JP4658477B2 - 2,4−ピリミジンジアミン化合物とその用途 - Google Patents
2,4−ピリミジンジアミン化合物とその用途 Download PDFInfo
- Publication number
- JP4658477B2 JP4658477B2 JP2003563490A JP2003563490A JP4658477B2 JP 4658477 B2 JP4658477 B2 JP 4658477B2 JP 2003563490 A JP2003563490 A JP 2003563490A JP 2003563490 A JP2003563490 A JP 2003563490A JP 4658477 B2 JP4658477 B2 JP 4658477B2
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- fluoro
- pyrimidinamine
- compounds
- dichloro
- 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.)
- Expired - Lifetime
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- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 title abstract description 87
- 150000001875 compounds Chemical class 0.000 claims abstract description 205
- -1 alkane sulfonate Chemical class 0.000 claims description 293
- TVKGTSHBQZEFEE-UHFFFAOYSA-N 3-[[5-fluoro-2-(3-hydroxyanilino)pyrimidin-4-yl]amino]phenol Chemical compound OC1=CC=CC(NC=2N=C(NC=3C=C(O)C=CC=3)C(F)=CN=2)=C1 TVKGTSHBQZEFEE-UHFFFAOYSA-N 0.000 claims description 107
- 239000000203 mixture Substances 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 23
- 150000004677 hydrates Chemical class 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims 2
- AJKPUNIYEMWTIL-UHFFFAOYSA-N 2-[5-[[4-[(2,2-difluoro-3-oxo-4H-1,4-benzoxazin-6-yl)amino]-5-fluoropyrimidin-2-yl]amino]-2-methylcyclohexa-1,5-dien-1-yl]oxy-N-methylacetamide Chemical compound CNC(=O)COC1=C(C)CCC(Nc2ncc(F)c(Nc3ccc4OC(F)(F)C(=O)Nc4c3)n2)=C1 AJKPUNIYEMWTIL-UHFFFAOYSA-N 0.000 claims 1
- 230000019491 signal transduction Effects 0.000 abstract description 82
- 108010073816 IgE Receptors Proteins 0.000 abstract description 66
- 102000009438 IgE Receptors Human genes 0.000 abstract description 66
- 238000000034 method Methods 0.000 abstract description 59
- 239000000126 substance Substances 0.000 abstract description 28
- 230000004913 activation Effects 0.000 abstract description 24
- 238000011282 treatment Methods 0.000 abstract description 18
- 239000000543 intermediate Substances 0.000 abstract description 17
- 108010073807 IgG Receptors Proteins 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 8
- 230000006806 disease prevention Effects 0.000 abstract description 7
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 102000009490 IgG Receptors Human genes 0.000 abstract 2
- 238000005481 NMR spectroscopy Methods 0.000 description 314
- 230000015572 biosynthetic process Effects 0.000 description 287
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 193
- 230000014759 maintenance of location Effects 0.000 description 175
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
- 238000006243 chemical reaction Methods 0.000 description 112
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 104
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 85
- 229940002612 prodrug Drugs 0.000 description 67
- 239000000651 prodrug Substances 0.000 description 67
- 125000001424 substituent group Chemical group 0.000 description 60
- ASRXSKWXNLKLKX-UHFFFAOYSA-N 2-chloro-n-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-fluoropyrimidin-4-amine Chemical compound FC1=CN=C(Cl)N=C1NC1=CC=C(OCCO2)C2=C1 ASRXSKWXNLKLKX-UHFFFAOYSA-N 0.000 description 58
- 229910052739 hydrogen Inorganic materials 0.000 description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 102000000551 Syk Kinase Human genes 0.000 description 57
- 108010016672 Syk Kinase Proteins 0.000 description 57
- 210000004027 cell Anatomy 0.000 description 56
- 239000001257 hydrogen Substances 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 50
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- 238000003786 synthesis reaction Methods 0.000 description 46
- 125000003118 aryl group Chemical group 0.000 description 44
- 125000001072 heteroaryl group Chemical group 0.000 description 44
- 239000000243 solution Substances 0.000 description 41
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical group [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 40
- 150000001412 amines Chemical class 0.000 description 39
- 239000007787 solid Substances 0.000 description 38
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 34
- 102000009109 Fc receptors Human genes 0.000 description 33
- 108010087819 Fc receptors Proteins 0.000 description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 33
- 108060003951 Immunoglobulin Proteins 0.000 description 29
- 201000010099 disease Diseases 0.000 description 29
- 210000003630 histaminocyte Anatomy 0.000 description 29
- 102000018358 immunoglobulin Human genes 0.000 description 29
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 28
- 102000005962 receptors Human genes 0.000 description 28
- 108020003175 receptors Proteins 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 210000003651 basophil Anatomy 0.000 description 26
- 230000000694 effects Effects 0.000 description 26
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 26
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 24
- 125000000217 alkyl group Chemical group 0.000 description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 24
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 23
- 239000003814 drug Substances 0.000 description 23
- 238000004519 manufacturing process Methods 0.000 description 23
- 125000006239 protecting group Chemical group 0.000 description 23
- YUQKNSWHTQTFCN-UHFFFAOYSA-N 2-chloro-5-fluoro-n-[3-(2h-tetrazol-5-yl)phenyl]pyrimidin-4-amine Chemical compound FC1=CN=C(Cl)N=C1NC1=CC=CC(C=2NN=NN=2)=C1 YUQKNSWHTQTFCN-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 229910052799 carbon Inorganic materials 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
- 125000000524 functional group Chemical group 0.000 description 21
- 150000002431 hydrogen Chemical group 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 239000007858 starting material Substances 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 20
- 238000000338 in vitro Methods 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 229940079593 drug Drugs 0.000 description 19
- 239000008187 granular material Substances 0.000 description 19
- 125000005842 heteroatom Chemical group 0.000 description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 150000001204 N-oxides Chemical class 0.000 description 18
- 239000013566 allergen Substances 0.000 description 18
- 125000005699 methyleneoxy group Chemical group [H]C([H])([*:1])O[*:2] 0.000 description 18
- 150000001721 carbon Chemical group 0.000 description 16
- 229910052736 halogen Inorganic materials 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 206010020751 Hypersensitivity Diseases 0.000 description 15
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 15
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 15
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- 238000004132 cross linking Methods 0.000 description 14
- IBGBOGKPIMZRRU-UHFFFAOYSA-N ethyl 2-(4-aminophenoxy)acetate Chemical compound CCOC(=O)COC1=CC=C(N)C=C1 IBGBOGKPIMZRRU-UHFFFAOYSA-N 0.000 description 14
- 150000002367 halogens Chemical class 0.000 description 14
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- 230000000236 ionophoric effect Effects 0.000 description 14
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- GWNVDXQDILPJIG-SHSCPDMUSA-N Leukotriene C4 Natural products CCCCCC=C/CC=C/C=C/C=C/C(SCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O)C(O)CCCC(=O)O GWNVDXQDILPJIG-SHSCPDMUSA-N 0.000 description 13
- 125000003710 aryl alkyl group Chemical group 0.000 description 13
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- 125000005843 halogen group Chemical group 0.000 description 13
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- GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 102000004127 Cytokines Human genes 0.000 description 12
- 108090000695 Cytokines Proteins 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
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- 238000001727 in vivo Methods 0.000 description 12
- 125000005647 linker group Chemical group 0.000 description 12
- TZHVYWAFFGEGHM-UHFFFAOYSA-N methyl 5-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2-methoxybenzoate Chemical compound C1=C(OC)C(C(=O)OC)=CC(NC=2C(=CN=C(Cl)N=2)F)=C1 TZHVYWAFFGEGHM-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 11
- SIKXIUWKPGWBBF-UHFFFAOYSA-N 5-bromo-2,4-dichloropyrimidine Chemical compound ClC1=NC=C(Br)C(Cl)=N1 SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 11
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- ACYLYCBZBFXXCU-UHFFFAOYSA-N diethyl 2-methyl-2-(3-nitrophenoxy)propanedioate Chemical compound CCOC(=O)C(C)(C(=O)OCC)OC1=CC=CC([N+]([O-])=O)=C1 ACYLYCBZBFXXCU-UHFFFAOYSA-N 0.000 description 11
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- SRJBDGLSCPDXBL-UHFFFAOYSA-N ethyl 2,4-dichloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)N=C1Cl SRJBDGLSCPDXBL-UHFFFAOYSA-N 0.000 description 11
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- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical group NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 9
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