ES2554513T3 - Derivados de quinolinas y quinoxalinas como inhibidores de la proteína tirosina quinasa - Google Patents
Derivados de quinolinas y quinoxalinas como inhibidores de la proteína tirosina quinasa Download PDFInfo
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- ES2554513T3 ES2554513T3 ES09749876.0T ES09749876T ES2554513T3 ES 2554513 T3 ES2554513 T3 ES 2554513T3 ES 09749876 T ES09749876 T ES 09749876T ES 2554513 T3 ES2554513 T3 ES 2554513T3
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- alkyl
- amino
- substituted
- phenyl
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title 2
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 title 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 125000001424 substituent group Chemical group 0.000 claims abstract description 26
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims 3
- 201000011510 cancer Diseases 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 230000001404 mediated effect Effects 0.000 claims 3
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 108091008794 FGF receptors Proteins 0.000 claims 2
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 claims 2
- 229940122361 Bisphosphonate Drugs 0.000 claims 1
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- 206010014733 Endometrial cancer Diseases 0.000 claims 1
- 206010014759 Endometrial neoplasm Diseases 0.000 claims 1
- 206010025323 Lymphomas Diseases 0.000 claims 1
- 208000034578 Multiple myelomas Diseases 0.000 claims 1
- 208000014767 Myeloproliferative disease Diseases 0.000 claims 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 claims 1
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
- 229940100198 alkylating agent Drugs 0.000 claims 1
- 239000002168 alkylating agent Substances 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 230000000340 anti-metabolite Effects 0.000 claims 1
- 230000001028 anti-proliverative effect Effects 0.000 claims 1
- 229940100197 antimetabolite Drugs 0.000 claims 1
- 239000002256 antimetabolite Substances 0.000 claims 1
- 150000004663 bisphosphonates Chemical class 0.000 claims 1
- 150000001639 boron compounds Chemical class 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 210000003679 cervix uteri Anatomy 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 208000010749 gastric carcinoma Diseases 0.000 claims 1
- 208000005017 glioblastoma Diseases 0.000 claims 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 201000002740 oral squamous cell carcinoma Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 208000010916 pituitary tumor Diseases 0.000 claims 1
- 150000003058 platinum compounds Chemical class 0.000 claims 1
- 201000001514 prostate carcinoma Diseases 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 201000000498 stomach carcinoma Diseases 0.000 claims 1
- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
- -1 amino, substituted mono amino Chemical group 0.000 abstract description 55
- 125000000217 alkyl group Chemical group 0.000 abstract description 31
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 16
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 14
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 13
- 125000003118 aryl group Chemical group 0.000 abstract description 12
- 125000006413 ring segment Chemical group 0.000 abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 10
- 239000001257 hydrogen Substances 0.000 abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 abstract description 6
- 125000004103 aminoalkyl group Chemical group 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 5
- 239000012453 solvate Substances 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 4
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical group 0.000 abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 abstract description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract 10
- 125000003282 alkyl amino group Chemical group 0.000 abstract 4
- 150000002431 hydrogen Chemical group 0.000 abstract 3
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract 2
- 125000004043 oxo group Chemical group O=* 0.000 abstract 2
- 125000002431 aminoalkoxy group Chemical group 0.000 abstract 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- BAJXNHZNYIZRLZ-UHFFFAOYSA-N 8-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)quinoxaline-5-carboxylic acid Chemical compound COC1=CC(OC)=C(Cl)C(C=2C3=NC=CN=C3C(C(O)=O)=CC=2)=C1F BAJXNHZNYIZRLZ-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- NWUOZTZYEOTHEM-UHFFFAOYSA-N 5-(2,6-dichloro-3,5-dimethoxyphenyl)quinoline-8-carboxylic acid Chemical compound COC1=CC(OC)=C(Cl)C(C=2C3=CC=CN=C3C(C(O)=O)=CC=2)=C1Cl NWUOZTZYEOTHEM-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- MEDCQWNTBHMAOQ-UHFFFAOYSA-N 8-(2,6-dichloro-3,5-dimethoxyphenyl)-n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]quinoxaline-5-carboxamide Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC(=O)C(C1=NC=CN=C11)=CC=C1C1=C(Cl)C(OC)=CC(OC)=C1Cl MEDCQWNTBHMAOQ-UHFFFAOYSA-N 0.000 description 3
- UXNYKUAVUQXHDG-UHFFFAOYSA-N 8-(2,6-difluoro-3,5-dimethoxyphenyl)quinoxaline-5-carboxylic acid Chemical compound COC1=CC(OC)=C(F)C(C=2C3=NC=CN=C3C(C(O)=O)=CC=2)=C1F UXNYKUAVUQXHDG-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- QLZNISOPACYKOR-UHFFFAOYSA-N quinoxaline-5-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=N1 QLZNISOPACYKOR-UHFFFAOYSA-N 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 2
- MMQCTXWUZNJUTF-UHFFFAOYSA-N 5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-amine Chemical compound C1CN(C)CCN1CC1=CC=C(N)N=C1 MMQCTXWUZNJUTF-UHFFFAOYSA-N 0.000 description 2
- JVMUJWRLQAYOBW-UHFFFAOYSA-N 8-(2,6-dichloro-3,5-dimethoxyphenyl)quinoxaline-5-carboxylic acid Chemical compound COC1=CC(OC)=C(Cl)C(C=2C3=NC=CN=C3C(C(O)=O)=CC=2)=C1Cl JVMUJWRLQAYOBW-UHFFFAOYSA-N 0.000 description 2
- XIFFUJNWCYQIBQ-UHFFFAOYSA-N 8-(2,6-difluoro-3,5-dimethoxyphenyl)-n-[5-[(dimethylamino)methyl]-1h-imidazol-2-yl]quinoxaline-5-carboxamide Chemical compound COC1=CC(OC)=C(F)C(C=2C3=NC=CN=C3C(C(=O)NC=3NC=C(CN(C)C)N=3)=CC=2)=C1F XIFFUJNWCYQIBQ-UHFFFAOYSA-N 0.000 description 2
- SJEJWCHLBWZBCO-UHFFFAOYSA-N 8-(2,6-difluoro-3,5-dimethoxyphenyl)-n-[6-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl]quinoxaline-5-carboxamide Chemical compound C1CN(CC)CCN1CC(N=C1)=CC=C1NC(=O)C(C1=NC=CN=C11)=CC=C1C1=C(F)C(OC)=CC(OC)=C1F SJEJWCHLBWZBCO-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 2
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004490 chloroalkoxy group Chemical group 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- CUJPFPXNDSIBPG-UHFFFAOYSA-N 1,3-propanediyl Chemical group [CH2]C[CH2] CUJPFPXNDSIBPG-UHFFFAOYSA-N 0.000 description 1
- OMIVCRYZSXDGAB-UHFFFAOYSA-N 1,4-butanediyl Chemical group [CH2]CC[CH2] OMIVCRYZSXDGAB-UHFFFAOYSA-N 0.000 description 1
- LGLCNXSABZEOSM-UHFFFAOYSA-N 2-amino-1h-imidazole-5-carbaldehyde Chemical compound NC1=NC(C=O)=CN1 LGLCNXSABZEOSM-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 1
- KEPUOYACJXZYTQ-UHFFFAOYSA-N 4-(4-ethylpiperazin-1-yl)aniline Chemical compound C1CN(CC)CCN1C1=CC=C(N)C=C1 KEPUOYACJXZYTQ-UHFFFAOYSA-N 0.000 description 1
- QRZMXADUXZADTF-UHFFFAOYSA-N 4-aminoimidazole Chemical compound NC1=CNC=N1 QRZMXADUXZADTF-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 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 description 1
- UGIIUHFLKZMUKD-UHFFFAOYSA-N 5-(2,6-dichloro-3,5-dimethoxyphenyl)quinoxaline Chemical compound ClC1=C(C(=C(C=C1OC)OC)Cl)C=1C=CC=C2N=CC=NC=12 UGIIUHFLKZMUKD-UHFFFAOYSA-N 0.000 description 1
- MDNVSSHQGBBOMB-UHFFFAOYSA-N 5-[(4-benzylpiperazin-1-yl)methyl]pyridin-2-amine Chemical compound C1=NC(N)=CC=C1CN1CCN(CC=2C=CC=CC=2)CC1 MDNVSSHQGBBOMB-UHFFFAOYSA-N 0.000 description 1
- MNJBMPQTXVZMFZ-UHFFFAOYSA-N 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine Chemical compound C1CN(CC)CCN1CC1=CC=C(N)N=C1 MNJBMPQTXVZMFZ-UHFFFAOYSA-N 0.000 description 1
- VSXVKEKDPQTIPW-UHFFFAOYSA-N 5-[[ethyl(methyl)amino]methyl]-1H-imidazol-2-amine Chemical compound CCN(C)CC1=CN=C(N)N1 VSXVKEKDPQTIPW-UHFFFAOYSA-N 0.000 description 1
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 1
- NZTCEWZBMOTKCJ-UHFFFAOYSA-N 6-(4-methylpiperazin-1-yl)pyridin-3-amine Chemical compound C1CN(C)CCN1C1=CC=C(N)C=N1 NZTCEWZBMOTKCJ-UHFFFAOYSA-N 0.000 description 1
- MVSKVMADGSHVMB-UHFFFAOYSA-N 8-(2,6-dichloro-3,5-dimethoxyphenyl)-2-[2-(dimethylamino)ethyl-methylamino]-n-pyridin-2-ylquinoxaline-5-carboxamide Chemical compound COC1=CC(OC)=C(Cl)C(C=2C3=NC(=CN=C3C(C(=O)NC=3N=CC=CC=3)=CC=2)N(C)CCN(C)C)=C1Cl MVSKVMADGSHVMB-UHFFFAOYSA-N 0.000 description 1
- GMDZNPMJEWPQFM-UHFFFAOYSA-N 8-(2,6-dichloro-3,5-dimethoxyphenyl)-n-pyridin-2-ylquinoxaline-5-carboxamide Chemical compound COC1=CC(OC)=C(Cl)C(C=2C3=NC=CN=C3C(C(=O)NC=3N=CC=CC=3)=CC=2)=C1Cl GMDZNPMJEWPQFM-UHFFFAOYSA-N 0.000 description 1
- QUJPTPPSAHJHGT-UHFFFAOYSA-N 8-(2,6-difluoro-3,5-dimethoxyphenyl)-n-[5-(morpholin-4-ylmethyl)-1h-imidazol-2-yl]quinoxaline-5-carboxamide Chemical compound COC1=CC(OC)=C(F)C(C=2C3=NC=CN=C3C(C(=O)NC=3NC=C(CN4CCOCC4)N=3)=CC=2)=C1F QUJPTPPSAHJHGT-UHFFFAOYSA-N 0.000 description 1
- FAEWKFBVYPEBAC-UHFFFAOYSA-N 8-(2,6-difluoro-3,5-dimethoxyphenyl)-n-[5-[(3-oxopiperazin-1-yl)methyl]-1h-imidazol-2-yl]quinoxaline-5-carboxamide Chemical compound COC1=CC(OC)=C(F)C(C=2C3=NC=CN=C3C(C(=O)NC=3NC=C(CN4CC(=O)NCC4)N=3)=CC=2)=C1F FAEWKFBVYPEBAC-UHFFFAOYSA-N 0.000 description 1
- YSHNXBWCXRAMLL-UHFFFAOYSA-N 8-(2,6-difluoro-3,5-dimethoxyphenyl)-n-[5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl]quinoxaline-5-carboxamide Chemical compound COC1=CC(OC)=C(F)C(C=2C3=NC=CN=C3C(C(=O)NC=3N=CC(CN4CCN(C)CC4)=CC=3)=CC=2)=C1F YSHNXBWCXRAMLL-UHFFFAOYSA-N 0.000 description 1
- NLZPNQSVIPUNQS-UHFFFAOYSA-N 8-(2,6-dimethylphenyl)quinoxaline-5-carboxylic acid Chemical compound CC1=CC=CC(C)=C1C1=CC=C(C(O)=O)C2=NC=CN=C12 NLZPNQSVIPUNQS-UHFFFAOYSA-N 0.000 description 1
- HKNCLTAHXPLYKK-UHFFFAOYSA-N 8-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-n-[5-[(3-oxopiperazin-1-yl)methyl]-1h-imidazol-2-yl]quinoxaline-5-carboxamide Chemical compound COC1=CC(OC)=C(Cl)C(C=2C3=NC=CN=C3C(C(=O)NC=3NC=C(CN4CC(=O)NCC4)N=3)=CC=2)=C1F HKNCLTAHXPLYKK-UHFFFAOYSA-N 0.000 description 1
- ODGCXWOTVCKKIR-UHFFFAOYSA-N 8-(2-fluoro-3,5-dimethoxyphenyl)quinoxaline-5-carboxylic acid Chemical compound COC1=CC(OC)=C(F)C(C=2C3=NC=CN=C3C(C(O)=O)=CC=2)=C1 ODGCXWOTVCKKIR-UHFFFAOYSA-N 0.000 description 1
- GCWCCPGQYYKLGC-UHFFFAOYSA-N COC1=CC(OC)=C(Cl)C(C=2C3=NC=CN=C3C(C(O)=O)=CC=2)=C1Cl.COC1=CC(OC)=C(Cl)C(C=2C3=NC=CN=C3C(C(=O)NC=3NC=C(CN4CC(=O)NCC4)N=3)=CC=2)=C1F Chemical compound COC1=CC(OC)=C(Cl)C(C=2C3=NC=CN=C3C(C(O)=O)=CC=2)=C1Cl.COC1=CC(OC)=C(Cl)C(C=2C3=NC=CN=C3C(C(=O)NC=3NC=C(CN4CC(=O)NCC4)N=3)=CC=2)=C1F GCWCCPGQYYKLGC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- 125000002474 dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- RLCBFICKSKDEDG-UHFFFAOYSA-N n-[5-(diethylaminomethyl)-1h-imidazol-2-yl]-8-(2,6-difluoro-3,5-dimethoxyphenyl)quinoxaline-5-carboxamide Chemical compound CCN(CC)CC1=CNC(NC(=O)C=2C3=NC=CN=C3C(C=3C(=C(OC)C=C(OC)C=3F)F)=CC=2)=N1 RLCBFICKSKDEDG-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- 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
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D403/12—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 linked by a chain containing hetero atoms as chain links
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Abstract
Un compuesto de la fórmula (I),**Fórmula** o sal, solvato, u óxido N del mismo, en donde X representa N o CH; R1 representa hidrógeno, halógeno, alquilo C1-12, alquilo C1-12 sustituido en donde los sustituyentes se seleccionan del grupo de heterociclilo mono, bi, o espirocíclico, saturado que tiene 5 a 10 átomos del anillo y cuyo heterociclilo se sustituye o no se sustituye por alquilo C1-12, amino, amino mono sustituido en donde el sustituyente se selecciona del grupo que consiste de alquilo C1-12, amino alquilo C1-12, alquilo C1-12-amino-alquilo C1-12, di-alquilo C1-12-amino-alquilo C1-12, amino disustituido en donde los sustituyentes se seleccionan del grupo que consiste de alquilo C1-12, amino alquilo C1-12, alquilo C1-12-amino-alquilo C1-12, di- alquilo C1-12-amino-alquilo C1-12, alcoxi C1-12, halo-alcoxi C1-12; R2 representa hidrógeno, halógeno, alquilo C1-12, alquilo C1-12 sustituido en donde los sustituyentes se seleccionan del grupo de heterociclilo mono, bi, o espirocíclico, saturado que tiene 5 a 10 átomos del anillo y cuyo heterociclilo se sustituye o no se sustituye por alquilo C1-12, amino, amino mono sustituido en donde el sustituyente se selecciona del grupo que consiste de alquilo C1-12, amino alquilo C1-12, alquilo C1-12-amino-alquilo C1-12, di-alquilo C1-12-amino-alquilo C1-12, amino disustituido en donde los sustituyentes se seleccionan del grupo que consiste de alquilo C1-12, amino alquilo C1-12, alquilo C1-12-amino-alquilo C1-12, di- alquilo C1-12-amino-alquilo C1-12, alcoxi C1-12, halo-alcoxi C1-12; A representa una unidad estructural aromática con 6 a 14 átomos de carbono del anillo o una unidad estructural heteroaromática con 5 - 13 átomos del anillo; por lo que dicha unidad estructural aromática o heteroaromática se sustituye o no se sustituye por uno o más sustituyentes -RA1-RA2; B representa una unidad estructural aromática con 6 a 14 átomos de carbono del anillo o una unidad estructural heteroaromática con 5 - 13 átomos del anillo; por lo que dicha unidad estructural aromática o heteroaromática se sustituye o no se sustituye por uno o más sustituyentes -RB1-RB2; RA1 representa hidrógeno; o formilo, alquilcarbonilo C1-7, alcoxicarbonilo C1-7, aminocarbonilo, N-alquilcarbonilo C1-7, N,N-di-alquilaminocarbonilo C1-7; bencilo; o hidroxi, alcoxi C1-7, amino-alcoxi C1-7, N-alquilamino C1-7- alcoxi C1-7, N,N-di-alquilamino C1-7-alcoxi C1-7; heterociclilalcoxi C1-7 por lo que dicho heterociclilo tiene 3 a 10 átomos del anillo, por lo menos un átomo de anillo es nitrógeno, se une por medio de nitrógeno, se sustituye opcionalmente por alquilo C1-7 y/o hidroxi; o un grupo -NRA3RA4 o un grupo -C(O)-NRA3RA4; RA2 representa un enlace directo o un alcanodiilo C1-12 de cadena recta o de cadena ramificada; RA3 y RA4 representa independientemente cada uno de hidrógeno, alquilo C1-7, hidroxi-alquilo C1-7, halógeno-alquilo C1-7, ciano-alquilo C1-7, amino-alquilo C1-7, N-alquilamino C1-7-alquilo C1-7, N,N-di-alquilamino C1-7- alquilo C1-7, aminocarbonil- alquilo C1-7, N-alquilaminocarbonilo C1-7-alquilo C1-7, N,N-di-alquilaminocarbonilo C1-7-alquilo C1-7, un heterociclo saturado, insaturado o parcialmente saturado que tiene 3 a 10 átomos del anillo, y que se sustituye opcionalmente por 1 a 3 sustituyentes seleccionados del grupo que consiste de alquilo C1-7, hidroxilo, oxo, hidroxialquilo C1-7, bencilo, metoxibencilo, amino, alquilamino C1-7, N,N-di-alquilamino C1-7 o RA3 y RA4 juntos representan con el nitrógeno al que se unen un heterociclo saturado, insaturado o parcialmente saturado que tiene 3 a 10 átomos del anillo, y que se sustituye opcionalmente por 1 a 3 sustituyentes seleccionados del grupo que consiste de alquilo C1-7, ciano, halógeno, hidroxilo, oxo, hidroxi-alquilo C1-7, alquilcarbonilo C1-7, bencilo, metoxibencilo, amino, alquilamino C1-7, N,N-di-alquilamino C1-7; RB1 representa halo, un alquilo C1-7 no sustituido de cadena recta o de cadena ramificada, un alcoxi C1-7 no sustituido de cadena recta o de cadena ramificada, halo-alquilo C1-7 de cadena recta o de cadena ramificada; RB2 representa un enlace directo; m representa un entero seleccionado de 0 a 3; y n representa un entero seleccionado de 0 a 5;
Description
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administrar independientemente al mismo tiempo o en forma separada dentro de intervalos de tiempo, especialmente cuando estos intervalos de tiempo permiten que los patrones de combinación muestren un efecto cooperativo, por ejemplo sinérgico. Los términos "coadministración" o "administración combinada" o similares como se utiliza aquí significa que abarcan la administración del socio de combinación seleccionado a un único sujeto en necesidad del mismo (por ejemplo un paciente), y se pretende que incluyan regímenes de tratamiento en los que los agentes no se administran necesariamente mediante la misma ruta de administración o al mismo tiempo. El término "combinación farmacéutica" como se utiliza aquí significa un producto que resulta de la mezcla o combinación de más de un ingrediente activo e incluye combinaciones fijas y no fijas de los ingredientes activos. El término "combinación fija" significa que los ingredientes activos, por ejemplo un compuesto de la fórmula (I) y un socio de combinación, se administran a un paciente en forma simultánea en la forma de una dosificación o entidad única. El término "combinación no fija" significa que los ingredientes activos, por ejemplo un compuesto de la fórmula (I) y un socio de combinación, se administran a un paciente como entidades separadas ya sea simultáneamente, concurrentemente o secuencialmente sin límites de tiempo específicos, en donde dicha administración proporciona niveles terapéuticamente efectivos de los dos compuestos en el cuerpo del paciente. El último también aplica a terapia de cóctel, por ejemplo la administración de tres o más ingredientes activos.
En realizaciones preferidas, que se prefieren independientemente, colectivamente o en cualquier combinación o subcombinación, la invención se relaciona con un compuesto de la fórmula (I), en forma de base libre o en forma de sal de adición ácida, en donde los sustituyentes son como se define aquí.
En una realización adicional 2, la invención se relaciona con un compuesto de la fórmula (I), o una sal, solvato, óxido N del mismo, en donde cuando el anillo B representa fenilo y n representa 2, los sustituyentes RB2-RB1 están en las posiciones orto; y en donde cuando el anillo B representa fenilo y n representa 4, los sustituyentes RB2-RB1 están en las posiciones orto y meta.
En una realización adicional 3, la invención se relaciona con un compuesto de la fórmula (I), o una sal, solvato, óxido N del mismo, en donde
m representa 0, 1, 2 o 3;
y
n representa 0, 1 o 2.
En una realización adicional 4, la invención se relaciona con un compuesto de la fórmula (I), o una sal, solvato, óxido N del mismo, en donde
R1 representa hidrógeno,
fluoro,
cloro,
alquilo C1-4,
alquilo C1-4 sustituido en donde los sustituyentes se seleccionan del grupo de heterociclilo monocíclico, saturado que tiene 5 a 6 átomos del anillo y cuyo heterociclilo se sustituye o no se sustituye por alquilo C1-4, amino, amino mono sustituido en donde el sustituyente se selecciona del grupo que consiste de alquilo C1-4, amino-alquilo C1-4, alquilo C1-4-amino-alquilo C1-4, di-alquilamino C1-4 alquilo C1-4, amino disustituido en donde los sustituyentes se seleccionan del grupo que consiste de alquilo C1-4, amino-alquilo C1-4, alquilo C1-4-amino-alquilo C1-4, di-alquilamino C1-4 -alquilo C1-4, alcoxi C1-4, fluoro-alcoxi C1-4, cloro-alcoxi C1-4;
R2 representa hidrógeno,
fluoro,
cloro,
alquilo C1-4,
alquilo C1-4 sustituido en donde los sustituyentes se seleccionan del grupo de heterociclilo monocíclico, saturado que tiene 5 a 6 átomos del anillo y cuyo heterociclilo se sustituye o no se sustituye por alquilo C1-4, amino, amino mono sustituido en donde el sustituyente se selecciona del grupo que consiste de alquilo C1-4, amino-alquilo C1-4, alquilo
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C1-4-amino-alquilo C1-4, di-alquilo C1-4-amino alquilo C1-4, amino disustituido en donde los sustituyentes se seleccionan del grupo que consiste de alquilo C1-4, amino-alquilo C1-4, alquilo C1-4-amino-alquilo C1-4, di-alquilamino C1-4 alquilo C1-4, alcoxi C1-4, fluoro-alcoxi C1-4, cloro-alcoxi C1-4;
A representa una unidad estructural aromática seleccionada del grupo que consiste de fenilo, naftilo o una unidad estructural heteroaromática con 5 a 6 anillos y por lo que por lo menos uno de los heteroátomos es nitrógeno, cada unidad estructural aromática o heteroaromática se sustituye o no se sustituye por uno o más sustituyentes -
RA1-RA2
;
B representa una unidad estructural aromática seleccionada del grupo que consiste de fenilo, naftilo o una unidad estructural heteroaromática con 5 a 10 anillos y por lo que por lo menos uno de los heteroátomos es nitrógeno o azufre, cada unidad estructural aromática o heteroaromática se sustituye o no se sustituye por uno o más sustituyentes -RB1-RB2;
RA1
representa hidrógeno; o alquilcarbonilo C1-4, alcoxicarbonil C1-4, aminocarbonilo, N,N-dialquilaminocarbonilo C1-4; o hidroxi, alcoxi C1-4, N,N-di-alquilamino C1-4-alcoxi C1-4; heterociclil-alcoxi C1-4 por lo que dicho heterociclilo tiene 5 a 6 átomos del anillo, por lo menos un átomo de anillo es nitrógeno, se une por medio de nitrógeno, se sustituye opcionalmente por alquilo C1-4; o un grupo -NRA3RA4;
RA2
representa un enlace directo o un alcanodiilo C1-6 de cadena recta o de cadena ramificada;
RA3
y RA4 representa independientemente cada uno de metilo, etilo, n-o iso-propilo, n-, iso-, sec-o tertbutilo, hidroximetilo, 2-hidroxietilo, amino-metilo o -etilo, dimetilaminometilo o etilo, aminocarbonil-metilo o etilo, N,Ndimetilaminocarbonil-metilo o etilo, N,N-dietilaminocarbonil-metilo o etilo o
RA3
y RA4 juntos representan con el nitrógeno al que se unen un heterociclo saturado, insaturado o parcialmente saturado seleccionados del grupo que consiste de azetidina, pirrolidinilo, piperidinilo, piperazinilo, morfolinilo, tiomorfolinilo, y que se sustituye opcionalmente por 1 sustituyente seleccionados del grupo que consiste de metilo, etilo, n-o iso-propilo, n-, iso-, sec-o tert-butilo, ciano, halógeno, hidroxi, oxo, hidroxietilo, bencilo, metoxibencilo, N,N-dimetilamino, N,N-dietilamino;
RB1
representa metilo, etilo, n-o iso-propilo, n-, iso-, sec-o tert-butilo, n-pentilo, n-hexilo, n-heptilo, metioxi, etioxi, n-o iso-propoxi, n-, iso-, sec-o tert-butoxi, n-pentoxi, n-hexoxi, n-heptoxi, fluormetilo, clormetilo, trifluorometilo, fluoro, cloro, bromo;
m representa 0 o 1;
n representa 0 o 1.
En una realización adicional 5, la invención se relaciona con un compuesto de la fórmula (I), o una sal, solvato, óxido N del mismo, en donde
R1 representa hidrógeno, (2-dimetilamino-etil)-metil-amino, 4-etil-piperazin-1-ilmetilo, metilo;
R2
representa hidrógeno, (2-dimetilamino-etil)-metil-amino, 4-etil-piperazin-1-il-metilo, metilo;
A representa arilo o heteroarilo opcionalmente sustituido en donde dicho arilo o heteroarilo se selecciona del grupo que consiste de fenilo, piridilo, pirimidilo, pirolilo, imidazolilo, pirazolilo, triazolilo y en donde dicho arilo o heteroarilo se sustituye o no se sustituye por uno o más sustituyentes -RA1-RA2;
B representa arilo o heteroarilo opcionalmente sustituido en donde dicho arilo o heteroarilo se selecciona del grupo que consiste de fenilo, naftilo, piridilo, piridil-N-óxido, quinilinilo, isoquinilinilo, tiofenilo, tionaftenilo y en donde dicho arilo o heteroarilo se sustituye o no se sustituye por uno o más sustituyentes -RB1-RB2;
RA1
representa hidrógeno; o metoxicarbonilo, tert.butoxicarbonilo, aminocarbonilo; o un grupo -NRA3RA4;
RA2
representa un enlace directo, metandiilo, 1,2-etanodiilo, 1,1-etanodiilo, 1,1-, 1,2-, 1,3-propanodiilo y 1,1-, 1,2-, 1,3-, 1,4-butanodiilo;
RB1
representa metilo, metoxi, trifluormetilo, fluoro, cloro.
En una realización adicional 6, la invención se relaciona con un compuesto de la fórmula (IA),
8
[6-(4-metil-piperazin-1-il)-piridin-3-il]-amida de ácido 8-(4-Metil-tiofen-3-il)-quinoxalina-5-carboxílico [4-(4-metil-piperazin-1-ilmetil)-1H-imidazol-2-il]-amida de ácido 8-(4-Metil-tiofen-3-il)-quinoxalina-5-carboxílico (1H-imidazol-2-il)-amida de ácido 8-(4-Metil-tiofen-3-il)-quinoxalina-5-carboxílico [3-(4-etil-piperazin-1-il)-fenil]-amida de ácido 8-(2,6-Dimetil-fenil)-quinoxalina-5-carboxílico [4-(4-etil-piperazin-1-il)-fenil]-amida de ácido 8-(2,6-Dimetil-fenil)-quinoxalina-5-carboxílico [4-(2-dimetilamino-etoxi)-fenil]-amida de ácido 8-(2,6-Dimetil-fenil)-quinoxalina-5-carboxílico (1H-imidazol-2-il)-amida de ácido 8-(2,6-Dimetil-fenil)-quinoxalina-5-carboxílico [5-(4-metil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2,6-Dimetil-fenil)-quinoxalina-5-carboxílico [6-(4-metil-piperazin-1-il)-piridin-3-il]-amida de ácido 8-(2,6-Dimetil-fenil)-quinoxalina-5-carboxílico [4-(4-metil-piperazin-1-ilmetil)-1 H-imidazol-2-il]-amida de ácido 8-(2,6-Dimetil-fenil)-quinoxalina-5-carboxílico piridin-3-ilamida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico piridin-2-ilamida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico (5-metil-piridin-2-il)-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico (5-{[(2-dimetilamino-etil)-metil-amino]-metil}-piridin-2-il)-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina
5-carboxílico piridin-3-ilamida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-3-(4-etil-piperazin-1-ilmetil)-quinoxalina-5-carboxílico piridin-3-ilamida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-2-(4-etil-piperazin-1-ilmetil)-quinoxalina-5-carboxílico piridin-2-ilamida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-2-(4-etil-piperazin-1-ilmetil)-quinoxalina-5-carboxílico (1 H-imidazol-2-il)-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-2-[(2-dimetilamino-etil)-metil-amino]-quinoxalina
5-carboxílico
piridin-2-ilamida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-2-[(2-dimetilamino-etil)-metil-amino]-quinoxalina-5carboxílico piridin-3-ilamida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-2-[(2-dimetilamino-etil)-metil-amino]-quinoxalina-5
carboxílico [6-(4-etil-piperazin-1-ilmetil)-piridin-3-il]-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico
[6-(4-metil-piperazin-1-ilmetil)-piridin-3-il]-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico piridin-3-ilamida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico piridin-2-ilamida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [5-(4-etil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico ( 4-pirrolidin-1-ilmetil-1 H-imidazol-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico (5-{[(2-dimetilamino-etil)-metil-amino]-metil}-piridin-2-il)-amida de ácido 8-(2-Fluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico [5-(4-etil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2-Fluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico
12
5
10
15
20
25
30
35
carboxílico
[5-(4-etil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5carboxílico (5-piperazin-1-ilmetil-piridin-2-il)-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [5-(3-oxo-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico
(5-{[(2-dimetilamino-etil)-metil-amino]-metil}-piridin-2-il)-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)quinoxalina-5-carboxílico {5-[(dimetilcarbamoilmetil-metilamino)-metil]-piridin-2-il}-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)
quinoxalina-5-carboxílico
{5-[(carbamoilmetil-metil-amino)-metil]-piridin-2-il}-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina5-carboxílico (5-imidazol-1-ilmetil-piridin-2-il)-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [5-(1,1-dioxo-tiomorfolin-4-ilmetil)-piridin-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico
(4-dimetilaminometil-1 H-imidazol-2-il)-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5carboxílico [4-(4-metil-piperazin-1-ilmetil)-1 Himidazol-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico
[4-(3-oxo-piperazin-1-ilmetil)-1H-imidazol-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5carboxílico [5-(4-bencil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico {4-[(etil-metil-amino)-metil]-1H-imidazol-2-il}-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico (4-dietilaminometil-1 H-imidazol-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [4-(4-etil-piperazin-1-il)-fenil]-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico (1-bencil-1 H-imidazol-2-il)-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico (1H-imidazol-2-il)-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico (3H-imidazol-4-il)-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico (4H-[1,2,4]triazol-3-il)-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [5-(4-metil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico [5-(4-etil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico {5-[4-(4-metoxi-bencil)-piperazin-1-ilmetil]-piridin-2-il}-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8
carboxílico (5-piperazin-1-ilmetil-piridin-2-il)-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico [6-(4-metil-piperazin-1-ilmetil)-piridin-3-il]-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico [6-(4-etil-piperazin-1-ilmetil)-piridin-3-il]-amida de ácido 5-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinolina-8-carboxílico
15
5
10
15
20
25
30
[5-(4-etil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [5-(4-metil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [6-(4-etil-piperazin-1-ilmetil)-piridin-3-il]-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico (5-{[(2-dimetilamino-etil)-metil-amino]-metil}-piridin-2-il)-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina
5-carboxílico
[6-(4-etil-piperazin-1-ilmetil)-piridin-3-il]-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [5-(4-etil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico (4-pirrolidin-1-ilmetil-1 H-imidazol-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [5-(4-metil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico (4-dimetilaminometil-1 H-imidazol-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico (5-{[(2-dimetilamino-etil)-metil-amino]-metil}-piridin-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)
quinoxalina-5-carboxílico (4-morfolin-4-ilmetil-1H-imidazol-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico [4-(4-metil-piperazin-1-ilmetil)-1 H-imidazol-2-il]-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico
[4-(3-oxo-piperazin-1-ilmetil)-1 H-imidazol-2-il]-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5carboxílico [5-(4-metil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico
[5-(4-etil-piperazin-1-ilmetil)-piridin-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5carboxílico (5-{[(2-dimetilamino-etil)-metil-amino]-metil}-piridin-2-il)-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)
quinoxalina-5-carboxílico
(4-dimetilaminometil-1 H-imidazol-2-il)-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5carboxílico [4-(4-metil-piperazin-1-ilmetil)-1Himidazol-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico
[4-(3-oxo-piperazin-1-ilmetil)-1H-imidazol-2-il]-amida de ácido 8-(2-Cloro-6-fluoro-3,5-dimetoxi-fenil)-quinoxalina-5carboxílico {4-[(etil-metil-amino)-metil]-1H-imidazol-2-il}-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5
carboxílico y (4-dietilaminometil-1H-imidazol-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico En una realización adicional 11, la invención se relaciona con un compuesto de la fórmula (I) que es (4
dimetilaminometil-1H-imidazol-2-il)-amida de ácido 8-(2,6-Dicloro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico:
17
Una mezcla de (4-dimetilaminometil-1Himidazol-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina5-carboxílico (30 mg, 0.64 mmol) (Etapa 187.1) y mCPBA (20.1 g, 0.064 mmol) se agita durante 30 min a 5° C, se diluye con DCM/solución acuosa saturada de NaHCO3 y se extrae con DCM/MeOH (9:1, v/v). La fase orgánica se seca (Na2SO4), se filtra y se concentra. El residuo se purifica mediante cromatografía de columna de gel de sílice
5 (DCM/Me-OH/NH3 ac, 89:10:1) para proporcionar 20 mg del compuesto del título como un sólido amarillo: ES-MS: 485 [M+H]+; tR= 3.21 min (Sistema 1); TLC: Rf = 0.05 (DCM/MeOH/NH3 ac, 89:10:1).
Etapa 187.1: (4-dimetilaminometil-1H-imidazol-2-il)-amida de ácido 8-(2,6-Difluoro-3,5-dimetoxi-fenil)-quinoxalina-5carboxílico
El compuesto del título se prepara en analogía al procedimiento descrito en el Ejemplo 180 pero utilizando
10 clorhidrato de dimetilamina (1.5 equiv.) en lugar de N,N,N’-trimetiletilenodiamina y (4-formil-1H-imidazol-2-il)-amida de ácido 8-(2,6-difluoro-3,5-dimetoxi-fenil)-quinoxalina-5-carboxílico (Ejemplo 7). Compuesto del título: ES-MS: 469 [M+H]+; tR= 3.14 min (Sistema 1); TLC: Rf = 0.22 (DCM/MeOH/NH3 ac, 91.5:7.5:1).
Se proporcionan datos 1 H RMN para los ejemplos seleccionados en la siguiente tabla:
- Ejemplo
- Datos de 1H RMN (400 MHz, DMSO-d6)
- 81
- δ (ppm): 2.11 (s, 6 H), 2.14 (s, 3 H), 2.30 -2.46 (m, 4 H), 3.49 (s, 2 H), 3.98 (s, 6 H), 7.05 (s, 1 H), 7.80 (d, J=8.4 Hz, 1 H), 7.93 (d, J=7.8 Hz, 1 H), 8.29 (s, 1 H), 8.35 (d, J=8.2 Hz, 1 H), 8.76 (d, J=7.4 Hz, 1 H), 9.06 (s, 1 H), 9.19 (s, 1 H), 12.70 (s, 1 H)
- 92
- δ (ppm): 0.96 (t, J=7.23 Hz, 3 H), 2.28 (q, J=7.43 Hz, 2 H), 2.30-2.60 (m, 8 H), 3.47 (s, 2 H), 3.92 (s, 6 H), 7.15 (t, J=8.41 Hz, 1 H), 7.80 (dd, J=8.60, 2.35 Hz, 1 H), 8.11 (d, J=7.82 Hz, 1 H), 8.29 (d, J=1.56 Hz, 1 H), 8.35 (d, J=8.60 Hz, 1 H), 8.71 (d, J=7.82 Hz, 1 H), 9.10 (d, J=1.56 Hz, 1 H), 9.20 (d, J=1.96 Hz, 1 H), 12.59 (s, 1 H)
- 122
- δ (ppm): 2.15 (s, 3 H), 2.20-2.58 (m, 8 H), 2.59 (s, 3 H), 2.84 (s, 3 H), 3.47 (s, 2 H), 3.98 (s, 6 H), 7.04 (s, 1 H), 7.75 (d, J=7.82 Hz, 1 H), 7.79 (d, J=8.60 Hz, 1 H), 8.32 (s, 1 H), 8.35 (d, J=8.60 Hz, 1 H), 8.70 (d, J=7.82 Hz, 1 H), 13.43 (s, 1 H)
- 127
- δ (ppm): 2.14 (s, 6 H), 3.32 (s, 2 H), 3.92 (s, 6 H), 6.67 (br s, 1 H), 7.15 (t, J=8.41 Hz, 1 H), 8.10 (d, J=7.82 Hz, 1 H), 8.62 (d, J=7.43 Hz, 1 H), 9.10 (s, 1 H), 9.18 (s, 1 H)
- 135
- δ (ppm): 2.38 (br s, 4 H), 3.31 (s, 2 H), 3.55 (br s, 4 H), 3.92 (s, 6 H), 6.74 (br s, 1 H), 7.15 (t, J=8.41 Hz, 1 H), 8.10 (d, J=7.43 Hz, 1 H), 8.64 (br. s., 1 H), 9.10 (s, 1 H), 9.19 (br s, 1 H), 11.77 (br s, 1 H), 12.68 (br s, 1 H)
- 141
- δ (ppm): 2.12 (s, 3 H), 2.20-2.50 (m, 8 H), 3.32 (s, 2 H), 3.92 (s, 6 H), 6.69 (br s, 1 H), 7.15 (t, J=8.41 Hz, 1 H), 8.10 (d, J=7.43 Hz, 1 H), 8.63 (d, J=7.04 Hz, 1 H), 9.10 (s, 1 H), 9.19 (s, 1 H)
- 142
- δ (ppm): 2.58 (br s, 2 H), 2.94 (s, 2 H), 3.13 (br s, 2 H), 3.41 (br s, 2 H), 3.92 (s, 6 H), 6.79 (brs, 1 H), 7.15 (t, J=8.4 Hz, 1 H), 7.71 (brs, 1 H), 8.10 (d, J=7.8 Hz, 1 H), 8.63 (d, J=5.5 Hz, 1 H), 9.10 (s, 1 H), 9.19 (brs, 1 H), 11.81 (brs, 1 H), 12.68 (br s, 1 H)
- 145
- δ (ppm): 0.96 (t, J=7.0 Hz, 3 H), 1.90-2.70 (m, 10 H), 3.47 (s, 2 H) 3.95 (br s, 6 H), 7.10 (d, J=7.8 Hz, 1 H), 7.80 (d, J=8.2 Hz, 1 H), 8.02 (d, J=7.8 Hz, 1 H), 8.28 (s, 1 H), 8.34 (d, J=8.6 Hz, 1 H), 8.73 (d, J=7.4 Hz, 1 H), 9.07 (s, 1 H), 9.19 (s, 1 H), 12.64 (s, 1 H)
- 152
- δ (ppm): 2.70-3.20 (m, 8 H), 3.70 (s, 2 H), 3.95 (d, J=3.13 Hz, 6 H), 7.10 (d, J=7.82 Hz, 1 H), 7.86 (d, J=8.60 Hz, 1 H), 8.02 (d, J=7.43 Hz, 1 H), 8.25 -8.48 (m, 2 H), 8.72 (d, J=7.43 Hz, 1 H), 9.07 (s, 1 H), 9.19 (s, 1 H), 12.65 (s, 1 H)
- 155
- δ (ppm): 2.58 (br s, 2 H), 2.94 (s, 2 H), 3.13 (br s, 2 H), 3.42 (br s, 2 H), 3.95 (s, 6 H), 6.79 (br s, 1 H), 7.10 (d, J=7.8 Hz, 1 H), 7.70 (br s, 1 H), 8.02 (d, J=7.4 Hz, 1 H,) 8.64 (br s, 1 H), 9.07 (s, 1 H), 9.18 (s, 1 H), 11.81 (br s, 1 H), 12.71 (br s, 1 H)
114
- Ejemplo
- Datos de 1H RMN (400 MHz, DMSO-d6)
- 157
- δ (ppm): 1.00 (t, J=7.2 Hz, 3 H), 2.13 (s, 3 H), 2.38 (q, J=7.0 Hz, 2 H), 3.39 (br s, 2 H), 3.92 (s, 6 H), 6.68 (br s, 1 H), 7.15 (t, J=8.2 Hz, 1 H), 8.10 (d, J=7.8 Hz, 1 H), 8.63 (d, J=7.4 Hz, 1 H), 9.10 (s, 1 H), 9.18 (s, 1 H)
- 158
- δ (ppm): 0.98 (t, J=7.04 Hz, 6 H), 2.36 -2.57 (m, 4 H), 3.46 (br s, 2 H), 3.92 (s, 6 H), 6.68 (br s, 1 H), 7.15 (t, J=8.21 Hz, 1 H), 8.09 (d, J=7.43 Hz, 1 H), 8.62 (d, J=7.43 Hz, 1 H), 9.09 (s, 1 H), 9.18 (s, 1 H)
- 177
- 1H RMN (600 MHz) δ (ppm): 2.20 (br s, 6 H), 3.45 (br s, 2 H), 3.99 (s, 6 H), 6.75 (br s, 1 H), 7.19 (d, J=7.9 Hz, 1 H), 7.75 (dd, J=8.3, 4.0 Hz, 1 H), 7.82 (d, J=7.7 Hz, 1 H), 8.03 (d, J=8.5 Hz, 1 H), 8.80 (br s, 1 H), 9.22 (br s, 1 H), 11.77 (br s, 1 H), 13.88 (br s, 1 H)
- 178
- 1H RMN (600 Mz) δ (ppm): 2.16 (s, 3 H), 2.33 -2.49 (m, 8 H), 3.34 (br s, 2 H), 3.99 (d, J=5.0 Hz, 6 H), 6.74 (br s, 1 H), 7.19 (d, J=7.9 Hz, 1 H), 7.75 (dd, J=8.5, 4.2 Hz, 1 H), 7.82 (d, J=7.5 Hz, 1 H), 8.03 (d, J=8.3 Hz, 1 H), 8.80 (d, J=7.7 Hz, 1 H), 9.23 (br s, 1 H), 11.76 (br s, 1 H), 13.86 (br s, 1 H)
- 180
- δ (ppm): 2.07 -2.23 (m, 9 H), 2.32 -2.39 (m, 2 H), 2.39 -2.46 (m, 2 H), 3.42 (br s, 2 H), 3.98 (s, 6 H), 6.67 (br s, 1 H), 7.06 (s, 1 H), 7.92 (d, J=7.43 Hz, 1 H), 8.67 (d, J=7.82 Hz, 1 H), 9.05 (d, J=1.56 Hz, 1 H), 9.16 (d, J=1.56 Hz, 1 H)
- 183
- δ (ppm): 3.30-4.20 (m, 13 H), 6.72 (br s, 1 H), 7.06 (s, 1 H), 7.92 (d, J=7.8 Hz, 1 H), 8.67 (d, J=6.6 Hz, 1 H), 9.05 (s, 1 H), 9.16 (s, 1 H), 11.77 (br s, 1 H), 12.73 (br s, 1 H)
- 186
- δ (ppm): 2.25 (s, 3 H), 3.52 (br s, 2 H), 3.92 (s, 6 H), 6.65 (br s, 1 H), 7.15 (t, J=8.21 Hz, 1 H), 8.10 (d, J=7.43 Hz, 1 H), 8.63 (d, J=7.43 Hz, 1 H), 9.09 (s, 1 H), 9.17 (s, 1 H)
- br: amplio; s: singulete; d: doblete; t: triplete; q: cuartete; Hz: Hertz; ppm: partes por millón
Se miden los espectros de 1H-RMN en un espectrómetro Varian Mercury 400 o en un espectrómetro Bruker Avance
600.
Ejemplo 188: Formulaciones farmacéuticas
5 Ejemplo 188.1: Cápsulas Blandas
Se preparan 5000 cápsulas de gelatina blanda, cada una comprende como ingrediente activo 0.05 g de uno cualquiera de los compuestos de la fórmula (I) mencionados en uno cualquiera de los ejemplos anteriores como sigue: se suspende 250 g de ingrediente activo pulverizado en 2 litros de Lauroglykol* (laurato de propilenglicol, Gattefossé S.A., Saint Priest, Francia) y se muele en un pulverizador húmedo para producir un tamaño de partícula
10 de aproximadamente 1 a 3 mm. Luego se introducen 0.419 g porciones de la mezcla en cápsulas de gelatina blanda utilizando una máquina de relleno de cápsula.
Ejemplo 188.2: Comprimidos
Los comprimidos, que comprenden, como ingrediente activo 100 mg de uno cualquiera de los compuestos de la fórmula (I) mencionados en uno cualquiera de los ejemplos anteriores se preparan con la siguiente composición de 15 acuerdo con procedimientos estándar.
Compuesto (I) 100 mg
Lactosa cristalina 240 mg
Avicel 80 mg
115
- Ejemplo
- FGFR3 IC50 (nM)
- 10
- 58*
- 11
- 31*
- 17
- >10000*
- 20
- 16*
- 22
- 10*
- 24
- 530*
- 25
- 41*
- 31
- 22*
- 34
- 54*
- 38
- 270
- 43
- 87
- 56
- 1200*
- 58
- 700*
- 62
- 8100*
- 69
- >10000*
- 77
- >10000
- 82
- 605
- 83
- 945
- 85
- 210
- 86
- 2550
- 91
- 485
- 93
- 7*
- 95
- 42
- 97
- 875
- 98
- 1050
- 99
- >10000
- 106
- 20
- 112
- 139
118
- Ejemplo
- FGFR3 IC50 (nM)
- 122
- 14
- 124
- 10
- 127
- 16
- 135
- 11
- 136
- 11
- 139
- 265
- 143
- 44
- 144
- 7
- 152
- 32
- 153
- 11
- 154
- 9
- 155
- 12
- 167
- 99
- 172
- 70
- 173
- 245
- 174
- 16
- 175
- 9
- 176
- 51
- 177
- 10
- Los valores IC50 son los valores IC50 promedio de 2 medidas independientes. * Valor único.
Adicionalmente, los compuestos seleccionados de la fórmula (I) se evalúan para medir su capacidad de inhibir otras quinasas, tales como KDR, cKIT, PDGF-R, LCK, cABL, RET como se describió anteriormente. Los resultados se proporcionan en la siguiente tabla:
- Enzima
- KDR cKIT PDGF-R LCK cABL RET
- Rango IC50 (µM)
- 0.003 – 50 0.240 -50 0.100 -50 0.170 -50 0.010 -50 0.390 -50
119
Claims (5)
-
imagen1 imagen2 imagen3 imagen4 imagen5 imagen6 imagen7 imagen8 imagen9 imagen10 imagen11 imagen12 imagen13 imagen14 agente alquilatante, un antimetabolito antiproliferativo, un compuesto de platino, un bisfosfonato, y un anticuerpo monoclonal. - 25. Un compuesto para uso, uso, la composición farmacéutica o la composición farmacéutica combinada como sereivindica en una cualquiera de las reivindicaciones 18, 19 o 22, en donde dicha enfermedad mediada por la proteína 5 tirosina quinasa es una enfermedad mediada por FGFR.
-
- 26.
- Un compuesto para uso, uso, la composición farmacéutica o la composición farmacéutica combinada como se define en la reivindicación 25, en donde dicha enfermedad mediada por FGFR es cáncer.
-
- 27.
- Un compuesto para uso, uso, método, composición farmacéutica o composición farmacéutica combinada como se define en la reivindicación 26, en donde dicho cáncer se selecciona de uno de más de cáncer de vejiga, cáncer
10 de cuello uterino, carcinoma epidermoide oral, mieloma múltiple, cáncer de mama, cáncer de endometrio, cáncer hepatocelular, cáncer de mama, un trastorno mieloproliferativo EMS, linfoma, glioblastoma, carcinoma gástrico, carcinoma pancreático, carcinoma de próstata y un tumor de pituitaria. - 28. Un proceso para la fabricación de un compuesto de la fórmula (I) de acuerdo con una cualquiera de las reivindicaciones 1 a 16 que comprende:15 Método A: hacer reaccionar un ácido carboxílico de la fórmula (II),
imagen15 en donde los sustituyentes son como se define para un compuesto de la fórmula (I), con una amina de la fórmula (III)imagen16 en la presencia de un diluyente y opcionalmente en la presencia de una base para obtener un compuesto de la 20 fórmula I; oMétodo B: hacer reaccionar un compuesto de la fórmula (X)imagen17 en donde los sustituyentes son como se define para un compuesto de la fórmula (I) y Hal representa halo con un compuesto de boro de la fórmula (V)134imagen18
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