RU2490269C2 - ПРОИЗВОДНЫЕ МОРФОЛИНОПУРИНА, ОБЛАДАЮЩИЕ PI3K И/ИЛИ mTOR ИНГИБИРУЮЩЕЙ АКТИВНОСТЬЮ - Google Patents

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Publication number

RU2490269C2

RU2490269C2 RU2011119525/04A RU2011119525A RU2490269C2 RU 2490269 C2 RU2490269 C2 RU 2490269C2 RU 2011119525/04 A RU2011119525/04 A RU 2011119525/04A RU 2011119525 A RU2011119525 A RU 2011119525A RU 2490269 C2 RU2490269 C2 RU 2490269C2

Authority

RU

Russia

Prior art keywords

group

mmol

morpholin

contain

purin

Prior art date

2008-10-14

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• 108091007960 PI3Ks Proteins 0.000 title claims abstract description 46
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 title claims abstract description 29
• 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 title claims abstract description 29
• 230000002401 inhibitory effect Effects 0.000 title claims description 16
• IBVOXEAVUMUIBU-UHFFFAOYSA-N 4-(7h-purin-2-yl)morpholine Chemical class C1COCCN1C1=NC=C(NC=N2)C2=N1 IBVOXEAVUMUIBU-UHFFFAOYSA-N 0.000 title abstract description 7
• 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 386
• -1 phenylsulphonyl group Chemical group 0.000 claims abstract description 88
• 150000003839 salts Chemical class 0.000 claims abstract description 64
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 55
• 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims abstract description 45
• 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims abstract description 44
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 42
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 40
• 238000000034 method Methods 0.000 claims abstract description 38
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 36
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 33
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 29
• 125000005843 halogen group Chemical group 0.000 claims abstract description 26
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 26
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 15
• 201000011510 cancer Diseases 0.000 claims abstract description 14
• 239000003112 inhibitor Substances 0.000 claims abstract description 8
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 7
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 7
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 4
• FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims abstract description 3
• 125000001424 substituent group Chemical group 0.000 claims description 222
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 139
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 71
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 46
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 29
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 26
• 239000003814 drug Substances 0.000 claims description 15
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
• 125000004043 oxo group Chemical group O=* 0.000 claims description 13
• 230000035772 mutation Effects 0.000 claims description 11
• 230000026731 phosphorylation Effects 0.000 claims description 11
• 238000006366 phosphorylation reaction Methods 0.000 claims description 11
• 239000012634 fragment Substances 0.000 claims description 8
• 229910052736 halogen Inorganic materials 0.000 claims description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims description 8
• 206010033128 Ovarian cancer Diseases 0.000 claims description 7
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
• 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 6
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 6
• 206010006187 Breast cancer Diseases 0.000 claims description 6
• 208000026310 Breast neoplasm Diseases 0.000 claims description 6
• 206010009944 Colon cancer Diseases 0.000 claims description 6
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
• 229910019142 PO4 Inorganic materials 0.000 claims description 6
• 108010011536 PTEN Phosphohydrolase Proteins 0.000 claims description 6
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
• 208000029742 colonic neoplasm Diseases 0.000 claims description 6
• 201000005202 lung cancer Diseases 0.000 claims description 6
• 208000020816 lung neoplasm Diseases 0.000 claims description 6
• 201000001441 melanoma Diseases 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 5
• 206010060862 Prostate cancer Diseases 0.000 claims description 5
• 229910052739 hydrogen Inorganic materials 0.000 claims description 5
• 239000001257 hydrogen Substances 0.000 claims description 5
• 230000002018 overexpression Effects 0.000 claims description 5
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
• 239000010452 phosphate Substances 0.000 claims description 5
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
• 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 3
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
• XUHRVZXFBWDCFB-QRTDKPMLSA-N (3R)-4-[[(3S,6S,9S,12R,15S,18R,21R,24R,27R,28R)-12-(3-amino-3-oxopropyl)-6-[(2S)-butan-2-yl]-3-(2-carboxyethyl)-18-(hydroxymethyl)-28-methyl-9,15,21,24-tetrakis(2-methylpropyl)-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octazacyclooctacos-27-yl]amino]-3-[[(2R)-2-[[(3S)-3-hydroxydecanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoic acid Chemical compound CCCCCCC[C@H](O)CC(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H]1[C@@H](C)OC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CO)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC1=O)[C@@H](C)CC XUHRVZXFBWDCFB-QRTDKPMLSA-N 0.000 claims 2
• 102100032543 Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN Human genes 0.000 claims 2
• 102100024547 Tensin-1 Human genes 0.000 claims 2
• 108010088950 Tensins Proteins 0.000 claims 2
• 239000000126 substance Substances 0.000 abstract description 12
• 230000000694 effects Effects 0.000 abstract description 7
• 230000004071 biological effect Effects 0.000 abstract 1
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 357
• 239000000203 mixture Substances 0.000 description 352
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 333
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 281
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 229
• 230000002829 reductive effect Effects 0.000 description 216
• 239000007787 solid Substances 0.000 description 198
• 238000005160 1H NMR spectroscopy Methods 0.000 description 194
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 176
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 174
• 239000002904 solvent Substances 0.000 description 153
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 153
• 239000011541 reaction mixture Substances 0.000 description 138
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 136
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 124
• 239000012044 organic layer Substances 0.000 description 121
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 117
• 239000000243 solution Substances 0.000 description 98
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 86
• 235000019341 magnesium sulphate Nutrition 0.000 description 86
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 82
• 229920006395 saturated elastomer Polymers 0.000 description 77
• 239000000706 filtrate Substances 0.000 description 72
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 66
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 66
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 62
• 235000017557 sodium bicarbonate Nutrition 0.000 description 62
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 61
• 238000001914 filtration Methods 0.000 description 59
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• 238000010898 silica gel chromatography Methods 0.000 description 56
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• 239000000741 silica gel Substances 0.000 description 51
• 229910002027 silica gel Inorganic materials 0.000 description 51
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• 238000001816 cooling Methods 0.000 description 46
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• 238000012746 preparative thin layer chromatography Methods 0.000 description 40
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• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 33
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 33
• 239000007864 aqueous solution Substances 0.000 description 33
• 239000012267 brine Substances 0.000 description 33
• 235000019253 formic acid Nutrition 0.000 description 33
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
• 238000002953 preparative HPLC Methods 0.000 description 30
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 29
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
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• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• 125000003277 amino group Chemical group 0.000 description 27
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• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical class CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 25
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 24
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 24
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 22
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• 238000002360 preparation method Methods 0.000 description 17
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 16
• PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 15
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
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• 125000004093 cyano group Chemical group *C#N 0.000 description 14
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• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 13
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 12
• BXEMEYQLLIFSLY-UHFFFAOYSA-N 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-ylpurin-2-yl]pyrimidin-2-amine Chemical compound C1=NC(N)=NC=C1C1=NC(N2CCOCC2)=C(N=C(Cl)N2CC3CC3)C2=N1 BXEMEYQLLIFSLY-UHFFFAOYSA-N 0.000 description 12
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 12
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• 238000003818 flash chromatography Methods 0.000 description 11
• KBDQYYDPHNMVNZ-UHFFFAOYSA-N 5-[9-(2-methylpropyl)-6-morpholin-4-yl-8-piperazin-1-ylpurin-2-yl]pyrimidin-2-amine Chemical compound N1=C2N(CC(C)C)C(N3CCNCC3)=NC2=C(N2CCOCC2)N=C1C1=CN=C(N)N=C1 KBDQYYDPHNMVNZ-UHFFFAOYSA-N 0.000 description 10
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• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
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• 150000001412 amines Chemical class 0.000 description 8
• 239000002585 base Substances 0.000 description 8
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• IFNWESYYDINUHV-OLQVQODUSA-N (2s,6r)-2,6-dimethylpiperazine Chemical compound C[C@H]1CNC[C@@H](C)N1 IFNWESYYDINUHV-OLQVQODUSA-N 0.000 description 7
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• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
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