WO2001030771A1 - Derives de thiazolidinedione - Google Patents

Derives de thiazolidinedione Download PDF

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Publication number
WO2001030771A1
WO2001030771A1 PCT/JP2000/007584 JP0007584W WO0130771A1 WO 2001030771 A1 WO2001030771 A1 WO 2001030771A1 JP 0007584 W JP0007584 W JP 0007584W WO 0130771 A1 WO0130771 A1 WO 0130771A1
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Prior art keywords
substituted
unsubstituted
compound
mmol
ppm
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PCT/JP2000/007584
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English (en)
Japanese (ja)
Inventor
Tsutomu Akama
Yutaka Kanda
Akira Asai
Yoshinori Yamashita
Yushi Kitamura
Chikara Murakata
Kazunori Komatsu
Kuniyuki Kishikawa
Yumiko Kobayashi
Setsuya Sasho
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to AU79618/00A priority Critical patent/AU7961800A/en
Publication of WO2001030771A1 publication Critical patent/WO2001030771A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a thiazolidinedione derivative used for treating a disease associated with telomerase activity such as a malignant tumor.
  • telomere shortening usually occurs in normal cells depending on the number of divisions, and when shortened to a certain length, the cells become senescent cells and stop dividing (Ml phase).
  • Ml phase stop dividing
  • telomere-prolonging enzyme telomerase (Journal of the NCI, 87, 884-894 (1995)] c this enzyme is reverse transcriptase which extends the Teromea RNA as ⁇ , consists protein (hTERT) is the catalytic Sabuyuni' preparative RNA (hTR) ing and ⁇ I have.
  • telomere hypothesis is based on the Proc. Natl. Acad. Sci. USA ), 89, 10114-10118 (1992). Have been.
  • telomere shortening for cancer cells
  • a substance that specifically inhibits telomerase is expected to be a new type of antitumor agent that induces telomere shortening and gives life to cancer cells.
  • telomerase is expressed only in cancer tissues with some exceptions such as germ cells, so it is expected to be a low-toxic antitumor agent that hardly affects normal tissues Have been.
  • AZTTP and ddGTP [Molecula 'and' Cellular 'biology (Mol. Cell. Biol.), 16, 53-65 (1996)], 7- Nucleic acid analogs such as Daza-dGTP [Biochemistry, 35, 15611-15617 (1996)], hetero 5-membered condensed pyridine derivatives (US Patent No. 5656638; US Patent No. 5760062), benzothiophene derivatives (US Patent No. 5703116) and phenylisothiazol derivatives (W099 / 08679) are known.
  • the RTECS Registration of Toxic Effects of Chemical Substances
  • database contains the compounds represented by the formula below. Is described.
  • telomerase inhibitory action of thiazolidinedione derivatives has not been known.
  • An object of the present invention is to provide a novel thiazolidinedione derivative having excellent telomerase inhibitory activity or antitumor activity.
  • the present invention relates to the following (1) to (8).
  • R 1 a and R lb represents the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ararukiru or substituted or is unsubstituted lower Arukanoiru, gamma 1 and gamma 2 represent identical or different and their respective single or double bond, X is formula (II)
  • Y is NR 2 (wherein R 2 is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted aryl) Substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted Substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted rubamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted lower alkylsulfonyl, substituted
  • R 4 is hydroxy, substituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or Unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted Or unsubstituted rubamoyl, cyano, substituted or unsubstituted aralkyloxy, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted cycloalkyloxy,
  • R 3 is hydroxy, substituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower alkoxy carbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted rubamoyl, cyano, substituted or unsubstituted aralkyloxy, Or when substituted or unsubstituted lower alkoxy, R 4 is hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted Or unsubstituted aryl, Substituted or
  • R 3 and R 4 are taken together with adjacent carbon atoms to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted alicyclic heterocyclic group)] or the formula (III)
  • n represents an integer of 0 to 2
  • W represents a hydrogen atom, substituted or unsubstituted arylthio, or substituted or unsubstituted arylsulfinyl.
  • Y a is NR 2 f (wherein, R 2 f is a hydrogen atom, a substituted or unsubstituted lower ⁇ alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Ari Le, substituted or unsubstituted Aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted rubamoyl, Represents a substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted lower alkylsulfonyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroarylcarbonyl), or C R 3 f R
  • R 3f is a hydrogen atom or an unsubstituted lower alkyl
  • R 4 f is human de port alkoxy, substituted lower alkyl, carboxy, substituted or unsubstituted lower an alkoxy carbonyl, substituted or unsubstituted force Lubamoyl, substituted or unsubstituted aralkyloxy, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted cycloalkyloxy,
  • R 3f is a substituted lower alkyl or a substituted or unsubstituted lower alkoxycarbonyl
  • R 4f is a hydroxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxycarbonyl or a substituted or unsubstituted lower alkoxycarbonyl. Represents a substituted lower alkoxy
  • R 3f and R 4f together represent two
  • R 3f and R 4f are taken together with adjacent carbon atoms to form a substituted or unsubstituted cycloalkyl or an alicyclic heterocyclic group).
  • the thiazolidinedione derivative according to the above (1) which represents a group represented by the formula, or a pharmacologically acceptable salt thereof.
  • Y b is NR 2g (where R 2g represents a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted lower alkoxycarbonyl), or CR 3g R 4g Wherein R 3g represents a hydrogen atom or a substituted or unsubstituted lower alkyl, and R 4g represents a substituted or unsubstituted aralkyloxy or a substituted or unsubstituted cycloalkyloxy.
  • R 3g represents a hydrogen atom or a substituted or unsubstituted lower alkyl
  • R 4g represents a substituted or unsubstituted aralkyloxy or a substituted or unsubstituted cycloalkyloxy.
  • a medicament comprising the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3).
  • a telomerase inhibitor comprising, as an active ingredient, the thiazolidinedione derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (3).
  • An antitumor agent comprising, as an active ingredient, the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3).
  • a method for treating a disease associated with telomerase activity which comprises administering an effective amount of the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3).
  • lower alkyl includes straight-chain or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Butyl, pentyl, hexyl and the like.
  • Lower alkenyl includes straight-chain or branched alkenyl having 2 to 6 carbon atoms, for example, vinyl, aryl, 1-propenyl, methacrylic, crotyl, 1-butenyl, 3-butenyl, 2-pentenyl, 4 —Pentenyl, 2-hexenyl, 5-hexenyl and the like.
  • the cycloalkyl of cycloalkyl and cycloalkyloxy includes cycloalkyl having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • lower alkynyl examples include straight-chain or branched alkynyl having 2 to 6 carbon atoms, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • the lower alkylidene examples include a straight or branched C1-6 alkylene such as methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, and isopropylidene.
  • aryl examples include aryl having 6 to 14 carbon atoms, such as phenyl, naphthyl, and anthryl.
  • the heteroaryl includes, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered fused ring.
  • the alicyclic heterocyclic group formed together with adjacent carbon atoms includes, for example, a 5- or 6-membered monocyclic ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Aralkyl, aralkyloxycarbonyl, aralkyloxy, aryloxy, arylsulfonyl, arylsulfinyl and aryl in aryloyl The rule part is synonymous with the above reel.
  • heteroaryl moiety in the heteroarylalkyl, the heteroarylalkyloxycarbonyl and the heteroarylcarbonyl has the same meaning as the above-mentioned heteroaryl.
  • the lower alkyl moiety in lower alkanoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower alkylsulfonyl and lower alkoxy has the same meaning as the above lower alkyl.
  • the alkylene moiety in aralkyl, aralkyloxycarbonyl, aralkyloxy, heteroarylalkyl, or heteroarylalkyloxycarbonyl represents a group obtained by removing one hydrogen atom from the above lower alkyl.
  • the substituent in the substituted cycloalkyloxy, the substituted cycloalkyl, the substituted alicyclic heterocyclic group and the substituted lower alkylidene includes a halogen atom having 1 to 3 substitutable numbers, preferably 1 to 3 substitutable numbers.
  • P 1 and P 2 are the same or different and represent an oxygen atom, a sulfur atom or NR 15 (wherein R 15 represents a hydrogen atom or lower alkyl), and Q 1 and Q 2 are the same or different Differently represents an oxygen atom or a sulfur atom].
  • the lower alkyl moiety in lower alkyl and lower alkoxy, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, and lower alkylthio includes the same as the above lower alkyl.
  • the lower alkenyl those similar to the aforementioned lower alkenyl can be mentioned.
  • Examples of the aryl moiety of aryl and aralkyl include the same as those described above, and the alkylene moiety of aralkyl represents a group obtained by removing one hydrogen atom from the lower alkyl.
  • Examples of the heteroaryl portion of the heteroaryl and the heteroarylalkyl include the same as the above-mentioned heteroaryl.
  • the alkylene portion of the alkoxyalkyl represents a group in which one hydrogen atom has been removed from the lower alkyl.
  • Examples of the alicyclic heterocyclic group include those similar to the alicyclic heterocyclic group.
  • Examples of the cycloalkyl include the same as the above-described cycloalkyl.
  • the number of halogen substitution in the halogen-substituted lower alkyl, the halogen-substituted lower alkoxy and the halogen-substituted lower alkylthio is from 1 to a substitutable number, preferably from 1 to 3.
  • halogen moiety of a halogen atom, a halogen-substituted lower alkyl, a halogen-substituted lower alkoxy and a halogen-substituted lower alkylthio include iodine, bromine, chlorine and fluorine atoms.
  • the number of substituted hydroxy in the hydroxy-substituted lower alkyl is 1 to a substitutable number, preferably 1 to 3.
  • heterocyclic group formed together with the adjacent nitrogen atom examples include, for example, a 5- or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic compound).
  • the ring group may contain another nitrogen atom, oxygen atom or sulfur atom), a bicyclic or tricyclic fused 3- to 8-membered ring containing at least one nitrogen atom Ring group (the condensed heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom), and more specifically, pyrrolidinyl, piberidin.no, piperazinyl, morpholino, thio
  • Examples include morpholino, homopiperidino, homobiradizinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, imidazolyl, pyrrolyl, benzimidazolyl and the like.
  • Examples of the substituent of the substituent are the same as the substituents in the above-mentioned substituted alkyl and the like, and in addition, the nitrogen atom in the substituent is combined with an adjacent substituent to form a heterocyclic group. It may be formed.
  • Examples of the heterocyclic group formed by combining a nitrogen atom with an adjacent substituent include those similar to the heterocyclic group formed by forming a nitrogen atom together with an adjacent nitrogen atom.
  • Examples of the substituent of the substituted thiocarbamoyl include the above-described substituents of the substituent of rubamoyl. And similar ones.
  • Pharmaceutically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include inorganic salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, quaterate, and the like.
  • Organic salts such as methanesulfonate, oxalate, malonate, succinate, and tartrate are listed.
  • alkali metal salts such as sodium salt and potassium salt , Magnesium salts, calcium salts and other alkaline earth metal salts, aluminum salts, zinc salts, and the like.
  • Pharmacologically acceptable ammonium salts include salts such as ammonium and tetramethylammonium.
  • examples of pharmacologically acceptable organic amine addition salts include addition salts of morpholine, piperidine and the like, and pharmacologically acceptable amino acid addition salts of glycine Phenylene Ruaranin, lysine, Asuparagin acid addition salts of the glutamic acid and the like.
  • Some of the compounds (I) in the present invention may have various stereoisomers, positional isomers, tautomers, and the like.
  • the present invention includes all of these possible isomers and mixtures thereof, and the mixing ratio may be any ratio.
  • the compound (Ia) in which R la and R lb are both hydrogen atoms in the formula (I) can be produced by the following reaction steps.
  • Compound (Ia) can be obtained by condensing compound (V) with compound (VI).
  • the compound (VI) as a raw material can be produced by a known production method, for example, a method described in Liebigs Ann. Chem., 409 (1984), or a reference example described later. Although it can be manufactured according to the methods described, etc., there are some that are available as commercial products.
  • a base catalyst In the condensation reaction, a base catalyst, a solvent, and the like may be used as necessary.
  • the base catalyst include piperidine, piperidinium acetate, getylamine, pyridine, sodium acetate, potassium carbonate, sodium carbonate, butyllithium, lithium diisopropylamide, potassium tert-butoxide, and lithium hydroxide. These are used in an amount of 0.1 to 10 equivalents to the compound (VI).
  • the solvent include alcohols such as methanol, ethanol, and propanol, ether, tetrahydrofuran (THF), 1,2-dimethyloxetane, and dioxane.
  • Ethers such as hexane, benzene, toluene, xylene and the like, N, N-dimethylformamide (DMF), N, N-dimethylacetamide and the like are used alone or in combination.
  • Compound (V) is used in an amount of 2 to 10 equivalents based on compound (VI). The reaction is carried out at room temperature to 200 ° C, preferably at 50 to 100 ° C, and is completed in 0.1 to 50 hours.
  • Compound (lb) can be obtained in the same manner as in the above step (1-1).
  • Compound (la) can also be obtained by treating compound (lb) with 0.5 equivalent to an excess amount of an acid in a solvent.
  • Examples of the acid include trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, P-toluenesulfonic acid, hydrochloric acid, and sulfuric acid.
  • Examples of the solvent include DMF, dimethylsulfoxide (DMS0), dichloromethane, chloroform, and methylform. Evening ethanol, ethanol, toluene, etc. are used alone or in combination. The reaction is carried out at ⁇ 78 to 50 ° C., preferably 0 to 30 ° C., and is completed in 0.5 to 48 hours.
  • R 1 a in (I) is a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ararukiru or substituted or unsubstituted compounds that are Arukanoiru of
  • 1 16 represents a group other than a hydrogen atom in the definition of 11 1! 1 , R lb , X and r ⁇ r 2 have the same meanings as above, and Z represents a halogen atom.
  • halogen atom in the definition of Z examples include the same as those described above.
  • Compound (I c), the compound (la), in an inert solvent, 0.5 presence of equivalents to an excess amount of a salt group, can be obtained by reacting 1 to 10 equivalents of R le Z.
  • the inert solvent DMF, DMS0, THF, 1,2-dimethoxetane, ether, dichloromethane, acetone, toluene, hexane and the like are used alone or as a mixture, and as the base, triethylamine, diisopropyl ester or the like is used.
  • Alkylamines such as tilamine and N-methylmorpholine
  • pyridines such as pyridine, lutidine, collidine and 4-dimethylaminoviridine
  • sodium hydride, potassium hydride, potassium tert-butoxide sodium methoxide, sodium Dimethoxide, lithium carbonate, sodium carbonate, butyllithium, etc.
  • the reaction is carried out at a temperature of from 78 to 50 ° C, preferably from 0 to 30 ° C, and is completed in 0.1 to 24 hours.
  • R 16 represents a hydrogen atom, a substituent of the above-mentioned substituted rubamoyl or a substituent of the above-described substituted rubamoyl, and Q 3 represents an oxygen atom or a sulfur atom). It can be produced by a reaction step.
  • Compound (Id) or (Ie) is a compound (the If), in an inert solvent, 0.5; 10 presence of one equivalent of base is reacted with one equivalent to an excess amount of R 2a Z or R 16 NCQ 3, This can be obtained.
  • inert solvent DMF, DMS0, THF, 1,2-dimethoxetane, ether, dichloromethane, toluene, hexane, etc. are used alone or in combination.
  • group sodium hydride, potassium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, butyllithium and the like are used. The reaction is carried out at ⁇ 78 to 50 ° C., preferably at about 78 to 30 ° C., and is completed in 0.1 to 20 hours.
  • R 3 a and R 4 a are the same as R 3 and R 4, respectively. However, at least one or more carboxyl groups are present in the R 3a or R 4a) der Ru compound ( Ih) can be produced by the following step 4.
  • C_ ⁇ 2 R 7 (wherein R 7 has the same meaning as defined above) represents a group containing, R 3b and R 4b is the same meaning as R 3 and R 4, respectively , provided that 1 31) or 1 at least one CO 2 R 7 in 4 is present, R la, R lb, R 2b, R 3a, R 4a, rr 2 each have the same meanings as defined above]
  • the compound (Ig) or (Ih) is obtained by hydrolyzing the compound (Ii) or (Ij) obtained according to the method described in Example 85 described below, etc. by an appropriate method.
  • compound (Ii) or (Ij) can be prepared by adding sodium hydroxide, potassium hydroxide, or hydroxide in dioxane, ethers such as THF, alcohols such as methanol and ethanol, water, or a mixed solvent thereof.
  • the compound (Ig) or (Ih) can be obtained by treating with an alkali metal hydroxide such as lithium at room temperature to the boiling point of the solvent for 0.5 to 48 hours.
  • an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as trifluoroacetic acid may be used in place of the alkali metal hydroxide.
  • the metal hydroxide or inorganic acid or organic acid is preferably used in an amount of 0 :! to 20 equivalents to the compound (Ii) or (Ij).
  • R 7 is aralkyl
  • Catalytic reduction is usually carried out at normal pressure in the presence of a catalytic amount of a catalyst such as palladium on carbon in a suitable solvent, such as 0.5 to 24 at a temperature between room temperature and the boiling point of the solvent in alcohols such as ethanol and ethanol, esters such as methyl acetate, ethyl acetate and butyl acetate, ethers such as THF and dioxane, or a mixed solvent thereof. End in time.
  • a catalyst such as palladium on carbon
  • a suitable solvent such as 0.5 to 24 at a temperature between room temperature and the boiling point of the solvent in alcohols such as ethanol and ethanol, esters such as methyl acetate, ethyl acetate and butyl acetate, ethers such as THF and dioxane, or a mixed solvent thereof.
  • Equation (I) X is the equation (l i e)
  • R 2d represents a group containing CONR 8 R 9 (wherein R 8 and R 9 are as defined above) in the definition of R 2 (I k ),
  • R 3 Where R 3 . And R 4. Is synonymous with R 3 and R 4 , respectively.
  • rr 2 is as defined above.
  • Compound (Ik) or (II) can be obtained by activating compound (Ig) or (Ih) by an appropriate method and then condensing with compound (VII).
  • the compound (Im) or (In) is converted to a suitable solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, tetrachloroethane, methyl acetate, ethyl acetate, butyl acetate, etc.
  • Esters such as ether, THF, and dioxane; non-protonic polar solvents such as acetonitrile, DMF, and DMS0; aromatic hydrocarbons such as benzene, toluene, and xylene, or mixtures thereof 1-20 equivalents of thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus oxychloride, phosphorus pentoxide, etc.
  • non-protonic polar solvents such as acetonitrile, DMF, and DMS0
  • aromatic hydrocarbons such as benzene, toluene, and xylene, or mixtures thereof 1-20 equivalents of thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus oxychloride, phosphorus pentoxide, etc.
  • the base include alkylamines such as triethylamine, diisopropylethylamine, and N-methylmorpholine; pyridines such as pyridine, lutidine, collidine, and 4-dimethylaminopyridine; and alkali metals such as potassium carbonate and sodium hydrogencarbonate. Alkali such as carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide Metal hydroxide and the like.
  • a condensing agent such as dicyclohexyl carpoimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carpo imide, hydrochloride (WSC HC1)
  • DCC dicyclohexyl carpoimide
  • WSC HC1 hydrochloride
  • a condensing agent such as rudimidazole (CDI)
  • convert the carboxyl group to a highly reactive group such as an ester such as p-ditophenoxy, benzene fluorophenoxy, or penfluorophenylthio according to a standard method. After conversion, it can be obtained according to the above method.
  • Compound (Io) can be obtained by dehydrating compound (Ip) by an appropriate method.
  • the reaction is carried out by halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and tetrachloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ether, THF and dioxane; In a mixed solvent or the like, or in the absence of a solvent, in the presence of 1 to an excess amount of a suitable dehydrating agent, for example, thionyl chloride, oxalyl chloride, acetic anhydride, etc., at room temperature to 200 ° C, preferably 50 to At 100 ° C, 0 :! ⁇ 24 hours to end.
  • R 15 has the same meaning as R 7 , and R lb , R le , X and Z have the same meanings as above.
  • Compound (Iq) is described in Chemical and Pharmaceutical Bretane (Chem. Pharm. Bull.), Vol. 30, No. 3, pages 3563-3573 (1982), pages 3580-3600 (1982), etc. Can be produced according to the process described in (1).
  • Compound (VI II) is obtained as a commercial product, or can be obtained by synthesizing according to or according to a known method.
  • X is a compound of the formula (II h)
  • Compound (X) is obtained by converting compound (VIII) into a ketone such as acetone or methyl ethyl ketone, an ether such as THF or dioxane, or water, or a mixed solvent thereof in an amount of 2 equivalents to an excess amount of an acid,
  • a ketone such as acetone or methyl ethyl ketone
  • an ether such as THF or dioxane
  • water or a mixed solvent thereof in an amount of 2 equivalents to an excess amount of an acid
  • 2 to equivalents of excess sodium nitrite are treated at 0 to 50 ° C for 0.1 to 2 hours to convert to diazonium salt, and then 2 equivalents to excess It can be obtained by treating the compound (IX) with a catalytic amount of copper oxide at 0 to 50 ° C for 0.1 to 2 hours.
  • Compound (XI) is prepared by converting compound (X) in a suitable solvent in an amount of from 2 equivalents to an excess amount of a suitable base, for example, an alkali metal salt such as sodium formate, potassium formate, sodium acetate, potassium acetate, etc. React with 2 equivalent to excess amount of thiourea in the presence of alkylamines such as lyethylamine, diisopropylethylamine, N-methylmorpholine, and pyridines such as pyridine, lutidine, collidine, and 4-dimethylaminopyridine. Can be obtained.
  • a suitable base for example, an alkali metal salt such as sodium formate, potassium formate, sodium acetate, potassium acetate, etc.
  • alkylamines such as lyethylamine, diisopropylethylamine, N-methylmorpholine
  • pyridines such as pyridine, lutidine, collidine, and 4-dimethylaminopyr
  • alcohols such as methanol, ethanol, propanol, and 2-methoxyethanol
  • nonprotonic polar solvents such as acetate nitrile, DMF, and DMS0 are used alone or as a mixture.
  • the reaction is carried out at room temperature to 150 ° C, preferably 50 to 100 ° C, and is completed in 0.1 to 24 hours.
  • Compound (Iq) is prepared by converting compound (XI) from 2 to 10 equivalents of an acid, for example, hydrochloric acid, sulfuric acid. It can be obtained by reacting in an appropriate solvent in the presence of an inorganic acid such as an acid or an organic acid such as trifluoroacetic acid.
  • an inorganic acid such as an acid or an organic acid such as trifluoroacetic acid.
  • alcohols such as methanol, ethanol, propanol and 2-methoxyethanol, or water and the like can be used alone or as a mixture.
  • the reaction is carried out at a temperature between room temperature and 150 ° C., preferably at 50-150 ° C., and is completed in 0.1-24 hours.
  • Compound (Ir) can be obtained by treating compound (Iq) according to the method described in Production Method 2.
  • the compounds (la) to (Iq) may be appropriately modified with a functional group (esterification of carboxyl group, hydrolysis of ester, acylation of amino group or alkylation) by a method commonly used in organic synthetic chemistry. , Amidation of carboxyl group, cyanation by dehydration of carbamoyl group, etc.) to obtain the desired compound.
  • a functional group esterification of carboxyl group, hydrolysis of ester, acylation of amino group or alkylation
  • the target compound in the above production method can be isolated and purified by a purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like.
  • compound (I) When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it may be purified as it is, and if compound (I) is obtained in a free form, it may be purified by a usual method, What is necessary is just to dissolve or suspend in a solvent, add a desired acid to form a salt, and isolate and purify.
  • Compound (I) or a pharmacologically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.
  • Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms, depending on its pharmacological action and its purpose of administration.
  • the pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a unit dosage form suitable for oral or parenteral administration such as injection.
  • excipients such as lactose, glucose, sucrose, mannite, methylcellulose, starch, sodium alginate, carboxymethylcellulose calcium, disintegrants such as crystal cell mouth, magnesium stearate, talc Lubricants such as gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropylcellulose, methylcellulose, etc., and surfactants such as sucrose fatty acid ester, sorbite fatty acid ester, etc. in accordance with the usual methods. Tablets containing 1 to 300 mg of active ingredient per tablet are preferred.
  • excipients such as lactose and sucrose
  • disintegrants such as starch, binders such as gelatin, and the like
  • excipients such as lactose and mannite
  • capsules for example, gelatin, water, sucrose, arabia gum, sorbitol, glycerin, crystalline cellulose, magnesium stearate, talc, and the like may be used in a conventional manner.
  • Capsules containing 1 to 300 mg of active ingredient per capsule are preferred.
  • injections for example, water, physiological saline, vegetable oils (eg, olive oil, peanut oil, etc.), solvents such as ethyl oleate, propylene glycol, etc., solubilization of sodium benzoate, sodium salicylate, urethane, etc.
  • Agents, tonicity agents such as sodium chloride, glucose, etc., preservatives such as phenol, cresol, p-hydroxybenzoate, chlorobutanol, and antioxidants such as ascorbic acid, sodium pyrosulfite, etc. It may be used by a conventional method.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally such as ointment or injection.
  • the effective dose and frequency of administration vary depending on the dosage form, patient age, body weight, symptoms, etc. Preferably, 20 mg / k is administered one to four times. "
  • telomerase inhibitory activity of compound (I) was measured according to a known method (US Pat. No. 5760062). That is, a DMS0 solution of a test compound is mixed with telomerase obtained by partially purifying a nuclear extract derived from HEK293 cells in the presence of oligodoxynucleotide and deoxynucleotide triphosphate as substrates. I had a base.
  • the obtained reaction product (DNA having a telomere sequence) was adsorbed on a membrane, and hybridization was performed using a lapelated oligonucleotide probe having a sequence complementary to the telomere sequence. .
  • the inhibition rate was calculated from the ratio of the signal intensity in the presence of the test compound to the signal intensity of the label on the membrane in the absence (control) of the test compound.
  • concentration of the compound that inhibits the enzyme activity by 50% relative to the control was defined as IC5fl .
  • compounds 3, 4, 16, 18, 43, 52, 56, 57, 92, 97, 100, 106, 110, 114, 122, 141 and 182 are represented as typical compounds of the present invention. It showed an IC 5fl value of 50 mol / L or less.
  • Test Example 2 In vivo telomerase inhibitory activity
  • a cell extract was prepared by a known method (US Pat. No. 5,629,154), and the enzyme activity was measured.
  • Sand A cell extract was prepared using a buffer containing 0.5% CHAPS (3-[(3-colamidopropyl) dimethylammonio] -1 propanesulfonic acid).
  • CHAPS 3-[(3-colamidopropyl) dimethylammonio] -1 propanesulfonic acid.
  • TRAP in in vitro (Telomeric Repeat Amplification Protocol) Atsusi was (Intergen Co., TRAP EZE TM EL ISA Telomerase Detection Kit) for enzyme activity of the extract from c test compound untreated cells
  • the ratio (%) of the enzyme activity value of the extract from the test compound-treated cells was calculated.
  • Compound 5 of the present invention inhibited telomerase activity by 50% or more at 30 / mol / L.
  • compound (I) has excellent telomerase inhibitory activity, and is useful as a therapeutic agent for diseases associated with telomerase activity such as malignant tumors.
  • Thigh JEOL Lambda 300 (300 MHz) / JE0L JNM-EX270 (270 MHz) / JE0L JNM-GX270 (270 MHz)
  • Tris (4-formylphenyl) amine (66 mg, 0.20 thigh 01), 2,4-thiazolidinedione (117 mg, 1.00 mmol) and piperidine (0.099 mL, 1.0 thigh ol) obtained in Reference Example 1 were added to ethanol. (8 mL) and refluxed for 7 hours. The reaction solution was cooled to room temperature, added with lmol / L hydrochloric acid (I mL), and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the compound 8 (40 mg, 58%) was obtained by recrystallizing from izopropyl ether. .
  • reaction solution was cooled to room temperature, lmol / L hydrochloric acid (20 mL) was added, and the organic layer c extracted with ethyl acetate was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and recrystallized from ethyl acetate to obtain compound 17 (1.72 g, 79%).
  • Step 1 Triphenylamine (5.24 g, 21.4 mmol) was dissolved in chloroform (50 mL) and cooled to 0 ° C. Next, concentrated nitric acid (2.33 mL, 32.1 tmol) was added, and the mixture was stirred at the same temperature for 30 minutes, heated to room temperature, and stirred at the same temperature for 20 minutes. A saturated aqueous solution of sodium hydrogen carbonate (100 mL) was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from isopropyl ether (250 mL) to obtain 4-nitrotriphenylamine (3.02 g, 49%).
  • Step 2 In the same manner as in Step 2 of Reference Example 15 from the above compound (2.83 g, 9.76 mmol) and hexamethylenetetramine (6.85 g, 48.9 mmol), 4,4'-diformyl-4 "-nitro Triphenylenylamine (967 mg, 21%) was obtained.
  • Step 3 The above compound (1.59 g, 4.58 mmol), 2,4-thiazolidinedione (2.15 g, 18.4 mmol), and piperidine (3.6 mL, 36 mmol) were mixed with argon (30 mL) under an argon atmosphere. The mixture was heated under reflux for 22 hours.
  • reaction solution is cooled to room temperature, water and 6 mol / L hydrochloric acid are added, and the crystals are collected by filtration, dried, and purified by silica gel column chromatography (100: 1 to 50: 1 chloroform / methanol) and preparative HPLC ( Purification with 0DS, 20:80 acetonitrile / 0.3% aqueous ammonia) gave compound 38 (30.1 mg, 1%), compound 39 (116 mg, 5%) and compound 40 (133 mg, 5%).
  • silica gel column chromatography 100: 1 to 50: 1 chloroform / methanol
  • preparative HPLC Purification with 0DS, 20:80 acetonitrile / 0.3% aqueous ammonia
  • N- (tert-butoxycarbonyl) -4,4'-diformyldiphenylamine (8.08 g, 24.8 mmol) and 2,4 obtained in Reference Example 16 were obtained.
  • Compound 43 (160 mg, 14%) and compound 44 (75.4 mg, 7%) were obtained from -thiazolidinedione (7.30 g, 62.3 mmol).
  • Step 1 Diphenylamine (2.04 g, 12.1 ol) was dissolved in DMF (10 m), 60% sodium hydride mineral oil dispersion (1.03 g, 25.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Isopropyl iodide (1.81 mL, 18.1 mol) was added, and the mixture was stirred at room temperature for 26 hours, 6 mol / L hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with chloroform.
  • Step 3 In the same manner as in Step 2 of Reference Example 6, N-isopropyl-4 was obtained from the above compound (375 mg, 0.774 tmol) and DMF (0.20 mL, 2.6 mmol). , 4'-Diformyldiphenylamine (209 mg, 100%) was obtained.
  • Step 4 The above compound (203 mg, 0.757 ol), 2,4-thiazolidinedione (424 mg, 3.62 mmol), and potassium tert-butoxide (653 mg, 5.82 mmol) were added to N, N-dimethylacetamide ( (5 mL) at room temperature for 21 hours. Methanol (5 mL), water (30 mL) and 6 mol / L hydrochloric acid (4 mL) were sequentially added to the reaction solution, and the resulting crystals were collected by filtration and silica gel column chromatography (100: 1 to 20: 1 gel form). / Methanol) to obtain Compound 52 (61.2 mg, 17%).
  • Step 1 N, N-diphenylbenzylamine (935 mg, 3.60 mmol) was suspended in acetic acid (20 mL), hexamethylenetetramine (1.12 g, 7.96 fractions) was added, and the mixture was stirred at 90 ° C for 12 hours. Stirred. The reaction solution was cooled to room temperature, a 6 mol / L sodium hydroxide aqueous solution and water were added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (20: 1 to 10: 1 hexane / ethyl acetate). N-Penzyl-4,4, -diformyldiphenylamine (100 mg, 9%).
  • Step 2 In the same manner as in Example 19, compound 53 (46.8 mg, 51%) was obtained from the above compound (61.8 mg, 0.196 mmol) and 2,4-thiazolidinedione.
  • Step 1 In the same manner as in Step 1 of Reference Example 6, 3,3-dimethyldiphenylamine (1.00 mL, 5.27 mmol) and di-tert-butyl dicarbonate (1.82 mL, 7.92 bandol) As a result, N- (tert-butoxycarbonyl) -3,3′-dimethyldiphenylamine (1.20 g, 77%) was obtained.
  • Step 2 The above compound (1.05 g, 3.53 cited ol) was dissolved in carbon tetrachloride (50 mL), and N-bromosuccinic acid imide (4.02 g, 22.6 mmol) and azobisisobutyronitrile (1992) were dissolved. mg, 1.21 mmol) and heated under reflux for 6 hours. The reaction solution was cooled to room temperature, a saturated aqueous solution of sodium thiosulfate was added, and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
  • Step 3 The above compound (790 mg, 1.25 cited ol) was dissolved in 1,4-dioxane (15 mL), 1.0 mol / L aqueous sodium carbonate solution (10 mL) was added, and the mixture was heated under reflux for 48 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with black hole form. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and purified by preparative thin-layer chromatography (4: 1 hexane / ethyl acetate) to give N- (tert-butoxycarbonyl) -3,3, -diformyldiphenylamine. (123 mg, 30%). ⁇ NMR (270MHz, CDC1 3) ⁇ (ppm) 1.46 (s, 9H), 7.46-7.58 (m, 4H), 7.70- 7.78 (m, 4H), 9.97 (s, 2H)
  • Step 4 The above compound (120 mg, 0.369 mmol), 2,4-thiazolidinedione (182 mg, 1.55 mmol), and lithium hydroxide (52.9 mg, 2.21 mmol) were heated to reflux in ethanol (10 mL) for 1 hour. . The reaction solution was cooled to room temperature, water and lmol / L hydrochloric acid were added, the resulting crystals were collected by filtration, dried, and purified by preparative thin-layer chromatography (90: 10: 1 pore-form / methanol / water). As a result, Compound 68 (137 mg, 71%) was obtained.
  • Step 1 Compound 69 (53.5 mg, 0.126 mmol) and 2-chloromouth phenyldiphenylmethyl chloride (202 mg, 0.646 mmol) were applied to the thiazolidine ring of compound 69 in the same manner as in Example 42. A compound (111 mg, 90%) in which the nitrogen atom was 2-methylphenylphenylphenyl methylated was obtained.
  • Step 2 In the same manner as in Example 48, Compound 70 (6.6 mg, 6.6 mg, 0.099 mml) and 3,4-dichlorobenzyl bromide (0.20 mL, 0.83 mol) were used. 11%).
  • Step 1 Iminostilbene (4.08 g, 25.1 g) was prepared in the same manner as in Step 1 of Example 46. mmol) and di-tert-butyl dicarbonate (11.0 mL, 47.9 mmol) to give N- (tert-butoxycarbonyl) iminostilbene (5.01 g, 68%).
  • Step 2 The above compound (2.51 g, 8.52 mol) was dissolved in 1,4-dioxane (50 m or water (10 mL)), and osmium tetroxide (2.5% by weight 2-methyl: 2-propanol solution; 1.0 mL, 0.080 t ol) and sodium periodate (10.8 g, 50.3 t ol) were added, and the mixture was stirred at room temperature for 48 hours, and a saturated aqueous solution of sodium thiosulfate was added to the reaction solution, followed by extraction with chloroform.
  • 1,4-dioxane 50 m or water (10 mL)
  • osmium tetroxide 2.5% by weight 2-methyl: 2-propanol solution; 1.0 mL, 0.080 t ol
  • sodium periodate (10.8 g, 50.3 t ol
  • Step 3 In the same manner as in Step 4 of Example 62, Compound 71 (6.3 mg, 4%) was obtained from the above compound (129 mg, 0.395 mmol) and 2,4-thiazolidinedione (192 mg, 1.64 t ol). ).
  • Step 1 In the same manner as in Step 1 of Example 46, N- (3,4) was obtained from iminostilbene (2.01 g, 10.4 thigh ol) and 3,4-dichlorobenzyl chloride (2.0 mL, 14 ol). -Dichloromouth benzyl) iminostilbene (3.31 g, 90%) was obtained.
  • Step 2 In the same manner as in Step 2 of Example 65, the above compound (2.49 g , 7.07 mmol), osmium tetroxide (2.5% by weight 2-methyl-2-propanol solution; 1.0 mL, 0.080 ol) and sodium periodate (7.29 g, 34.1 mmol) from N- (3,4- Benzyl dichloro) -2,2'-diformyldiphenylamine (81.5 mg, 11%) was obtained.
  • Step 1 In the same manner as in Step 1 of Example 46, 4,4'-diformyldiphenylamine (76.0 mg, 0.337 mmol) obtained in Reference Example 17 and 2,6-difluorobenzyl bromide (76.0 mg, 0.337 mmol) N- (2,6-difluorobenzyl) -4,4'-diformyldiphenylamine (94.5 mg, 80%) was obtained from 424 mg, 2.05 mmol).
  • Step 2 Compound 73 (46.6 mg, 33%) was obtained from the above compound (90.0 mg, 0.256 mmol) and 2,4-thiazolidinedione (120 mg, 1.03 mmol) in the same manner as in Step 4 of Example 6 2. Obtained.
  • Step 1 4,4, -Diformyldiphenylamine (75.1 mg, 0.333 mmol) obtained in Reference Example 17 and 2,6-dichlorobenzyl bromide obtained in Reference Example 17 in the same manner as in Step 1 of Example 46 From (473 mg, 1.97 mmol), N- (2,6-dichlorobenzyl) -4,4'-diformyldiphenylamine (106 mg, 83%) was obtained.
  • Step 2 Compound 74 (54.3 mg 5 36%) from the above compound (98.5 mg, 0.256 mmol) and 2,4-thiazolidinedione (126 mg, 1.08 mmol) in the same manner as in Step 4 of Example 6 2. I got .
  • Step 1 4,4'-Diformyldiphenylamine (80.3 mg, 0.356 mmol) and 4-fluorobenzyl bromide (0.174 mL) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. , 1.40 mmol) to give N- (4-fluorobenzyl) -4,4'-diformyldiphenylamine (79.4 mg, 67%).
  • Step 2 In the same manner as in Step 4 of Example 6, 2, the compound 75 (39.2 mg, 34%) was prepared from the above compound (73.4 mg, 0.220 mol) and 2,4-thiazolidinedione (196 mg, 1.67 mmol). ).
  • Step 1 In the same manner as in Step 1 of Example 46, 4,4'-diformyldiphenylamine (75.3 mg, 0.334 mmol) obtained in Reference Example 17 and 3-fluorobenzyl bromide (0.171 mL) , 1.39 mmol) to give N- (3-fluorobenzyl) -4,4'-diformyldiphenylamine (67.2 mg, 60%).
  • Step 2 In the same manner as in Step 6 of Example 62, Compound 7 6 (56.6 mg, 0.16 ol) and 2,4-thiazolidinedione (189 mg, 1.61 wake ol) were used. 54%).
  • Step 1 4,4′-Diformyldiphenylamine (78.2 mg, 0.347 mmol) obtained in Reference Example 17 and 2-fluorobenzyl bromide (0.168 mL) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. , 1.39 mmol) to give N- (2-fluorobenzyl) -4,4'-diformyldiphenylamine (75.2 mg, 65%).
  • Step 2 Compound 77 (34.3 mg, 31%) from the above compound (68.2 mg, 0.205 mmol) and 2,4-thiazolidinedione (225 mg, 1.92 referred to as ol) in the same manner as in Step 4 of Example 6 2 I got
  • Step 1 4,4′-Diformyldiphenylamine (80.4 mg, 0.357 mmol) and 4-methylbenzyl bromide (230 mg) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46 , 1.24 mmol) to give 4,4'-diformyl-N- (4-methylbenzyl) diphenylamine (68.1 mg, 58%).
  • Step 2 In a similar manner to Step 4 of Example 6 2, the compound (61.1mg, 0,185 ⁇ ol); and 2, 4-thiazolidinedione (202 mg, 1.72 mmol) from compound 7 8 (22.7 mg, 233 ⁇ 4 ).
  • Step 1 4,4′-Diformyldiphenylamine (75.3 mg, 0.334 mmol) obtained in Reference Example 17 and 3-methylbenzyl bromide (0.189 mL) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46 , 1.40 mmol) to give 4,4'-diformyl-N- (3-methylbenzyl) diphenylamine (74.1 mg, 67%).
  • Step 2 In the same manner as in Step 4 of Example 62, Compound 79 (41.0 mg, 37 mg) was obtained from the above compound (68.7 mg, 0.209 bandol) and 2,4-thiazolidinedione (214 mg, 1.82 mol). %).
  • Step 1 4,4′-Diformyldipheniramine (74.1 mg, 0.329 mmol) and 2-methylpentyl bromide (0.188 mL, 1.40 mmol) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. ), 4,4'-Diformyl-N- (2-methylbenzyl) diphenylamine (95.2 mg, 88%) was obtained.
  • Step 2 In the same manner as in Step 4 of Example 62, the above compound (90.3 mg, 0.274 reference ol) and 2,4-thiazolidinedione Compound (80 mg, 40%) was obtained from (228 mg, 1.94 mol).
  • Step 1 In the same manner as in Step 1 of Example 46, 4,4, -diformyldiphenylamine (78.9 mg, 0.350 mol) obtained in Reference Example 17 and 4-trifluoromethylbenzyl bromide (326 mg, 1.36 mmol) to give 4,4′-diformyl-N- (4-trifluoromethylbenzyl) diphenylamine (111 mg, 83%).
  • Step 2 In the same manner as in Example 4, step 4 of Example 2, Compound 81 (58.8 mg, 36%) was obtained from the above compound (107 mg, 0.279 bandol) and 2,4-thiazolidinedione (209 mg, 1.78 bandol). ).
  • Step 1 In the same manner as in Step 1 of Example 46, 4,4′-diformyldipheniramine (74.9 mg, 0.333 t) obtained in Reference Example 17 and 3-trifluoromethylbenzyl bromide (0.214 mL, From 1,40 fractions, 4,4′-diformyl-N- (3-trifluoromethylbenzyl) diphenylamine (103 mg, 80%) was obtained.
  • Step 2 Compound 62 (42.9 mg, 29%) from the above compound (97.1 mg, 0.253 mmol) and 2,4-thiazolidinedione (184 mg, 1.57 mmol) in the same manner as in Step 4 of Example 6 2. I got
  • Step 1 4,4′-Diformyldiphenylamine (80.5 mg, 0.357 mmol) obtained in Reference Example 17 and 2-trifluoromethylpentyl bromide (332 mg, 1.39) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. mmol) to give 4,4'-diformyl-N- (2-trifluoromethylbenzyl) diphenylamine (46.3 mg, 34%).
  • Step 2 In the same manner as in Step 4 of Example 62, Compound 83 (8.1 mg, 12 mg) was obtained from the above compound (44.2 mg, 0.115 mol) and 2,4-thiazolidinedione (97.5 mg, 0.83 mol). %).
  • Step 1 4,4′-Diformyldiphenylamine (75.0 mg, 0.333 mmol) obtained in Reference Example 17 and 3,5-dichloropentane bromide obtained in Reference Example 17 in the same manner as in Step 1 of Example 46 N- (3,5-dichlorobenzyl) -4,4'-diformyldiphenylamine (73.7 mg, 58%) was obtained from toluene (319 mg, 1.33 mmol).
  • Step 2- In the same manner as in Step 4 of Example 62, Compound 84 (12.7 mg, 137.9 mg) was obtained from the above compound (65.7 mg, 0.171 mol) and 2,4-thiazolidinedione (210 mg, 1.79 mol). %).
  • Step 1 Dissolve 4,4'-diformyldiphenylamine (100 mg, 0.444 tmol) obtained in Reference Example 17 in DMF (2 mL), and add 60% sodium hydride mineral oil After stirring at the same temperature for 5 minutes, 2-picolyl chloride hydrochloride (87.4 mg, 0.553 hall) and sodium iodide (110 mg, 0.734 mmol) were added. The mixture was further stirred for 12 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate.
  • Step 2 In the same manner as in Step 4 of Example 6, 2, the compound 85 (43.2 mg) was obtained from the above compound (84.8 mg, 0.268 alcohol) and 2,4-thiazolidinedione (125 mg, 1.07 marl). mg, 31%).
  • Step 1 Example 4 In the same manner as in Step 1 of Example 9, 4,4'-diformyldiphenylamine (100 mg, 0.444 mmol) obtained in Reference Example 17 and 3-picolyl chloride hydrochloride (87.4 mg) , 0.553 mmol) to give 4,4, -diformyl-N- (pyridine-3-ylmethyl) diphenylamine (67.1 mg, 48%).
  • Step 2 In the same manner as in Step 4 of Example 6, 2, the compound 86 (28.2 mg, 28.2 mg, 0.848 mol) was prepared from the above compound (67.1 mg, 0.212 rec. 26%).
  • Step 1 4,4′-Diformyldiphenylamine (50.0 mg, 0.222 mmol) obtained in Reference Example 17 and 5,6-dichloro-3-bromide obtained in Reference Example 17 in the same manner as in Step 1 of Example 46.
  • Step 2 In the same manner as in Step 4 of Example 6 2, the above compound (69.1 mg, 0.179 marl ol) Compound 87 (17.5 mg, 17%) was obtained from 2,4-thiazolidinedione (83.9 mg, 0.716 thigh ol). .
  • Step 1 Example 7 In the same manner as in Step 1 of Example 9, 4,4'-diformyldiphenylamine (100 mg, 0.444 mmol) obtained in Reference Example 17 and 4-chloromethyl-2-methylthiazo 4,4, -Diformyl-N- (2-methylthiazol-4-ylmethyl) diphenylamine (73.2 mg, 49%) was obtained from monohydrochloride (98.1 mg, 0.553 t).
  • Step 2 In the same manner as in Step 4 of Example 62, Compound 88 (47.2 mg, 43%) was obtained from the above compound (69.5 mg, 0.207 mmol) and 2,4-thiazolidinedione (100 mg, 0.856 mol). I got
  • Step 1 Example 7, 4,4′-diformyldiphenylamine (100 mg, 0.444 mmol) and 3-chloromethyl-5-methyl obtained in Reference Example 17 in the same manner as in Step 1 of 9 4,4′-Diformyl-N- (5-methylisoxazol-3-ylmethyl) diphenylamine (49.7 mg, 35%) was obtained from isoxazole (87.6 mg, 0.666 mmol).
  • Step 2 In the same manner as in Example 4, step 4 of Example 2, compound 89 (19.7 mg, 25%) was obtained from the above compound (49.7 mg, 0.155 mmol) and 2,4-thiazolidinedione (72.6 mg, 0.620 ol). ).
  • Step 1 In the same manner as in Step 1 of Example 46, 4,4-dibromodiphenylamine (9.11 g, 27.9 mmol) and acrylyl bromide (10.2 g, 84 mol) were converted to N-aryl- 4,4'-Dibromodiphenylamine (9.51 g, 93%) was obtained.
  • Step 2 The above compound (2.61 g, 7.11 bandol) was dissolved in a mixed solvent of acetonitrile (34 mL) and water (17 mL), and then 4-methylmorpholine-4-oxide (682 mg, 5.82 mmol) And osmium tetroxide (2.5% by weight 2-methyl-2-propanol solution; 1.7 mL, 0.26 recited ol) were added. After heating under reflux for 5 hours, a saturated aqueous solution of sodium sulfite was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an N- (2,3-dihydroxypropyl) compound (2.76 g, 97%) of the above compound.
  • Step 3 The above compound (2.49 g, 6.21 ol) was dissolved in DMF (60 mL) and stirred at room temperature. Next, 2-methoxypropene (0.89 ml, 9.3 mmol) and (1R)-(-)-camphorsulfonic acid (13.9 mg, 0.06 ol) were added, and the mixture was stirred at the same temperature for 36 hours. An aqueous solution (20 mL) and water (100 mL) were added, and the mixture was extracted with black hole form. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Purification was performed by silica gel column chromatography (cloth form) to obtain an acetate (1.21 g, 44%) of the above compound.
  • Step 4 In a similar manner to Step 2 of Reference Example 1 6, the compound (1.21 g, 2.73 mmol) from and DMF (2 mL), 4,4' diformyl of the compound (177 mg 3 19%) Obtained.
  • Step 5 In the same manner as in Step 4 of Example 62, Compound 90 (37 * mg, 234 mg, 2.00 black ol) was obtained from the above compound (170 mg, 0.50 cited 01) and 2,4-thiazolidinedione. 14%).
  • Compound 96 was obtained in the same manner as in Example 89, except that getyl ketomalonate was used in Example 18 instead of ethyl bilate.
  • Example 94 The compound 100 (300 mg, 0.62 mol) obtained in Example 94 was dissolved in thionyl chloride (20 mL), and the mixture was heated under reflux for 9 hours and 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was azeotropically distilled. The compound was purified by silica gel column chromatography (2: 1 to 1: 1 hexane Z ethyl acetate) and recrystallized from ethanol to obtain compound 105 (50 mg, 18%).
  • Example 1 0 1, 1 0 the compound described in 2 1 0 7 1 0 8, reference Example 18 Synthesized according to the method of obtaining compounds 95 and 97 described in Example 89 and Example 91 except that in step 1 instead of pyruvic acid ethyl ester, trifluorovirbic acid ethyl ester was used. .
  • Reference Example 27 1,1-bis (4-formylphenyl) cyclohexane (580 mg, 2.0 mmol), 2,4-thiazolidinedione (775 mg, 6.0 mmol) and piperidine (0.47 mL, .7) obtained in Reference Example 27. (4.8 mmol) was refluxed for 4 hours and 40 minutes in ethanol (20 mL). The reaction solution was cooled to room temperature, 2 mol / L hydrochloric acid (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ethyl acetate and acetonitrile to obtain Compound 110 (338 mg, 35%).
  • Compound 114 was prepared in the same manner as in Example 106 except that 3,3'-diformylbenzhydrol was used instead of 4,4'-diformylbenzhydrol in Reference Example 29. And synthesized.
  • H9 Z S 9 0 8 ' H 6 3 ⁇ 4 + (H + W) 9T9 z / ra SW9VJ ⁇ c s)''(H8 (s) 09 ⁇ C (HC c m) 0Z'Z-9S'i' ( HI c s) 9Z * S C (H2 's) 9 () 9 ( 9 P-0SWa' ZHW OLZ) 3 ⁇ 4HN H,
  • Step 1 Dissolve 2,2-bis (4-aminophenyl) hexafluoropropane (2.0 g, 6.0 mL) in acetone (40 mL) and concentrate with concentrated hydrochloric acid (5.2 mL) under ice-cooling. Sodium nitrite (1.2 g, 18 ol) dissolved in water (5 mL) was added and stirred at room temperature for 3 minutes. The reaction solution was heated to 35 ° C, methyl acrylate (3.2 mL, 36 ol) and copper (I) oxide (catalyst amount) were added, and the mixture was stirred at room temperature for 30 minutes.
  • reaction solution was concentrated under reduced pressure to 1/3, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (4: 1 hexane / ethyl acetate) to give 2,2-bis ⁇ 4-[(2-chloro-2-methoxycarbonyl) ethyl] phenyl. Nil ⁇ -1,1,1,1,3,3,3-hexafluopropane (2.0 g, 61 mg) was obtained.
  • Step 2 The above compound (200 mg, 0.37 mmol) is dissolved in 2-methoxyethanol (5 mL), and thiopurea (84 mg, 1.1 ol) and sodium acetate (60 mg, 0.73 mmol) are added. The mixture was stirred at C for 3 hours. The reaction solution was cooled to room temperature, water and hexane were added, and the precipitated crystals were collected by filtration. The crystals were dissolved again in 2-methoxyethanol (5 mL), and thioperia (84 mg, 1.1 mmol) and sodium acetate (60 mg, 0.73 mmol) were added, followed by stirring at 100 ° C for 6 hours and 45 minutes.
  • Reference Example 5 2- ⁇ 4- [bis (4_formylphenyl) amino] phenyl ⁇ thiophene 4-bromo-4 ', 4 "-diformyltriphenylamine obtained in Reference Example 2 (38 mg, 0.10 mmol) In the same manner as in Reference Example 4, the title compound (34 mg, 89%) was obtained from, and 2-triptylsylthiophene (0.063 mL, 0.20 mmol).
  • Tris (4-formylphenyl) amine (165 mg, 0.502 mmol) obtained in Reference Example 1 was dissolved in methanol (8 mL) and chloroform (5 mL), and sodium borohydride (9.5 mg) was added under ice-cooling. , 0.25 mmol) and stirred at room temperature for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (20: 1 to 10: 1 chloroform / acetonitrile) to obtain the title compound (107 mg, 64%).
  • N- (4-bromobenzyl) diphenylamine (34 mg, 0.10 mmol) and Xamethylenetetramine (280 mg, 2.0 mmol) was dissolved in trifluoroacetic acid (4 mL) and heated under reflux for 20 minutes.
  • the solvent was distilled off under reduced pressure to about half, water was added, the pH was adjusted to 8 with an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (3: 1 hexane / ethyl acetate) to obtain the title compound (17 mg, 43%).
  • the organic layer was washed with a 0.1 mol / L aqueous solution of citric acid, water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was dissolved in ethyl acetate (15 mL), 10% palladium on carbon (200 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (9: 1 hexane / ethyl acetate). 4-methyltriphenylamine (373 mg, 79% in three steps) ).
  • diphenylamine (3,38 g, 20.0 mmol) was dissolved in DMF (30 m), and under ice-cooling, arylpromide (2.1 mL, 24 t ol) and sodium hydride (960 mg, 24 recitation) ol), and the mixture was stirred at room temperature for 4 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. Then, N-aryldiphenylamine (4.49 g, quantitative) was obtained.
  • Step 1 4- (diphenylamino) benzaldehyde (10.2 g, 37.3 mmol) was suspended in 2-methyl-2-propanol (100 mL), and 2-methyl-2-butene (40 mL, 380 mmol) chlorite was added. Sodium (13.5 g, 150 mmol) and sodium dihydrogen phosphate (13.6 g, 113 mmmoD water (50 mL) were added, and the mixture was stirred at room temperature for 26 hours. After adding until pH 1, it was extracted with black-mouthed form. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and recrystallized from hexane (500 mL) to obtain 4- (diphenylamino) benzoic acid (9.34 g, 87%).
  • Step 2 The above compound (9.09 g, 31.4 mol) was dissolved in trifluoroacetic acid (200 mL), hexamethylenetetramine (22.6 g, 161 mmol) was added, and the mixture was heated under reflux for 24 hours. The reaction solution was cooled to room temperature, concentrated hydrochloric acid and water were added, and the mixture was extracted with black hole form. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (100: 10: 1 column / methanol / water) to obtain the title compound (6,47 g, 60%).
  • Step 2 The above compound (1.47 g, 3.46 mmol) was dissolved in THF (20 mL) and cooled to -78 ° C. Then n-butyl lithium (1.50 mol / L hexane solution; 6.0 mL, After adding 9.0 mmol) and stirring at the same temperature for 40 minutes, DMF (1.10 mL, 14.3 mol) was added, and the mixture was further stirred at the same temperature for 30 minutes. Then, the mixture was heated to room temperature and stirred at the same temperature for 8 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with black hole form.
  • Step 3 Ethyl 2,2-bis (4-acetoxymethylphenyl) propionate
  • Ethyl 2,2-bis (4-bromomethylphenyl) propionate (16 g, 35 t) was added to DMF (98 mL). ), Sodium acetate (12 g, 140 ol) was added thereto, and the mixture was stirred at 120 ° C for 5 hours.
  • the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and then with a saturated saline solution, and dried over anhydrous magnesium sulfate.
  • Step 4 Ethyl 2,2-bis (4-hydroxymethylphenyl) propionate
  • Ethyl 2,2-bis (4-acetoxymethylphenyl) propionate (6.8 g, 18 ol) was added to methanol (180 Then, a 2 mol / L aqueous sodium hydroxide solution (53 mL, 110 mol / l) was added thereto, and the mixture was stirred at room temperature for 2 hours and 15 minutes. After 2 mol / L hydrochloric acid was added to the reaction solution to neutralize it, methanol was distilled off under reduced pressure. Water and then 2 mol / L hydrochloric acid were added to the residue to make it acidic, followed by extraction with ethyl acetate.
  • Step 1 1, tribis (4-bromophenyl) ethanol
  • Step 2 1,1-bis (4-formylph: r: nil) ethanol
  • the title compound was obtained in the same manner as in Reference Example 22 except for using methyl iodide instead of methyl iodide.
  • Step 2 1- (3,4-dichlorobenzyloxy) -1,2- [bis (3-promophenyl)] ethane
  • Step 3 1- (3,4-dichlorobenzyloxy) -1, tri [bis (3-formylphenyl)]
  • step 2 4,4,-(hexafluoroisopropylidene) bis (benzaldehyde) 4,4 '-(hexafluoro) Loisopropylidene) bis (benzyl alcohol) (2.3 g, 6.9 t) was dissolved in chloroform (110 mL), and manganese dioxide (18 g, 210 t) was added thereto. The reaction solution was filtered using celite, and the filtrate was evaporated under reduced pressure to obtain the title compound (1.9 g, 84).
  • Benzophenone-4,4'-dicarboxylic acid (23 g, 85 t) was dissolved in thionyl chloride (100 mL), DMF (catalytic amount) was added, and the mixture was heated under reflux for 45 minutes. Excess thionyl chloride was distilled off under reduced pressure, and dichloromethane (100 mL) was added to the residue. This solution was slowly added dropwise to methanol (1000 mL), and the precipitated crystals were collected by filtration. The title compound (23 g, 89%) was obtained.
  • Step 2 2,2-bis (4-methoxycarbonylphenyl) -1,3-dioxolane
  • Lithium aluminum hydride (480 mg, 13 mmol.) was suspended in THF (33 mL) under an argon atmosphere, and the above 2,2-bis (4-methoxycarbonylphenyl) -1.3 was suspended on ice.
  • Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.5 g, 85%).
  • Lithium aluminum hydride (350 mg, 9.2 mmol) was suspended in THF (20 mL) under an argon atmosphere, and the mixture was cooled with ice under a method described in EP414062 published in Europe.
  • a THF solution (11 mL) of 4-carboxylphenyl) cyclohexane (1 g, 3.1 ol) was added dropwise, and the mixture was stirred at 70 ° C for 2 hours.
  • Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (830 mg, 91%).
  • 4,4'-Dibromobenzhydryl (500 mg, 1.5 mmol) was dissolved in THF (20 mL) and cooled to 178 ° C under an argon atmosphere. To this, n-butyllithium (1.5 mol / L hexane solution; 5.9 mL, 8.8 mmol) and then DMF (0.7 mL) were added dropwise at an internal temperature of -60 ° C or lower, and the temperature was raised to 0 ° C. Stir for 15 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer is washed with water and a saturated saline solution, and dried over anhydrous magnesium sulfate. Dried.
  • 3-Bromobenzaldehyde (3 g, 16.2 mmol) was dissolved in methanol (150 mL), and triethyl orthoformate (5 mL, 30 mmol) and p-toluenesulfonic acid (catalytic amount) were added. The mixture was stirred for 2 hours and 15 minutes. After adding sodium methoxide (catalytic amount) to the reaction solution, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the reaction crude product, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (3.72 g, 100%).
  • the solvent was evaporated under reduced pressure, the crude product was dissolved in THF (5 mL), after adding 2 mol / LH 2 S0 4 a (5 mL), was carried out for 7 hours pressurized heat reflux. Water was added to the reaction solution, and after extraction with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the reaction crude product was purified by silica gel column chromatography (10: 1: 2.5 to 1: 4: 2.5 hexane / ethyl acetate / chloroform) to obtain the title compound (179 mg, 51%).
  • the title compound was synthesized in the same manner as in Reference Example 30 using 2-bromobenzaldehyde instead of 3-bromobenzaldehyde.
  • Lithium aluminum hydride (1.78 g, 46.9 mmol) was suspended in THF (70 mL) under an argon atmosphere, and THF (90 mL) of 4,4'-dimethoxycarbonylbenzoylphenzophenone (3.5 g, 12 bandol) was suspended in ice (70 mL).
  • THF 90 mL
  • Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours.
  • the reaction solution was subjected to celite filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.6 g, 91%).
  • Step 2 1, tribis (4-benzoyloxymethylphenyl) methanol
  • Step 3 1, tribis (4-benzoyloxymethylphenyl) methoxymethane
  • the above compound (1.58 g, 3.69 mmol) was dissolved in methanol, and methanesulfonic acid (4607.1 mmol) was added. The mixture was heated under reflux for an hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue to separate the layers. Organic layer is saturated saline , And dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound.
  • Step 5 1, tribis (4-formylphenyl) -trimethoxymethane

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Abstract

L'invention concerne des dérivés de thiazolidinédione de formule générale (I), ou des sels de ceux-ci pharmaceutiquement acceptables, qui présentent un effet inhibant la télomérase. R?1a et R1b¿ représentent chacun hydrogène, alkyle faible, ou analogue; r1 et r2 représentent chacun une liaison simple ou double; et X représente un groupe de formule générale (II), [dans laquelle Y représente NR2 (R2 représentant hydrogène, ou analogue) ou analogue] ou analogue.
PCT/JP2000/007584 1999-10-28 2000-10-27 Derives de thiazolidinedione WO2001030771A1 (fr)

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JP2009525335A (ja) * 2006-02-01 2009-07-09 メルク エンド カムパニー インコーポレーテッド カリウムチャネル阻害剤
US20100267667A1 (en) * 2007-06-04 2010-10-21 Ben-Gurion University Of The Negev Research And Development Authority Telomerase activating compounds and methods of use thereof
US10111880B2 (en) 2013-11-05 2018-10-30 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
WO2019181714A1 (fr) * 2018-03-20 2019-09-26 国立大学法人広島大学 Composé permettant d'inhiber une protéine de liaison au télomère, et inhibiteur de protéine de liaison au télomère le contenant

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JPH1146976A (ja) * 1997-07-30 1999-02-23 Zojirushi Corp 電気調理器
JPH1160573A (ja) * 1997-08-22 1999-03-02 Nippon Kayaku Co Ltd トリアジン誘導体及びテロメラーゼ阻害剤
JPH11130676A (ja) * 1997-08-15 1999-05-18 Chugai Pharmaceut Co Ltd テロメラーゼ阻害剤
WO2000032598A1 (fr) * 1998-12-04 2000-06-08 Structural Bioinformatics Inc. Methodes et compositions destines au traitement de maladiesnflammatoires a base d'inhibiteurs de l'activite du facteur de necrose tumorale
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JPS4885570A (fr) * 1972-01-26 1973-11-13
WO1991017151A1 (fr) * 1990-04-27 1991-11-14 Orion-Yhtymä Oy Nouveaux derives de pyrocatechine a activite pharmacologique
WO1997000249A1 (fr) * 1995-06-16 1997-01-03 Takeda Chemical Industries, Ltd. Composes heterocycliques et production et utilisation de ces derniers
WO1998053790A2 (fr) * 1997-05-30 1998-12-03 Texas Biotechnology Corporation Composes pouvant inhiber le facteur de croissance de l'endothelium vasculaire pour l'empecher de se fixer a ses recepteurs
JPH1146976A (ja) * 1997-07-30 1999-02-23 Zojirushi Corp 電気調理器
JPH11130676A (ja) * 1997-08-15 1999-05-18 Chugai Pharmaceut Co Ltd テロメラーゼ阻害剤
JPH1160573A (ja) * 1997-08-22 1999-03-02 Nippon Kayaku Co Ltd トリアジン誘導体及びテロメラーゼ阻害剤
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Publication number Priority date Publication date Assignee Title
JP2009525335A (ja) * 2006-02-01 2009-07-09 メルク エンド カムパニー インコーポレーテッド カリウムチャネル阻害剤
AU2007209981B2 (en) * 2006-02-01 2011-11-24 Merck Sharp & Dohme Corp. Potassium channel inhibitors
US20100267667A1 (en) * 2007-06-04 2010-10-21 Ben-Gurion University Of The Negev Research And Development Authority Telomerase activating compounds and methods of use thereof
US8609736B2 (en) * 2007-06-04 2013-12-17 Ben-Gurion University Of The Negev Research And Development Authority Telomerase activating compounds and methods of use thereof
US9663448B2 (en) 2007-06-04 2017-05-30 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
US9670139B2 (en) 2007-06-04 2017-06-06 Ben-Gurion University Of The Negev Research And Development Authority Telomerase activating compounds and methods of use thereof
US9670138B2 (en) 2007-06-04 2017-06-06 Ben-Gurion University Of The Negev Research And Development Authority Telomerase activating compounds and methods of use thereof
US10214481B2 (en) 2007-06-04 2019-02-26 Ben-Gurion University Of The Negev Research And Development Aithority Telomerase activating compounds and methods of use thereof
US10111880B2 (en) 2013-11-05 2018-10-30 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
WO2019181714A1 (fr) * 2018-03-20 2019-09-26 国立大学法人広島大学 Composé permettant d'inhiber une protéine de liaison au télomère, et inhibiteur de protéine de liaison au télomère le contenant
JPWO2019181714A1 (ja) * 2018-03-20 2021-04-08 国立大学法人広島大学 テロメア結合タンパク質を阻害する化合物、及びそれを含むテロメア結合タンパク質阻害剤
JP7284518B2 (ja) 2018-03-20 2023-05-31 国立大学法人広島大学 テロメア結合タンパク質を阻害する化合物、及びそれを含むテロメア結合タンパク質阻害剤

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