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WO2005113550A1 - Dérivé d'aminopyrimidine et utilisation médicinale de celui-ci - Google Patents

Dérivé d'aminopyrimidine et utilisation médicinale de celui-ci Download PDF

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Publication number
WO2005113550A1
WO2005113550A1 PCT/JP2005/009119 JP2005009119W WO2005113550A1 WO 2005113550 A1 WO2005113550 A1 WO 2005113550A1 JP 2005009119 W JP2005009119 W JP 2005009119W WO 2005113550 A1 WO2005113550 A1 WO 2005113550A1
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Prior art keywords
alkyl
atom
represent
hydrogen atom
same
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PCT/JP2005/009119
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English (en)
Japanese (ja)
Inventor
Hideo Tomozane
Ryoichi Ando
Shinsuke Oike
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Mitsubishi Pharma Corporation
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Priority to JP2006513710A priority Critical patent/JPWO2005113550A1/ja
Publication of WO2005113550A1 publication Critical patent/WO2005113550A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel aminovirimidine conjugate and a drug containing the same as an active ingredient.
  • Protein kinases are known to be involved in signal transduction that controls cell activation, growth and division in response to extracellular mediators and environmental changes. In general, protein kinases are classified into two gnolops, serine Z-threonkinase and thymic synkinase, depending on their phosphorylation substrate.
  • abnormal activity of protein kinases causes a number of diseases accompanied by abnormal cell proliferation.
  • diseases include hyperproliferative disorders such as cancer, tumors, hyperplasia, pulmonary fibrosis, angiogenesis, psoriasis, atheroma, intravascular smooth muscle proliferation such as stenosis or restenosis after angioplasty.
  • malignant tumors are generated as a result of cancer cells undergoing cell control breakdown through multi-step genetic changes.
  • Typical cancer cells have acquired an abnormally high proliferative capacity in addition to the ability to invade surrounding tissues and to metastasize to different organ sites. Loss of normal regulation of cell growth is precluded from generating abnormal forces in the signaling system that controls cell cycle progression.
  • the cell cycle is mainly controlled by the signal transduction pathway of the protein phosphorylation, and several protein kinases involved in this control have been identified.
  • Aurora kinase is Aurora kinase.
  • the Aurora kinase family is currently at least three related protein families.
  • O Mouth lakinase is a highly conserved serine Z-threonine kinase, and is considered an important enzyme in the progression of the M phase because it is expressed in the M phase of the cell cycle.
  • This key has also been demonstrated from inhibition of the function of the Aurora 2 kinase homologous gene using yeast, Drosophila and nematodes.
  • the importance of the Nase family in the M phase was suggested (Non-Patent Document 1 and Non-Patent Document 2).
  • Non-patent Document 8 the fact that Aurora 2 kinase is overexpressed in many cancers (Non-patent Document 3, Non-patent Document 4, Non-patent Document 5, Non-patent Document 6, and Non-patent Document 7), Thus, the fact that cells overexpress Aurora 2 kinase showed signs of canceration became apparent (Non-Patent Document 8).
  • Patent Document 2 Patent Document 3
  • Patent Document 5 Patent Document 5
  • Non-Patent Document 9 Several small molecules that inhibit Aurora 2 kinase have been reported in patents and the like.
  • Patent Document 2 Patent Document 3
  • Patent Document 5 Patent Document 5
  • Non-Patent Document 9 Non-Patent Document 9 are mentioned.
  • Patent Document 2 WO2001--21595
  • Patent Document 3 WO2002--22601
  • Patent Document 4 WO2002--96905
  • Patent Document 5 WO2004--5283
  • Patent Document 6 W01997-19065
  • Patent Document 7 WO2001--72745
  • Patent Document 8 WO2002- -46170
  • Patent Document 9 WO2003-11838
  • Patent Document 10 WO2003-29249
  • Non-patent literature l David M. Glover et al., Cell, 81, 95-105 1995
  • Non-Patent Document 2 Daniela Berdnik et al., Current Biology, 12 vol. 640-647 2002
  • Non-patent document 3 Hongyi Zhou et al., Nature Genetics ⁇ 20 vol. 189-193 1998
  • Non-patent document 4 Takuji Tanaka et al., Cancer Research, 59 vol. 2041-2044 1999
  • Non-patent document 5 C. Sakakura et al. British Journal of Cancer, 84, 824-831 2001
  • Non-Patent Document 6 Subrata Sen et al., Journal of the National Cancer Institute, 94, 1320-1329 2002
  • Non-Patent Document 7 Donghui Li et al., Clinical Cancer Research, 9 Volume 991-997 2003
  • Non-Patent Document 8 James R. Bischol3 ⁇ 4, EMBO Journal, 17 Volume 3052-3065 1998
  • Non-Patent Document 9 Elizabeth A. Harrington et al., Nature Medicine Advanced Online Publication, February 22, 2004
  • Non-Patent Document 10 Shudong Wang et al., Jounal of Medicinal Chemistry, 47 Vol. 1662-167, paragraph 5, 2004
  • An object of the present invention is to provide an Aurora 2 kinase inhibitor useful for treating cell proliferative diseases including cancer. Means for solving the problem
  • the present invention has been intensively studied in view of the powerful circumstances, and as a result, an aminobirimidine conjugate, a pharmaceutically acceptable salt, a hydrate, and a water adduct represented by the following general formula (I) Further, they have found that solvates are compounds that strongly inhibit protein kinases, particularly Aurora 2 kinase, and can sufficiently act in vivo, and have completed the present invention.
  • the gist of the present invention is as follows.
  • R 1 and R 2 are the same or different and represent a halogen atom, alkyl, hydroxy, alkoxy, aminoaminoalkylamino or acylamino,
  • R 3 and R 4 are the same or different and each represent a hydrogen atom, a halogen atom, alkyl, hydroxy or alkoxy;
  • R 5 represents a hydrogen atom, alkyl or acyl
  • R 6 and R 7 may be the same or different and represent a hydrogen atom, a halogen atom, alkyl, hydroxy, alkoxy, alkylamino, acylamino, rubamoyl, alkylrubamoyl, carboxy, alkoxycarbonyl, sulfamoyl, alkylsulfamoyl, nitrite Show mouth or cyano,
  • R 8 is COR 10, CO R 10, CONR
  • R 1C may be the same or different from each other; —T—R 12 (where T is absent or
  • R 14 and R 15 are the same or different and represent hydrogen or alkyl
  • R 12 is hydrogen, a halogen atom, hydroxy, alkyl, alkyl having an amino group, Indicates a heterocycle or aryl.
  • R 1C and R 11 represent a group that forms a 5- to 7-membered ring with the nitrogen atom bonded to each other.
  • R 9 represents a hydrogen atom, a force indicating alkyl, hydroxy, alkoxy or acyl.
  • R 8 represents OR 10
  • R 9 represents a hydrogen atom
  • R 8 and R 9 each represent a group which forms a 5- to 7-membered ring together with a nitrogen atom bonded to each other.
  • R 3 and R 4 are the same or different and represent a hydrogen atom or an alkyl
  • R 6 and R 7 are the same or different and represent a hydrogen atom, a halogen atom, an alkyl, a hydroxy or an alkoxy,
  • R 8 represents COR 10 , CONR′V 1 , SOR 10 or OR 10 [wherein R 10 and R 11 are the same or
  • T is absent, C alkylene or its alkylene
  • R 1C> and R 11 may further contain an oxygen atom, a sulfur atom, and a heteroatom whose NH force is also selected.
  • it represents a group forming a 5- to 7-membered ring.
  • R 9 represents a hydrogen atom, an alkyl or acyl group, or
  • R 8 and R 9 each represent a group forming a 5- to 7-membered ring together with a nitrogen atom bonded to each other, the compound described in (1) above, a pharmaceutically acceptable salt, hydrate, water adduct or Solvate.
  • R 1 and R 2 are the same or different and each represents alkyl or acylamino.
  • R 3 and R 4 each represent a hydrogen atom.
  • R 5 represents a hydrogen atom, (1) the compound of any one of (3) above, a pharmaceutically acceptable salt, hydrate, water adduct or solvent Japanese food.
  • R 3 and R 4 each represent a hydrogen atom
  • R 5 represents a hydrogen atom.
  • the compound is selected from the group consisting of aminovirimidine conjugates represented by the general formula (I), pharmaceutically acceptable salts, hydrates, water adducts, and solvates.
  • a therapeutic agent for cancer containing a substance as an active ingredient can be provided.
  • the “halogen atom” represented by R 1 or R 2 includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • Alkyl for R 1 or R 2 includes C 1 alkyl (eg, methyl, ethyl, propyl)
  • Mouth pill isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), and alkyl of C (eg, methyl, ethyl, propyl, isopropyl)
  • Particularly preferred is methyl.
  • Alkoxy for R 1 or R 2 includes, for example, C 1 alkoxy,
  • alkylamino represented by R 1 or R 2 includes, for example, alkylamino of C 1
  • the “acylamino” represented by R 1 or R 2 includes, for example, C-acylamino
  • alkyl, alkoxy, alkylamino or acylamino represented by R 1 or R 2 may have a substituent.
  • substituent for example, alkyl of C (eg, methyl
  • halogen atoms eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
  • acyl e.g., formyl, etc.
  • acylyloxy aminoalkylamino, dialkylamino, amide, alkylamide, carbamoyl, sulfalyl, anolequinolenosphenol Nole, Snolefuino, Anolequinoresnoreho-nore (eg, methinoresnoreho-nore, ethylsulfol and the like), sulfamoyl, alkylsulfamoyl and the like.
  • halogen atoms eg, fluorine atom, chlorine atom, bromine atom, iodine
  • the “alkyl” represented by R 3 or R 4 includes the same as the “alkyl” represented by R 1 or R 2 , and preferably includes methyl.
  • the alkyl or alkoxy represented by R 3 or R 4 has a substituent! /, Or! /.
  • substituents include those similar to the substituents represented by R 1 or R 2 .
  • the “alkyl” represented by R 5 is the same as the “alkyl” represented by R 1 or R 2 above, and preferably includes methyl.
  • the alkyl or acyl represented by R 5 has a substituent! /, Or may be! /.
  • substituents include those similar to the substituents represented by R 1 or R 2 .
  • the “nodogen atom” represented by R 6 and R 7 is the same as the “halogen atom” represented by R 1 or R 2 , and is preferably a chlorine atom.
  • the “alkyl” represented by R 6 and R 7 is the same as the “alkyl” represented by R 1 or R 2 , and is preferably methyl.
  • the “alkoxy” represented by R 6 and R 7 includes the same as the “alkoxy” represented by R 1 or R 2 , and preferably includes methoxy.
  • alkylamino represented by R 6 and R 7
  • the same as “alkylamino” represented by R 1 or R 2 can be mentioned, and preferably, dimethylamino with methylamine is exemplified.
  • acylamino represented by R 6 and R 7
  • those similar to the “acylamino” represented by R 1 or R 2 can be mentioned.
  • alkyl power rubamoyl represented by R 6 and R 7 includes, for example, an alkyl power
  • Lubamoyl specifically, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, ethylmethylcarbamoyl, and the like.
  • the "alkoxycarbon” represented by R 6 and R 7 includes, for example,
  • alkylsulfamoyl represented by R 6 and R 7 includes, for example, C alkyls
  • Ruffamoyl specifically, methylsulfamoyl, ethylsulfamoyl and the like.
  • alkyl, alkoxy, Arukiruamino, Ashiruamino, alkylcarbamoyl, alkoxycarbonyl - le or alkylsulfamoyl may have a substituent.
  • substituents include those similar to the substituents represented by R 1 or R 2 .
  • the “alkyl” represented by R 9 includes the same as the “alkyl” represented by R 1 or R 2 above, and preferably includes methyl.
  • Alkyl, alkoxy or acyl represented by R 9 has a substituent! /, Or may be! /.
  • substituents include those similar to the substituents represented by R 1 or R 2 .
  • R 8 and R 9 forces The group forming a 5- to 7-membered ring together with a nitrogen atom bonded to each other includes an oxygen atom, a sulfur atom and N—R 13 (R 13 is hydrogen Atom, alkyl, aralkyl or acyl).).
  • R 13 is hydrogen Atom, alkyl, aralkyl or acyl.
  • Examples of the 5- to 7-membered ring include pyrrolidine, piperidine, piperazine, monoreforin, and thiomonorefurol. Thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, thiazole, and isooxazole.
  • the 5- to 7-membered ring may have a substituent.
  • examples of the substituent include those similar to the substituents represented by R 1 or R 2 , and also include an oxygen atom.
  • the group in which R 1C> and R 11 form a 5- to 7-membered ring together with a nitrogen atom bonded to each other includes a heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in a 5- to 7-membered ring. May be included.
  • Examples of the 5- to 7-membered ring include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, thiazole and isoxazole.
  • the 5-membered or 7-membered ring may have a substituent.
  • examples of the substituent include the same substituents as those represented by R 1 or.
  • alkyl for R 12 , those similar to the “alkyl” for the above R 1 or R 2 can be mentioned, and preferred are C 1 alkyl, and specifically, methyl,
  • Nono androgenic atom represented by R 12
  • the R 1 or the same “Nono androgenic atom” represented by R 2 can be mentioned, preferably a chlorine atom and a bromine atom.
  • “Cycloalkyl” for R 12 includes, for example, C 1 cycloalkyl
  • cyclopropyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and preferred examples include cyclopropyl and cyclohexyl.
  • the "heterocycle" represented by R 12 includes, for example, one or two hetero atoms selected from one or two selected from a nitrogen atom, a sulfur atom and an oxygen-nuclear atom, in addition to a carbon atom, And a 5- to 7-membered aromatic heterocyclic ring or non-aromatic heterocyclic ring.
  • Specific examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiophene, furan, pyrrole, imidazole, and pyrazole.
  • the “aryl” represented by R 12 includes a single ring or a condensed ring, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl and the like, and preferably includes phenyl.
  • alkyl represented by R 12 Ami input cycloalkyl, heterocyclic or Ariru may optionally have a substituent.
  • substituents include those similar to the substituents represented by R 1 or R 2 , and in addition, a heterocyclic ring (eg, 4-methylbiperazinomethyl, morpholinomethyl, etc.) and the like. No.
  • “Aralkyl” represented by R 13 includes, for example, C aralkyl.
  • Typical examples include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl and the like.
  • alkyl represented by R 14 and R 15 , the same as “alkyl” represented by R 1 or R 2 can be mentioned.
  • the alkyl represented by R 14 and R 15 may have a substituent.
  • substituents include those similar to the substituents represented by R 1 or R 2 .
  • the pharmaceutically acceptable salt of the compound of the general formula (I) of the present invention includes an acid addition salt with an inorganic acid or an organic acid.
  • the compound of the present invention may exist as a water adduct, hydrate and solvate, these water adducts, hydrates and solvates are also included in the present invention. Is done.
  • the compound of the general formula (I) of the present invention can be produced by the method described below.
  • R 3 , R 4 , R 5 , R 6 , R 7 or R 9 is as defined above. Is as
  • the compound represented by the above general formula (IV) (Shudong Wang et al., Jounal of Medicinal Chemistry, Vol. 47, pp. 1662-1675, 2004) is prepared under appropriate reducing conditions, that is, in the presence of a catalyst such as iron.
  • a catalyst such as iron.
  • a suitable acid e.g., acetic acid or hydrochloric acid
  • a suitable solvent e.g., ethanol, dioxane, water, or a mixture thereof
  • the compound represented by the above general formula (III) is represented by X—R 9 ′ (wherein, R 9 ′ represents a group excluding the R 9 hydrogen atom, hydroxy or alkoxy group defined above, and X represents Reacting with a halogen atom or a good leaving group) to produce a compound represented by the above general formula ( ⁇ ) (wherein R 9 is other than a hydrogen atom, hydroxy or alkoxy).
  • R 9 ′ represents a group excluding the R 9 hydrogen atom, hydroxy or alkoxy group defined above, and X represents Reacting with a halogen atom or a good leaving group
  • the compound represented by the above general formula (IV) is subjected to a hydrogen addition reaction in the presence of palladium-carbon (Pd-C), and a suitable solvent (for example, methanol, ethanol, water or any mixture thereof) is added. Solvent, etc.) at room temperature for 1 hour to 12 hours to produce a compound represented by the above general formula ( ⁇ ) (wherein R 9 represents a hydrogen atom, hydroxy or alkoxy) be able to.
  • a suitable solvent for example, methanol, ethanol, water or any mixture thereof
  • R 1G — NCS or X—SO R 1G R 1G is as described above, X is a halogen atom, hydroxy
  • the compound represented by the general formula (I) (wherein R) can be obtained by reacting any of the compounds of the formula (I) or, in some cases, further reacting with a generally used alkylating agent. 8 is COR CO R 10 , CONR
  • the compound represented by the above general formula (IV) is subjected to a hydrogenation reaction in the presence of palladium-carbon (Pd-C), and a suitable solvent (for example, ethanol, ethanol, water or a mixture thereof). In an arbitrary mixed solvent, etc.) at room temperature for 1 hour to 12 hours to obtain a compound represented by the following general formula (la) wherein R 8 in the general formula (I) represents OR
  • each compound when applicable in each of the above synthesis steps, each compound can be derived and converted to another compound using a method well known in the art.
  • the compound of the general formula (I) obtained by the above method, or a pharmaceutically acceptable salt, carohydrate with water, hydrate and solvate thereof has a strong Aurora 2 kinase inhibitory action, It is useful as a cancer prevention and Z or therapeutic agent.
  • the method of administration when the compound of the present invention is used as a medicament can be appropriately selected by those skilled in the art.
  • parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or the like, or a different administration route of oral administration can be selected.
  • the dose can be appropriately determined depending on conditions such as the age, health condition, and body weight of the patient, the type and frequency of administration of a drug to be administered at the same time, if any, or the nature of the desired effect.
  • the daily dose of the active ingredient is 0.5 to 300 mgZkg body weight, usually 1 to 30 mgZkg body weight, and it can be administered once or more per day.
  • the compound of the present invention is used as a medicament, it is preferable to prepare and administer a pharmaceutical composition containing the above active ingredient and one or more kinds of pharmaceutical additives.
  • compositions suitable for oral administration include, for example, tablets, capsules, powders, liquids, and elixirs.
  • Pharmaceutical compositions suitable for parenteral administration include, for example, liquids Alternatively, a sterilized liquid pharmaceutical composition such as a suspending agent can be exemplified.
  • the type of the pharmaceutical additive used for preparing the pharmaceutical composition is not particularly limited, and an appropriate pharmaceutical additive can be selected according to the form of the various pharmaceutical compositions.
  • a solid or liquid carrier for example, a solid carrier or a liquid carrier can be used.
  • a usual gelatin type capsule can be used.
  • the active ingredient can be tableted with or without one or more pharmaceutical additives, or can be prepared as a powder and packaged.
  • These capsules, tablets and powders may generally contain from 5 to 95% by weight, preferably from 5 to 90% by weight, of the active ingredient, based on the total weight of the formulation, the dosage unit form being from 5 to 500 mg, It preferably contains 25 to 250 mg of the active ingredient.
  • Liquid carriers include water, petroleum, peanut oil, soybean oil, mineral oil, sesame oil, etc. Or an oil of animal or plant origin or a synthetic oil.
  • physiological saline, dextrol or a similar sucrose solution, and glycols such as ethylene daricol, propylene glycol, and polyethylene glycol are preferred as liquid carriers.
  • glycols such as ethylene daricol, propylene glycol, and polyethylene glycol
  • it can be usually prepared to contain 0.5 to 20%, preferably 1 to 10% by weight of the active ingredient.
  • N- (3- (4 (2,4 dimethylthiazol-5yl) pyrimidine-2-ylamino) phenyl) butanamide was prepared in the same manner as in the production method of compound 8 in Table 1. Obtained.
  • N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) isobutanamide was prepared in the same manner as in the preparation of compound 8 in Table 1. Obtained.
  • Transformation ⁇ , ⁇ cumulative ⁇ I ( s os'o) rinse ⁇ , ⁇ /, ⁇ . ; ( ⁇ ) ve c ⁇ ⁇ i ⁇ o) ( ⁇ 3 ⁇ 4 ⁇
  • N- (4- (2,4-dimethylthiazol-5-yl) pyrimidine-2-yl) benzene obtained by Production Example 4-1,3 diamine (0.30 g, l.Olmmol) and triethylamine (0.17 ml) ) was added to a solution of (10) in tetrahydrofuran (86 ml) and left at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. After drying, the solvent was distilled off under reduced pressure.
  • N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) butanesnolide was prepared using n-butanesulfuric acid and obtained in the same manner as in the preparation of compound 28 in Table 1. Honamide was obtained.
  • a solution of (4) in tetrahydrofuran (6 ml) and methanol (4 ml) was added a 4M aqueous solution of lithium hydroxide (0.59 ml), and the mixture was stirred at 60 ° C for 30 minutes. After cooling the reaction solution to room temperature, water and a 1N aqueous hydrochloric acid solution were added to make the solution acidic, and the solution was left at room temperature.
  • Bebebe ⁇ ⁇ — ⁇ (/ ⁇ -Be (— s— one,
  • Example 64 Compound 46 in Table 1 80 ⁇ 3 ⁇ 4? ⁇ ) ⁇ 3 ⁇ 4 19 ⁇ ⁇ [63 TO]
  • the amplified Aurora 2 kinase encoding gene was transformed into an E. coli expression vector.
  • An Escherichia coli strain for large-scale expression of Aurora 2 kinase was cultured in an LB medium containing Ampidlin (50 ug / ml). After culturing with shaking at 37 ° C for 1 hour, the culture temperature is set to 25 ° C and the final concentration is O.lmM IPTG (SIGMA) to induce the expression of Aurora 2 kinase. C. The cells were cultured with shaking for 24 hours. Thereafter, the culture solution was centrifuged at 7000 rpm for 10 minutes to recover the cells.
  • the recovered cells were treated with 36 ml of lysis buffer [50 mM Tris pH 6.8, 150 mM NaCl, 20 mM ⁇ -Glycerophspate, 0.3 mM Na3V04, 50 mM NaF, 2 mM PMSF (fluoromethyl methyl sulfol), protease inhibitor Cocktail tablet (Boehringer Mannheim) 1 tablet] and sonicated. Further, 4 ml of 10% NP-40 (Wako Pure Chemical Industries) was added to dissociate non-specific binding between proteins.
  • lysis buffer 50 mM Tris pH 6.8, 150 mM NaCl, 20 mM ⁇ -Glycerophspate, 0.3 mM Na3V04, 50 mM NaF, 2 mM PMSF (fluoromethyl methyl sulfol), protease inhibitor Cocktail tablet (Boehringer Mannheim) 1 tablet
  • NP-40 Novo Pure Chemical Industries
  • a novel aminobirimidine conjugate can be provided.

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Abstract

Composé d'aminopyrimidine représenté par la formule générale (I) suivante, sel, hydrate, produit d'addition avec de l'eau et solvate acceptables du point de vue pharmaceutique. On a trouvé que ces composés inhibent puissamment les protéines kinases, en particulier l'aurora 2 kinase et sont capables d'agir suffisamment dans le corps vivant. L'invention a ainsi été réalisée. [Formule chimique 1] (I)
PCT/JP2005/009119 2004-05-20 2005-05-19 Dérivé d'aminopyrimidine et utilisation médicinale de celui-ci WO2005113550A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076473A3 (fr) * 2005-12-23 2007-10-18 Kalypsys Inc Urees pyrimidinyloxy substituees utiles comme inhibiteurs des proteines kinases
WO2007132221A1 (fr) * 2006-05-12 2007-11-22 Cyclacel Limited Inhibiteurs de la kinase aurora à base de pyrimidine-thiazole, anticancéreux, combinés
JP2008500320A (ja) * 2004-05-26 2008-01-10 サイクラセル リミテッド 増殖性障害の治療に有用な２−置換−４−ヘテロアリール−ピリミジン
US7427626B2 (en) 2003-05-16 2008-09-23 Astrazeneca Ab 2-Anilino-4-(imidazol-5-yl)-pyrimidine derivatives and their use as cdk (cdk2) inhibitors
US7442697B2 (en) 2002-03-09 2008-10-28 Astrazeneca Ab 4-imidazolyl substituted pyrimidine derivatives with CDK inhibitory activity
US7446105B2 (en) 2002-03-09 2008-11-04 Astrazeneca Ab Pyrimidine compounds
US7465728B2 (en) 2002-03-09 2008-12-16 Astrazeneca Ab Derivatives of 4-(imidazol-5-yl)-2-(4-sulfoanilino)pyrimidine with CDK inhibitory activity
JP2009503060A (ja) * 2005-08-05 2009-01-29 イル−ヤン ファーム カンパニー リミテッド Ｎ−フェニル−２−ピリミジン−アミン誘導体及びそれの調製のための工程
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US7579344B2 (en) 2003-05-16 2009-08-25 Astrazeneca Ab Pyrimidine derivatives possessing cell-cycle inhibitors activity
US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
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US7442697B2 (en) 2002-03-09 2008-10-28 Astrazeneca Ab 4-imidazolyl substituted pyrimidine derivatives with CDK inhibitory activity
US7446105B2 (en) 2002-03-09 2008-11-04 Astrazeneca Ab Pyrimidine compounds
US7465728B2 (en) 2002-03-09 2008-12-16 Astrazeneca Ab Derivatives of 4-(imidazol-5-yl)-2-(4-sulfoanilino)pyrimidine with CDK inhibitory activity
US7485638B2 (en) 2002-03-09 2009-02-03 Astrazeneca Ab Pyrimidine compounds
US7427626B2 (en) 2003-05-16 2008-09-23 Astrazeneca Ab 2-Anilino-4-(imidazol-5-yl)-pyrimidine derivatives and their use as cdk (cdk2) inhibitors
US7579344B2 (en) 2003-05-16 2009-08-25 Astrazeneca Ab Pyrimidine derivatives possessing cell-cycle inhibitors activity
JP2008500320A (ja) * 2004-05-26 2008-01-10 サイクラセル リミテッド 増殖性障害の治療に有用な２−置換−４−ヘテロアリール−ピリミジン
JP2009503060A (ja) * 2005-08-05 2009-01-29 イル−ヤン ファーム カンパニー リミテッド Ｎ−フェニル−２−ピリミジン−アミン誘導体及びそれの調製のための工程
US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
WO2007076473A3 (fr) * 2005-12-23 2007-10-18 Kalypsys Inc Urees pyrimidinyloxy substituees utiles comme inhibiteurs des proteines kinases
WO2007132221A1 (fr) * 2006-05-12 2007-11-22 Cyclacel Limited Inhibiteurs de la kinase aurora à base de pyrimidine-thiazole, anticancéreux, combinés
US8278450B2 (en) 2007-04-18 2012-10-02 Takeda Pharmaceutical Company Limited Kinase inhibitors

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