derivatives (methotrexate), purine derivatives (6-mercaptopurine, 6-thioguanine), and pyrimidine derivatives (5-fluorouracil, Cytarabine).
  • Alkylating agents that introduce an anti-cancer effect by introducing an alkyl group to DNA guanine and modifying the structure of the DNA and cleaving the chain include nitrogen mustard compounds (chlorambucil, cyclophosphamide), ethyleneimine compounds (thiotepa), alkylsulfonate compounds ( busulfan), nitrosourea compounds (carmustine), triazane compounds (dacarbazine).
  • Mitosis inhibitors that inhibit mitosis by blocking mitosis as drugs that are specific to mitosis include plants such as actinomycin D, anti-cancer drugs such as doxorubicin, bleomycin and mitomycin, and vincristine and vinblastine. Alkaloids, taxoids including mitosis inhibitors including taxane rings, and the like.
  • hormones such as corticosteroids and progesterone and platinum-containing compounds such as cisplatin are used as anticancer agents.
  • NF- ⁇ B has recently received much attention as a target for developing effective and safe anticancer drugs and overcoming drug resistance, and has been found to discover effective organic small molecules that inhibit the expression of NF- ⁇ B target genes, and to prevent and treat cancer. Efforts have been made to develop anticancer drugs. [M. Karin et al., Nature Reviews Cancer 2002, 2, 301-310; B. Haefner, Drug Discovery Today 2002, 7, 653-663; C. Nakanishi et al., Nature Reviews Cancer 2005, 5, 297-309; S. Olivier et al., Biochemical Pharmacology 2006, 1054-1068; J. Adams, Drug Discovery Today 2003, 8, 307-315; A. Albini et al., Nature Reviews Cancer 2007, 7, 139-147].
  • R 1 represents a hydrogen atom or an acyl group of C 1 -C 6
  • R 2 represents an aryl or heteroaryl group selected from phenyl, pyridinyl, isoxazolyl, thiazolyl, triazolyl, benzothiazolyl, benzisothiazolyl, and thiadiazolyl
  • A is a hydrogen atom, Halogen atom, C 1 -C 6 alkyl group, or C 1 -C 6 alkoxy group.
  • the compound represented by the formula (1) characterized by the present invention is a compound of a novel structure that has not been disclosed in the related prior art, and has an excellent NF- ⁇ B target gene expression inhibitory activity as an anticancer agent for cancer prevention and treatment Can be utilized.
  • the present invention relates to novel 6-alkyl of 2-methyl-2-amido -2 H - there is provided a benzopyran derivative.
  • the present invention has another object to provide a pharmaceutical use using the novel compound as an anticancer agent, because the novel compound has an NF- ⁇ B target gene expression inhibitory activity.
  • FIG -2 represented by the following formula 1 H - is a benzopyran derivative in its features.
  • A is a hydrogen atom; Halogen atom; C 1 -C 5 alkyl group; Or a C 1 -C 5 alkoxy group, R 1 is a hydrogen atom; Acetyl group; C 1 -C 5 alkyl group; Or a C 6 -C 10 aryl C 1 -C 5 alkyl group, R 2 is a C 1 -C 5 alkyl group; C 3 -C 8 cycloalkyl group; C 2 -C 5 alkenyl group; C 6 -C 10 aryl group; Or a 5- to 7-membered heteroaryl group including a hetero atom selected from oxygen or sulfur, and the aryl or heteroaryl used in the definition of R 1 and R 2 is halo, nitro, amino, hydroxy, acetamido, respectively.
  • Mono (C 1 -C 5 alkyl) amino, di (C 1 -C 5 alkyl) amino, C 2 -C 5 acyl, C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, C 1 -C 5 0 to 3 substituents selected from alkoxy, C 1 -C 5 haloalkoxy and C 1 -C 5 alkylthio may be substituted.
  • A is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a C 1 -C 5 alkyl group at the same time is excluded.
  • the compound represented by Chemical Formula 1 according to the present invention may also exist in the form of a solvate (for example, a hydrate).
  • the compound represented by Chemical Formula 1 according to the present invention may have one or more asymmetric centers, and in the case of such compounds, enantiomers or diastereomers may be present. Accordingly, the present invention includes each isomer or a mixture of these isomers.
  • novel compounds according to the present invention have excellent NF- ⁇ B target gene expression inhibitory activity, it is useful for developing new anticancer drugs for cancer prevention and treatment.
  • halogen atom in the present invention means fluorine, chlorine, bromine and iodine atoms.
  • the alkyl group of C 1 -C 5 is methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, t -butyl, n -pentyl, i -pentyl, neopentyl or an aliphatic saturated hydrocarbon group having 1 to 5 carbon atoms including t -pentyl and the like.
  • C 3 -C 8 cycloalkyl group refers to an aliphatic having 3 to 8 carbon atoms including cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, cyclohexyl, and the like. It means a saturated hydrocarbon group.
  • C 1 -C 5 haloalkyl group means a C 1 -C 5 alkyl group in which a hydrogen atom is substituted by one or more halogen atoms, such as a trifluoromethyl group.
  • 'C 1 -C 5 alkoxy group' means methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy, t -butoxy
  • C 1 -C 5 refers to a hydroxy group substituted with a hydrogen atom by a substituent selected from an alkyl group.
  • C 1 -C 5 haloalkoxy group means a C 1 -C 5 alkoxy group in which a hydrogen atom is substituted by one or more halogen atoms, such as a difluoromethoxy group.
  • C 1 -C 5 alkylthio group means a mercapto group in which a hydrogen atom is substituted by a substituent selected from a C 1 -C 5 alkyl group.
  • aryl group in the present invention means a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group including phenyl, naphthyl, anthranilyl, phenanthryl, and the like.
  • the aryl group may be substituted or unsubstituted by a substituent, and the substituted aryl group may be halo, nitro, amino, hydroxy, acetamido, mono (C 1 -C 5 alkyl) amino, di (C 1 -C 5 alkyl) amino, C 2 -C 5 acyl, C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 haloalkoxy, C 1 -C 5 alkylthio It may be substituted by 1 to 3 substituents selected from among.
  • heteroaryl group means pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxa Diazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, benzofurazanyl, dibenzofuranyl, Isobenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolin
  • heteroaryl group may be substituted or unsubstituted by a substituent, and the substituted heteroaryl group may be halo, nitro, amino, hydroxy, acetamido, mono (C 1 -C 5 alkyl) amino, di (C 1 -C 5 alkyl) amino, C 2 -C 5 acyl, C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 haloalkoxy, C 1 -C 5 alkyl It may be substituted by 1 to 3 substituents selected from thio and the like.
  • A is a hydrogen atom; Or a C 1 -C 5 alkyl group, R 1 is a hydrogen atom; An alkyl group of C 1 -C 5 ; Benzyl groups; Or C 1 -C represents a substituted benzyl with 1 to 3 substituents selected from the group consisting of alkyl and alkoxy of C 1 -C 5 5, wherein R 2 is C 1 -C 5 alkyl group; C 3 -C 8 cycloalkyl group; C 2 -C 5 alkenyl group; Phenyl group; Halo, nitro, amino, acetamido, mono (C 1 -C 5 alkyl) amino, di (C 1 -C 5 alkyl) amino, C 2 -C 5 acyl, C 1 -C 5 alkyl, C 1 -C A phenyl group substituted with 1 to 3 substituents selected from 5 haloalkyl, and C
  • A represents a hydrogen atom, a methyl group, an ethyl group, or a propyl group
  • R 1 represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, or 2-methic.
  • the present invention includes a method for producing a compound represented by the formula (1).
  • the preparation method according to the present invention comprises a total of two steps of preparation as shown in Scheme 1 below:
  • the first step in the preparation method according to Scheme 1 is a process for preparing an amine compound represented by Chemical Formula 3 by reducing the nitro compound represented by Chemical Formula 2.
  • the nitro compound represented by Formula 2 used as a raw material in the reduction reaction is J. Med. Chem. It can be prepared using the method disclosed in 2001, 44, 4207-4215 or a general organic synthesis method.
  • the reduction reaction is carried out in the presence of a tin (Sn) compound such as tin chloride (SnCl 2 ) or tin chloride dihydrate (SnCl 2 2H 2 O).
  • a tin (Sn) compound such as tin chloride (SnCl 2 ) or tin chloride dihydrate (SnCl 2 2H 2 O).
  • the reduction solvent for example, ethyl acetate, dichloromethane, toluene, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide and the like can be used.
  • the reduction reaction temperature is maintained at a boiling point range of room temperature to a solvent, specifically, at a temperature range of 20 ° C. to 150 ° C., and preferably a reflux reaction is performed at a boiling point of the solvent.
  • the reduction reaction time is generally 5 to 24 hours, preferably 15 to 24 hours.
  • the amine compound represented by Chemical Formula 3 is acylated with an acyl halide represented by R 2 -C (O) X (where X is a halogen) to be represented by Chemical Formula 1.
  • an acyl halide represented by R 2 -C (O) X where X is a halogen
  • the acylating agent uses, for example, pivaloyl chloride, cyclopropoyl chloride, 2-furanoyl chloroid, 4-fluorobenzoyl chloride and the like as the acyl chloride compound.
  • the acylation reaction can be carried out in the presence of a conventional organic base, for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 2,6- Lutidine, 1,8-diazabicyclo [5.4.0] -undeth-7-ene (DBU), and the like.
  • a conventional organic base for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 2,6- Lutidine, 1,8-diazabicyclo [5.4.0] -undeth-7-ene (DBU), and the like.
  • the acylation reaction solvent is a conventional organic solvent, for example, dichloromethane, toluene, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide and the like.
  • the acylation reaction temperature is in the boiling point range of 0 ° C. to the solvent, preferably in the temperature range of 20 ° C. to 150 ° C., and preferably in the temperature range of 50 ° C. to 150 ° C.
  • the reduction reaction time is generally 5 to 24 hours, preferably 10 to 24 hours.
  • the compound represented by the formula (1) according to the present invention has excellent NF- ⁇ B target gene expression inhibitory activity can be usefully used as an anticancer agent.
  • the present invention includes a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient contains a pharmaceutical composition effective as an agent for preventing and treating various cancers caused by abnormal growth of cells.
  • Pharmaceutically acceptable salts in the present invention can be prepared by conventional methods in the art.
  • Pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like; Formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gustyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) Salts with the same organic acid; Salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline and the like; Salts with sul
  • the pharmaceutical composition of the present invention can be added to the compound represented by the formula (1) or pharmaceutically acceptable salts thereof by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient, etc. as a conventional formulation in the pharmaceutical field It can be formulated.
  • a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient, etc. as a conventional formulation in the pharmaceutical field It can be formulated.
  • it can be prepared by oral or parenteral administration such as tablets, capsules, troches, solutions, suspensions, and the like, and can be used for the prevention and treatment of various types of tumors.
  • Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like.
  • lactose dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
  • the dosage of the compound represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, based on an adult patient with a weight of 70 kg In general, 0.01 mg to 5000 mg per day, and may be dividedly administered once to several times a day at regular intervals according to the judgment of a doctor or pharmacist.
  • Example 1 (a) and 2-propyl-6-amino-2-methyl -2 H obtained in the same way - the benzopyran in Example 1, was reacted with cyclo pro foil chloride in the same manner as in (b) the compound Got it.
  • Example 1 (a) obtained in the same manner as 2-propyl-2-methyl-6-amino-7-methyl -2 H - benzopyran of Example 1, pivaloyl chloride and the reaction in the same manner as in (b) To obtain the compound.
  • Example 1 (a) and 2-propyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way - the benzopyran in Example 1, was reacted with cyclo pro foil chloride in the same manner as in (b) The compound was obtained.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1 (b) and reacted with a cycle profile foil chloride in the same manner as the compound Got.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1 (b) to avoid reaction with the same procedure just as with the chloride compound Got.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way - the benzopyran in Example 1 (b) with a cycle profile foil chloride in the same manner Reaction to obtain the compound.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1 (b) and reacted with a cyclo hexyl soil chloride in the same manner as the compound Got.
  • Example 1 2- (4-methoxy-phenylethyl) -2-amino-2-methyl-6-H obtained in the same manner as in (a) - cyclo pro foil in the same manner benzopyran, as in Example 1 (b) Reaction with chloride afforded the compound.
  • Example 1 (a) obtained in the same manner as 2- (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - pivaloyl a benzopyran, in the same manner as in Example 1 (b) Reaction with chloride afforded the compound.
  • Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - cyclo hexyl soil a benzopyran, in the same manner as in Example 1 (b) Reaction with chloride afforded the compound.
  • Example 1 (a) 2- amino-6-phenyl-2-methyl -2 H obtained in the same manner as in-the-benzopyran, in the same manner as in Example 1 (b) 2- Pew pyrano one is reacted with chloride The compound was obtained.
  • Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - benzopyran performed, for example, 1 (b) in the same manner as 2-Pugh Reaction with ranoyl chloride afforded the compound.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way - the benzopyran, in the same manner as in Example 1 (b) 2-Wallis one Llano Reaction with chloride afforded the compound.
  • Example 1 (a) 2-phenylethylamine obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - benzopyran for Example 1, 2-Im Opaque Russo in the same way as (b) Reaction with chloride afforded the compound.
  • Example 1 (a) 2- profile obtained in the same manner as 2-amino-6-methyl -2 H - a benzopyran, Example 1 (b) by the same procedure as a reaction with benzoyl chloride and the 4-fluoro The compound was obtained.
  • Example 1 (a) obtained in the same manner as 2-propyl-6-amino-2-methyl -2 H - benzopyran to Example 1 (b) and the same method as methyl chloride and reaction with 2-trifluoromethyl To obtain the compound.
  • Example 1 (a) 2- profile obtained in the same manner as 2-amino-6-methyl -2 H - benzopyran to Example 1 (b) to the 2,4,6-trichloroethane in the same manner methylbenzoyl Reaction with chloride afforded the compound.
  • Example 1 2-Propyl-2-methyl-6-amino -2 H obtained in the same manner as in (a) - the benzopyran in Example 1, is reacted with a 1-naphthyl chloride by the same method as (b) The compound was obtained.
  • Example 1 2-phenyl-2-methyl-6-amino -2 H obtained in the same manner as in (a) - the benzopyran in Example 1 (b) is reacted with benzoyl chloride in the same manner as to give the compound .
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1, was reacted with benzoyl chloride 2-fluoro in the same way as (b) The compound was obtained.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same manner - the benzopyran in Example 1 (b) by the same manner as the reaction with 2-chlorobenzoyl chloride and the The compound was obtained.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1, was reacted with 4-fluoro benzoyl chloride in the same manner as in (b) The compound was obtained.
  • Example 1 (a) the same manner as 2-phenylethyl-2-methyl-6-amino -2 H obtained and at the same manner a benzopyran, as in Example 1 (b) 4- nitrobenzoyl chloride is reacted with the The compound was obtained.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same manner - the benzopyran in Example 1 (b) by the same manner as reaction with 4-methylbenzoyl chloride and the The compound was obtained.
  • Example 1 (a) the same procedure 2-ethyl-2-phenyl-6-amino-2, obtained by the H - benzopyran to Example 1 (b) and reaction with chloride in the same manner as 1-naphthyl To obtain the compound.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same manner-benzo pyran-methyl-a, as in Example 1 (b) and 2-trifluoromethyl-benzoyl chloride in the same manner as Reaction to obtain the compound.
  • Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - benzopyran performed, for example, 1 (b) in the same manner as 2-chloro Reaction with benzoyl chloride afforded the compound.
  • Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - a benzopyran, Example 1 (b) in the same manner as 4-chloro Reaction with benzoyl chloride afforded the compound.
  • Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - a benzopyran, in the same manner as in Example 1 (b) 4-nitro Reaction with benzoyl chloride afforded the compound.
  • Example 1 (a) obtained in the same manner as 2- (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - a benzopyran, in the same manner as in Example 1 (b) 4-methyl Reaction with benzoyl chloride afforded the compound.
  • Example 1 obtained in the same manner as 2- (4-methoxyphenyl ethyl) -2-methyl-6-amino -2 H - 2- tree benzopyran, in the same manner as in Example 1 (b) Reaction with fluoromethylbenzoyl chloride afforded the compound.
  • Example 1 (a) obtained in the same manner as 2- (4-methoxyphenyl ethyl) -2-methyl-6-amino -2 H - 2- naphthyl a benzopyran, in the same manner as in Example 1 (b) Reaction with tyloyl chloride afforded the compound.
  • Example 1 (a) obtained in the same manner as 2-propyl-2-methyl-6-amino-7-methyl -2 H - a benzopyran, Example 1 (b) in the same manner as 4-acetyl chloride and the reaction To obtain the compound.
  • Example 1 (a) and 2-propyl-2-methyl-6-amino-7-methyl -2 H obtained in the same manner benzo pyran conducted, Example 1 4-nitrobenzoyl in the same way as (b) chloride and Reaction to obtain the compound.
  • Example 1 (a) and 2-propyl-2-methyl-6-amino-7-methyl -2 H obtained by the same method - carried out benzopyran, Example 1 4-methylbenzoyl in the same way as (b) chloride and Reaction to obtain the compound.
  • Example 1 (a) 2- propyl-2-methyl-6-amino-7-methyl -2 H obtained in the same manner as in-the-benzopyran, in the same manner as in Example 1 (b) 4- methoxybenzoyl chloride And the compound was obtained.
  • Example 1 (a) 2- profile obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - in the same way a benzopyran, as in Example 1 (b) 3,4- di high The compound was obtained by reacting with lerofuranobenzoyl chloride.
  • Example 1 (a) 2- profile obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - a benzopyran, in the same manner as in Example 1 (b) 4- acetamido-benzoyl Reaction with chloride afforded the compound.
  • Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - benzopyran to Example 1 3- N, in the same way as (b) N- Reaction with dimethylaminobenzoyl chloride afforded the compound.
  • Example 1 (a) 2- phenyl obtained in the same manner as ethyl-2-methyl-6-amino-7-methyl -2 H - a benzopyran, Example 1 (b) in the same manner as 4-chlorobenzoyl chloride And the compound was obtained.
  • Example 1 (a) 2- phenylethyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - a benzopyran, in the same manner as in Example 1 (b) 4- acetyl chloride And the compound was obtained.
  • Example 1 (a) 2- phenylethyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - a benzopyran, in the same manner as in Example 1 (b) 4- methylbenzoyl chloride And the compound was obtained.
  • Example 1 (a) 2- phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way as - in the same way a benzopyran, as in Example 1 (b) 4- (t- Reaction with butyl) benzoyl chloride afforded the compound.
  • Example 1 (a) and 2-phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way - the benzopyran in Example 1 (b) and in the same manner as 4-trifluoromethyl Reaction with methylbenzoyl chloride afforded the compound.
  • Example 1 2-phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same manner as in (a) - in the same way a benzopyran, as in Example 1 (b) 4- N, N -dimethylamino by reaction with benzoyl chloride to give the above compound.
  • NF-kB transcriptional regulatory activity of the test compound was measured by the following method.
  • NF-kB / A549 cells were cultured by treating hygromycin 100 ug / mL in RPMI medium containing 10% FBS. After incubating the cells in 96 well plates (10 4 / well) for 24 hours, the compound was treated with PMA 10 ng / mL after 1 hour and then maintained at 37 ° C. and 5% carbon dioxide for 6 hours. Cultured in a cell culture. After rinsing with phosphate buffer solution (PBS), the activity of luciferase was evaluated using Dual Glo Luciferase Assay System (Promega) by adding phosphate buffer solution. A liminometer (Victor II) was used for the measurement.
  • PBS phosphate buffer solution
  • novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • Injectables were prepared by containing 100 mg of active ingredient, and otherly, 180 mg of mannitol, 26 mg of Na 2 HPO 4 12H 2 O and 2974 mg of distilled water.

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Abstract

La présente invention concerne des dérivés inédits de 2-méthyl-2-alkyl-6-amido-2H-benzopyrane présentant une remarquable activité inhibitrice contre l'expression du gène cible du facteur NF-KB, ainsi que des sels pharmaceutiquement acceptables de ceux-ci, un procédé de préparation dudit composé et l'utilisation dudit composé en tant qu'agent anticancéreux.
PCT/KR2012/001971 2011-03-21 2012-03-20 Dérivés de 2-méthyl-2-alkyl-6-amido-2h-benzopyrane ayant une activité anticancéreuse Ceased WO2012128530A2 (fr)

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KR1020110025075A KR101071359B1 (ko) 2011-03-21 2011-03-21 항암 활성을 가지는 2-메틸-2-알킬-6-아미도-2ｈ-벤조피란 유도체
KR10-2011-0025075 2011-03-21

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US5164509A (en) * 1990-11-26 1992-11-17 E. R. Squibb & Sons, Inc. Benzodiazolo analogs
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KR100704009B1 (ko) * 2005-08-30 2007-04-04 한국화학연구원 염증억제 활성을 가지는6-알킬아미노-2-메틸-2'-(ｎ-메틸치환술폰아미도)메틸-2ｈ-1-벤조피란 유도체
KR100907475B1 (ko) * 2007-08-29 2009-07-13 한국화학연구원 2-메틸-2'-하이드록시메틸-6-아미도 벤조피란 유도체 또는 약제학적으로 허용 가능한 그의 염 및 그를 유효성분으로 함유하는 치매 및 뇌졸중 치료를 위한 약학적 조성물
KR20090022398A (ko) * 2007-08-30 2009-03-04 한국화학연구원 2-메틸-2'-하이드록시메틸-6-아미도벤조피란 유도체 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 알레르기 질환 치료제
KR101627602B1 (ko) * 2009-07-29 2016-06-14 한국화학연구원 2-메틸-2ｈ-크로멘-2-카르복사미드 화합물

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