DK2311825T3 - Pyrimidinamines AS ANGIOGENESEMODULATORER - Google Patents

Info

Publication number

DK2311825T3

DK2311825T3 DK09159138.8T DK09159138T DK2311825T3 DK 2311825 T3 DK2311825 T3 DK 2311825T3 DK 09159138 T DK09159138 T DK 09159138T DK 2311825 T3 DK2311825 T3 DK 2311825T3

Authority

DK

Denmark

Prior art keywords

methyl

amino

indazol

pyrimidinyl

hydrogen

Prior art date

2000-12-21

Links

• Espacenet
• Global Dossier
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• LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical class NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 title 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
• 238000011282 treatment Methods 0.000 claims abstract description 30
• 201000010099 disease Diseases 0.000 claims abstract description 11
• 150000001875 compounds Chemical class 0.000 claims description 148
• 229910052739 hydrogen Inorganic materials 0.000 claims description 148
• 239000001257 hydrogen Substances 0.000 claims description 139
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 132
• -1 {4- [methyl (3-methyl-1H-indazol-6-yl) amino] -2-pyrimidinyl} amino Chemical group 0.000 claims description 97
• 125000000217 alkyl group Chemical group 0.000 claims description 60
• 150000003839 salts Chemical class 0.000 claims description 57
• 229910052736 halogen Inorganic materials 0.000 claims description 48
• 150000002367 halogens Chemical class 0.000 claims description 48
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 48
• 239000012453 solvate Substances 0.000 claims description 47
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 40
• 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 37
• 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims description 34
• 230000000694 effects Effects 0.000 claims description 31
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
• 239000000460 chlorine Substances 0.000 claims description 26
• 229910052801 chlorine Inorganic materials 0.000 claims description 24
• 239000008194 pharmaceutical composition Substances 0.000 claims description 24
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 21
• 230000033115 angiogenesis Effects 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 18
• 125000001188 haloalkyl group Chemical group 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 17
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 12
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
• 230000001404 mediated effect Effects 0.000 claims description 9
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 7
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 238000002560 therapeutic procedure Methods 0.000 claims description 6
• MGSXZPZPZIPVHO-UHFFFAOYSA-N 2-[(3-methyl-2h-indazol-6-yl)-[2-[3-(methylsulfonylmethyl)anilino]pyrimidin-4-yl]amino]acetonitrile Chemical compound C=1C=C2C(C)=NNC2=CC=1N(CC#N)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 MGSXZPZPZIPVHO-UHFFFAOYSA-N 0.000 claims description 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• MQYXDHFLBFNMAM-UHFFFAOYSA-N 2-[(3-methyl-2h-indazol-6-yl)-[2-[4-(methylsulfonylmethyl)anilino]pyrimidin-4-yl]amino]acetonitrile Chemical compound C=1C=C2C(C)=NNC2=CC=1N(CC#N)C(N=1)=CC=NC=1NC1=CC=C(CS(C)(=O)=O)C=C1 MQYXDHFLBFNMAM-UHFFFAOYSA-N 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 9
• 125000006125 ethylsulfonyl group Chemical group 0.000 claims 2
• 238000004519 manufacturing process Methods 0.000 claims 2
• UGINXJBANWOKBM-UHFFFAOYSA-N 1-phenylpropane-2-sulfonamide Chemical compound NS(=O)(=O)C(C)CC1=CC=CC=C1 UGINXJBANWOKBM-UHFFFAOYSA-N 0.000 claims 1
• COABLFOXQFCPON-UHFFFAOYSA-N 2-n-(2-fluoro-5-methylsulfonylphenyl)-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC(S(C)(=O)=O)=CC=C1F COABLFOXQFCPON-UHFFFAOYSA-N 0.000 claims 1
• OMGYUNINHJCHHA-UHFFFAOYSA-N 2-n-(2-methoxy-5-methylsulfonylphenyl)-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)pyrimidine-2,4-diamine Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1NC1=NC=CC(N(C)C=2C=C3NN=C(C)C3=CC=2)=N1 OMGYUNINHJCHHA-UHFFFAOYSA-N 0.000 claims 1
• UYVJGZKGQJTVOP-UHFFFAOYSA-N 2-n-(2-methoxy-5-propan-2-ylsulfonylphenyl)-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)pyrimidine-2,4-diamine Chemical compound COC1=CC=C(S(=O)(=O)C(C)C)C=C1NC1=NC=CC(N(C)C=2C=C3NN=C(C)C3=CC=2)=N1 UYVJGZKGQJTVOP-UHFFFAOYSA-N 0.000 claims 1
• YBDLZENVOVHCTJ-UHFFFAOYSA-N 2-n-(4-ethylsulfonylphenyl)-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)pyrimidine-2,4-diamine Chemical compound C1=CC(S(=O)(=O)CC)=CC=C1NC1=NC=CC(N(C)C=2C=C3NN=C(C)C3=CC=2)=N1 YBDLZENVOVHCTJ-UHFFFAOYSA-N 0.000 claims 1
• ALQFBYVDVDYXAA-UHFFFAOYSA-N 2-n-(5-ethylsulfonyl-2-methoxyphenyl)-4-n-(3-methyl-2h-indazol-6-yl)pyrimidine-2,4-diamine Chemical compound CCS(=O)(=O)C1=CC=C(OC)C(NC=2N=C(NC=3C=C4NN=C(C)C4=CC=3)C=CN=2)=C1 ALQFBYVDVDYXAA-UHFFFAOYSA-N 0.000 claims 1
• VTXJRGSOKKDRGH-UHFFFAOYSA-N 2-n-(5-ethylsulfonyl-2-methoxyphenyl)-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)pyrimidine-2,4-diamine Chemical compound CCS(=O)(=O)C1=CC=C(OC)C(NC=2N=C(C=CN=2)N(C)C2=CC3=NNC(C)=C3C=C2)=C1 VTXJRGSOKKDRGH-UHFFFAOYSA-N 0.000 claims 1
• KFHRYSKELLEUHL-UHFFFAOYSA-N 2-n-[2-methoxy-5-(2-methylpropylsulfonyl)phenyl]-4-n-(3-methyl-2h-indazol-6-yl)pyrimidine-2,4-diamine Chemical compound COC1=CC=C(S(=O)(=O)CC(C)C)C=C1NC1=NC=CC(NC=2C=C3NN=C(C)C3=CC=2)=N1 KFHRYSKELLEUHL-UHFFFAOYSA-N 0.000 claims 1
• QDVXRMFTKAQZOJ-UHFFFAOYSA-N 4-n-(1,3-dimethylindazol-6-yl)-4-n-methyl-2-n-[3-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NN(C)C2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 QDVXRMFTKAQZOJ-UHFFFAOYSA-N 0.000 claims 1
• MQQRHGLRDSKDKI-UHFFFAOYSA-N 4-n-(1h-indazol-6-yl)-4-n-methyl-2-n-[3-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C=1C=C2C=NNC2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 MQQRHGLRDSKDKI-UHFFFAOYSA-N 0.000 claims 1
• CMYGIORLGUFXRP-UHFFFAOYSA-N 4-n-(2,3-dimethylindazol-6-yl)-2-n-(5-ethylsulfonyl-2-methoxyphenyl)-4-n-methylpyrimidine-2,4-diamine Chemical compound CCS(=O)(=O)C1=CC=C(OC)C(NC=2N=C(C=CN=2)N(C)C2=CC3=NN(C)C(C)=C3C=C2)=C1 CMYGIORLGUFXRP-UHFFFAOYSA-N 0.000 claims 1
• OKMPHEGFRRVGRS-UHFFFAOYSA-N 4-n-(2,3-dimethylindazol-6-yl)-4-n-methyl-2-n-[3-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 OKMPHEGFRRVGRS-UHFFFAOYSA-N 0.000 claims 1
• KXBDNZQPXYWKNP-UHFFFAOYSA-N 4-n-(2,3-dimethylindazol-6-yl)-4-n-methyl-2-n-[4-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(CS(C)(=O)=O)C=C1 KXBDNZQPXYWKNP-UHFFFAOYSA-N 0.000 claims 1
• ZDDUYAXPVKACHH-UHFFFAOYSA-N 4-n-ethynyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-[3-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C#C)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 ZDDUYAXPVKACHH-UHFFFAOYSA-N 0.000 claims 1
• RMDKFQYENKBLIS-UHFFFAOYSA-N 4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-(3-methylsulfinylphenyl)pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(S(C)=O)=C1 RMDKFQYENKBLIS-UHFFFAOYSA-N 0.000 claims 1
• HVTDKMBYNAHFSS-UHFFFAOYSA-N 4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-(3-methylsulfonylphenyl)pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(S(C)(=O)=O)=C1 HVTDKMBYNAHFSS-UHFFFAOYSA-N 0.000 claims 1
• AJJWFOBQWWYSKG-UHFFFAOYSA-N 4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-[3-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 AJJWFOBQWWYSKG-UHFFFAOYSA-N 0.000 claims 1
• VHICZWHVIFZTFD-UHFFFAOYSA-N 4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-[3-(propan-2-ylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound CC(C)S(=O)(=O)CC1=CC=CC(NC=2N=C(C=CN=2)N(C)C=2C=C3NN=C(C)C3=CC=2)=C1 VHICZWHVIFZTFD-UHFFFAOYSA-N 0.000 claims 1
• NTOREKWHRRSTTO-UHFFFAOYSA-N 4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-[4-(propan-2-ylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C1=CC(CS(=O)(=O)C(C)C)=CC=C1NC1=NC=CC(N(C)C=2C=C3NN=C(C)C3=CC=2)=N1 NTOREKWHRRSTTO-UHFFFAOYSA-N 0.000 claims 1
• YDHRSWAPJJCSGX-UHFFFAOYSA-N n-[3-[[4-[ethyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]phenyl]acetamide Chemical compound C=1C=C2C(C)=NNC2=CC=1N(CC)C(N=1)=CC=NC=1NC1=CC=CC(NC(C)=O)=C1 YDHRSWAPJJCSGX-UHFFFAOYSA-N 0.000 claims 1
• AXBKRLMNVZOBIH-UHFFFAOYSA-N n-[3-[[4-[methyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]phenyl]acetamide Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(NC(C)=O)=C1 AXBKRLMNVZOBIH-UHFFFAOYSA-N 0.000 claims 1
• RBENAORRCGKTLF-UHFFFAOYSA-N n-[3-[[4-[methyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]phenyl]methanesulfonamide Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(NS(C)(=O)=O)=C1 RBENAORRCGKTLF-UHFFFAOYSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 41
• 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 abstract description 5
• 150000003230 pyrimidines Chemical class 0.000 abstract description 5
• 229940091171 VEGFR-2 tyrosine kinase inhibitor Drugs 0.000 abstract 1
• 230000003463 hyperproliferative effect Effects 0.000 abstract 1
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 104
• 238000001819 mass spectrum Methods 0.000 description 92
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 61
• 239000000203 mixture Substances 0.000 description 57
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 52
• 239000000243 solution Substances 0.000 description 52
• 239000000543 intermediate Substances 0.000 description 49
• 235000002639 sodium chloride Nutrition 0.000 description 49
• 239000007787 solid Substances 0.000 description 40
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• 238000006243 chemical reaction Methods 0.000 description 33
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
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• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 20
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• 239000000047 product Substances 0.000 description 18
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• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 125000003118 aryl group Chemical group 0.000 description 15
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• WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 10
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