MX2007002254A - Derivados de pirimidina. - Google Patents
Derivados de pirimidina.Info
- Publication number
- MX2007002254A MX2007002254A MX2007002254A MX2007002254A MX2007002254A MX 2007002254 A MX2007002254 A MX 2007002254A MX 2007002254 A MX2007002254 A MX 2007002254A MX 2007002254 A MX2007002254 A MX 2007002254A MX 2007002254 A MX2007002254 A MX 2007002254A
- Authority
- MX
- Mexico
- Prior art keywords
- amino
- methoxy
- methyl
- phenyl
- chloro
- Prior art date
Links
- 150000003230 pyrimidines Chemical class 0.000 title abstract description 4
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 6
- -1 2-morpholin-4-yl-ethoxy Chemical group 0.000 claims description 298
- 125000004432 carbon atom Chemical group C* 0.000 claims description 190
- 150000001875 compounds Chemical class 0.000 claims description 118
- 125000000217 alkyl group Chemical group 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 69
- 239000001257 hydrogen Substances 0.000 claims description 68
- 125000000623 heterocyclic group Chemical group 0.000 claims description 55
- 229940124530 sulfonamide Drugs 0.000 claims description 50
- 229910052799 carbon Inorganic materials 0.000 claims description 47
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 37
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 125000006413 ring segment Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 239000004480 active ingredient Substances 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 15
- 230000005764 inhibitory process Effects 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 150000002367 halogens Chemical group 0.000 claims description 13
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 10
- 241001024304 Mino Species 0.000 claims description 10
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 9
- 230000001613 neoplastic effect Effects 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 7
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 210000000987 immune system Anatomy 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 229940088679 drug related substance Drugs 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 230000002062 proliferating effect Effects 0.000 claims description 5
- ZRZOYHQAGNRVDV-UHFFFAOYSA-N ClC=1C(=NC(=NC1)NC1=C(C=C(C=C1)N1CC(CCC1)(C(=O)O)C)OC)NC1=C2C(N(CC2=CC=C1)C)=O Chemical compound ClC=1C(=NC(=NC1)NC1=C(C=C(C=C1)N1CC(CCC1)(C(=O)O)C)OC)NC1=C2C(N(CC2=CC=C1)C)=O ZRZOYHQAGNRVDV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- QNZSRUNDCIMEQW-UHFFFAOYSA-N 1-[4-[[5-chloro-4-[(2-methyl-3-oxo-1h-isoindol-4-yl)amino]pyrimidin-2-yl]amino]-3-methoxyphenyl]-3-methylpiperidine-3-carboxamide Chemical compound C=1C=C(NC=2N=C(NC=3C=4C(=O)N(C)CC=4C=CC=3)C(Cl)=CN=2)C(OC)=CC=1N1CCCC(C)(C(N)=O)C1 QNZSRUNDCIMEQW-UHFFFAOYSA-N 0.000 claims description 3
- VBOFRRPQWRDUBS-UHFFFAOYSA-N 2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-5-(4-hydroxypiperidin-1-yl)-n-methylbenzamide Chemical compound CNC(=O)C1=CC(N2CCC(O)CC2)=CC=C1NC(C(=CN=1)Cl)=NC=1NC(C(=C1)OC)=CC=C1N1CCOCC1 VBOFRRPQWRDUBS-UHFFFAOYSA-N 0.000 claims description 3
- BJSYJIMZQJENEB-UHFFFAOYSA-N 2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-n-(2,2-dimethylpropyl)benzenesulfonamide Chemical compound COC1=CC(N2CCOCC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1S(=O)(=O)NCC(C)(C)C BJSYJIMZQJENEB-UHFFFAOYSA-N 0.000 claims description 3
- JSWCGIVZNHQNNP-UHFFFAOYSA-N 2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)oxyanilino]pyrimidin-4-yl]amino]-n-(2-methylpropyl)benzenesulfonamide Chemical compound C=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)NCC(C)C)C(Cl)=CN=2)C(OC)=CC=1OC1CCN(C)CC1 JSWCGIVZNHQNNP-UHFFFAOYSA-N 0.000 claims description 3
- BYLQQUZTDRWOLF-UHFFFAOYSA-N 5-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1C1=CN=C(N)N=C1N BYLQQUZTDRWOLF-UHFFFAOYSA-N 0.000 claims description 3
- 208000037765 diseases and disorders Diseases 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 230000002611 ovarian Effects 0.000 claims description 3
- 210000002307 prostate Anatomy 0.000 claims description 3
- 210000001685 thyroid gland Anatomy 0.000 claims description 3
- YBQXFJXKEHAULY-UHFFFAOYSA-N 2-[[5-bromo-2-(2-methoxy-5-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-n-propan-2-ylbenzenesulfonamide Chemical compound COC1=CC=C(N2CCOCC2)C=C1NC(N=1)=NC=C(Br)C=1NC1=CC=CC=C1S(=O)(=O)NC(C)C YBQXFJXKEHAULY-UHFFFAOYSA-N 0.000 claims description 2
- DPNOHAJQDSAHNP-UHFFFAOYSA-N 2-[[5-chloro-2-(2-methoxy-5-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-5-(4-hydroxypiperidin-1-yl)-n-methylbenzamide Chemical compound CNC(=O)C1=CC(N2CCC(O)CC2)=CC=C1NC(C(=CN=1)Cl)=NC=1NC(C(=CC=1)OC)=CC=1N1CCOCC1 DPNOHAJQDSAHNP-UHFFFAOYSA-N 0.000 claims description 2
- HIIUXPYHIPMBLF-UHFFFAOYSA-N 2-[[5-chloro-2-(2-methoxy-5-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-n-methyl-5-(4-methylpiperazin-1-yl)benzamide Chemical compound CNC(=O)C1=CC(N2CCN(C)CC2)=CC=C1NC(C(=CN=1)Cl)=NC=1NC(C(=CC=1)OC)=CC=1N1CCOCC1 HIIUXPYHIPMBLF-UHFFFAOYSA-N 0.000 claims description 2
- CCTCVOLEBOWMOS-UHFFFAOYSA-N 8-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-2-ethyl-3,4-dihydroisoquinolin-1-one Chemical compound C=12C(=O)N(CC)CCC2=CC=CC=1NC(C(=CN=1)Cl)=NC=1NC(C(=C1)OC)=CC=C1N1CCOCC1 CCTCVOLEBOWMOS-UHFFFAOYSA-N 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- XBJSNLHFYPKXLS-INIZCTEOSA-N 2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-n-[(2s)-2-hydroxypropyl]benzenesulfonamide Chemical compound COC1=CC(N2CCOCC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1S(=O)(=O)NC[C@H](C)O XBJSNLHFYPKXLS-INIZCTEOSA-N 0.000 claims 1
- PNRBKALNMAMFQZ-UHFFFAOYSA-N 2-[[5-chloro-2-[2-methoxy-4-(4-piperidin-1-ylpiperidin-1-yl)anilino]pyrimidin-4-yl]amino]-n-(2-methylpropyl)benzenesulfonamide Chemical compound COC1=CC(N2CCC(CC2)N2CCCCC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1S(=O)(=O)NCC(C)C PNRBKALNMAMFQZ-UHFFFAOYSA-N 0.000 claims 1
- SOMWMBIMDBWDCT-UHFFFAOYSA-N 2-[[5-chloro-2-[4-(4-hydroxypiperidin-1-yl)-2-methoxyanilino]pyrimidin-4-yl]amino]-n-(2-methylpropyl)benzenesulfonamide Chemical compound COC1=CC(N2CCC(O)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1S(=O)(=O)NCC(C)C SOMWMBIMDBWDCT-UHFFFAOYSA-N 0.000 claims 1
- GGBAQRBKKXXBGB-UHFFFAOYSA-N 7-[[5-chloro-2-(2,4-dimethoxyanilino)pyrimidin-4-yl]amino]-2-methyl-3h-isoindol-1-one Chemical compound COC1=CC(OC)=CC=C1NC1=NC=C(Cl)C(NC=2C=3C(=O)N(C)CC=3C=CC=2)=N1 GGBAQRBKKXXBGB-UHFFFAOYSA-N 0.000 claims 1
- 241001139947 Mida Species 0.000 claims 1
- 230000002496 gastric effect Effects 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 208000014500 neuronal tumor Diseases 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 239000000203 mixture Substances 0.000 description 66
- 239000000243 solution Substances 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- 210000004027 cell Anatomy 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 38
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 38
- 235000002639 sodium chloride Nutrition 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 239000012267 brine Substances 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 29
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
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- 206010028980 Neoplasm Diseases 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
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- 238000006243 chemical reaction Methods 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
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- 230000014759 maintenance of location Effects 0.000 description 11
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 10
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- 125000003118 aryl group Chemical group 0.000 description 9
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 7
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- C—CHEMISTRY; METALLURGY
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| US8796255B2 (en) | 2010-11-10 | 2014-08-05 | Celgene Avilomics Research, Inc | Mutant-selective EGFR inhibitors and uses thereof |
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| GB0004890D0 (en) * | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| WO2003030909A1 (en) * | 2001-09-25 | 2003-04-17 | Bayer Pharmaceuticals Corporation | 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer |
| GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
| WO2003095448A1 (en) * | 2002-05-06 | 2003-11-20 | Bayer Pharmaceuticals Corporation | Pyridinyl amino pyrimidine derivatives useful for treating hyper-proliferative disorders |
| GB0305929D0 (en) * | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
| JP4607879B2 (ja) * | 2003-08-15 | 2011-01-05 | ノバルティス アーゲー | 新生物疾患、炎症および免疫障害の処置に有用な2,4−ピリミジンジアミン |
| CA2538413A1 (en) * | 2003-09-18 | 2005-03-24 | Novartis Ag | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
| GB0419160D0 (en) * | 2004-08-27 | 2004-09-29 | Novartis Ag | Organic compounds |
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- 2005-08-26 US US11/574,019 patent/US20090131436A1/en not_active Abandoned
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| ECSP077271A (es) | 2007-03-29 |
| JP2008510763A (ja) | 2008-04-10 |
| TW200621729A (en) | 2006-07-01 |
| KR20070054223A (ko) | 2007-05-28 |
| PE20060622A1 (es) | 2006-08-14 |
| AR054081A1 (es) | 2007-06-06 |
| HRP20070076A2 (en) | 2007-07-31 |
| BRPI0514681A (pt) | 2008-06-17 |
| AU2005276582B2 (en) | 2009-07-16 |
| RU2007110950A (ru) | 2008-10-10 |
| GT200500237A (es) | 2006-03-29 |
| US20090131436A1 (en) | 2009-05-21 |
| RU2401260C2 (ru) | 2010-10-10 |
| TNSN07075A1 (en) | 2008-06-02 |
| IL181433A0 (en) | 2007-07-04 |
| WO2006021454A3 (en) | 2006-05-04 |
| NO20071593L (no) | 2007-05-22 |
| ZA200701406B (en) | 2008-08-27 |
| GB0419161D0 (en) | 2004-09-29 |
| WO2006021454A2 (en) | 2006-03-02 |
| MA28824B1 (fr) | 2007-08-01 |
| CN101048386A (zh) | 2007-10-03 |
| CA2577251A1 (en) | 2006-03-02 |
| AU2005276582A1 (en) | 2006-03-02 |
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