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WO2005040172A1 - Dérivé proline tricyclique - Google Patents

Dérivé proline tricyclique Download PDF

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Publication number
WO2005040172A1
WO2005040172A1 PCT/JP2004/016353 JP2004016353W WO2005040172A1 WO 2005040172 A1 WO2005040172 A1 WO 2005040172A1 JP 2004016353 W JP2004016353 W JP 2004016353W WO 2005040172 A1 WO2005040172 A1 WO 2005040172A1
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Prior art keywords
substituted
compound
unsubstituted
pharmaceutically acceptable
acceptable salt
Prior art date
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PCT/JP2004/016353
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English (en)
Japanese (ja)
Inventor
Daisuke Machii
Hiroshi Umehara
Yoshinori Yamashita
Toshio Suda
Ichiro Miki
Horst Ambrosi
Sven Frormann
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KH Neochem Co Ltd
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Kyowa Hakko Kogyo Co Ltd
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Priority to JP2005515062A priority Critical patent/JPWO2005040172A1/ja
Publication of WO2005040172A1 publication Critical patent/WO2005040172A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a tricyclic proline derivative useful as an antitumor agent, a skin aging inhibitor, a skin quality improving agent, a wound healing agent, a therapeutic agent for dermatitis or a therapeutic agent for arthritis.
  • Tribasic proline derivatives useful as antitumor agents are known (see JP-A-63-101336 and US Pat. No. 6,362,331).
  • Hydroxyproline and hydroxyproline derivatives have the effect of promoting the proliferation of epidermal cells, the effect of promoting the synthesis of collagen by fibroblasts, the effect of increasing the water retention function of the epidermis, and the effect of suppressing or improving the formation of wrinkles. It is known to be effective for improving skin quality (see WO 00/51561).
  • An object of the present invention is to provide a novel trivalent proline derivative having an antitumor effect, a skin aging inhibitory effect, a skin quality improving effect, a wound healing effect, a dermatitis therapeutic effect or an arthritis therapeutic effect.
  • the present invention relates to the following (1) to (8).
  • R 1 is hydroxy, lower alkoxy, lower alkynyloxy, lower alkylsulfanyl, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroarylalkylsulfanyl, cycloalkylalkyloxy or thigh
  • R 1 is hydroxy, lower alkoxy, lower alkynyloxy, lower alkylsulfanyl, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroarylalkylsulfanyl, cycloalkylalkyloxy or thigh
  • R 1 is hydroxy, lower alkoxy, lower alkynyloxy, lower alkylsulfanyl, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroarylalkylsulfanyl, cycloalkylalkyloxy or thigh
  • R 4 represents lower alkyl, cycloalkyl or a substituted or unsubstituted aryl.
  • R 2 represents a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl,
  • R s represents a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl, carboxy, carbamoyl or cycloaliphatic heterocarbonyl.
  • R 5X has the same meaning as R 5
  • R 5X has the same meaning as R 5
  • R 1 is NHR 3a (wherein, R 3a is a substituted or unsubstituted lower alkanoyl, a substituted or unsubstituted aroyl, a substituted or unsubstituted heteroaroyl, a substituted or unsubstituted aliphatic heterocyclic carbonyl, Lower alkylsulfonyl, substituted or unsubstituted arylsulfur Phonyl or substituted or unsubstituted heteroarylsulfonyl)
  • R 4a represents a substituted or unsubstituted aryl
  • a pharmaceutically acceptable salt thereof according to the above (1).
  • R 5a represents a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or an alicyclic heterocyclic carbonyl.
  • R 5 a is a substituted or unsubstituted Ariru, substituted or Teroari one represents the LE or alicyclic heterocyclic carbonyl unsubstituted into the) according to any one of a (1) to (4) A compound or a pharmaceutically acceptable salt thereof.
  • lower alkyl includes, for example, linear or branched alkyl having 1 to 6 carbon atoms, more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -Butyl, pentyl, neopentyl, hexyl, etc. I can get lost.
  • cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • aryl examples include a monocyclic, bicyclic or tricyclic aromatic ring group, and more specifically, phenyl, naphthyl, anthryl and the like.
  • the heteroaryl includes, for example, a monocyclic, bicyclic or tricyclic aromatic heterocyclic group, more specifically pyridyl, chenyl, furyl, pivalyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl , Virazolyl, pyrazinyl, quinolyl, quinoxalinyl, quinazolyl, benzopyranyl, benzozoenyl, benzofuryl, indolinole, benzoimidazolyl, benzothiazolyl, benzopyrazolyl, benzodioxanyl, and benzoxazolyl.
  • the lower alkyl part of the lower alkoxy, the lower alkylsulfanyl, the lower alkanoyl and the lower alkylsulfonyl has the same meaning as the above lower alkyl.
  • the lower alkynyl moiety of the lower alkynyloxy includes, for example, alkynyl having 2 to 6 carbon atoms, more specifically, ethynyl, provinyl, butynyl, pentynyl, hexynyl and the like.
  • the aryl portion of arylalkyloxy has the same meaning as the above aryl
  • the alkylene portion has the same meaning as the group obtained by removing one hydrogen from the lower alkyl
  • the heteroaryl portion of the heteroarylalkylsulfanyl has the same meaning as the above. It has the same meaning as teloaryl
  • the alkylene moiety has the same meaning as the group obtained by removing one hydrogen from the lower alkyl.
  • cycloalkyl portion of cycloalkylalkyloxy has the same meaning as the above-described cycloalkyl, and the alkylene portion has the same meaning as the above-described lower alkyl group obtained by removing one hydrogen.
  • aryl portion of aryloyl and arylsulfonyl and the heteroaryl portion of heteroaroyl and heteroarylyl and heteroarylsulfonyl are the same as the aryl and heteroaryl portions, respectively. .
  • Examples of the alicyclic heterocyclic group portion of the alicyclic heterocyclic carbonyl include, for example, pyrrolidinyl, imidazolidinyl, vilazolidinyl, piperidino, piperidyl, piperidinyl, e Mopiperazinyl, morpholino, thiomorpholino and the like.
  • Substituents in the substituted aryl, substituted heteroaryl, substituted arylalkyloxy, substituted heteroarylalkylsulfanyl, substituted aryloyl, substituted heteroaroyl, substituted arylsulfonyl and substituted heteroarylsulfonyl are the same or different.
  • substitutions is 1 to 5 or more, preferably 1 to 5, for example, substituted or unsubstituted lower alkyl (substituents in the substituted lower alkyl include, for example, 1 to 3 substituents, Specific examples include the same as those exemplified in the definition of the substituent in the substituted lower alkanoyl described below), hydroxy, lower alkoxy, lower alkanoylamino, lower alkylsulfanyl, nitro, halogen, methylenedioxy, Carboxy and the like.
  • Lower alkyl, lower alkoxy and lower alkylsulfanyl have the same meanings as described above, respectively, and the lower alkyl part of lower alkylaminoylamino has the same meaning as the above lower alkyl.
  • Halogen means iodine, bromine, chlorine or fluorine atoms.
  • Substituents in the substituted lower alkanol and the substituted aliphatic heterocyclic carbonyl may be the same or different and have 1 to 1 substitutable number, preferably 1 to 3 substituents, for example, substituted or unsubstituted aryl.
  • substituents in the substituted aryl include 1 to 3 substituents, specifically lower alkoxy, etc.), hydroxy, halogen, lower alkoxy, lower alkanol, lower alkylsulfanyl, carboxymethoxy, carboxymethyl. Sulfanyl, carboxy, heteroaryl, alicyclic heterocyclic groups and the like can be mentioned.
  • Aryl, halogen, lower alkoxy, lower alkyl, lower alkylsulfanyl and heteroaryl are as defined above, and the alicyclic heterocyclic group is an alicyclic heterocyclic carboxy group. It has the same meaning as the heterocyclic group portion.
  • Pharmaceutically acceptable salts of compound (I) include pharmaceutically 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, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate And the like.
  • pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, and magnesium salts, calcium salts and the like.
  • Lithium earth metal salts, aluminum salts, zinc salts, and the like, and pharmaceutically acceptable ammonium salts include, for example, salts of ammonium, tetramethylammonium, and the like.
  • organic amine addition salts include addition salts such as morpholine and piperidine
  • pharmaceutically acceptable amino acid addition salts include addition salts such as glycine, phenylalanine, lysine, aspartic acid, and glutamic acid.
  • R 1 is as defined above, and R 2a is as defined above.
  • R 5X is as defined above, and Boc is a t-butoxycarbonyl group Represents
  • Compound (Ia) is deprotected from Boc of a benzoylproline derivative ( ⁇ ) supported on a polystyrene resin obtained by the method described below, and then treated with a base to make the molecule intramolecularly closed. Can be obtained by cleaving the ester bond with
  • Boc can be deprotected under the usual deprotection conditions of adding an acid to compound (II) in the presence of a solvent.
  • a solvent haloalkanes such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, dimethylformamide and the like are used. Used alone or as a mixture. The reaction is completed at a temperature from room temperature to a temperature lower than the boiling point of the solvent in 1 to 24 hours.
  • Step 2 (Cleaning from resin by cyclization)
  • a base By adding a base to the deprotected product obtained in Step 1 in the presence of a solvent, it is possible to promote intramolecular closure and simultaneously cut the ester bond with the polystyrene resin to produce compound (la). it can.
  • a base an excess of ammonia or the like is used, and as a solvent, an alcohol such as methanol or ethanol, a haloalkane such as dichloromethane or chloroform, an ether such as tetrahydrofuran or dioxane, or dimethylformamide is used alone or as a mixture.
  • a solvent an alcohol such as methanol or ethanol, a haloalkane such as dichloromethane or chloroform, an ether such as tetrahydrofuran or dioxane, or dimethylformamide is used alone or as a mixture.
  • Can be The reaction is completed in 1 to 24 hours at a temperature between 0 ° C and the boiling point of the solvent.
  • R 1 is NHR 3 (where R 3 is as defined above), and R 2a is
  • Step 3 Introduction of proline derivative to polystyrene resin
  • a proline derivative (II la) which can be synthesized commercially or by a combination of known methods, and a polystyrene resin having a hydroxyl group, for example, 4-hydroxymethylbenzoic acid amide resin (thigh 8- ⁇ 3111) are used, if necessary, in the presence of a base.
  • the compound (ia) can be produced by treating with an appropriate condensing agent below.
  • the proline derivative (111a) is usually used in an amount of 1 to 5 equivalents to the hydroxyl group on the polystyrene resin (hereinafter, the equivalent when not specified indicates the equivalent to the hydroxyl group on the polystyrene resin).
  • the condensing agent 1 to 5 equivalents of a carbodiimide such as dicyclohexylcarbodiimide diisopropylcarbodiimide is used, and as the base, an organic base such as 1-methylimidazoyl is used. Used 5 equivalents.
  • the reaction is usually carried out in a solvent, and haloalkanes such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, dimethylformamide and the like are used alone or in combination. The reaction is completed at room temperature to a temperature lower than the boiling point of the solvent in 1 to 24 hours. 2) Step 4 (Deprotection of Fmoc protecting group)
  • the deprotection of Fmoc is carried out in a solvent under the usual deprotection conditions, that is, in the presence of 1 equivalent to a solvent amount of a secondary amine such as piperidine or piperidine.
  • a solvent amount of a secondary amine such as piperidine or piperidine.
  • the solvent include haloalkanes such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, and dimethylformamide, etc., alone or in combination.
  • the secondary amine is used in a solvent amount, secondary is used.
  • Amine may be used as a solvent.
  • the reaction is completed in 5 minutes to 24 hours at a temperature between 0 ° C. and the boiling point of the solvent.
  • Compound (iia) can be produced by modifying the primary amine obtained in step 4 with isocyanate, carboxylic acid or carboxylic anhydride, or by modifying with sulfonyl chloride.
  • Method 1 Modification with isocyanate is usually carried out using 1 to 10 equivalents of isocyanate, in a solvent such as haloalkanes such as dichloromethane, chloroform, ethers such as tetrahydrofuran and dioxane, or a solvent such as dimethylformamide or a mixed solvent thereof. It is done in. The reaction is completed in 1 to 24 hours at a temperature between 0 ° C and the boiling point of the solvent.
  • a solvent such as haloalkanes such as dichloromethane, chloroform, ethers such as tetrahydrofuran and dioxane, or a solvent such as dimethylformamide or a mixed solvent thereof.
  • Method 2 Modification with carboxylic acid usually uses 1 to 10 equivalents of carboxylic acid and 1 to 10 equivalents of 2- (1H-benzo'triazol-1-yl) -1,1,3,3-tetramethyl In the presence of a condensing agent such as perfluorotetrafluoroborate and, if necessary, 1 to 10 equivalents of a base such as diisopropylethylamine, ethers such as haloalkanes such as dichloromethane and chloroform, tetrahydrofuran and dioxane. And dimethylformamide or a mixed solvent thereof. The reaction is completed at a temperature between 0 ° C. and the boiling point of the solvent, in 1 to 24 hours.
  • a condensing agent such as perfluorotetrafluoroborate
  • ethers such as haloalkanes such as dichloromethane and chloroform, tetrahydrofuran and dioxane.
  • Method 3 Modification with carboxylic anhydride is usually performed using 1 to 10 equivalents of carboxylic anhydride, and in the presence of 1 equivalent to a solvent amount of a base such as pyridine, Q.l to 10 equivalents of 4-dimethyl as required.
  • the reaction is performed in a solvent such as haloalkanes such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, dimethylformamide and the like, or a mixed solvent thereof, by adding a catalyst such as aminoviridine.
  • the reaction is completed in 1 hour to 1 week at a temperature between Q ° C and the boiling point of the solvent.
  • Method 4 Modification with sulfonyl chloride usually requires 1 to 10 equivalents of sulfonyl chloride. If necessary, add 0.1 to 10 equivalents of a catalyst such as 4-dimethylaminoviridine in the presence of 1 equivalent to a solvent amount of a base such as pyridine. In other cases, the reaction is performed in a solvent such as haloalkanes such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, and solvents such as dimethylformamide, or a mixed solvent thereof. The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent, and takes 7 UJI in 1 hour to 1 week.
  • a catalyst such as 4-dimethylaminoviridine
  • Deprotection of Boc of compound (iia) can be performed under the same reaction conditions as in step 1.
  • the compound (iiiaa) can be produced by reacting the compound obtained in Step 6 with the Nt-butoxycarbonylanthranilic acid derivative (IVa) under the same reaction conditions as in Method 2 of Step 5 .
  • the catalyst include 0.1 to 1 equivalent of a palladium catalyst such as tetrakistriphenylphosphine phenol, and 1 to 10 equivalents of a quaternary ammonium salt such as tetra-N-butylammonium chloride. 1 to 10 equivalents of triethylamine or the like is used. If necessary, 1 to 1 equivalent of triphenylphosphine or the like may be added.
  • a haloalkane such as dichloromethane or chloroform
  • an ether such as tetrahydrofuran or dioxane
  • a solvent such as dimethylformamide, or a mixed solvent thereof
  • the reaction is completed at a temperature between room temperature and the boiling point of the solvent in 1 to 36 hours.
  • R 1 is NHR 3 (where is as defined above), and R 2a is
  • R 3 Boc and Fmoc are as defined above, and R 2b is a group other than those defined in the definition of R 2 (wherein R 5 is as defined above) and
  • Step 3 Deprotection of Boc of compound (ia) obtained in Step 3 can be performed under the same reaction conditions as in Step 1.
  • the compound (iiiab) can be produced by reacting the compound obtained in Step 9 with the N-t-butoxycarbonylanthranilic acid derivative (IVb) under the same reaction conditions as in Method 2 of Step 5.
  • the compound (Ilab) can be produced by reacting the primary amine obtained in Step 11 under the same reaction conditions as in Step 5. Step 12 to Step 15
  • R 1 is a group other than ⁇ R 3 (wherein R 3 is as defined above), and R 2a is
  • R 5 , X and Boc are as defined above, and R lb is a group other than NHR 3 in the definition of R 1 , wherein is as defined above.
  • a proline derivative (lllb) that can be synthesized by a combination of sales or known methods By reacting under the same reaction conditions as in 3, the compound (ib) can be produced.
  • Deprotection of Boc of compound (ib) can be performed under the same reaction conditions as in step 1.
  • Compound (iiiba) can be produced by reacting the compound obtained in Step 13 with the N-t-butoxycarborylanthranilic acid derivative (IVa) under the same reaction conditions as in Method 2 of Step 5.
  • R 1 is a group other than NHR 3 (where R 3 is as defined above), and R 2a is
  • R lb , R 2b and Boc are as defined above.
  • Deprotection of Boc of compound (ib) obtained in Step 12 can be performed under the same reaction conditions as in Step 1.
  • R 2b , X and Boc are as defined above.
  • An anthranilic acid derivative (IVa) produced by referring to the method shown in a sales or journal “Organic” Chemistry (J. Org. Chem), 1997, Vol. 62, p. 1240;
  • the compound (iv) can be produced by force coupling an equivalent amount of an aryl or heteroarylboronic acid derivative [R 2b B (OH) 2 ] in a solvent in the presence of a catalyst.
  • a catalyst palladium (II) acetate or the like is usually used in an amount of 0.01 to 1 equivalent based on the compound (IVa). If necessary, the ligand may be used in an amount of 0.01 to 1 equivalent based on the compound (IVa).
  • a phosphine ligand such as phosphine or 2- (di-t-butylphosphino) biphenyl is used.
  • 1 to 10 equivalents of cesium fluoride relative to compound (IVa) may be used if necessary.
  • the reaction is carried out in a solvent such as tetrahydrofuran or dioxane or a solvent such as dimethylformamide or a mixed solvent thereof at a temperature from room temperature to the boiling point of the solvent and is completed in 1 to 24 hours.
  • Compound (IVb) can be produced by hydrolyzing compound (iv) obtained in step 18 in a solvent with addition of a base.
  • a base 1 to 5 equivalents of lithium hydroxide, sodium hydroxide and the like are used with respect to compound (iv).
  • the solvent usually, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and the like are used.
  • the reaction is performed in a mixed solvent thereof, and water may be added as necessary. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent, and is completed in 1 to 24 hours.
  • R 5X has the same meaning as described above, and the compound (lb) is a compound (la) wherein R 2a is
  • R 1 has the same meaning as described above, and R 5 and R 5X have the same meanings and the same as described above.
  • compound (lb) by catalytically reducing compound (Ic) in a solvent, adding a catalyst, and under a hydrogen atmosphere or in a hydrogen stream, and adding a compound that becomes a hydrogen source for certain V ⁇ . it can.
  • a solvent water, tetrahydrofuran, methanol, ethanol, ⁇ , ⁇ -dimethylformamide or the like is used alone or as a mixture, and as a catalyst, 180 to 1/3 weight of palladium / A catalytic reduction catalyst such as carbon is used.
  • a compound serving as a hydrogen source 1 to 10 equivalents of ammonium formate and the like are used.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent, and is completed in 1 to 24 hours.
  • Non-commercially available compounds (Ilia) and (Illb) as raw materials are described, for example, in Aug. Lett., 2001, vol. 3, p. 2481, and in 2002, vol. J. Org. Chem., 2002, 67, p.3923, or the journal 'Ob' Combinatorial 'Chemistry, J. Comb. Chem. ), 2001, vol. 3, p. 367, or a method combining them. can do.
  • the target compound in each of the above production methods 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.
  • the intermediate can be subjected to the next reaction without purification.
  • the resin When the target compound is supported on a polystyrene resin, the resin can be washed with various solvents commonly used in ordinary solid-phase reactions, thereby allowing the resin to remain on the polystyrene resin. Step.
  • Some of the compounds (I) may have stereoisomers such as geometric isomers, optical isomers and tautomers, and all the possible isomers including these and any ratios thereof are possible. Are also included in the present invention.
  • compound (I) when it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is, and when compound (I) is obtained in a free form, compound (I) may be dissolved in an appropriate solvent. It may be dissolved or suspended, and then isolated and purified by adding an acid or a base.
  • the compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
  • the cell growth inhibition rate of the test substance with respect to the human acute myeloid leukemia cell line ML-1 and the human chronic myeloid leukemia cell line K562 was measured by the following method.
  • Each cell culture contains Roswell Park memorial Institute's Medium 1640 (RPMI) containing 10% fetal calf serum (Gibco, Cat.No. 10437-028) and 1% penicillin / streptomycin (Gibco, Cat.No. 15140-122). ) Medium (Gibco, catalog number 11875-093) was used.
  • ML-1 cells and K562 cells prepared at 2.5 ⁇ 10 4 cells / mL were seeded at 80 ⁇ L each on a TCMICROWELL 96Uplate (Nalgen Nunc Co., Ltd., 163320) and 5% at 37 ° C for 4 hours.
  • the cells were cultured in a carbon dioxide incubator, and 80 L of RPMI medium alone was added to the blank wells. Add 20 ⁇ L each of the test substance adjusted to a final concentration of 10 ⁇ mol / L, and add 20 ⁇ L of the dimethyl sulfoxide solution adjusted to a final concentration of 0.1% to the control and blank gels. Each L was added. After the addition of the test substance, the cells were cultured at 37 ° C.
  • WST-1 [3- (4-Iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazolio] -l, 3-benzene disulfonate
  • SPECTRA max 340PC Molecular Devices
  • 450 nm reference wavelength 690 nm
  • the value of the blank gel is 0%
  • the growth rate of the well to which the test substance is added is calculated, and the value obtained by subtracting the value from 100% is the cell growth inhibition rate of the test substance /. ). This value is large The higher the value, the stronger the growth inhibitory activity on cells.
  • Human neonatal skin-derived fibroblast cell line NB1RGB (RIKEN Cell Bank, Ibaraki) was treated with 10vol% fetal calf serum (Hyclone, Logan, UT, USA) penicillin G potassium 50U / mL and streptomycin 50 ⁇ g / mL.
  • 10vol% fetal calf serum Hyclone, Logan, UT, USA
  • penicillin G potassium 50U / mL penicillin G potassium 50U / mL
  • streptomycin 50 ⁇ g / mL Using the added minimum essential medium alpha medium (Invitrogen, MEM Alpha medium, Carlsbad, CA, USA), the cells were cultured at 37 ° 5% CO 2 until stationary phase.
  • Cells were collected by treatment with trypsin / EDTA solution (manufactured by Boehringer Mannheim, Mannheim, Germany) and adjusted to 2.1 ⁇ 10 4 cells / mL in MEM alpha medium containing lvol% fetal bovine serum. Seed 250 ⁇ L each in a microplate (Falcon 48-well multi-well tissue culture plate, manufactured by BV Biosciences, Frankl in Lakes, NJ, USA) at 37 ° C. and cultured further overnight in 5% C0 2 conditions. The next day, after removing the medium, the test substance dissolved in MEM alpha medium containing lvol% fetal calf serum was added to each well. Subsequently, after culturing for 3 days at 37 ° C.
  • trypsin / EDTA solution manufactured by Boehringer Mannheim, Mannheim, Germany
  • Human neonatal skin-derived fibroblast cell line NB1RGB was cultured overnight in a 48-well microplate in accordance with Experimental Example 2. The next day, the medium was removed, lvol% with fetal bovine serum test substance dissolved in MEM alpha medium containing each Uweru, 37 ° C, 5% C0 3 days or 6 days after incubation in 2 conditions, The supernatant was collected. As a control, a medium to which only MEM alpha medium containing lvol% fetal bovine serum was added was used.
  • the amount of hyaluronic acid produced in the supernatant was determined using a hyaluronic acid-specific binding protein.
  • the following method was used. That is, 0.5 ⁇ g / mL of a hyaluronic acid-binding protein (Seikagaku Corporation, Tokyo, Japan) diluted with a phosphate buffer (PBS, manufactured by ICN Biochemical, Aurora, OH, USA) was added to a 96-well microphone opening plate (Roskilde, Denmark, manufactured by Nargennunc Co.) at 50 zL / well and coated at 4 ° C.
  • PBS phosphate buffer
  • Hyaluronic acid concentration Hyaluronic acid concentration in the presence of test substance
  • mice were treated on the rostral back with an acetone / getyl ether mixture (1: 1) for 15 seconds, and then with distilled water for 60 seconds twice a day for 4 days at intervals of 8 hours or more. Was. 5 days On the 6th and 7th days, a 0.33% solution of the test substance in acetone was applied to the rostral back at 50 L each. Acetone was applied to the control group. Six animals were used in each group. 5.
  • TEWL keratin moisture transpiration
  • Equation 3 Amount of horny water transpiration TEWL value at each measurement
  • Keratin moisture transpiration suppression rate (%, average soil standard error)
  • Comparison with the control group Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is. It is desirable to provide as.
  • the pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention can be used as an antitumor agent, a skin aging inhibitor, a skin quality improving agent, a wound healing agent, a dermatitis therapeutic agent or an arthritis therapeutic agent.
  • the compound (I) or a pharmaceutically acceptable salt thereof may be used alone as the active ingredient, or may be used as an active ingredient (fibroblast growth factor (FGF), for example, an immunosuppressant such as evening chlorimus) for any other treatment.
  • FGF fibroblast growth factor
  • Bimin D derivatives steroids, antibiotics, antivirals, non-steroid anti-inflammatory, e.g.
  • hyaluronic acid for example, hyaluronic acid, anti-rheumatic drugs such as 9,10-dihydro-4,5-dihydroxy-9,10-dioxy-2-anthracenate diacetate) or as a mixture.
  • these pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmaceutically acceptable carriers and by any method well-known in the technical field of pharmaceuticals.
  • the administration route it is desirable to use the most effective one in the treatment, and it can be oral or parenteral, for example, transdermal, intravenous, nasal, pulmonary and the like.
  • Examples of the administration form include tablets, powders, ointments, injections, and solutions for external use.
  • tablets and powders suitable for oral administration can be manufactured using excipients such as lactose and starch, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like. .
  • Ointments and the like suitable for transdermal administration for example, ointments and the like can be prepared using ointment bases such as petrolatum, paraffin, lanolin, macrogol and the like, and emulsifiers such as sodium lauryl sulfate and sorbin fatty acid esters.
  • ointment bases such as petrolatum, paraffin, lanolin, macrogol and the like
  • emulsifiers such as sodium lauryl sulfate and sorbin fatty acid esters.
  • Formulations suitable for intravenous administration preferably comprise a sterile aqueous preparation containing the active compound which is isotonic with the blood of the recipient.
  • a solution for injection is prepared using a salt solution, a glucose solution, or a mixture of a salt solution and a budou sugar solution.
  • Suitable for nasal and pulmonary administration, etc. are manufactured using isotonic agents such as sodium chloride and boric acid, pH adjusters such as sodium hydrogen phosphate, and thickeners such as methyl cellulose it can.
  • isotonic agents such as sodium chloride and boric acid
  • pH adjusters such as sodium hydrogen phosphate
  • thickeners such as methyl cellulose it can.
  • auxiliary ingredients selected from diluents, preservatives, flavors, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. Can also be added.
  • the dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the mode of administration, the age and weight of the patient, and the nature or severity of the condition to be treated. 0.01 mg to lg, preferably 0.05 to 50 mg per person is administered once or several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 10 mg, per adult is administered once or several times a day. However, the dose and the number of administrations vary depending on the various conditions described above. Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples. For carrying out the invention: ⁇ Good form
  • ESIMS Waters ZQ solid-phase synthesis was performed by using a polystyrene resin sealed in a macrocan [MacroKan Ichiri (IR0RI)] reaction vessel. In addition, using the enclosed radio frequency tag [AccuTag], the reactions of multiple compounds were performed in parallel in the same flask while distinguishing each macrocan.
  • IR0RI macroKan Ichiri
  • AccuTag enclosed radio frequency tag
  • the compound obtained in the second step was added to a solution of isocyanate (4 equivalents) in dichloromethane (4 mL per macrocan), and the mixture was heated under reflux for 5 hours.
  • the resin encapsulated in the macrocan was washed twice with N, N-dimethylformamide, dichloromethane, and methanol in this order, followed by dimethyl ether. And dried under vacuum.
  • a dichloromethane solution of trifluoroacetic acid (50 vol%, 4 mL per macrocan) was added to the compound obtained in the third step, and the mixture was shaken at room temperature for 2 hours. After the reaction solution was removed by decantation, the resin encapsulated in macrocan was alternately washed three times with ⁇ , ⁇ -dimethylformamide and dichloromethane, and then successively with ⁇ , ⁇ -diisopropylpropylethylamine in dichloromethane. (2 vol ° /.), Then washed with getyl ether and dried under vacuum.
  • the resin encapsulated in macrocan is washed twice with ⁇ , ⁇ -dimethylformamide, dichloromethane and methanol in this order, then washed with getyl ether and dried under vacuum. did.
  • Step 6 Power coupling with ARKEN
  • Step 8 Cutting out of resin by cyclization
  • Compound 420 shown in Table 1-6 was produced according to the following synthesis method.
  • a novel tricyclic proline derivative having an antitumor effect, a skin aging inhibitory effect, a skin quality improving effect, a wound healing effect, a dermatitis therapeutic effect or an arthritis therapeutic effect can be provided.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un dérivé proline tricyclique présentant une activité antitumorale et capable d'inhiber le vieillissement de la peau, d'en améliorer la nature, ou de guérir les lésions, la dermatite ou l'arthrite. Il s'agit d'un composé représenté par la formule (I), l'un de ses sels pharmaceutiquement admis, ou un autre dérivé du composé. Dans cette formule, R1 est notamment hydroxy, alcoxy inférieur, alkynyloxy inférieur, alkylsulfanyle inférieur, arylalkyloxy éventuellement substitué, hétéroarylalkylsulfanyle éventuellement substitué, cycloalkylméthoxy. Enfin, R2 est notamment aryle éventuellement substitué ou hétéroaryle éventuellement substitué.
PCT/JP2004/016353 2003-10-29 2004-10-28 Dérivé proline tricyclique Ceased WO2005040172A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009515925A (ja) * 2005-11-16 2009-04-16 エフ．ホフマン−ラ ロシュ アーゲー 凝固第Ｘａ因子のインヒビターとしての新規なピロリジン誘導体

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002525285A (ja) * 1998-08-27 2002-08-13 スパイロジエン・リミテツド ピロロベンゾジアゼピン類

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002525285A (ja) * 1998-08-27 2002-08-13 スパイロジエン・リミテツド ピロロベンゾジアゼピン類

Non-Patent Citations (1)

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Title
ADDICKS, E. ET AL.: "Synthesis and Biological Investigation of Novel Tricyclic Benzodiazepinedione-based RGD Analogues", CHEMBIOCHEM, vol. 3, no. 11, 2002, pages 1078 - 1088, XP002983747 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009515925A (ja) * 2005-11-16 2009-04-16 エフ．ホフマン−ラ ロシュ アーゲー 凝固第Ｘａ因子のインヒビターとしての新規なピロリジン誘導体

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