WO2010044401A1 - モルホリノプリン誘導体 - Google Patents

モルホリノプリン誘導体 Download PDF

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Publication number
WO2010044401A1
WO2010044401A1 PCT/JP2009/067738 JP2009067738W WO2010044401A1 WO 2010044401 A1 WO2010044401 A1 WO 2010044401A1 JP 2009067738 W JP2009067738 W JP 2009067738W WO 2010044401 A1 WO2010044401 A1 WO 2010044401A1
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WO
WIPO (PCT)
Prior art keywords
group
alkylamino
substituents
substituents selected
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2009/067738
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English (en)
French (fr)
Japanese (ja)
Inventor
清 中山
杉田　和幸
正樹 瀬戸口
裕一 冨永
正規 齋藤
高志 小田桐
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Sankyo Co Ltd
Original Assignee
Daiichi Sankyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN200980151585.4A priority Critical patent/CN102245607B/zh
Priority to NZ592761A priority patent/NZ592761A/en
Priority to AU2009304789A priority patent/AU2009304789B2/en
Priority to ES09820579.2T priority patent/ES2452541T3/es
Priority to RU2011119525/04A priority patent/RU2490269C2/ru
Priority to BRPI0920199A priority patent/BRPI0920199A2/pt
Priority to MX2011003490A priority patent/MX2011003490A/es
Priority to CA2740471A priority patent/CA2740471C/en
Priority to EP09820579.2A priority patent/EP2336132B1/en
Application filed by Daiichi Sankyo Co Ltd filed Critical Daiichi Sankyo Co Ltd
Priority to DK09820579.2T priority patent/DK2336132T3/da
Priority to HK11112477.4A priority patent/HK1158189B/en
Priority to PL09820579T priority patent/PL2336132T3/pl
Publication of WO2010044401A1 publication Critical patent/WO2010044401A1/ja
Priority to ZA2011/02449A priority patent/ZA201102449B/en
Priority to IL212278A priority patent/IL212278A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • a tumor in which overexpression of phosphatidylinositol 3-kinase (PI3K) is observed which comprises administering the compound according to any one of [1] to [18] or a salt thereof Method of treatment.
  • Treatment of a tumor in which a mutation of phosphatidylinositol 3-kinase (PI3K) is observed comprising administering the compound according to any one of [1] to [18] or a salt thereof Method.
  • a method for treating a tumor exhibiting enhanced phosphorylation of Akt comprising administering the compound according to any one of [1] to [18] or a salt thereof.
  • the “C 1 -C 6 alkylaminocarbonyl group” means a group in which the above C 1 -C 6 alkylamino group is substituted on the carbonyl group.
  • the “C 1 -C 6 alkylaminosulfonyl group” means a group in which the above C 1 -C 6 alkylamino is substituted on the sulfonyl group.
  • the “di-C 1 -C 6 alkylaminosulfonyl group” means a group in which the di-C 1 -C 6 alkylamino group is substituted on the sulfonyl group.
  • substituents of “aryl group which may be present” include one or more halogen atoms, hydroxy group, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, amino group, C 1 -C 6.
  • Archi Amino group, di C 1 ⁇ C 6 alkylamino group, a cyano group, C 1 ⁇ C 6 alkylamino C 1 ⁇ C 6 alkyl group or a C 1 ⁇ C 6 alkylcarbonylamino group are preferred.
  • substituents may be on the same atom or different atoms.
  • X represents a 6-membered aromatic nitrogen-containing heterocyclic group containing one or two nitrogen atoms, which may have one or a plurality of substituents.
  • X includes a group derived from pyridine, pyridazine or pyrimidine. X may be bonded at any position to the imidazolopyrimidine ring in the general formula (1).
  • X is preferably a group derived from pyrimidine, particularly preferably bonded at the 2-position to the imidazolopyrimidine ring.
  • Rb and Rc each independently represent a C 1 -C 6 alkyl group which may have one or more substituents, or a hydrogen atom, or Rb and Rc are taken together This indicates that a 4- to 7-membered alicyclic nitrogen-containing heterocyclic group which may have one or more substituents together with the nitrogen atom to which Rb and Rc are bonded may be formed.
  • Conversion from compound 6 (when one or more of the substituents on the nitrogen atom bonded to X in the figure is hydrogen) to compound 7 is an excess mole of Boc 2 O, preferably 1 mole of compound 6.
  • a base such as 4-dimethylaminopyridine
  • N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone and the like are not adversely affected.
  • the reaction is carried out in a solvent at room temperature to 80 ° C. for about 1 to 10 hours.
  • Conversion from compound 7 to compound 8 is carried out by using a commonly used halogenating agent such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, iodine, BrI and the like with respect to 1 mole of compound 7.
  • a commonly used halogenating agent such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, iodine, BrI and the like with respect to 1 mole of compound 7.
  • Molar to excess molar, preferably 1 to 3 molar, in an appropriate solvent that does not adversely influence the reaction eg, N, N-dimethylformamide, acetonitrile, chloroform, methylene chloride
  • a radical initiator may be added.
  • reaction temperature 0. C. to 300.degree. C. is preferred, and room temperature to 200.degree. C. is more preferred.
  • the halogen reagent, mesylate reagent, and the like and the base are used in an amount of 1 to an excess mole, preferably 1 to 5 moles relative to 1 mole of Compound 13.
  • the reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
  • the conversion from compound 15 to compound 8 can be carried out by using an organic base or an inorganic salt in a suitable solvent or a mixed solvent thereof that does not exert an adverse effect such as N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or acetonitrile.
  • a base potassium carbonate, potassium t-butoxide, triethylamine, etc.
  • an appropriate additive for example, triethylbenzylammonium chloride, etc.
  • an alkyl halide compound or a methanesulfonyloxyalkyl compound is used. It is done by processing. It is preferable to use 1 to excess moles, preferably 1 to 5 moles of each of the alkyl halide or base, relative to 1 mole of Compound 15.
  • the reaction time is preferably 30 minutes to 72 hours, and more preferably 30 minutes to 24 hours.
  • optical isomer exists when the compound (1) of the present invention or the production intermediate has an asymmetric carbon.
  • These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) for recrystallization with an appropriate salt and column chromatography.
  • References for methods for resolution of optical isomers from racemates include: “Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.” by Jacques et al.
  • Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromomycin A Examples include 3 or actinomycin D.
  • anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromomycin A
  • anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pir
  • Antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, sorafenib, etc.
  • 2,6-dichloropurine (21 g, 113 mmol), (tetrahydrofuran-3-yl) methanol (11.5 g, 113 mmol) was dissolved in tetrahydrofuran (250 ml), triphenylphosphine (33 g, 125 mmol), diisopropylazodicarboxyl.
  • a rate (24.5 ml, 125 mmol) / tetrahydrofuran (50 ml) solution was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours.
  • 2,2,6,6-tetramethylpiperidine (26.5 ml, 157 mmol) was dissolved in tetrahydrofuran (200 ml), and n-butyllithium (2.6 M hexane solution, 54 ml) was added dropwise at room temperature under an argon atmosphere. It stirred for 15 minutes after completion
  • Step 2 2- ⁇ 4- [2- (2-Aminopyrimidin-5-yl) -6-morpholin-4-yl-9- (2,2,2-trifluoroethyl) -9H-purine-8 -Yl] piperazin-1-yl ⁇ -N, N-dimethyl-2-oxoacetamide tert-butyl ⁇ 5- [8- ⁇ 4-[(dimethylamino) (oxo) acetyl] piperazin-1-yl ⁇ -6-morpholin-4-yl-9- (2,2,2-trifluoroethyl) Trifluoroacetic acid (5 ml) was added to -9H-purin-2-yl] pyrimidin-2-yl ⁇ carbamate (148 mg, 0.22 mmol) and stirred for 30 minutes.
  • Step 3 7-Benzyl-4,7-diazaspiro [2.5] octane Borane-tetrahydrofuran complex (0.93M tetrahydrofuran solution) (375 ml, 0.35 mol) was added to a tetrahydrofuran (200 ml) solution of the compound obtained in Step 2 above (20 g, 86.8 mmol) under ice-cooling, followed by heating for 19 hours.
  • Step 2 2-Chloro-6-[(3S) -3-methylmorpholin-4-yl] -9- (2,2,2-trifluoroethyl) -9H-purine
  • potassium carbonate 86 mg, 0.62 mmol
  • N, N-dimethylformamide 5 ml
  • 2,2,2-trifluoroethyl trifluoromethylsulfonate 83 ⁇ l, 0.57 mmol
  • Step 4 Di-tert-butyl (5- ⁇ 6-[(3S) -3-methylmorpholin-4-yl] -9- (2,2,2-trifluoroethyl) -9H-purine-2- Yl ⁇ pyrimidin-2-yl) imide dicarbonate 5- ⁇ 6-[(3S) -3-Methylmorpholin-4-yl] -9- (2,2,2-trifluoroethyl) -9H-purin-2-yl ⁇ pyrimidin-2-amine (423 mg, 1.07 mmol), 4-dimethylaminopyridine (26 mg, 0.21 mmol) in N, N-dimethylformamide (4 ml) in di-tert-butyl dicarbonate (1.17 g, 5.36 mmol) in N, N— Dimethylformamide (4 ml) solution was added.
  • Step 7 5- ⁇ 6-[(3S) -3-Methylmorpholin-4-yl] -8- [4- (methylsulfonyl) piperazin-1-yl] -9- (2,2,2-tri Fluoroethyl) -9H-purin-2-yl ⁇ pyrimidin-2-amine tert-butyl (5- ⁇ 6-[(3S) -3-methylmorpholin-4-yl] -8- [4- (methylsulfonyl) piperazin-1-yl] -9- (2,2,2-tri Fluoroethyl) -9H-purin-2-yl ⁇ pyrimidin-2-yl) carbamate (199 mg, 0.30 mmol) and trifluoroacetic acid (1 ml) in methylene chloride (5 ml) were stirred at room temperature for 1.5 hours.
  • Step 2 Di-tert-butyl (5- ⁇ 9- (cyclopropylmethyl) -6-[(3S) -3-methylmorpholin-4-yl] -9H-purin-2-yl ⁇ -4-methyl Pyrimidin-2-yl) imide dicarbonate 2-Chloro-9- (cyclopropylmethyl) -6-[(3S) -3-methylmorpholin-4-yl] -9H-purine (248 mg, 0.81 mmol), di-tert-butyl [4-methyl- 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl] imide dicarbonate (178 mg, 0.81 mmol), tetrakistriphenylphosphine palladium (93 mg , 0.08 mmol), a suspension of sodium carbonate (256 mg, 2.42 mmol) in 1,4-dioxane (5 ml) / water (1 ml)
  • Step 4 5- ⁇ 8- (4-acetylpiperazin-1-yl) -9- (cyclopropylmethyl) -6-[(3S) -3-methylmorpholin-4-yl] -9H-purine-2 -Yl ⁇ -4-methylpiperazin-2-amine
  • Di-tert-butyl (5- ⁇ 8-chloro-9- (cyclopropylmethyl) -6-[(3S) -3-methylmorpholin-4-yl] -9H-purin-2-yl ⁇ -4-methyl
  • a solution of pyrimidin-2-yl) imide dicarbonate (344 mg, 0.56 mmol) and trifluoroacetic acid (1 ml) in methylene chloride (3 ml) was stirred at room temperature for 2 hours and concentrated under reduced pressure.
  • reaction mixture was returned to room temperature.
  • a solution of the residue, acetic anhydride (56 ⁇ l, 0.59 mmol) and triethylamine (91 ⁇ l, 0.65 mmol) in methylene chloride (5 ml) was stirred at room temperature for 16 hours and concentrated under reduced pressure.
  • Ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • Formulation Example 1 Powder A powder can be obtained by mixing 5 g of the compound of an Example, 895 g of lactose, and 100 g of corn starch with a blender.
  • Formulation Example 2 Granule After mixing 5 g of the compound of Example, 895 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. When this is granulated using an extrusion granulator and dried, granules can be obtained.
  • P Measured value of well containing PI3K ⁇ and test compound
  • an optimal curve was calculated with GraphPad Prism 4, and the concentration showing 50% inhibition was taken as the IC50 value of PI3K ⁇ inhibitory activity. Calculated.
  • Ratio 10000 ⁇ 665 nm fluorescence value / 620 nm fluorescence value (1)
  • the mTOR enzyme inhibitory activity (%) was calculated by the following formula (2).
  • Test Example 3 In Vitro Test of Test Compound: Cell Growth Inhibition Test The cell growth inhibition test was performed by treating a cultured cancer cell line with a test compound for a certain period of time and then treating MTT (3- (4,5-dimethylthiazol-2-yl). ) -2,5-diphenyltetrazole bromide) method was performed by measuring the number of viable cells.
  • MTT 3- (4,5-dimethylthiazol-2-yl).
  • MTT -2,5-diphenyltetrazole bromide
  • Human endometrial cancer cell line AN3CA, human ovarian cancer cell line IGROV1, and human colon cancer cell line HT29 were seeded at 5000, 1000, and 5000 cells per well of a 96-well plate, respectively.
  • a test compound having a predetermined concentration was added, and the culture at 37 ° C. and 5% CO 2 was continued for 3 days.
  • an MTT reaction solution was added and reacted for 4 hours to perform a formazan formation reaction with dehydrogenase held by living cells.
  • the culture solution was removed, DMSO was added to solubilize formazan, and the amount of formazan produced was measured by measuring the absorbance at 540 nm with a microplate reader.
  • the compounds of Examples 3, 8, 57, 60-65, 68-71, 75-77, 79-86, 90, 92-93, 96, 98, 100-116, 119, 130-134 are dosed 10 mg / kg.
  • S-6 phosphorylation after 6 hours was inhibited by 90% or more.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP2009/067738 2008-10-14 2009-10-13 モルホリノプリン誘導体 Ceased WO2010044401A1 (ja)

Priority Applications (14)

Application Number Priority Date Filing Date Title
EP09820579.2A EP2336132B1 (en) 2008-10-14 2009-10-13 Morpholinopurine derivative
AU2009304789A AU2009304789B2 (en) 2008-10-14 2009-10-13 Morpholinopurine derivatives
ES09820579.2T ES2452541T3 (es) 2008-10-14 2009-10-13 Derivado de morfolinopurina
RU2011119525/04A RU2490269C2 (ru) 2008-10-14 2009-10-13 ПРОИЗВОДНЫЕ МОРФОЛИНОПУРИНА, ОБЛАДАЮЩИЕ PI3K И/ИЛИ mTOR ИНГИБИРУЮЩЕЙ АКТИВНОСТЬЮ
BRPI0920199A BRPI0920199A2 (pt) 2008-10-14 2009-10-13 composto ou um sal do mesmo, metanossulfonato do composto, sulfato do composto, composicao farm,aceutica, inibidores de fostatidilisitol 3-quinase, e do alvo mamifero da rapamicina, e, uso de um composto
MX2011003490A MX2011003490A (es) 2008-10-14 2009-10-13 Derivados de morfolinopurina.
CA2740471A CA2740471C (en) 2008-10-14 2009-10-13 Morpholinopurine derivatives
CN200980151585.4A CN102245607B (zh) 2008-10-14 2009-10-13 吗啉代嘌呤衍生物
DK09820579.2T DK2336132T3 (da) 2008-10-14 2009-10-13 Morpholinpurinderivat
NZ592761A NZ592761A (en) 2008-10-14 2009-10-13 6-Morpholino-purine derivatives
HK11112477.4A HK1158189B (en) 2008-10-14 2009-10-13 Morpholinopurine derivative
PL09820579T PL2336132T3 (pl) 2008-10-14 2009-10-13 Pochodne morfolinopuryny
ZA2011/02449A ZA201102449B (en) 2008-10-14 2011-04-01 Morpholinopurine derivatives
IL212278A IL212278A (en) 2008-10-14 2011-04-12 Phosphatidylinositol suppressants 3-kinase (p13k) and mammalian rapamycin (mtor) suppressor derivatives morpholinophorin, preparations containing them and their uses

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2008264797 2008-10-14
JP2008-264797 2008-10-14
JP2009-121690 2009-05-20
JP2009121690 2009-05-20

Publications (1)

Publication Number Publication Date
WO2010044401A1 true WO2010044401A1 (ja) 2010-04-22

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Application Number Title Priority Date Filing Date
PCT/JP2009/067738 Ceased WO2010044401A1 (ja) 2008-10-14 2009-10-13 モルホリノプリン誘導体

Country Status (21)

Country Link
US (2) US8097622B2 (enExample)
EP (1) EP2336132B1 (enExample)
JP (1) JP5090423B2 (enExample)
KR (1) KR101614976B1 (enExample)
CN (1) CN102245607B (enExample)
AU (1) AU2009304789B2 (enExample)
BR (1) BRPI0920199A2 (enExample)
CA (1) CA2740471C (enExample)
CO (1) CO6362009A2 (enExample)
DK (1) DK2336132T3 (enExample)
ES (1) ES2452541T3 (enExample)
IL (1) IL212278A (enExample)
MX (1) MX2011003490A (enExample)
MY (1) MY156456A (enExample)
NZ (1) NZ592761A (enExample)
PL (1) PL2336132T3 (enExample)
PT (1) PT2336132E (enExample)
RU (1) RU2490269C2 (enExample)
TW (1) TWI378933B (enExample)
WO (1) WO2010044401A1 (enExample)
ZA (1) ZA201102449B (enExample)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014185368A1 (ja) * 2013-05-13 2014-11-20 第一三共株式会社 ５－｛８－［（３ｒ）－４－アセチル－３－メチルピペラジン－１－イル］－６－モルホリン－４－イル－９－（２，２，２－トリフルオロエチル）－９ｈ－プリン－２－イル｝ピリミジン－２－アミン、およびその薬理上許容される塩の新規な結晶、およびその製造方法
WO2014185367A1 (ja) * 2013-05-13 2014-11-20 第一三共株式会社 モルホリノプリン誘導体の製造方法
WO2016157074A1 (en) 2015-03-30 2016-10-06 Daiichi Sankyo Company, Limited 6-morpholinyl-2-pyrazolyl-9h-purine derivatives and their use as pi3k inhibitors
WO2020111234A1 (ja) 2018-11-29 2020-06-04 第一三共株式会社 組み合わせ医薬として用いられるｅｚｈ１／２二重阻害剤を含有する医薬組成物
US11208442B2 (en) 2016-12-02 2021-12-28 Daiichi Sankyo Company, Limited Endo-beta-N-acetylglucosaminidase
WO2022197892A1 (en) * 2021-03-17 2022-09-22 Tango Therapeutics, Inc. Purine derivatives as anticancer agents

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8158624B2 (en) * 2008-05-30 2012-04-17 Genetech, Inc. Purine PI3K inhibitor compounds and methods of use
TWI378933B (en) * 2008-10-14 2012-12-11 Daiichi Sankyo Co Ltd Morpholinopurine derivatives
MX2012005463A (es) * 2009-11-12 2012-09-12 Hoffmann La Roche Compuestos de purina n/9 sustituida, composiciones y metodos de uso.
CN102260263A (zh) * 2010-05-26 2011-11-30 四川大学 一类二苯胺基嘌呤衍生物及制备方法和医药用途
CN103003279B (zh) 2010-07-14 2015-09-23 弗·哈夫曼-拉罗切有限公司 对PI3K P110δ具有选择性的嘌呤化合物及其使用方法
EP3053925A1 (en) 2010-12-16 2016-08-10 F. Hoffmann-La Roche AG Tricyclic pi3k inhibitor compounds and methods of use
WO2013061305A1 (en) 2011-10-28 2013-05-02 Novartis Ag Novel purine derivatives and their use in the treatment of disease
CN103012284A (zh) * 2012-12-26 2013-04-03 无锡捷化医药科技有限公司 一种2-氨基-5-溴嘧啶类化合物的制备方法
CA2928568A1 (en) 2013-07-26 2015-01-29 Update Pharma Inc. Combinatorial methods to improve the therapeutic benefit of bisantrene
RU2669696C2 (ru) * 2013-10-04 2018-10-15 Университет Базель КОНФОРМАЦИОННО ОГРАНИЧЕННЫЕ ИНГИБИТОРЫ PI3K И mTOR
CN108602825A (zh) * 2016-02-05 2018-09-28 中央研究院 具有抗癌活性的嘌呤化合物
US10722484B2 (en) 2016-03-09 2020-07-28 K-Gen, Inc. Methods of cancer treatment
EP3360865A1 (en) 2017-02-13 2018-08-15 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Process for the preparation of cyclopropyldiketopiperazines, and of a key intermediate of ds-5272
CN113368114B (zh) * 2020-03-10 2022-04-22 四川大学 一种吗啉嘧啶类化合物的抗肿瘤应用

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EP2336132B1 (en) 2014-01-01
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ZA201102449B (en) 2011-12-28
EP2336132A4 (en) 2012-03-21
CN102245607B (zh) 2014-07-02
US8097622B2 (en) 2012-01-17
KR101614976B1 (ko) 2016-04-22
NZ592761A (en) 2012-05-25
AU2009304789A1 (en) 2010-04-22
CA2740471A1 (en) 2010-04-22
IL212278A (en) 2016-07-31
PT2336132E (pt) 2014-04-02
MX2011003490A (es) 2011-04-21
JP2011001339A (ja) 2011-01-06
IL212278A0 (en) 2011-06-30
PL2336132T3 (pl) 2014-06-30
US8309546B2 (en) 2012-11-13
RU2011119525A (ru) 2012-11-27
BRPI0920199A2 (pt) 2019-09-24
CO6362009A2 (es) 2012-01-20
ES2452541T3 (es) 2014-04-01
DK2336132T3 (da) 2014-04-07
TWI378933B (en) 2012-12-11
CN102245607A (zh) 2011-11-16
KR20110067038A (ko) 2011-06-20
US20100130492A1 (en) 2010-05-27
MY156456A (en) 2016-02-26
EP2336132A1 (en) 2011-06-22
RU2490269C2 (ru) 2013-08-20
CA2740471C (en) 2013-09-17
AU2009304789B2 (en) 2012-04-05
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