CA2463989C - Pyrimidine derivatives, pharmaceutical compositions containing these compounds, the use thereof and process for the preparation thereof - Google Patents
Pyrimidine derivatives, pharmaceutical compositions containing these compounds, the use thereof and process for the preparation thereof Download PDFInfo
- Publication number
- CA2463989C CA2463989C CA2463989A CA2463989A CA2463989C CA 2463989 C CA2463989 C CA 2463989C CA 2463989 A CA2463989 A CA 2463989A CA 2463989 A CA2463989 A CA 2463989A CA 2463989 C CA2463989 C CA 2463989C
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- CA
- Canada
- Prior art keywords
- group
- alkyl
- substituted
- imino
- hydroxy
- 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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- 150000001875 compounds Chemical class 0.000 title claims abstract description 80
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 238000000034 method Methods 0.000 title abstract description 599
- 150000003230 pyrimidines Chemical class 0.000 title description 9
- 238000002360 preparation method Methods 0.000 title description 4
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 2
- -1 tri-substituted pyrimidines Chemical class 0.000 claims abstract description 766
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 230000004663 cell proliferation Effects 0.000 claims abstract description 8
- 230000002159 abnormal effect Effects 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 282
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 138
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 137
- 125000003545 alkoxy group Chemical group 0.000 claims description 134
- 125000003118 aryl group Chemical group 0.000 claims description 130
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 114
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 111
- 125000004432 carbon atom Chemical group C* 0.000 claims description 103
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 99
- 229910052760 oxygen Inorganic materials 0.000 claims description 99
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 96
- 125000003282 alkyl amino group Chemical group 0.000 claims description 96
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 95
- 239000001301 oxygen Substances 0.000 claims description 95
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 92
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 86
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 84
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 84
- 229910052801 chlorine Inorganic materials 0.000 claims description 78
- 239000000460 chlorine Substances 0.000 claims description 74
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 73
- 229910052731 fluorine Inorganic materials 0.000 claims description 71
- 239000011737 fluorine Substances 0.000 claims description 71
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 69
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 65
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 64
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 62
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 61
- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 56
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 52
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 50
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 47
- 229910052794 bromium Inorganic materials 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 42
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 40
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 37
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 36
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 35
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 35
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 34
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 33
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 32
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 30
- 125000004104 aryloxy group Chemical group 0.000 claims description 30
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 27
- 125000002947 alkylene group Chemical group 0.000 claims description 27
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 24
- 150000001721 carbon Chemical group 0.000 claims description 23
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 22
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 18
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 18
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 16
- 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 16
- 125000004429 atom Chemical group 0.000 claims description 15
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000005126 aryl alkyl carbonyl amino group Chemical group 0.000 claims description 14
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 12
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims description 10
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 10
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 10
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 10
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 8
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 8
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 6
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 6
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
- 125000001769 aryl amino group Chemical group 0.000 claims description 6
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 6
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 6
- 125000004984 dialkylaminoalkoxy group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000005184 naphthylamino group Chemical group C1(=CC=CC2=CC=CC=C12)N* 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 5
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 4
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 4
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 4
- 125000004537 indazol-5-yl group Chemical group N1N=CC2=CC(=CC=C12)* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical group C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000004992 haloalkylamino group Chemical group 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 3
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Chemical group 0.000 claims 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 1
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims 1
- HJGMRAKQWLKWMH-UHFFFAOYSA-N 8-methyl-8-azabicyclo[3.2.1]octan-3-amine Chemical compound C1C(N)CC2CCC1N2C HJGMRAKQWLKWMH-UHFFFAOYSA-N 0.000 claims 1
- 229920001774 Perfluoroether Polymers 0.000 claims 1
- 125000005096 aminoalkylaminocarbonyl group Chemical group 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 563
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 164
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 131
- 238000002844 melting Methods 0.000 description 75
- 230000008018 melting Effects 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 60
- 239000000741 silica gel Substances 0.000 description 57
- 229910002027 silica gel Inorganic materials 0.000 description 57
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000000047 product Substances 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
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- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
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- 229960003087 tioguanine Drugs 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
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- 230000009385 viral infection Effects 0.000 description 1
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Classifications
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| US60/330,145 | 2001-10-17 | ||
| PCT/EP2002/011453 WO2003032997A1 (de) | 2001-10-17 | 2002-10-14 | Pyrimidinderivate, arzneimittel enthaltend diese verbindungen, deren verwendung und verfahren zu ihrer herstellung |
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| CA2463989A1 CA2463989A1 (en) | 2003-04-24 |
| CA2463989C true CA2463989C (en) | 2012-01-31 |
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| CA2463989A Expired - Lifetime CA2463989C (en) | 2001-10-17 | 2002-10-14 | Pyrimidine derivatives, pharmaceutical compositions containing these compounds, the use thereof and process for the preparation thereof |
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| UY (1) | UY27487A1 (cg-RX-API-DMAC7.html) |
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| US8815848B2 (en) | 2005-06-08 | 2014-08-26 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the JAK pathway |
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-
2002
- 2002-10-14 EP EP10178604A patent/EP2332924A1/de not_active Withdrawn
- 2002-10-14 DK DK02774710T patent/DK1438053T3/da active
- 2002-10-14 EP EP02774710A patent/EP1438053B1/de not_active Expired - Lifetime
- 2002-10-14 DE DE50212771T patent/DE50212771D1/de not_active Expired - Lifetime
- 2002-10-14 PT PT02774710T patent/PT1438053E/pt unknown
- 2002-10-14 EP EP08163784A patent/EP2090571B1/de not_active Expired - Lifetime
- 2002-10-14 ES ES02774710T patent/ES2314106T3/es not_active Expired - Lifetime
- 2002-10-14 JP JP2003535800A patent/JP4460292B2/ja not_active Expired - Lifetime
- 2002-10-14 CA CA2463989A patent/CA2463989C/en not_active Expired - Lifetime
- 2002-10-14 UY UY27487A patent/UY27487A1/es not_active Application Discontinuation
- 2002-10-14 WO PCT/EP2002/011453 patent/WO2003032997A1/de not_active Ceased
- 2002-10-14 AT AT02774710T patent/ATE407678T1/de active
- 2002-10-16 US US10/271,763 patent/US7173028B2/en not_active Expired - Lifetime
-
2005
- 2005-12-21 US US11/313,380 patent/US7709480B2/en not_active Expired - Lifetime
-
2008
- 2008-12-02 CY CY20081101391T patent/CY1110442T1/el unknown
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- 2010-02-24 US US12/711,364 patent/US8420630B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8815848B2 (en) | 2005-06-08 | 2014-08-26 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the JAK pathway |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2463989A1 (en) | 2003-04-24 |
| JP2005509624A (ja) | 2005-04-14 |
| US7709480B2 (en) | 2010-05-04 |
| EP1438053B1 (de) | 2008-09-10 |
| UY27487A1 (es) | 2003-05-30 |
| ES2314106T3 (es) | 2009-03-16 |
| US20030171359A1 (en) | 2003-09-11 |
| US20100152167A1 (en) | 2010-06-17 |
| EP2332924A1 (de) | 2011-06-15 |
| US20060100211A1 (en) | 2006-05-11 |
| JP4460292B2 (ja) | 2010-05-12 |
| DK1438053T3 (da) | 2008-12-08 |
| ATE407678T1 (de) | 2008-09-15 |
| US7173028B2 (en) | 2007-02-06 |
| PT1438053E (pt) | 2008-09-25 |
| EP2090571B1 (de) | 2012-05-16 |
| EP2090571A1 (de) | 2009-08-19 |
| EP1438053A1 (de) | 2004-07-21 |
| US8420630B2 (en) | 2013-04-16 |
| CY1110442T1 (el) | 2015-04-29 |
| DE50212771D1 (de) | 2008-10-23 |
| WO2003032997A1 (de) | 2003-04-24 |
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