SA516370384B1 - مركبات فعّالة علاجياً وطرق استخدامها - Google Patents
مركبات فعّالة علاجياً وطرق استخدامها Download PDFInfo
- Publication number
- SA516370384B1 SA516370384B1 SA516370384A SA516370384A SA516370384B1 SA 516370384 B1 SA516370384 B1 SA 516370384B1 SA 516370384 A SA516370384 A SA 516370384A SA 516370384 A SA516370384 A SA 516370384A SA 516370384 B1 SA516370384 B1 SA 516370384B1
- Authority
- SA
- Saudi Arabia
- Prior art keywords
- alkyl
- alkylene
- compound
- halo
- phenyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 335
- 238000000034 method Methods 0.000 title abstract description 98
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 75
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- 201000011510 cancer Diseases 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 551
- -1 pyridinyl pyrimidinyl Chemical group 0.000 claims description 187
- 238000006467 substitution reaction Methods 0.000 claims description 167
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 154
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 117
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 115
- 125000005843 halogen group Chemical group 0.000 claims description 97
- 125000002947 alkylene group Chemical group 0.000 claims description 89
- 229910052739 hydrogen Inorganic materials 0.000 claims description 72
- 239000001257 hydrogen Substances 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 65
- 125000001188 haloalkyl group Chemical group 0.000 claims description 57
- 125000001424 substituent group Chemical group 0.000 claims description 55
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 48
- 125000004429 atom Chemical group 0.000 claims description 41
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 39
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 34
- 125000001153 fluoro group Chemical group F* 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 125000004076 pyridyl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 229940124597 therapeutic agent Drugs 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 125000004122 cyclic group Chemical group 0.000 claims description 19
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 19
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 16
- 150000004985 diamines Chemical class 0.000 claims description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
- 125000001475 halogen functional group Chemical group 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- MISVBCMQSJUHMH-UHFFFAOYSA-N pyrimidine-4,6-diamine Chemical compound NC1=CC(N)=NC=N1 MISVBCMQSJUHMH-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000002207 metabolite Substances 0.000 claims description 6
- 229920000728 polyester Polymers 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 5
- FJNLCHNQVJVCPY-UHFFFAOYSA-N 2-n-methoxy-2-n-methyl-4-n,6-n-dipropyl-1,3,5-triazine-2,4,6-triamine Chemical compound CCCNC1=NC(NCCC)=NC(N(C)OC)=N1 FJNLCHNQVJVCPY-UHFFFAOYSA-N 0.000 claims description 4
- BQDMPXSEKDAUOD-UHFFFAOYSA-N C(C)(CC)NC1=NC(=NC(=N1)NC(C)CC)C1=CC=CC=C1 Chemical compound C(C)(CC)NC1=NC(=NC(=N1)NC(C)CC)C1=CC=CC=C1 BQDMPXSEKDAUOD-UHFFFAOYSA-N 0.000 claims description 4
- 125000005038 alkynylalkyl group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 241000272522 Anas Species 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 101100309713 Arabidopsis thaliana SD129 gene Proteins 0.000 claims description 2
- 125000005418 aryl aryl group Chemical group 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 239000000039 congener Substances 0.000 claims description 2
- 230000004060 metabolic process Effects 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 4
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 3
- 241000380131 Ammophila arenaria Species 0.000 claims 2
- 125000004171 alkoxy aryl group Chemical group 0.000 claims 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 2
- ABYZSYDGJGVCHS-ZETCQYMHSA-N (2s)-2-acetamido-n-(4-nitrophenyl)propanamide Chemical compound CC(=O)N[C@@H](C)C(=O)NC1=CC=C([N+]([O-])=O)C=C1 ABYZSYDGJGVCHS-ZETCQYMHSA-N 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 241000196324 Embryophyta Species 0.000 claims 1
- 235000000177 Indigofera tinctoria Nutrition 0.000 claims 1
- 241000347485 Silurus glanis Species 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims 1
- 125000000068 chlorophenyl group Chemical group 0.000 claims 1
- 125000006450 cyclopropyl cyclopropyl group Chemical group 0.000 claims 1
- 125000006346 halo alkyl hydroxy alkyl group Chemical group 0.000 claims 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 1
- 229940097275 indigo Drugs 0.000 claims 1
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 claims 1
- 239000003350 kerosene Substances 0.000 claims 1
- 239000011800 void material Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 465
- 238000005160 1H NMR spectroscopy Methods 0.000 description 367
- 239000000203 mixture Substances 0.000 description 205
- 238000002360 preparation method Methods 0.000 description 137
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 129
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- 239000000243 solution Substances 0.000 description 104
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 90
- 239000000047 product Substances 0.000 description 89
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 88
- 239000000460 chlorine Substances 0.000 description 82
- 238000010561 standard procedure Methods 0.000 description 78
- 230000035772 mutation Effects 0.000 description 74
- 239000011541 reaction mixture Substances 0.000 description 71
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 62
- 239000012044 organic layer Substances 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 53
- 230000002829 reductive effect Effects 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 46
- 238000011282 treatment Methods 0.000 description 46
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 45
- 239000000706 filtrate Substances 0.000 description 45
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 43
- 238000000746 purification Methods 0.000 description 42
- FIDRAVVQGKNYQK-UHFFFAOYSA-N 1,2,3,4-tetrahydrotriazine Chemical compound C1NNNC=C1 FIDRAVVQGKNYQK-UHFFFAOYSA-N 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- 125000001309 chloro group Chemical group Cl* 0.000 description 38
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 28
- 239000007858 starting material Substances 0.000 description 27
- 238000001035 drying Methods 0.000 description 26
- 239000000725 suspension Substances 0.000 description 25
- 229920002554 vinyl polymer Polymers 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 21
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 20
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 18
- DKCPKDPYUFEZCP-UHFFFAOYSA-N 2,6-di-tert-butylphenol Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=C1O DKCPKDPYUFEZCP-UHFFFAOYSA-N 0.000 description 18
- AUQDITHEDVOTCU-UHFFFAOYSA-N cyclopropyl cyanide Chemical compound N#CC1CC1 AUQDITHEDVOTCU-UHFFFAOYSA-N 0.000 description 18
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 18
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- 229940125898 compound 5 Drugs 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 15
- 239000012141 concentrate Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 150000002431 hydrogen Chemical class 0.000 description 15
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 14
- 108090000790 Enzymes Proteins 0.000 description 14
- 150000001721 carbon Chemical group 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 229940088598 enzyme Drugs 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 101000599886 Homo sapiens Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 13
- 230000001419 dependent effect Effects 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- 239000004471 Glycine Substances 0.000 description 11
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 210000004556 brain Anatomy 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 125000001841 imino group Chemical group [H]N=* 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
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- 239000011734 sodium Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 150000003918 triazines Chemical class 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 10
- 206010025323 Lymphomas Diseases 0.000 description 10
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 10
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
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- 125000002619 bicyclic group Chemical group 0.000 description 10
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 10
- 125000006001 difluoroethyl group Chemical group 0.000 description 10
- 238000004811 liquid chromatography Methods 0.000 description 10
- OFAPSLLQSSHRSQ-UHFFFAOYSA-N 1H-triazine-2,4-diamine Chemical compound NN1NC=CC(N)=N1 OFAPSLLQSSHRSQ-UHFFFAOYSA-N 0.000 description 9
- PQBPPTHYTOKQMC-UHFFFAOYSA-N 6-[6-(trifluoromethyl)pyridin-2-yl]-1,3,5-triazine-2,4-diamine Chemical compound Nc1nc(N)nc(n1)-c1cccc(n1)C(F)(F)F PQBPPTHYTOKQMC-UHFFFAOYSA-N 0.000 description 9
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- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 description 9
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 description 9
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
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- 238000010992 reflux Methods 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
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- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 8
- VHPZCVVQXALXER-UHFFFAOYSA-N C(Nc1nc(NCC2CCCCC2)nc(n1)-c1ccccc1)C1CCCCC1 Chemical compound C(Nc1nc(NCC2CCCCC2)nc(n1)-c1ccccc1)C1CCCCC1 VHPZCVVQXALXER-UHFFFAOYSA-N 0.000 description 8
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- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 7
- 108700028369 Alleles Proteins 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- CJKJNTJPOYSDQL-UHFFFAOYSA-N 2-methylsulfonylbenzamide Chemical compound CS(=O)(=O)C1=CC=CC=C1C(N)=O CJKJNTJPOYSDQL-UHFFFAOYSA-N 0.000 description 6
- QSLBPUPBLLYFAS-UHFFFAOYSA-N 4-n-(oxan-4-yl)-6-phenyl-2-n-propan-2-yl-1,3,5-triazine-2,4-diamine Chemical compound N=1C(C=2C=CC=CC=2)=NC(NC(C)C)=NC=1NC1CCOCC1 QSLBPUPBLLYFAS-UHFFFAOYSA-N 0.000 description 6
- MLAXPKYHTUUIQX-UHFFFAOYSA-N 6-n-benzyl-4-n-cyclopentyl-2-phenylpyrimidine-4,6-diamine Chemical compound C=1C=CC=CC=1CNC(N=C(N=1)C=2C=CC=CC=2)=CC=1NC1CCCC1 MLAXPKYHTUUIQX-UHFFFAOYSA-N 0.000 description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 6
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
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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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| PCT/CN2014/081957 WO2015003640A1 (en) | 2013-07-11 | 2014-07-10 | Therapeutically active compounds and their methods of use |
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| CN102827073A (zh) | 2011-06-17 | 2012-12-19 | 安吉奥斯医药品有限公司 | 治疗活性组合物和它们的使用方法 |
| US9474779B2 (en) | 2012-01-19 | 2016-10-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compositions and their methods of use |
| WO2014062511A1 (en) | 2012-10-15 | 2014-04-24 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
| US9579324B2 (en) | 2013-07-11 | 2017-02-28 | Agios Pharmaceuticals, Inc | Therapeutically active compounds and their methods of use |
| CA2917671A1 (en) | 2013-07-11 | 2015-01-15 | Agios Pharmaceuticals, Inc. | 2,4-or 4,6-diaminopyrimidine compounds as idh2 mutants inhibitors for the treatment of cancer |
| WO2015003360A2 (en) | 2013-07-11 | 2015-01-15 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
| WO2015003355A2 (en) | 2013-07-11 | 2015-01-15 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
| US20150031627A1 (en) | 2013-07-25 | 2015-01-29 | Agios Pharmaceuticals, Inc | Therapeutically active compounds and their methods of use |
| KR20220070066A (ko) | 2014-03-14 | 2022-05-27 | 아지오스 파마슈티컬스 아이엔씨. | 치료적으로 활성인 화합물의 약제학적 조성물 |
| CN104672093B (zh) * | 2015-03-22 | 2016-04-13 | 成都塞恩斯医药科技有限公司 | 一种双环丙基甲胺的制备方法 |
| ES2881695T3 (es) * | 2015-07-30 | 2021-11-30 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Derivado de 1,3,5-triazina y método de uso del mismo |
| EP3331866B1 (en) * | 2015-08-05 | 2023-07-26 | Les Laboratoires Servier | Methods of preparing a 6-heteroaryl-1,3,5-triazine-2,4-diol and a 6-heteroaryl-1,3,5-triazine-2,4-diamine |
| PT3362065T (pt) | 2015-10-15 | 2024-06-21 | Servier Lab | Terapia de combinação compreendendo ivosidenib, citarabina e daunorubicina ou idarubicina para o tratamento de leucemia mielóide aguda |
| US10653710B2 (en) | 2015-10-15 | 2020-05-19 | Agios Pharmaceuticals, Inc. | Combination therapy for treating malignancies |
| WO2017069878A1 (en) | 2015-10-21 | 2017-04-27 | NeuForm Pharmaceuticals, Inc. | Deuterated compounds for treating hematologic malignancies, and compositions and methods thereof |
| WO2017140758A1 (en) | 2016-02-19 | 2017-08-24 | Debiopharm International S.A. | Derivatives of 2-amino-4-(2-oxazolidinon-3-yl)-pyrimidine fused with a five-membered heteroaromatic ring in 5,6-position which are useful for the treatment of various cancers |
| US10774064B2 (en) | 2016-06-02 | 2020-09-15 | Cadent Therapeutics, Inc. | Potassium channel modulators |
| KR102232614B1 (ko) * | 2016-07-21 | 2021-03-29 | 난징 산홈 팔마세우티칼 컴퍼니 리미티드 | 이소시트레이트 탈수소효소 억제제의 화학적 화합물 및 이의 적용 |
| CN109563027A (zh) * | 2016-07-28 | 2019-04-02 | 拜耳作物科学股份公司 | 氟代烷基腈和相应的氟代烷基四唑的制备方法 |
| HRP20220079T1 (hr) | 2017-01-23 | 2022-04-15 | Cadent Therapeutics, Inc. | Modulatori kalijevih kanala |
| CA3067035A1 (en) | 2017-06-12 | 2018-12-20 | Agios Pharmaceuticals, Inc. | Methods of treating brain tumors using combination therapy |
| EP3638245A1 (en) * | 2017-06-12 | 2020-04-22 | Agios Pharmaceuticals, Inc. | Methods of treating brain tumors using combination therapy |
| CN109265444B (zh) * | 2017-07-17 | 2022-03-11 | 南京圣和药业股份有限公司 | 取代的三嗪类idh抑制剂的光学异构体及其应用 |
| CN109467538A (zh) * | 2017-09-07 | 2019-03-15 | 和记黄埔医药(上海)有限公司 | 环烯烃取代的杂芳环类化合物及其用途 |
| EA202091112A1 (ru) * | 2017-11-02 | 2020-07-23 | Аджиос Фармасьютикалз, Инк. | Сокристаллы, фармацевтические композиции на их основе и способы лечения, предусматривающие их применение |
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| JP7736678B2 (ja) | 2019-10-16 | 2025-09-09 | ケモセントリックス,インコーポレイティド | Pd-l1疾患の処置のためのヘテロアリール-ビフェニルアミド |
| KR20230042065A (ko) | 2020-07-21 | 2023-03-27 | 다이이찌 산쿄 가부시키가이샤 | 테모졸로마이드와 돌연변이 idh1 효소 억제제의 조합 의약 |
| US11865079B2 (en) * | 2021-02-12 | 2024-01-09 | Servier Pharmaceuticals Llc | Therapeutically active compounds and their methods of use |
| AU2022219973A1 (en) | 2021-02-12 | 2023-09-07 | Les Laboratoires Servier | Therapeutically active compounds and their methods of use |
| CN113461660B (zh) * | 2021-06-11 | 2022-08-02 | 浙江大学 | 2,4,6-三取代-1,3,5-均三嗪类化合物及制备和应用 |
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