ES2221904T3 - Imidazolo-5-il-2-anilino-pirimidinas como agentes para la inhibicion de la proliferacion celular. - Google Patents
Imidazolo-5-il-2-anilino-pirimidinas como agentes para la inhibicion de la proliferacion celular.Info
- Publication number
- ES2221904T3 ES2221904T3 ES01963159T ES01963159T ES2221904T3 ES 2221904 T3 ES2221904 T3 ES 2221904T3 ES 01963159 T ES01963159 T ES 01963159T ES 01963159 T ES01963159 T ES 01963159T ES 2221904 T3 ES2221904 T3 ES 2221904T3
- Authority
- ES
- Spain
- Prior art keywords
- sulfamoyl
- alkyl
- formula
- compound
- pharmaceutically acceptable
- 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
- 230000004663 cell proliferation Effects 0.000 title description 13
- 230000005764 inhibitory process Effects 0.000 title description 11
- -1 nitro, cyano, hydroxy, amino, carboxy, carbamoyl Chemical group 0.000 claims abstract description 401
- 150000001875 compounds Chemical class 0.000 claims abstract description 230
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 150
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 128
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 63
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 58
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 56
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000001257 hydrogen Substances 0.000 claims abstract description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 52
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 51
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 43
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 26
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 20
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 14
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 8
- 125000005236 alkanoylamino group Chemical group 0.000 claims abstract description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims abstract description 7
- 150000002829 nitrogen Chemical group 0.000 claims abstract description 4
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 183
- 150000003839 salts Chemical class 0.000 claims description 67
- 239000007787 solid Substances 0.000 claims description 65
- 150000002148 esters Chemical class 0.000 claims description 64
- 238000001727 in vivo Methods 0.000 claims description 64
- 238000011282 treatment Methods 0.000 claims description 38
- 206010028980 Neoplasm Diseases 0.000 claims description 28
- 241001465754 Metazoa Species 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 238000004519 manufacturing process Methods 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- 230000002401 inhibitory effect Effects 0.000 claims description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 230000022131 cell cycle Effects 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 208000032839 leukemia Diseases 0.000 claims description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 230000035755 proliferation Effects 0.000 claims description 8
- 210000002307 prostate Anatomy 0.000 claims description 8
- 230000001154 acute effect Effects 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 206010051113 Arterial restenosis Diseases 0.000 claims description 6
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 208000037260 Atherosclerotic Plaque Diseases 0.000 claims description 6
- 208000020084 Bone disease Diseases 0.000 claims description 6
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
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- 208000035475 disorder Diseases 0.000 claims description 6
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- 230000000893 fibroproliferative effect Effects 0.000 claims description 6
- 201000011066 hemangioma Diseases 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 210000004072 lung Anatomy 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 210000001210 retinal vessel Anatomy 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 208000038016 acute inflammation Diseases 0.000 claims description 5
- 230000006022 acute inflammation Effects 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 210000000481 breast Anatomy 0.000 claims description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 4
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 4
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 4
- 208000030090 Acute Disease Diseases 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 230000001028 anti-proliverative effect Effects 0.000 claims description 4
- 208000037976 chronic inflammation Diseases 0.000 claims description 4
- 230000006020 chronic inflammation Effects 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 230000012010 growth Effects 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 210000000496 pancreas Anatomy 0.000 claims description 4
- 230000000306 recurrent effect Effects 0.000 claims description 4
- 210000003491 skin Anatomy 0.000 claims description 4
- 210000001519 tissue Anatomy 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 230000002611 ovarian Effects 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- KVJXNCXRESCVKS-UHFFFAOYSA-N 4-[[4-(3-ethyl-2-methylimidazol-4-yl)pyrimidin-2-yl]amino]-n-(2-methoxyethyl)benzenesulfonamide Chemical compound CCN1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(=O)(=O)NCCOC)=N1 KVJXNCXRESCVKS-UHFFFAOYSA-N 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 210000000936 intestine Anatomy 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 230000017066 negative regulation of growth Effects 0.000 claims description 2
- 230000001012 protector Effects 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 210000003905 vulva Anatomy 0.000 claims description 2
- SGMLRJXBDRNXBJ-UHFFFAOYSA-N 4-[[4-(2,3-dimethylimidazol-4-yl)pyrimidin-2-yl]amino]-n-(2,2,2-trifluoroethyl)benzenesulfonamide Chemical compound CN1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(=O)(=O)NCC(F)(F)F)=N1 SGMLRJXBDRNXBJ-UHFFFAOYSA-N 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- BUPDQZDNTBNFFR-UHFFFAOYSA-N n-(cyclopropylmethyl)-4-[[4-(2,3-dimethylimidazol-4-yl)pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound CN1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(=O)(=O)NCC2CC2)=N1 BUPDQZDNTBNFFR-UHFFFAOYSA-N 0.000 claims 1
- ZJDZXCYQBNODMM-UHFFFAOYSA-N n-(cyclopropylmethyl)-4-[[4-(3-ethyl-2-methylimidazol-4-yl)pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound CCN1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(=O)(=O)NCC2CC2)=N1 ZJDZXCYQBNODMM-UHFFFAOYSA-N 0.000 claims 1
- QSHDCKRJZSDIGZ-UHFFFAOYSA-N n-(cyclopropylmethyl)-4-[[4-(3-methyl-2-propan-2-ylimidazol-4-yl)pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound CN1C(C(C)C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(=O)(=O)NCC2CC2)=N1 QSHDCKRJZSDIGZ-UHFFFAOYSA-N 0.000 claims 1
- DYOCFCUPENQNPU-UHFFFAOYSA-N n-cyclobutyl-4-[[4-(2,3-dimethylimidazol-4-yl)pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound CN1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(=O)(=O)NC2CCC2)=N1 DYOCFCUPENQNPU-UHFFFAOYSA-N 0.000 claims 1
- YUBLGYSOQYIMIG-UHFFFAOYSA-N n-cyclopropyl-4-[[4-(2,3-dimethylimidazol-4-yl)pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound CN1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(=O)(=O)NC2CC2)=N1 YUBLGYSOQYIMIG-UHFFFAOYSA-N 0.000 claims 1
- MDUHIEIIDZPVRB-UHFFFAOYSA-N n-cyclopropyl-4-[[4-(3-ethyl-2-methylimidazol-4-yl)pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound CCN1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(=O)(=O)NC2CC2)=N1 MDUHIEIIDZPVRB-UHFFFAOYSA-N 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 1
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 abstract 1
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 164
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 153
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
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- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
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- REULQIKBNNDNDX-UHFFFAOYSA-M sodium;2,3-dihydroxypropyl hydrogen phosphate Chemical compound [Na+].OCC(O)COP(O)([O-])=O REULQIKBNNDNDX-UHFFFAOYSA-M 0.000 description 1
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- 229960003604 testosterone Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
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- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Inks, Pencil-Leads, Or Crayons (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Adhesives Or Adhesive Processes (AREA)
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| GB0004888D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
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| US7129242B2 (en) | 2000-12-06 | 2006-10-31 | Signal Pharmaceuticals, Llc | Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto |
| US7122544B2 (en) * | 2000-12-06 | 2006-10-17 | Signal Pharmaceuticals, Llc | Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto |
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| AR039241A1 (es) * | 2002-04-04 | 2005-02-16 | Biogen Inc | Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos |
| DE10239042A1 (de) * | 2002-08-21 | 2004-03-04 | Schering Ag | Makrozyclische Pyrimidine, deren Herstellung und Verwendung als Arzneimittel |
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| CA2583812A1 (en) * | 2004-10-28 | 2006-05-11 | Irm Llc | Compounds and compositions as hedgehog pathway modulators |
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| CN1939910A (zh) * | 2004-12-31 | 2007-04-04 | 孙飘扬 | 氨基嘧啶类化合物及其盐和其制备方法与药物用途 |
| GB0504753D0 (en) * | 2005-03-08 | 2005-04-13 | Astrazeneca Ab | Chemical compounds |
| JP4278172B2 (ja) * | 2005-07-30 | 2009-06-10 | アストラゼネカ アクチボラグ | 増殖性疾患の治療において使用するためのイミダゾリル−ピリミジン化合物 |
| KR100674813B1 (ko) * | 2005-08-05 | 2007-01-29 | 일양약품주식회사 | Ｎ-페닐-2-피리미딘-아민 유도체 및 그의 제조방법 |
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| TW200815418A (en) * | 2006-06-27 | 2008-04-01 | Astrazeneca Ab | New compounds I |
| JP2011518769A (ja) * | 2008-03-14 | 2011-06-30 | ビーエーエスエフ ソシエタス・ヨーロピア | 殺菌剤として使用するための置換ピラジニルメチルスルホンアミド |
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