MX2008016488A

MX2008016488A - Combinaciones que comprenden estaurosporinas.

Combinaciones que comprenden estaurosporinas.

Info

Publication number: MX2008016488A
Authority: MX; Mexico
Prior art keywords: phenyl; mcl; lower alkyl; amino; methyl
Prior art date: 2006-06-23

Application number

MX2008016488A

Other languages

English (en)

Spanish (es)

Inventor

Peter Valent

Original Assignee

Novartis Ag

Priority date

2006-06-23

Filing date

2007-06-22

Publication date

2009-01-22

2007-06-22 Application filed by Novartis Ag filed Critical Novartis Ag

2009-01-22 Publication of MX2008016488A publication Critical patent/MX2008016488A/es

Links

101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 claims abstract description 236
102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 claims abstract description 228
239000000074 antisense oligonucleotide Substances 0.000 claims abstract description 75
238000012230 antisense oligonucleotides Methods 0.000 claims abstract description 75
108091034117 Oligonucleotide Proteins 0.000 claims abstract description 72
239000003814 drug Substances 0.000 claims abstract description 48
FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 claims abstract description 43
102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims abstract description 43
101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims abstract description 43
230000009368 gene silencing by RNA Effects 0.000 claims abstract description 43
238000000034 method Methods 0.000 claims abstract description 30
206010028980 Neoplasm Diseases 0.000 claims abstract description 27
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
201000010099 disease Diseases 0.000 claims abstract description 15
229940043355 kinase inhibitor Drugs 0.000 claims abstract description 14
208000032839 leukemia Diseases 0.000 claims abstract description 14
238000004519 manufacturing process Methods 0.000 claims abstract description 14
239000003757 phosphotransferase inhibitor Substances 0.000 claims abstract description 14
206010025323 Lymphomas Diseases 0.000 claims abstract description 13
201000003793 Myelodysplastic syndrome Diseases 0.000 claims abstract description 12
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
230000036210 malignancy Effects 0.000 claims abstract description 10
108091030071 RNAI Proteins 0.000 claims abstract 9
229940121372 histone deacetylase inhibitor Drugs 0.000 claims abstract 2
239000003276 histone deacetylase inhibitor Substances 0.000 claims abstract 2
-1 di-substituted amino, cyano, nitro, mercapto, substituted mercapto, carboxyl Chemical group 0.000 claims description 401
125000000217 alkyl group Chemical group 0.000 claims description 144
125000004432 carbon atom Chemical group C* 0.000 claims description 76
229910052757 nitrogen Inorganic materials 0.000 claims description 66
102000039446 nucleic acids Human genes 0.000 claims description 65
108020004707 nucleic acids Proteins 0.000 claims description 65
150000007523 nucleic acids Chemical class 0.000 claims description 64
150000001875 compounds Chemical class 0.000 claims description 49
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
150000003839 salts Chemical class 0.000 claims description 42
229910052739 hydrogen Inorganic materials 0.000 claims description 41
239000001257 hydrogen Substances 0.000 claims description 41
239000003112 inhibitor Substances 0.000 claims description 41
239000004055 small Interfering RNA Substances 0.000 claims description 38
125000002252 acyl group Chemical group 0.000 claims description 33
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
229960002411 imatinib Drugs 0.000 claims description 31
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 claims description 31
239000005517 L01XE01 - Imatinib Substances 0.000 claims description 29
125000005037 alkyl phenyl group Chemical group 0.000 claims description 28
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 claims description 27
125000003545 alkoxy group Chemical group 0.000 claims description 26
239000002773 nucleotide Substances 0.000 claims description 25
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
125000003729 nucleotide group Chemical group 0.000 claims description 24
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 22
206010009944 Colon cancer Diseases 0.000 claims description 20
208000001333 Colorectal Neoplasms Diseases 0.000 claims description 20
125000000623 heterocyclic group Chemical group 0.000 claims description 20
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 19
230000000295 complement effect Effects 0.000 claims description 19
229910052760 oxygen Inorganic materials 0.000 claims description 19
239000001301 oxygen Substances 0.000 claims description 19
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
150000002431 hydrogen Chemical class 0.000 claims description 18
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
239000013598 vector Substances 0.000 claims description 17
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
125000005842 heteroatom Chemical group 0.000 claims description 16
108091027967 Small hairpin RNA Proteins 0.000 claims description 15
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 15
229910052736 halogen Inorganic materials 0.000 claims description 15
150000002367 halogens Chemical class 0.000 claims description 15
125000003277 amino group Chemical group 0.000 claims description 13
125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 13
125000005036 alkoxyphenyl group Chemical group 0.000 claims description 12
125000002837 carbocyclic group Chemical group 0.000 claims description 12
208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 11
HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical class C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 claims description 11
208000020816 lung neoplasm Diseases 0.000 claims description 10
206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
125000004093 cyano group Chemical group *C#N 0.000 claims description 9
201000005202 lung cancer Diseases 0.000 claims description 9
208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 9
238000002360 preparation method Methods 0.000 claims description 9
125000001931 aliphatic group Chemical group 0.000 claims description 8
241000124008 Mammalia Species 0.000 claims description 5
125000000547 substituted alkyl group Chemical group 0.000 claims description 5
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
239000013604 expression vector Substances 0.000 claims description 4
229940002612 prodrug Drugs 0.000 claims description 3
239000000651 prodrug Substances 0.000 claims description 3
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
239000004593 Epoxy Substances 0.000 claims 1
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230000014509 gene expression Effects 0.000 description 58
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150000003254 radicals Chemical class 0.000 description 50
230000001613 neoplastic effect Effects 0.000 description 44
125000003118 aryl group Chemical group 0.000 description 43
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230000000694 effects Effects 0.000 description 40
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238000012228 RNA interference-mediated gene silencing Methods 0.000 description 34
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108020004999 messenger RNA Proteins 0.000 description 31
229910052799 carbon Inorganic materials 0.000 description 29
208000000516 mast-cell leukemia Diseases 0.000 description 28
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 26
125000001424 substituent group Chemical group 0.000 description 26
108020004414 DNA Proteins 0.000 description 25
238000002474 experimental method Methods 0.000 description 23
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230000004083 survival effect Effects 0.000 description 21
102000040650 (ribonucleotides)n+m Human genes 0.000 description 19
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
108091093037 Peptide nucleic acid Proteins 0.000 description 18
229910052717 sulfur Inorganic materials 0.000 description 18
108020000948 Antisense Oligonucleotides Proteins 0.000 description 17
108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 17
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125000003282 alkyl amino group Chemical group 0.000 description 17
230000006907 apoptotic process Effects 0.000 description 16
230000001640 apoptogenic effect Effects 0.000 description 15
229920006395 saturated elastomer Polymers 0.000 description 15
230000000875 corresponding effect Effects 0.000 description 14
230000035772 mutation Effects 0.000 description 14
238000001262 western blot Methods 0.000 description 14
201000009004 Indolent systemic mastocytosis Diseases 0.000 description 13
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
230000012010 growth Effects 0.000 description 13
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 12
125000003342 alkenyl group Chemical group 0.000 description 12
235000001014 amino acid Nutrition 0.000 description 12
239000002585 base Substances 0.000 description 12
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
125000001183 hydrocarbyl group Chemical group 0.000 description 12
239000011593 sulfur Substances 0.000 description 12
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239000005536 L01XE08 - Nilotinib Substances 0.000 description 11
230000003833 cell viability Effects 0.000 description 11
239000002679 microRNA Substances 0.000 description 11
BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 11
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IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 9
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238000004458 analytical method Methods 0.000 description 9
238000006467 substitution reaction Methods 0.000 description 9
125000001544 thienyl group Chemical group 0.000 description 9
125000004001 thioalkyl group Chemical group 0.000 description 9
238000001890 transfection Methods 0.000 description 9
JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 8
125000002015 acyclic group Chemical group 0.000 description 8
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125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 7
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125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 7
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