WO2011050120A1 - Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity - Google Patents
Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity Download PDFInfo
- Publication number
- WO2011050120A1 WO2011050120A1 PCT/US2010/053459 US2010053459W WO2011050120A1 WO 2011050120 A1 WO2011050120 A1 WO 2011050120A1 US 2010053459 W US2010053459 W US 2010053459W WO 2011050120 A1 WO2011050120 A1 WO 2011050120A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mono
- phenyl
- alkyi
- substituted
- amino
- Prior art date
Links
- 230000000694 effects Effects 0.000 title claims abstract description 16
- 230000002062 proliferating effect Effects 0.000 title claims abstract description 15
- 230000001575 pathological effect Effects 0.000 title claims abstract description 13
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 230000001404 mediated effect Effects 0.000 title claims abstract description 10
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 title claims abstract description 9
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 title claims abstract description 9
- 108091000080 Phosphotransferase Proteins 0.000 title claims abstract description 8
- 102000020233 phosphotransferase Human genes 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims description 9
- 101100498819 Caenorhabditis elegans ddr-1 gene Proteins 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- 102100036723 Discoidin domain-containing receptor 2 Human genes 0.000 claims abstract description 17
- 101710127786 Discoidin domain-containing receptor 2 Proteins 0.000 claims abstract description 17
- 102100036725 Epithelial discoidin domain-containing receptor 1 Human genes 0.000 claims abstract description 17
- 101710131668 Epithelial discoidin domain-containing receptor 1 Proteins 0.000 claims abstract description 17
- 108091008606 PDGF receptors Proteins 0.000 claims abstract description 17
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 102000027450 oncoproteins Human genes 0.000 claims abstract description 7
- 108091008819 oncoproteins Proteins 0.000 claims abstract description 7
- -1 cycloalkyi Chemical group 0.000 claims description 84
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000002950 monocyclic group Chemical group 0.000 claims description 13
- 125000003373 pyrazinyl group Chemical class 0.000 claims description 13
- 125000000714 pyrimidinyl group Chemical class 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000002619 bicyclic group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 9
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 claims description 9
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 208000009905 Neurofibromatoses Diseases 0.000 claims description 6
- 201000008736 Systemic mastocytosis Diseases 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 201000004931 neurofibromatosis Diseases 0.000 claims description 6
- 206010016654 Fibrosis Diseases 0.000 claims description 5
- 206010039710 Scleroderma Diseases 0.000 claims description 5
- 230000004761 fibrosis Effects 0.000 claims description 5
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000007033 Dysgerminoma Diseases 0.000 claims description 3
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 3
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010027406 Mesothelioma Diseases 0.000 claims description 3
- 206010036030 Polyarthritis Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 201000010208 Seminoma Diseases 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims description 3
- 208000030428 polyarticular arthritis Diseases 0.000 claims description 3
- 201000001514 prostate carcinoma Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims 2
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 claims 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- 239000007787 solid Substances 0.000 abstract description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 24
- 229960001346 nilotinib Drugs 0.000 description 24
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 24
- 125000003282 alkyl amino group Chemical group 0.000 description 15
- 150000003254 radicals Chemical class 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 125000001589 carboacyl group Chemical group 0.000 description 6
- 229940126534 drug product Drugs 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 238000011269 treatment regimen Methods 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 230000009246 food effect Effects 0.000 description 4
- YCBPQSYLYYBPDW-UHFFFAOYSA-N 4-methyl-n-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide;hydrate;hydrochloride Chemical compound O.Cl.C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 YCBPQSYLYYBPDW-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 235000021152 breakfast Nutrition 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 125000005236 alkanoylamino group Chemical group 0.000 description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000005237 alkyleneamino group Chemical group 0.000 description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 235000021471 food effect Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- UIOAQJNADLELPQ-UHFFFAOYSA-N C[C]1OCCO1 Chemical group C[C]1OCCO1 UIOAQJNADLELPQ-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- ZGBAJMQHJDFTQJ-DEOSSOPVSA-N bafetinib Chemical compound C1[C@@H](N(C)C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=NC=3)C(C)=CC=2)C=C1C(F)(F)F ZGBAJMQHJDFTQJ-DEOSSOPVSA-N 0.000 description 1
- 229950002365 bafetinib Drugs 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000029640 digestive system melanoma Diseases 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006610 n-decyloxy group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 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
- A61K31/495—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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D401/14—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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
Definitions
- the present invention relates to a regimen for the administration of a
- R represents hydrogen, lower alkyi, lower alkoxy-lower alkyi, acyloxy-lower alkyi, carboxy- lower alkyi, lower alkoxycarbonyl-lower alkyi, or phenyl-lower alkyi;
- R 2 represents hydrogen, lower alkyi, optionally substituted by one or more identical or different radicals R 3 , cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and
- R 3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or ⁇ , ⁇ -disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
- R and R 2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyi, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N- disubstituted carbamoyl-lower alkyl, cycloalkyl, lower al
- R 4 represents hydrogen, lower alkyl, or halogen
- the Bcr-Abl oncoprotein for the treatment of proliferative disorders, particularly solid and liquid tumors, and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase activity.
- Nilotinib (4-methyl- 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-/ ⁇ /-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)- phenyl] benzamide) is approved and marketed in the form of its monohydrochloride monohydrate salt under the brand name TasignaTM.
- Nilotinib is an ATP-competitive inhibitor for Bcr-Abl and also inhibits c-Kit, DDR1 , DDR2 and PDGF-R kinase activity at clinically relevant concentrations.
- TasignaTM is available as 200 mg hard capsule for oral
- CML Philadelphia-positive chronic myeloid leukaemia
- AP accelerated phase
- imatinib a daily dose of 800 mg of nilotinib is applied in two doses of 400 mg each.
- nilotinib The effect of food on the pharmacokinetic parameters of 400 mg oral dose of nilotinib in the formulation mentioned above was studied in human subjects.
- the total exposure (AUC 0 . t ) was 82 % and C ma x was 112 % after a high fat breakfast, whereas the increase in total exposure (AUC 0 -t) was 29 % and C max was 55 % after a light breakfast given 30 minutes prior to dosing.
- a statement in this regard is, for instance, included in sections 4.2, 4.4 and 4.5 of the SPC (Summary of Product Characteristics) of the marketing authorization for TasignaTM issued by the European Medicines Agency (EMEA).
- the present invention is based on the conclusion that once daily bedtime dosing (QHS) of niiotinib is associated with a systemic exposure comparable to that of the current used dosing of 300 mg BID, so that the total daily dose of drug products comprising niiotinib can be reduced compared to the dose required under the same medical circumstances when using a conventional treatment regimen.
- QHS bedtime dosing
- Niiotinib exposure was shown to be up to 20 % higher following the evening dose than the morning dose.
- the instant treatment regimen provides patients with a convenient once daily dosing, thus improving patient compliance.
- the instant treatment regimen offers the benefit of maintaining efficacy of the pyrimidylaminobenzamide of formula I while reducing the food effect observed when using a conventional treatment regimen.
- the present invention relates to the use of pyrimidylaminobenzamides of formula I
- radicals have the meanings as provided above, or of a pharmaceutically acceptable salt thereof alone or in combination with other active compounds for the preparation of a medicament for the treatment of proliferative disorders and other pathological conditions mediated by Bcr-Abl, c-Kit, DDR1 , DDR2 or PDGF-R kinase activity, wherein the medicament is adjusted in manner to be used once daily at bedtime (QHS).
- QHS bedtime
- the prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
- Lower alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl.
- Preferably lower alkyl is methyl, propyl or tert-butyl.
- Lower acyl is preferably formyl or lower alkylcarbonyl, in particular acetyl.
- aryl group is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical.
- aryl is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphthyl,
- tetrahydronaphthyl, fluorenyl or phenanthrenyl and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, mono- or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or ⁇ , ⁇ -disubstituted carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower alkylphenylthio, lower alkylsulfinyl, phenyl
- Aryl is more preferably phenyl, naphthyl or tetrahydronaphthyl, which in each case is either unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine, or bromine; hydroxy; hydroxy etherified by lower alkyi, e.g. by methyl, by halogen-lower alkyi, e.g. trifluoromethyl, or by phenyl; lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy, lower alkyi, e.g. methyl or propyl; halogen-lower alkyi, e.g.
- hydroxy-lower alkyi e.g. hydroxymethyl or 2-hydroxy-2-propyl
- lower alkoxy-lower alkyi e.g. methoxymethyl or 2-methoxyethyl
- lower alkoxycarbonyl-lower alkyi e.g. methoxy- carbonylmethyl
- lower alkynyl such as 1-propynyl
- esterified carboxy especially lower alkoxycarbonyl, e.g. methoxycarbonyl, n-propoxy carbonyl or iso-propoxy carbonyl
- N-mono- substituted carbamoyl in particular carbamoyl monosubstituted by lower alkyi, e.g.
- lower alkylamino e.g. methylamino
- di-lower alkylamino e.g. dimethylamino or diethylamino
- a cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, and may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyi, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and further by oxo or fused to a benzo ring, such as in benzcyclopentyl or benzcyclohexyl.
- Substituted alkyi is alkyi as last defined, especially lower alkyi, preferably methyl;
- substituents may be present, primarily from the group selected from halogen, especially fluorine, amino, N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is especially preferred.
- Mono- or disubstituted amino is especially amino substituted by one or two radicals selected independently of one another from lower alkyi, such as methyl; hydroxy-lower alkyi, such as 2-hydroxyethyl; lower alkoxy lower alkyi, such as methoxy ethyl; phenyl-lower alkyi, such as benzyl or 2-phenylethyl; lower alkanoyi, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is especially substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radical is unsubstituted or especially
- Disubstituted amino is also lower alkylene-amino, e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino, e.g.
- piperazino or N-substituted piperazino such as N-methylpiperazino or N- methoxycarbonylpiperazino.
- Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
- Etherified hydroxy is especially C 8 -C 2 oalkyloxy, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy, halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2- trifluoroethoxy or 1 ,1 ,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic heteroaryl comprising one or two nitrogen atoms, preferably lower alkoxy which is substituted by imidazolyl, such as 1 H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1- benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyr
- Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower
- alkoxycarbonyloxy such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.
- Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, iso- propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.
- Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g. acetyl.
- N-Mono- or ⁇ , ⁇ -disubstituted carbamoyl is especially substituted by one or two substituents independently selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or aza-lower alkylene optionally substituted at the terminal nitrogen atom.
- a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted, refers to a heterocyclic moiety that is unsaturated in the ring binding the heteroaryl radical to the rest of the molecule in formula I and is preferably a ring, where in the binding ring, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the binding ring preferably has 5 to 12, more preferably 5 or 6 ring atoms; and which may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy.
- the mono- or bicyclic heteroaryl group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinnolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo[d]pyrazolyl, thienyl and furanyl.
- the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyl, such as 1 H-imidazol-1-yl, benzimidazolyl, such as 1- benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl,
- the pyridyl radical is substituted by hydroxy in ortho position to the nitrogen atom and hence exists at least partially in the form of the corresponding tautomer which is pyridin-(1H)2-one.
- the pyrimidinyl radical is substituted by hydroxy both in position 2 and 4 and hence exists in several tautomeric forms, e.g. as pyrimidine-(1 H, 3H)2,4-dione.
- Heterocyclyl is especially a five, six or seven-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo, or heteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5- pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl- piperazinyl, morpholinyl, e.g. 2- or 3-morpholinyl, 2-oxo-1 H-azepin-3-yl, 2-tetrahydrofuranyl, or 2-methyl-1 ,3-dioxolan-2-
- the compound, its manufacture and pharmaceutical compositions suitable for its administration are disclosed in EP1533304A.
- nilotinib is employed in the form of its monohydrochloride monohydrate.
- WO2007/015870 discloses certain polymorphs of nilotinib and pharmaceutically acceptable salts thereof useful for the present invention.
- a suitable formulation for the administration of nilotinib monohydrochloride monohydrate is described in WO2008/037716.
- the expression "proliferative disorders, particularly solid and liquid tumors, and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase” activity means melanoma, especially melanoma harboring c-KIT mutations, breast cancer, cancer of the colon, lung cancer, cancer of the prostate or Kaposi's sarcoma,
- GIST gastrointestinal stromal tumors
- AML acute myeloid leukemia
- CML chronic myeloid leukemia
- Ph+ ALL Philadelphia chromosome positive acute lymphoblastic leukemia
- mesothelioma mesothelioma
- systemic mastocytosis mesothelioma
- HES hypereosinophilic syndrome
- fibrosis especially hepatic fibrosis and renal fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft-versus host diseases, neurofibromatosis, pulmonary
- hypertension especially, pulmonary arterial hypertension, Alzheimer's disease, seminomas and dysgerminomas and psoriasis.
- the regime described herein is applied in the following disorders and conditions: GIST, CML, Ph+ ALL, systemic mastocytosis, HES, fibrosis, scleroderma, neurofibromatosis, pulmonary arterial hypertension.
- the disorder is selected from CML and Ph+ ALL, more preferably CML.
- the disorder is selected from GIST and melanoma, especially melanoma harboring c-KIT mutations.
- the disorder is selected from systemic mastocytosis and HES.
- the disorder is selected from systemic scleroderma, neurofibromatosis and pulmonary arterial hypertension.
- C max means maximum peak concentration in plasma.
- AUC means area under the plasma concentration curve.
- the expression "QHS” means that the drug product containg a compound of formula (I) is taken by the human subjects just before bedtime, preferably evening bedtime. Importantly, the subject is not permitted to take any food at least for the last two hours before taking the drug product.
- bedtime implies that the subject is taking the drug product before resting or, preferably, sleeping for 3 to 12 hours, preferably 5 to 10 hours, more preferably between 6 and 8 hours. Sleeping can be night time sleep (preferred) or sleep any time during the day.
- nilotinib can be applied in a total daily dose of 400 to 1000 mg depending, in particular on the disease to be treated and the disease status of the patient under treatment.
- the treatment regimen described herein allows to lower the total daily dose applied to patients suffering from Philadelphia positive leukemia, especially CML CP, to 500 to 700 mg/day, especially to 600 mg/day.
- a lower dose is reducing the incidence of side effects correlating with the total drug load.
- the present inventions also provides a method of treating or preventing proliferative disorders and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase activity in a subject in need thereof comprising administering a pyrimidylaminobenzamide derivatives of formula (I):
- RT represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy- lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R 2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R 3 , cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly- substituted; and
- R 3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or ⁇ /,/V-di-substituted carbamoyl, amino, mono- or di-substituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bi-cyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; or
- Ri and R 2 together, represent alkylene with 4, 5 or 6 carbon atoms optionally mono- or di- substituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or di-substituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with 4 or 5 carbon atoms; oxaalkylene with 1 oxygen and 3 or 4 carbon atoms; or azaalkylene with 1 nitrogen and 3 or 4 carbon atoms, wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl- lower alkyl, ⁇ -mono- or A/,A/-di-substituted carbamoyl-lower alkyl, cycloalkyl
- the subject is not permitted to take any food at least for the last two hours before taking the drug product.
- Example 1 Study in CML Patients obtaining 400 mg Nilotinib twice daily
- Example 2 Simulation of 600 mg QHS vs. 400 mg twice daily
- Fig. 2 The simulation depicted in Fig. 2 is based on the hypothesis that QHS dosing is associated with increased bioavailability of nilotinib. Based on that assumption, C max appears to be similar for both treatment approaches.
- Example 3 PK Study in Healthy Volunteers
- HV pharmacokinetics in healthy volunteers
- HV group A was administered 300 mg nilotinib (in the form of nilotinib
- HV group B was administered 300 mg nilotinib (in the form of nilotinib monohydrochloride monohydrate) in the evening, 2 hours after diner
- HV group C was administered 600 mg nilotinib (in the form of nilotinib monohydrochloride monohydrate) in the evening, 2 hours after diner
- HV group D was administered 600 mg nilotinib (in the form of nilotinib monohydrochloride
- nilotinib PK was compared when administered in the evening versus administration in the morning (B vs. A) and the potential residual food effect on nilotinib absorption was assessed (D vs. C).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Psychiatry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a regimen for the administration of a pyrimidylaminobenzamide of formula I as defined herein for the treatment of proliferative disorders, particularly solid and liquid tumors, and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase activity.
Description
METHOD OF TREATING PROLIFERATIVE DISORDERS AND OTHER PATHOLOGICAL CONDITIONS MEDIATED BY BCR-ABL, C-KIT. DDR1. DDR2 OR PDGF-R KINASE ACTIVITY
The present invention relates to a regimen for the administration of a
pyrimidylaminobenzamide of formula I
(a) Py denotes 3-pyridyl,
R represents hydrogen, lower alkyi, lower alkoxy-lower alkyi, acyloxy-lower alkyi, carboxy- lower alkyi, lower alkoxycarbonyl-lower alkyi, or phenyl-lower alkyi;
R2 represents hydrogen, lower alkyi, optionally substituted by one or more identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or Ν,Ν-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
or wherein R and R2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyi, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms
wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N- disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
R4 represents hydrogen, lower alkyl, or halogen;
or
(b) Py denotes 5-pyrimidyl, is hydrogen, R2 is [[(3S)-3-(dimethylamino)- 1-pyrrolidinyl]- methyl]-3-(trifluoromethyl)phenyl and R4 is methyl;
or of a pharmaceutically acceptable salt thereof,
for the treatment of proliferative disorders, particularly solid and liquid tumors, and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase activity.
The compound of formula I, wherein Py denotes 3-pyridyl, R-i represents hydrogen, R2 represents 5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)-phenyl and R represents methyl, is known under the International Non-proprietary Name "nilotinib". Nilotinib (4-methyl- 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-/\/-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)- phenyl] benzamide) is approved and marketed in the form of its monohydrochloride monohydrate salt under the brand name Tasigna™. Nilotinib is an ATP-competitive inhibitor for Bcr-Abl and also inhibits c-Kit, DDR1 , DDR2 and PDGF-R kinase activity at clinically relevant concentrations. Tasigna™ is available as 200 mg hard capsule for oral
administration for the treatment of Philadelphia-positive chronic myeloid leukaemia (CML) in the chronic phase (CP) and accelerated phase (AP) in patients resistant to or intolerant of at least one prior therapy including imatinib. For the treatment of CML a daily dose of 800 mg of nilotinib is applied in two doses of 400 mg each.
The effect of food on the pharmacokinetic parameters of 400 mg oral dose of nilotinib in the formulation mentioned above was studied in human subjects. The concomitant administration of nilotinib with food significantly increased subjects exposure, especially in high fat meals. In said study the total exposure (AUC0.t) was 82 % and Cmax was 112 % after a high fat breakfast, whereas the increase in total exposure (AUC0-t) was 29 % and Cmax was 55 % after a light breakfast given 30 minutes prior to dosing. In view of these findings, it is recommended that nilotinib shall not be taken with a meal in order to minimize the effect of
food on niiotinib bioavailability. A statement in this regard is, for instance, included in sections 4.2, 4.4 and 4.5 of the SPC (Summary of Product Characteristics) of the marketing authorization for Tasigna™ issued by the European Medicines Agency (EMEA).
The present invention is based on the conclusion that once daily bedtime dosing (QHS) of niiotinib is associated with a systemic exposure comparable to that of the current used dosing of 300 mg BID, so that the total daily dose of drug products comprising niiotinib can be reduced compared to the dose required under the same medical circumstances when using a conventional treatment regimen.
In a study in healthy volunteers as described in the Examples, a slight diurnal effect on niiotinib pharmacokinetics (PK) was confirmed. Niiotinib exposure was shown to be up to 20 % higher following the evening dose than the morning dose.
Further, it was found that when a pyrimidylaminobenzamide of formula I is
administered to a human once daily QHS the risk of food drug interaction is minimized. The instant treatment regimen provides patients with a convenient once daily dosing, thus improving patient compliance. The instant treatment regimen offers the benefit of maintaining efficacy of the pyrimidylaminobenzamide of formula I while reducing the food effect observed when using a conventional treatment regimen.
Hence, the present invention relates to the use of pyrimidylaminobenzamides of formula I
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
The prefix "lower" denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Lower alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Preferably lower alkyl is methyl, propyl or tert-butyl.
Lower acyl is preferably formyl or lower alkylcarbonyl, in particular acetyl.
An aryl group is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical. In a preferred embodiment, aryl is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphthyl,
tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, mono- or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or Ν,Ν-disubstituted carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower alkylphenylthio, lower alkylsulfinyl, phenylsulfinyl, phenyl-lower alkylsulfinyl, lower alkylphenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, lower alkylphenylsulfonyl, halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, such as especially trifluoromethanesulfonyl, dihydroxybora (-B(OH)2), heterocyclyl, a mono- or bicyclic heteroaryl group and lower alkylene dioxy bound at adjacent C-atoms of the ring,
such as methylene dioxy. Aryl is more preferably phenyl, naphthyl or tetrahydronaphthyl, which in each case is either unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine, or bromine; hydroxy; hydroxy etherified by lower alkyi, e.g. by methyl, by halogen-lower alkyi, e.g. trifluoromethyl, or by phenyl; lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy, lower alkyi, e.g. methyl or propyl; halogen-lower alkyi, e.g. trifluoromethyl; hydroxy-lower alkyi, e.g. hydroxymethyl or 2-hydroxy-2-propyl; lower alkoxy-lower alkyi; e.g. methoxymethyl or 2-methoxyethyl; lower alkoxycarbonyl-lower alkyi, e.g. methoxy- carbonylmethyl; lower alkynyl, such as 1-propynyl; esterified carboxy, especially lower alkoxycarbonyl, e.g. methoxycarbonyl, n-propoxy carbonyl or iso-propoxy carbonyl; N-mono- substituted carbamoyl, in particular carbamoyl monosubstituted by lower alkyi, e.g. methyl, n-propyl or iso-propyl; amino; lower alkylamino, e.g. methylamino; di-lower alkylamino, e.g. dimethylamino or diethylamino; lower alkylene-amino, e.g. pyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, lower azaalkylene-amino, e.g. piperazino, acylamino, e.g. acetylamino or benzoylamino; lower alkylsulfonyl, e.g. methylsulfonyl; sulfamoyl; or phenylsulfonyl.
A cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, and may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyi, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and further by oxo or fused to a benzo ring, such as in benzcyclopentyl or benzcyclohexyl.
Substituted alkyi is alkyi as last defined, especially lower alkyi, preferably methyl;
where one or more, especially up to three, substituents may be present, primarily from the group selected from halogen, especially fluorine, amino, N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is especially preferred.
Mono- or disubstituted amino is especially amino substituted by one or two radicals selected independently of one another from lower alkyi, such as methyl; hydroxy-lower alkyi, such as 2-hydroxyethyl; lower alkoxy lower alkyi, such as methoxy ethyl; phenyl-lower alkyi, such as benzyl or 2-phenylethyl; lower alkanoyi, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is especially substituted by one or more, preferably one or two,
substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radical is unsubstituted or especially substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and is preferably N-lower alkylamino, such as N-methylamino, hydroxy-lower alkylamino, such as 2-hydroxyethylamino or 2- hydroxypropyl, lower alkoxy lower alkyl, such as methoxy ethyl, phenyl-lower alkylamino, such as benzylamino, N,N-di-lower alkylamino, N-phenyl-lower alkyl-N-lower alkylamino, N,N-di-lower alkylphenylamino, lower alkanoylamino, such as acetylamino, or a substituent selected from the group comprising benzoylamino and phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or especially substituted by nitro or amino, or also by halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl or aminocarbonylamino. Disubstituted amino is also lower alkylene-amino, e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino, e.g.
piperazino or N-substituted piperazino, such as N-methylpiperazino or N- methoxycarbonylpiperazino.
Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
Etherified hydroxy is especially C8-C2oalkyloxy, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy, halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2- trifluoroethoxy or 1 ,1 ,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic heteroaryl comprising one or two nitrogen atoms, preferably lower alkoxy which is substituted by imidazolyl, such as 1 H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1- benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, indolyl or thiazolyl.
Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower
alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.
Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, iso- propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.
Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g. acetyl.
N-Mono- or Ν,Ν-disubstituted carbamoyl is especially substituted by one or two substituents independently selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or aza-lower alkylene optionally substituted at the terminal nitrogen atom.
A mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted, refers to a heterocyclic moiety that is unsaturated in the ring binding the heteroaryl radical to the rest of the molecule in formula I and is preferably a ring, where in the binding ring, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the binding ring preferably has 5 to 12, more preferably 5 or 6 ring atoms; and which may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy. Preferably the mono- or bicyclic heteroaryl group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinnolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo[d]pyrazolyl, thienyl and furanyl. More preferably the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyl, such as 1 H-imidazol-1-yl, benzimidazolyl, such as 1- benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl,
benzo[d]pyrazolyl, thienyl, and furanyl. In one preferred embodiment of the invention the pyridyl radical is substituted by hydroxy in ortho position to the nitrogen atom and hence
exists at least partially in the form of the corresponding tautomer which is pyridin-(1H)2-one. In another preferred embodiment, the pyrimidinyl radical is substituted by hydroxy both in position 2 and 4 and hence exists in several tautomeric forms, e.g. as pyrimidine-(1 H, 3H)2,4-dione.
Heterocyclyl is especially a five, six or seven-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo, or heteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5- pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl- piperazinyl, morpholinyl, e.g. 2- or 3-morpholinyl, 2-oxo-1 H-azepin-3-yl, 2-tetrahydrofuranyl, or 2-methyl-1 ,3-dioxolan-2-yl.
Pyrimidylaminobenzamides within the scope of formula I, wherein py is 3-pyridyl and the process for their manufacture are disclosed in WO 04/005281 , which is hereby incorporated into the present application by reference.
The pyrimidylaminobenzamide of formula I wherein Py denotes 5-pyrimidyl, is hydrogen, R2 is [[(3S)-3-(dimethylamino)-1-pyrrolidinyl]methyl]-3-(trifluoromethyl)phenyl and R4 is methyl is also known as INNO-406. The compound, its manufacture and pharmaceutical compositions suitable for its administration are disclosed in EP1533304A.
Pharmaceutically acceptable salts of pyrimidylaminobenzamides of formula I, wherein py is 3-pyridyl, are especially those disclosed in WO2007/015871. In one preferred embodiment nilotinib is employed in the form of its monohydrochloride monohydrate.
WO2007/015870 discloses certain polymorphs of nilotinib and pharmaceutically acceptable salts thereof useful for the present invention. A suitable formulation for the administration of nilotinib monohydrochloride monohydrate is described in WO2008/037716.
As used herein, the expression "proliferative disorders, particularly solid and liquid tumors, and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase"
activity means melanoma, especially melanoma harboring c-KIT mutations, breast cancer, cancer of the colon, lung cancer, cancer of the prostate or Kaposi's sarcoma,
gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), leukemia which responds to an inhibition of the Abl tyrosine kinase activity, such as chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), mesothelioma, systemic mastocytosis, hypereosinophilic syndrome (HES), fibrosis, especially hepatic fibrosis and renal fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft-versus host diseases, neurofibromatosis, pulmonary
hypertension, especially, pulmonary arterial hypertension, Alzheimer's disease, seminomas and dysgerminomas and psoriasis. Preferably, the regime described herein is applied in the following disorders and conditions: GIST, CML, Ph+ ALL, systemic mastocytosis, HES, fibrosis, scleroderma, neurofibromatosis, pulmonary arterial hypertension.
In one embodiment of the present invention the disorder is selected from CML and Ph+ ALL, more preferably CML.
In another embodiment of the present invention the disorder is selected from GIST and melanoma, especially melanoma harboring c-KIT mutations.
In another embodiment of the present invention the disorder is selected from systemic mastocytosis and HES.
In a further embodiment of the present invention the disorder is selected from systemic scleroderma, neurofibromatosis and pulmonary arterial hypertension.
As used herein, the expression "Cmax" means maximum peak concentration in plasma.
As used herein, the expression "AUC" means area under the plasma concentration curve.
As used herein, the expression "QHS" means that the drug product containg a compound of formula (I) is taken by the human subjects just before bedtime, preferably evening bedtime. Importantly, the subject is not permitted to take any food at least for the last two hours before taking the drug product. The term "bedtime" implies that the subject is
taking the drug product before resting or, preferably, sleeping for 3 to 12 hours, preferably 5 to 10 hours, more preferably between 6 and 8 hours. Sleeping can be night time sleep (preferred) or sleep any time during the day.
For the purposes of the present invention, nilotinib can be applied in a total daily dose of 400 to 1000 mg depending, in particular on the disease to be treated and the disease status of the patient under treatment.
In a further aspect of the invention, the treatment regimen described herein allows to lower the total daily dose applied to patients suffering from Philadelphia positive leukemia, especially CML CP, to 500 to 700 mg/day, especially to 600 mg/day. A lower dose is reducing the incidence of side effects correlating with the total drug load.
The present inventions also provides a method of treating or preventing proliferative disorders and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase activity in a subject in need thereof comprising administering a pyrimidylaminobenzamide derivatives of formula (I):
wherein
(a) Py denotes 3-pyridyl,
RT represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy- lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
R2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or
bicyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly- substituted; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or Λ/,/V-di-substituted carbamoyl, amino, mono- or di-substituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bi-cyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; or
Ri and R2, together, represent alkylene with 4, 5 or 6 carbon atoms optionally mono- or di- substituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or di-substituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with 4 or 5 carbon atoms; oxaalkylene with 1 oxygen and 3 or 4 carbon atoms; or azaalkylene with 1 nitrogen and 3 or 4 carbon atoms, wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl- lower alkyl, Λί-mono- or A/,A/-di-substituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl; R4 represents hydrogen, lower alkyl or halogen;
or
(b) Py denotes 5-pyrimidyl, is hydrogen, R2 is [[(3S)-3-(dimethylamino)- 1-pyrrolidinyl]- methyl]-3-(trifluoromethyl)phenyl and R is methyl;
or a pharmaceutically acceptable salt of such a compound, wherein the compound of formula I is administered once daily, preferably in the evening, just before bedtime.
In a preferred embodiment of the invention, the subject is not permitted to take any food at least for the last two hours before taking the drug product.
EXAMPLES
Example 1 : Study in CML Patients obtaining 400 mg Nilotinib twice daily
21 Patients were treated with 400 mg nilotinib twice daily. The mean concentration over time is shown in Fig. 1. Blood samples were collected prior to morning dose (CO) and prior to evening dose (C12). It was found that the ratio C0/C12 is 1.7. With other words, the trough
concentration of nilotinib in the morning was 60 to 80 % higher than that observed in the evening.
Example 2: Simulation of 600 mg QHS vs. 400 mg twice daily
The simulation depicted in Fig. 2 is based on the hypothesis that QHS dosing is associated with increased bioavailability of nilotinib. Based on that assumption, Cmax appears to be similar for both treatment approaches.
Example 3: PK Study in Healthy Volunteers
The increased exposure with QHS was confirmed in a study investigating nilotinib
pharmacokinetics in healthy volunteers (HV) comparing cohorts receiving 600 mg morning dose or 600 mg morning dose QHS, respectively. In a single center, 4-way crossover study (n = 16-24), HV group A was administered 300 mg nilotinib (in the form of nilotinib
monohydrochloride monohydrate) in the morning, 2 hours after breakfast; HV group B was administered 300 mg nilotinib (in the form of nilotinib monohydrochloride monohydrate) in the evening, 2 hours after diner; HV group C was administered 600 mg nilotinib (in the form of nilotinib monohydrochloride monohydrate) in the evening, 2 hours after diner; and HV group D was administered 600 mg nilotinib (in the form of nilotinib monohydrochloride
monohydrate) in the evening, 4 hours after diner.
Table 1 - Study Results - Summary of PK Parameters
Parameter A B C D Geometric Mean Ratio
(N =20) (N=18) (N = 22) (N = 22) (90% Cls)
B vs A D vs C tmax (h) 4.0 (3.0, 8.0) 4.0 (3.0, 4.0 (3.0, 4.0 (2.0, 0.49 (-1.00, -0.49 (-5.96,
10.0) 10.0) 10.2) 6.00) 7.00)
577 (35) 655 (18) 854 (29) 782 (46) 1.14 (1.01 , 0.92 (0.82,
(ng/mL) 1.27) 1.02)
AUC0.t|asl 13650 (27) 15556 (18) 20819 (22) 19591 (30) 1.14 (1.06, 0.94 (0.88,
(ng«h/ml_) 1.23) 1.01)
AUC0.inf 14920 (31) 16272 (19) 23216 (21) 21937 (34) 1.09 (1.00, 0.94 (0.87, (ng'h/mL) 1.19) 1.03)
AUCO-12 4577 (33) 5537 (16) 7124 (29) 6650 (41) 1.21 (1.09, 0.93 (0.85, (ng« /mL) 1.34) 1.03)
AUCO-24 7781 (30) 9435 (18) 11857 (26) 111064 1.21 (1.11, 0.93 (0.86, (ng- /mL) (36) 1.32) 1.01) ti/2 (h) 20.3 (38) 14.5 (21) 20.5 (39) 19.9 (38) NA NA
The nilotinib PK was compared when administered in the evening versus administration in the morning (B vs. A) and the potential residual food effect on nilotinib absorption was assessed (D vs. C).
Example 4: Phase III Study in CML Patients
The benefits described herein can be confirmed in a randomized phase III study in patients with newly diagnosed CML CP comparing 300 mg nilotinib twice daily with 600 mg QHS.
Claims
1. The use of a pyrimidylaminobenzamide of formula I
wherein
(a) Py denotes 3-pyridyl,
P represents hydrogen, lower alkyi, lower alkoxy-lower alkyi, acyloxy-lower alkyi, carboxy- lower alkyi, lower alkoxycarbonyl-lower alkyi, or phenyl-lower alkyi;
R2 represents hydrogen, lower alkyi, optionally substituted by one or more identical or different radicals R3, cycloalkyi, benzcycloalkyi, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or N,N-disubst'ituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyi, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
or wherein and R2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyi, cycloalkyi, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyi, phenyl-lower alkyi, lower alkoxycarbonyl-lower alkyi, carboxy-lower alkyi, carbamoyl-lower alkyi, N-mono- or N,N- disubstituted carbamoyl-lower alkyi, cycloalkyi, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
R4 represents hydrogen, lower alkyi, or halogen; wherein the prefix "lower" denotes a radical having up to and including a maximum of 7 carbon atoms,
or
(b) Py denotes 5-pyrimidyl, R-i is hydrogen, R2 is [[(3S)-3-(dimethylamino)- 1-pyrrolidinyl]- methyl]-3-(trifluoromethyl)phenyl and R4 is methyl;
or of a pharmaceutically acceptable salt thereof, respectively,
for the preparation of a medicament for the treatment of proliferative disorders and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase activity, wherein the medicament is adjusted in manner to be taken just before bedtime (QHS).
2. The use according to claim 1, wherein the pynmidylaminobenzamide of formula I is 4- methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-/V-[5-(4-methyl-1H-imidazol-1-yl)-3- (trifluoromethyl)phenyl] benzamide.
3. The use according to claim 2, wherein the pyrimidylaminobenzamide is employed in the form of its hydrochloride monohydrate.
4. The use according to any one of claims 1 to 3, wherein the proliferative disorder or other pathological condition is selected from melanoma, breast cancer, cancer of the colon, lung cancer, cancer of the prostate or Kaposi's sarcoma, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), leukemia which responds to an inhibition of the Abl tyrosine kinase activity, mesothelioma, systemic mastocytosis, hypereosinophilic syndrome (HES), fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft-versus host diseases, neurofibromatosis, pulmonary hypertension, Alzheimer's disease, seminomas and dysgerminomas and psoriasis.
5. The use according to claim 4 wherein the proliferative disorder or other pathological condition is selected from GIST, CML, Ph+ ALL, systemic mastocytosis, HES, fibrosis, scleroderma, neurofibromatosis and pulmonary arterial hypertension.
6. The use according to any one of claims 1 to 3, wherein the proliferative disorder is Philadelphia positive leukemia and the dose applied is between 500 mg/day and 700 mg/day.
7. A method of treating or preventing proliferative disorders and other pathological conditions mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c- Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase activity comprising administering a pyrimidylaminobenzamide derivatives of formula (I):
(a) Py denotes 3-pyridyl,
Ri represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy- lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
R2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or Λ/,/V-di-substituted carbamoyl, amino, mono- or di-substituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bi-cyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; or
and R2, together, represent alkylene with 4, 5 or 6 carbon atoms optionally mono- or di- substituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or di-substituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with 4 or 5 carbon atoms; oxaalkylene with 1 oxygen and 3 or 4 carbon atoms; or azaalky!ene with 1 nitrogen and 3 or 4 carbon atoms, wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, /V-mono- or Λ/,/V-di-substituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl;
R represents hydrogen, lower alkyl or halogen;
or
(b) Py denotes 5-pyrimidyl, is hydrogen, R2 is [[(3S)-3-(dimethy!amino)- 1-pyrrolidinyl]- methyl]-3-(trifluoromethyl)phenyl and R4 is methyl;
or a pharmaceutically acceptable salt of such a compound, wherein the compound of formula I is administered once daily just before bedtime (QHS).
8. The method according to claim 7, wherein the pyrimidylaminobenzamide is 4-methyl-3-[[4- (3-pyridinyl)-2-pyrimidinyl]amino]-A/-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)- phenyl] benzamide.
9. The method according to claim 8, wherein the pyrimidylaminobenzamide is employed in the form of its hydrochloride monohydrate.
10. The method according to any one of claims 7 to 9, wherein the proliferative disorder or other pathological condition is selected from melanoma, breast cancer, cancer of the colon, lung cancer, cancer of the prostate or Kaposi's sarcoma, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), leukemia which responds to an inhibition of the Abl tyrosine kinase activity, mesothelioma, systemic mastocytosis, hypereosino- philic syndrome (HES), fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft-versus host diseases, neurofibromatosis, pulmonary hypertension, Alzheimer's disease, seminomas and dysgerminomas and psoriasis.
11. The method according to any one of claims 7 to 9, wherein the proliferative disorder is Philadelphia positive leukemia and the dose administered is between 500 mg/day and 700 mg/day.
12. A commercial package containing a pharmaceutical composition comprising a pyrimidylaminobenzamide of formula I
(a) Py denotes 3-pyridyl,
R-i represents hydrogen, lower alkyi, lower alkoxy-lower alkyi, acyloxy-lower alkyi, carboxy- lower alkyi, lower alkoxycarbonyl-lower alkyi, or phenyl-lower alkyi;
R2 represents hydrogen, lower alkyi, optionally substituted by one or more identical or different radicals R3, cycloalkyi, benzcycloalkyi, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or Ν,Ν-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyi, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
or wherein and R2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyi, cycloalkyi, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyi, phenyl-lower alkyi, lower alkoxycarbonyl-lower alkyi, carboxy-lower alkyi, carbamoyl-lower alkyi, N-mono- or N,N- disubstituted carbamoyl-lower alkyi, cycloalkyi, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
R4 represents hydrogen, lower alkyi, or halogen; wherein the prefix "lower" denotes a radical having up to and including a maximum of 7 carbon atoms,
or
(b) Py denotes 5-pyrimidyl, is hydrogen, R2 is [[(3S)-3-(dimethylamino)- 1-pyrrolidinyl]- methyl]-3-(trifluoromethyl)phenyl and R4 is methyl;
or of a pharmaceutically acceptable salt thereof, respectively,
together with instructions for use for the treatment of a proliferative disorder or a pathological condition mediated by the Bcr-Abl oncoprotein, the cell transmembrane tyrosine kinase receptor c-Kit, DDR1 (discoidin domain receptor 1), DDR2 (discoidin domain receptor 2) or PDGF-R (platelet derived growth factor receptor) kinase activity, wherein the medicament shall be used once daily just before bedtime (QHS).
Priority Applications (18)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX2012004709A MX2012004709A (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity. |
| CN2010800461900A CN102647986A (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by BCR-ABL, C-KIT, DDR1, DDR2 or PDGF-R kinase activity |
| JP2012535351A JP5948246B2 (en) | 2009-10-23 | 2010-10-21 | Methods for treating proliferative disorders and other conditions mediated by kinase activity of BCR-ABL, C-KIT, DDR1, DDR2 or PDGF-R |
| US13/501,274 US20120202836A1 (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| CA2777019A CA2777019A1 (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| NZ599217A NZ599217A (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| RU2012120901/04A RU2012120901A (en) | 2009-10-23 | 2010-10-21 | METHOD FOR TREATING PROLIFERATIVE DISORDERS AND OTHER PATHOLOGICAL CONDITIONS mediated by the action of kinases BCR-ABL, C-KIT, DDR1, DDR2 OR PDGF-R |
| EP10773472A EP2490690A1 (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| KR1020177001075A KR101853596B1 (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| BR112012009094A BR112012009094A8 (en) | 2009-10-23 | 2010-10-21 | method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| AU2010310705A AU2010310705A1 (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by Bcr-Abl, c-Kit, DDR1, DDR2 or PDGF-R kinase activity |
| TNP2012000150A TN2012000150A1 (en) | 2009-10-23 | 2012-04-02 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| ZA2012/02413A ZA201202413B (en) | 2009-10-23 | 2012-04-03 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| IL219109A IL219109A (en) | 2009-10-23 | 2012-04-05 | Use of pyrimidyl aminobenzamide for the preparation of medicaments for the treatiment of proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| MA34769A MA33666B1 (en) | 2009-10-23 | 2012-04-10 | METHOD FOR TREATMENT OF PROLIFERATIVE DISORDERS AND OTHER MEDIATION CONDITIONS TO MEDIATION BY BCR-ABL, C-KIT, DDR1, DDR2 OR PDGF-R KINASE ACTIVITY |
| US14/264,357 US20140350037A1 (en) | 2009-10-23 | 2014-04-29 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| US14/797,716 US20150313900A1 (en) | 2009-10-23 | 2015-07-13 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| US15/425,417 US20170143716A1 (en) | 2009-10-23 | 2017-02-06 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25432309P | 2009-10-23 | 2009-10-23 | |
| US61/254,323 | 2009-10-23 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US13/501,274 A-371-Of-International US20120202836A1 (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
| US14/264,357 Continuation US20140350037A1 (en) | 2009-10-23 | 2014-04-29 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011050120A1 true WO2011050120A1 (en) | 2011-04-28 |
Family
ID=43222136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2010/053459 WO2011050120A1 (en) | 2009-10-23 | 2010-10-21 | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
Country Status (18)
| Country | Link |
|---|---|
| US (4) | US20120202836A1 (en) |
| EP (1) | EP2490690A1 (en) |
| JP (1) | JP5948246B2 (en) |
| KR (2) | KR20120099650A (en) |
| CN (1) | CN102647986A (en) |
| AU (3) | AU2010310705A1 (en) |
| BR (1) | BR112012009094A8 (en) |
| CA (1) | CA2777019A1 (en) |
| CL (1) | CL2012001012A1 (en) |
| IL (1) | IL219109A (en) |
| MA (1) | MA33666B1 (en) |
| MX (1) | MX2012004709A (en) |
| NZ (1) | NZ599217A (en) |
| RU (1) | RU2012120901A (en) |
| TN (1) | TN2012000150A1 (en) |
| TW (1) | TWI592157B (en) |
| WO (1) | WO2011050120A1 (en) |
| ZA (1) | ZA201202413B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013068836A1 (en) | 2011-11-07 | 2013-05-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A ddr1 antagonist or an inhibitor of ddr1 gene expression for use in the prevention or treatment of crescentic glomerulonephritis |
| WO2013161851A1 (en) * | 2012-04-24 | 2013-10-31 | 中外製薬株式会社 | Benzamide derivative |
| WO2013161853A1 (en) * | 2012-04-24 | 2013-10-31 | 中外製薬株式会社 | Quinazolinedione derivative |
| CN105102983A (en) * | 2012-12-27 | 2015-11-25 | 奎斯特诊断投资股份有限公司 | Ddr2 mutations as targetable features of melanoma or basal cell carcinoma |
| US10005739B2 (en) | 2013-10-23 | 2018-06-26 | Chugai Seiyaku Kabushiki Kaisha | Quinazolinone and isoquinolinone derivative |
| WO2020207611A1 (en) * | 2019-04-09 | 2020-10-15 | Rottapharm Biotech S.R.L. | Phenazines as inhibitors of discoidin domain receptors 2 (ddr2) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2013256227B2 (en) | 2012-05-02 | 2017-06-15 | Georgetown University | Treating neural disease with tyrosine kinase inhibitors |
| CN103965195B (en) * | 2013-02-01 | 2016-09-28 | 中国科学院广州生物医药与健康研究院 | Compound and application thereof for discoidin domain receptor micromolecular inhibitor |
| AU2014286892A1 (en) * | 2013-07-05 | 2016-01-28 | Integra Medical Inc. | Oral compositions |
| MX2018000677A (en) * | 2015-08-31 | 2018-05-07 | Toray Industries | Urea derivative and use therefor. |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004005281A1 (en) | 2002-07-05 | 2004-01-15 | Novartis Ag | Inhibitors of tyrosine kinases |
| EP1533304A1 (en) | 2002-06-28 | 2005-05-25 | Nippon Shinyaku Co., Ltd. | Amide derivative |
| WO2007015871A1 (en) | 2005-07-20 | 2007-02-08 | Novartis Ag | Salts of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
| WO2007015870A2 (en) | 2005-07-20 | 2007-02-08 | Novartis Ag | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
| WO2007065898A1 (en) * | 2005-12-06 | 2007-06-14 | Novartis Ag | Pyrimidylaminobenzamide derivatives for the treatment of neurofibromatosis |
| WO2008037716A2 (en) | 2006-09-27 | 2008-04-03 | Novartis Ag | Pharmaceutical compositions comprising nilotinib or its salt |
| WO2009026075A1 (en) * | 2007-08-16 | 2009-02-26 | Irm Llc | Methods and compositions for treating cancers |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7729791B2 (en) * | 2006-09-11 | 2010-06-01 | Apple Inc. | Portable media playback device including user interface event passthrough to non-media-playback processing |
-
2010
- 2010-10-21 KR KR1020127010179A patent/KR20120099650A/en not_active Application Discontinuation
- 2010-10-21 NZ NZ599217A patent/NZ599217A/en not_active IP Right Cessation
- 2010-10-21 WO PCT/US2010/053459 patent/WO2011050120A1/en active Application Filing
- 2010-10-21 JP JP2012535351A patent/JP5948246B2/en not_active Expired - Fee Related
- 2010-10-21 BR BR112012009094A patent/BR112012009094A8/en not_active IP Right Cessation
- 2010-10-21 KR KR1020177001075A patent/KR101853596B1/en active IP Right Grant
- 2010-10-21 CN CN2010800461900A patent/CN102647986A/en active Pending
- 2010-10-21 US US13/501,274 patent/US20120202836A1/en not_active Abandoned
- 2010-10-21 MX MX2012004709A patent/MX2012004709A/en unknown
- 2010-10-21 CA CA2777019A patent/CA2777019A1/en not_active Abandoned
- 2010-10-21 RU RU2012120901/04A patent/RU2012120901A/en not_active Application Discontinuation
- 2010-10-21 EP EP10773472A patent/EP2490690A1/en not_active Withdrawn
- 2010-10-21 AU AU2010310705A patent/AU2010310705A1/en not_active Abandoned
- 2010-10-22 TW TW099136217A patent/TWI592157B/en not_active IP Right Cessation
-
2012
- 2012-04-02 TN TNP2012000150A patent/TN2012000150A1/en unknown
- 2012-04-03 ZA ZA2012/02413A patent/ZA201202413B/en unknown
- 2012-04-05 IL IL219109A patent/IL219109A/en not_active IP Right Cessation
- 2012-04-10 MA MA34769A patent/MA33666B1/en unknown
- 2012-04-20 CL CL2012001012A patent/CL2012001012A1/en unknown
-
2014
- 2014-04-29 US US14/264,357 patent/US20140350037A1/en not_active Abandoned
- 2014-05-30 AU AU2014202963A patent/AU2014202963A1/en not_active Abandoned
-
2015
- 2015-07-13 US US14/797,716 patent/US20150313900A1/en not_active Abandoned
-
2016
- 2016-08-18 AU AU2016216636A patent/AU2016216636B2/en not_active Expired - Fee Related
-
2017
- 2017-02-06 US US15/425,417 patent/US20170143716A1/en not_active Abandoned
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1533304A1 (en) | 2002-06-28 | 2005-05-25 | Nippon Shinyaku Co., Ltd. | Amide derivative |
| WO2004005281A1 (en) | 2002-07-05 | 2004-01-15 | Novartis Ag | Inhibitors of tyrosine kinases |
| WO2007015871A1 (en) | 2005-07-20 | 2007-02-08 | Novartis Ag | Salts of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
| WO2007015870A2 (en) | 2005-07-20 | 2007-02-08 | Novartis Ag | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
| WO2007065898A1 (en) * | 2005-12-06 | 2007-06-14 | Novartis Ag | Pyrimidylaminobenzamide derivatives for the treatment of neurofibromatosis |
| WO2008037716A2 (en) | 2006-09-27 | 2008-04-03 | Novartis Ag | Pharmaceutical compositions comprising nilotinib or its salt |
| WO2009026075A1 (en) * | 2007-08-16 | 2009-02-26 | Irm Llc | Methods and compositions for treating cancers |
Non-Patent Citations (4)
| Title |
|---|
| HENKES MARTIN ET AL: "Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec, Gleevectrade mark)", THERAPEUTICS AND CLINICAL RISK MANAGEMENT, DOVE MEDICAL PRESS LTD, NZ, vol. 4, no. 1, 1 February 2008 (2008-02-01), pages 163 - 187, XP009142188, ISSN: 1176-6336 * |
| JABBOUR, ELIAS ET AL: "Optimizing treatment with Bcr-Abl tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia: focus on dosing schedules", CLINICAL LYMPHOMA & MYELOMA , 8(SUPPL. 3), S75-S81 CODEN: CLMLBP; ISSN: 1557-9190, 2008, XP002613583 * |
| KANTARJIAN HAGOP ET AL: "NILOTINIB IN IMATINIB-RESISTANT CML AND PHILADELPHIA CHROMOSOME-POSITIVE", NEW ENGLAND JOURNAL OF MEDICINE, MASSACHUSETTS MEDICAL SOCIETY, BOSTON, MA, US, vol. 354, no. 24, 15 June 2006 (2006-06-15), pages 2542 - 2551, XP009072571, ISSN: 1533-4406, DOI: DOI:10.1056/NEJMOA055104 * |
| TANAKA C ET AL: "Clinical Pharmacokinetics of the BCR-ABL Tyrosine Kinase Inhibitor Nilotinib", CLINICAL PHARMACOLOGY AND THERAPEUTICS, NATURE PUBLISHING GROUP, US, vol. 87, no. 2, 1 February 2010 (2010-02-01), pages 197 - 203, XP009142210, ISSN: 0009-9236 * |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013068836A1 (en) | 2011-11-07 | 2013-05-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A ddr1 antagonist or an inhibitor of ddr1 gene expression for use in the prevention or treatment of crescentic glomerulonephritis |
| US9567304B2 (en) | 2012-04-24 | 2017-02-14 | Chugai Seiyaku Kabushiki Kaisha | Quinazolinedione derivative |
| CN104379560A (en) * | 2012-04-24 | 2015-02-25 | 中外制药株式会社 | Benzamide derivative |
| WO2013161851A1 (en) * | 2012-04-24 | 2013-10-31 | 中外製薬株式会社 | Benzamide derivative |
| CN104379568A (en) * | 2012-04-24 | 2015-02-25 | 中外制药株式会社 | Quinazolinedione derivative |
| US9695118B2 (en) | 2012-04-24 | 2017-07-04 | Chugai Seiyaku Kabushiki Kaisha | Benzamide derivative |
| JPWO2013161853A1 (en) * | 2012-04-24 | 2015-12-24 | 中外製薬株式会社 | Quinazolinedione derivatives |
| WO2013161853A1 (en) * | 2012-04-24 | 2013-10-31 | 中外製薬株式会社 | Quinazolinedione derivative |
| CN105102983A (en) * | 2012-12-27 | 2015-11-25 | 奎斯特诊断投资股份有限公司 | Ddr2 mutations as targetable features of melanoma or basal cell carcinoma |
| CN107236816A (en) * | 2012-12-27 | 2017-10-10 | 奎斯特诊断投资股份有限公司 | DDR2 mutation are used as melanoma or the feature targetted of basal-cell carcinoma |
| EP2939027A4 (en) * | 2012-12-27 | 2016-08-10 | Quest Diagnostics Invest Inc | Ddr2 mutations as targetable features of melanoma or basal cell carcinoma |
| US9617579B2 (en) | 2012-12-27 | 2017-04-11 | Quest Diagnostics Investments Incorporated | DDR2 mutations as targetable features of melanoma or basal cell carcinoma |
| US10155994B2 (en) | 2012-12-27 | 2018-12-18 | Quest Diagnostics Investments Incorporated | Methods of detecting DDR2 mutations |
| EP3473250A1 (en) * | 2012-12-27 | 2019-04-24 | Quest Diagnostics Investments Incorporated | Ddr2 mutations as targetable features of melanoma or basal cell carcinoma |
| US11118232B2 (en) | 2012-12-27 | 2021-09-14 | Quest Diagnostics Investments Llc | Methods of detecting DDR2 mutations |
| US10005739B2 (en) | 2013-10-23 | 2018-06-26 | Chugai Seiyaku Kabushiki Kaisha | Quinazolinone and isoquinolinone derivative |
| WO2020207611A1 (en) * | 2019-04-09 | 2020-10-15 | Rottapharm Biotech S.R.L. | Phenazines as inhibitors of discoidin domain receptors 2 (ddr2) |
| WO2020207570A1 (en) * | 2019-04-09 | 2020-10-15 | Rottapharm Biotech S.R.L. | Phenazines as inhibitors of discoidin domain receptors 2 (ddr2) |
Also Published As
| Publication number | Publication date |
|---|---|
| CL2012001012A1 (en) | 2012-10-26 |
| BR112012009094A8 (en) | 2017-10-10 |
| TWI592157B (en) | 2017-07-21 |
| MX2012004709A (en) | 2012-05-23 |
| US20170143716A1 (en) | 2017-05-25 |
| KR101853596B1 (en) | 2018-04-30 |
| IL219109A (en) | 2017-12-31 |
| EP2490690A1 (en) | 2012-08-29 |
| KR20170007868A (en) | 2017-01-20 |
| KR20120099650A (en) | 2012-09-11 |
| CN102647986A (en) | 2012-08-22 |
| MA33666B1 (en) | 2012-10-01 |
| TN2012000150A1 (en) | 2013-12-12 |
| US20140350037A1 (en) | 2014-11-27 |
| AU2016216636A1 (en) | 2016-09-01 |
| TW201127383A (en) | 2011-08-16 |
| ZA201202413B (en) | 2013-03-27 |
| AU2014202963A1 (en) | 2014-06-19 |
| JP5948246B2 (en) | 2016-07-06 |
| IL219109A0 (en) | 2012-06-28 |
| AU2016216636B2 (en) | 2018-06-07 |
| AU2010310705A1 (en) | 2012-04-19 |
| US20150313900A1 (en) | 2015-11-05 |
| NZ599217A (en) | 2014-05-30 |
| RU2012120901A (en) | 2013-12-10 |
| US20120202836A1 (en) | 2012-08-09 |
| JP2013508393A (en) | 2013-03-07 |
| BR112012009094A2 (en) | 2016-05-03 |
| CA2777019A1 (en) | 2011-04-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2016216636B2 (en) | Method of treating proliferative disorders and other pathological conditions mediated by Bcr-Abl, c-Kit, DDR1, DDR2 or PDGF-R kinase activity | |
| AU2010322102B2 (en) | Method of treating proliferative disorders and other pathological conditions mediated by Bcr-Abl, c-Kit, DDR1, DDR2 or PDGF-R kinase activity | |
| EP2315592A1 (en) | Treatment of pulmonary arterial hypertension | |
| KR101276425B1 (en) | Combination of pyrimidylaminobenzamide compounds and imatinib for treating or preventing proliferative diseases | |
| AU2006208638B2 (en) | Use of pyrimidylaminobenzamides for the treatment of diseases that respond to modulation of tie-2 kinase activity | |
| AU2006242311A1 (en) | Use of pyrimidylamimobenzamide derivatives for the treatment of systematic mastocytosis | |
| US20080255171A1 (en) | Combination of Nilotinib with Farnesyl Transferase Inhibitors | |
| WO2007051862A1 (en) | Combination of organic compounds | |
| EP2186514B1 (en) | Treatment of Malignant Peripheral Nerve Sheath Tumors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase |
Ref document number: 201080046190.0 Country of ref document: CN |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10773472 Country of ref document: EP Kind code of ref document: A1 |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2010310705 Country of ref document: AU |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 219109 Country of ref document: IL Ref document number: 2777019 Country of ref document: CA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 13501274 Country of ref document: US |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2010773472 Country of ref document: EP |
|
| ENP | Entry into the national phase |
Ref document number: 2010310705 Country of ref document: AU Date of ref document: 20101021 Kind code of ref document: A |
|
| ENP | Entry into the national phase |
Ref document number: 20127010179 Country of ref document: KR Kind code of ref document: A |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2012001012 Country of ref document: CL Ref document number: 2012535351 Country of ref document: JP Ref document number: MX/A/2012/004709 Country of ref document: MX |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1201001822 Country of ref document: TH Ref document number: 12012500797 Country of ref document: PH |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2012120901 Country of ref document: RU |
|
| REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112012009094 Country of ref document: BR |
|
| ENP | Entry into the national phase |
Ref document number: 112012009094 Country of ref document: BR Kind code of ref document: A2 Effective date: 20120418 |