ES2239779T3 - Derivados de pirimidina y procedimientos para la preparacion de los mismos. - Google Patents
Derivados de pirimidina y procedimientos para la preparacion de los mismos.Info
- Publication number
- ES2239779T3 ES2239779T3 ES97911163T ES97911163T ES2239779T3 ES 2239779 T3 ES2239779 T3 ES 2239779T3 ES 97911163 T ES97911163 T ES 97911163T ES 97911163 T ES97911163 T ES 97911163T ES 2239779 T3 ES2239779 T3 ES 2239779T3
- Authority
- ES
- Spain
- Prior art keywords
- amino
- phenylamino
- mmol
- pyrazolo
- pyrimidine
- 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
Links
- 238000000034 method Methods 0.000 title claims description 38
- 238000002360 preparation method Methods 0.000 title claims description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- LHCPRYRLDOSKHK-UHFFFAOYSA-N 7-deaza-8-aza-adenine Chemical class NC1=NC=NC2=C1C=NN2 LHCPRYRLDOSKHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- -1 cyano, amino Chemical group 0.000 claims description 155
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 150000003839 salts Chemical class 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- 125000001589 carboacyl group Chemical group 0.000 claims description 36
- 150000003254 radicals Chemical class 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 229910052717 sulfur Chemical group 0.000 claims description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 239000011593 sulfur Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- QPOFLULXCIQXNC-UHFFFAOYSA-N 4-n-(3-chlorophenyl)-3-n-methyl-3-n-pyridin-4-yl-1h-pyrazolo[3,4-d]pyrimidine-3,4-diamine Chemical compound C=1C=NC=CC=1N(C)C(C=12)=NNC2=NC=NC=1NC1=CC=CC(Cl)=C1 QPOFLULXCIQXNC-UHFFFAOYSA-N 0.000 claims description 2
- UWCMSAAJPUQSML-UHFFFAOYSA-N 4-n-(3-chlorophenyl)-3-n-pyridin-3-yl-2h-pyrazolo[3,4-d]pyrimidine-3,4-diamine Chemical compound ClC1=CC=CC(NC=2C3=C(NC=4C=NC=CC=4)NN=C3N=CN=2)=C1 UWCMSAAJPUQSML-UHFFFAOYSA-N 0.000 claims description 2
- UWXBALRSGLYKKX-UHFFFAOYSA-N [4-[[4-(3-chloroanilino)-2h-pyrazolo[3,4-d]pyrimidin-3-yl]amino]phenyl]methylurea Chemical compound C1=CC(CNC(=O)N)=CC=C1NC1=C2C(NC=3C=C(Cl)C=CC=3)=NC=NC2=NN1 UWXBALRSGLYKKX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000002512 chemotherapy Methods 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- OXNGKCPRVRBHPO-XLMUYGLTSA-N alpha-L-Fucp-(1->2)-beta-D-Galp-(1->3)-[alpha-L-Fucp-(1->4)]-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](CO)O[C@@H](O)[C@@H]2NC(C)=O)O[C@H]2[C@H]([C@H](O)[C@H](O)[C@H](C)O2)O)O[C@H](CO)[C@H](O)[C@@H]1O OXNGKCPRVRBHPO-XLMUYGLTSA-N 0.000 claims 1
- 230000008707 rearrangement Effects 0.000 claims 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 10
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 10
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 abstract description 6
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 102000020233 phosphotransferase Human genes 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 364
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 201
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 186
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 174
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 155
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 127
- 239000000203 mixture Substances 0.000 description 119
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 101
- 238000001914 filtration Methods 0.000 description 101
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 90
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 86
- 238000001704 evaporation Methods 0.000 description 81
- 230000008020 evaporation Effects 0.000 description 81
- 239000000243 solution Substances 0.000 description 74
- 238000004128 high performance liquid chromatography Methods 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 65
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 63
- WVRNRMIYOAEDJT-UHFFFAOYSA-N 4-n-(3-chlorophenyl)-2h-pyrazolo[3,4-d]pyrimidine-3,4-diamine Chemical compound C=12C(N)=NNC2=NC=NC=1NC1=CC=CC(Cl)=C1 WVRNRMIYOAEDJT-UHFFFAOYSA-N 0.000 description 58
- 238000006243 chemical reaction Methods 0.000 description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 55
- 238000003756 stirring Methods 0.000 description 55
- 229960000583 acetic acid Drugs 0.000 description 52
- 239000002253 acid Substances 0.000 description 45
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 44
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 39
- 238000005406 washing Methods 0.000 description 39
- 235000002639 sodium chloride Nutrition 0.000 description 38
- 239000007858 starting material Substances 0.000 description 38
- 238000010992 reflux Methods 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 28
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- 238000001816 cooling Methods 0.000 description 26
- 239000000725 suspension Substances 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000009835 boiling Methods 0.000 description 24
- 238000007792 addition Methods 0.000 description 23
- 239000012267 brine Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 230000007717 exclusion Effects 0.000 description 22
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
- 238000002425 crystallisation Methods 0.000 description 19
- 230000008025 crystallization Effects 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 230000009467 reduction Effects 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- 238000001953 recrystallisation Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 230000029087 digestion Effects 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- XJDQSAYWBRBWSM-UHFFFAOYSA-N 3-n-[4-(aminomethyl)phenyl]-4-n-(3-chlorophenyl)-2h-pyrazolo[3,4-d]pyrimidine-3,4-diamine Chemical compound C1=CC(CN)=CC=C1NC1=C2C(NC=3C=C(Cl)C=CC=3)=NC=NC2=NN1 XJDQSAYWBRBWSM-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000013543 active substance Substances 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 11
- 235000008504 concentrate Nutrition 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 235000012239 silicon dioxide Nutrition 0.000 description 11
- BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical compound CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- 229910052681 coesite Inorganic materials 0.000 description 10
- 229910052906 cristobalite Inorganic materials 0.000 description 10
- 239000013067 intermediate product Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- 229910052682 stishovite Inorganic materials 0.000 description 10
- 229910052905 tridymite Inorganic materials 0.000 description 10
- FICQFRCPSFCFBY-UHFFFAOYSA-N 2-[bis(methylsulfanyl)methylidene]propanedinitrile Chemical compound CSC(SC)=C(C#N)C#N FICQFRCPSFCFBY-UHFFFAOYSA-N 0.000 description 9
- FKOVCGDDQULJSS-UHFFFAOYSA-N 3-n-[3-(aminomethyl)phenyl]-4-n-(3-chlorophenyl)-2h-pyrazolo[3,4-d]pyrimidine-3,4-diamine Chemical compound NCC1=CC=CC(NC2=C3C(NC=4C=C(Cl)C=CC=4)=NC=NC3=NN2)=C1 FKOVCGDDQULJSS-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 238000013019 agitation Methods 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
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- 150000002148 esters Chemical class 0.000 description 8
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 7
- NMGHWHCTRGZZOP-UHFFFAOYSA-N 3-chloroaniline;hydron;chloride Chemical compound Cl.NC1=CC=CC(Cl)=C1 NMGHWHCTRGZZOP-UHFFFAOYSA-N 0.000 description 7
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
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- 229920001223 polyethylene glycol Polymers 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 6
- 102000001253 Protein Kinase Human genes 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
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- 238000010438 heat treatment Methods 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 108060006633 protein kinase Proteins 0.000 description 6
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
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- FCXFJTBDSHWNQI-UHFFFAOYSA-N tert-butyl n-[3-[[4-(3-chloroanilino)-1h-pyrazolo[3,4-d]pyrimidin-3-yl]amino]propyl]carbamate Chemical compound C=12C(NCCCNC(=O)OC(C)(C)C)=NNC2=NC=NC=1NC1=CC=CC(Cl)=C1 FCXFJTBDSHWNQI-UHFFFAOYSA-N 0.000 description 1
- NNMGBPICEFOJCR-UHFFFAOYSA-N tert-butyl n-[4-[[4-(3-chloroanilino)-1h-pyrazolo[3,4-d]pyrimidin-3-yl]amino]butyl]carbamate Chemical compound C=12C(NCCCCNC(=O)OC(C)(C)C)=NNC2=NC=NC=1NC1=CC=CC(Cl)=C1 NNMGBPICEFOJCR-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
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- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Compounds Of Unknown Constitution (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2399/96 | 1996-10-02 | ||
| CH239996 | 1996-10-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2239779T3 true ES2239779T3 (es) | 2005-10-01 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES97911163T Expired - Lifetime ES2239779T3 (es) | 1996-10-02 | 1997-09-30 | Derivados de pirimidina y procedimientos para la preparacion de los mismos. |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US6251911B1 (enExample) |
| EP (1) | EP0929553B1 (enExample) |
| JP (1) | JP4205168B2 (enExample) |
| AT (1) | ATE291022T1 (enExample) |
| AU (1) | AU720135B2 (enExample) |
| CA (1) | CA2266519C (enExample) |
| DE (1) | DE69732780T2 (enExample) |
| ES (1) | ES2239779T3 (enExample) |
| WO (1) | WO1998014450A1 (enExample) |
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| AU711592B2 (en) * | 1995-04-03 | 1999-10-14 | Novartis Ag | Pyrazole derivatives and processes for the preparation thereof |
| ES2297864T3 (es) | 1996-08-23 | 2008-05-01 | Novartis Ag | Pirrolopirimidinas sustituidas y procesos para su preparacion. |
| EP1017823B1 (en) | 1997-02-07 | 2004-07-14 | Princeton University | Engineered protein kinases which can utilize modified nucleotide triphosphate substrates |
| EP1159273A1 (en) | 1999-03-02 | 2001-12-05 | Boehringer Ingelheim Pharmaceuticals Inc. | Compounds useful as reversible inhibitors of cathepsin s |
| US6440959B1 (en) | 1999-04-21 | 2002-08-27 | Hoffman-La Roche Inc. | Pyrazolobenzodiazepines |
| US6610483B1 (en) * | 1999-07-23 | 2003-08-26 | Princeton University | Methods for identifying cellular responses attributable to signaling molecule inhibition and inhibitors thereof |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| US6660731B2 (en) | 2000-09-15 | 2003-12-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| ATE346064T1 (de) * | 2000-09-15 | 2006-12-15 | Vertex Pharma | Pyrazolverbindungen als protein-kinasehemmer |
| RU2340611C2 (ru) * | 2000-09-15 | 2008-12-10 | Вертекс Фармасьютикалз Инкорпорейтед | Производные пиразола, используемые в качестве ингибиторов протеинкиназы |
| EP1698627A1 (en) * | 2000-09-15 | 2006-09-06 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| US7473691B2 (en) | 2000-09-15 | 2009-01-06 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| US6613776B2 (en) | 2000-09-15 | 2003-09-02 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| ATE354573T1 (de) | 2000-12-21 | 2007-03-15 | Vertex Pharma | ßPYRAZOLVERBINDUNGEN, DIE SICH ALS PROTEINKINASEINHIBITOREN EIGNENß |
| US6593349B2 (en) | 2001-03-19 | 2003-07-15 | Icagen, Inc. | Bisarylamines as potassium channel openers |
| US20050119251A1 (en) * | 2001-12-21 | 2005-06-02 | Jian-Min Fu | Nicotinamide derivatives and their use as therapeutic agents |
| MY141867A (en) | 2002-06-20 | 2010-07-16 | Vertex Pharma | Substituted pyrimidines useful as protein kinase inhibitors |
| CA2494061C (en) * | 2002-07-31 | 2011-06-14 | Wayne R. Danter | Protein tyrosine kinase inhibitors |
| CN1319968C (zh) | 2002-08-02 | 2007-06-06 | 沃泰克斯药物股份有限公司 | 用作gsk－3的抑制剂的吡唑组合物 |
| WO2004033446A1 (en) * | 2002-10-09 | 2004-04-22 | Danter Wayne R | Protein tyrosine kinase inhibitors |
| US8362017B2 (en) | 2003-08-29 | 2013-01-29 | Exelixis, Inc. | C-kit modulators and methods of use |
| US20050187389A1 (en) * | 2004-01-13 | 2005-08-25 | Ambit Biosciences Corporation | Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases |
| MX2007003319A (es) | 2004-09-20 | 2007-06-05 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como agentes terapeuticos. |
| BRPI0515477A (pt) * | 2004-09-20 | 2008-07-22 | Xenon Pharmaceuticals Inc | derivados heterocìclicos bicìclicos e o uso dos mesmos como inibidores de estaroil-coa-desaturase (scd) |
| CA2580857A1 (en) | 2004-09-20 | 2006-09-28 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| TW200626138A (en) | 2004-09-20 | 2006-08-01 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives and their use as therapeutic agents |
| CA2580855A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| MX2007003318A (es) | 2004-09-20 | 2007-05-18 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como agentes terapeuticos. |
| US8071603B2 (en) | 2004-09-20 | 2011-12-06 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
| CN101084212A (zh) | 2004-09-20 | 2007-12-05 | 泽农医药公司 | 杂环衍生物及其作为硬脂酰CoA去饱和酶介导剂的用途 |
| BRPI0518286A2 (pt) * | 2004-11-18 | 2008-11-11 | Bristol Myers Squibb Co | microesfera com revestimento entÉrico contendo ixabepilona e sua preparaÇço |
| JP2008520744A (ja) * | 2004-11-19 | 2008-06-19 | ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア | 抗炎症性ピラゾロピリミジン |
| US7947676B2 (en) | 2004-12-14 | 2011-05-24 | Astrazeneca Ab | Pyrazolo[3,4-d]pyrimidine compounds as antitumor agents |
| EP2029138A1 (en) | 2005-06-03 | 2009-03-04 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
| JP5249770B2 (ja) | 2005-11-03 | 2013-07-31 | バーテックス ファーマシューティカルズ インコーポレイテッド | キナーゼインヒビターとして有用なアミノピリジン |
| JP2009529047A (ja) * | 2006-03-07 | 2009-08-13 | アレイ バイオファーマ、インコーポレイテッド | ヘテロ二環系ピラゾール化合物およびその使用 |
| WO2008033745A2 (en) * | 2006-09-11 | 2008-03-20 | Curis, Inc. | Fused bicyclic pyrimidines as ptk inhibitors containing a zinc binding moiety |
| WO2008033747A2 (en) * | 2006-09-11 | 2008-03-20 | Curis, Inc. | Multi-functional small molecules as anti-proliferative agents |
| US20100298557A1 (en) * | 2006-12-28 | 2010-11-25 | Taisho Pharmaceutical Co., Ltd | Pyrazolopyrimidine compound |
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| EP2120558B1 (de) * | 2007-03-12 | 2016-02-10 | Bayer Intellectual Property GmbH | 3,4-Disubstituierte Phenoxyphenylamidin-Derivate und deren Verwendung als Fungizide |
| EP1969932A1 (de) * | 2007-03-12 | 2008-09-17 | Bayer CropScience AG | Phenoxyphenylamidine und deren Verwendung als Fungizide |
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| BRPI0808846A2 (pt) | 2007-03-12 | 2019-09-24 | Bayer Cropscience Ag | fenoxifenilamidinas 3-substituídas e seu uso como fungicidas |
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| AU2008282156B2 (en) | 2007-07-31 | 2014-07-17 | Vertex Pharmaceuticals Incorporated | Process for preparing 5-fluoro-1H-pyrazolo [3, 4-b] pyridin-3-amine and derivatives thereof |
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- 1997-09-30 CA CA002266519A patent/CA2266519C/en not_active Expired - Fee Related
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- 1997-09-30 DE DE69732780T patent/DE69732780T2/de not_active Expired - Lifetime
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- 1997-09-30 WO PCT/EP1997/005369 patent/WO1998014450A1/en not_active Ceased
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| JP2001501216A (ja) | 2001-01-30 |
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| WO1998014450A1 (en) | 1998-04-09 |
| DE69732780T2 (de) | 2006-04-06 |
| US6251911B1 (en) | 2001-06-26 |
| CA2266519C (en) | 2007-01-23 |
| EP0929553B1 (en) | 2005-03-16 |
| DE69732780D1 (de) | 2005-04-21 |
| ATE291022T1 (de) | 2005-04-15 |
| CA2266519A1 (en) | 1998-04-09 |
| AU720135B2 (en) | 2000-05-25 |
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