CA2655724A1

CA2655724A1 - Combinations comprising staurosprorines

Combinations comprising staurosprorines Download PDF

Info

Publication number: CA2655724A1
Authority: CA; Canada
Prior art keywords: mcl; typically; lower alkyl; cells; hydrogen
Prior art date: 2006-06-23
Legal status : Abandoned

Application number

CA002655724A

Other languages

English (en)

French (fr)

Inventor

Peter Valent

Current Assignee

Novartis AG

Original Assignee

Individual

Priority date

2006-06-23

Filing date

2007-06-22

Publication date

2007-12-27

2007-06-22 Application filed by Individual filed Critical Individual

2007-12-27 Publication of CA2655724A1 publication Critical patent/CA2655724A1/en

Status Abandoned legal-status Critical Current

Links

101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 claims abstract description 181
102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 claims abstract description 176
239000000074 antisense oligonucleotide Substances 0.000 claims abstract description 88
238000012230 antisense oligonucleotides Methods 0.000 claims abstract description 88
239000003814 drug Substances 0.000 claims abstract description 44
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
108091034117 Oligonucleotide Proteins 0.000 claims abstract description 42
230000009368 gene silencing by RNA Effects 0.000 claims abstract description 41
238000000034 method Methods 0.000 claims abstract description 32
206010028980 Neoplasm Diseases 0.000 claims abstract description 23
208000032839 leukemia Diseases 0.000 claims abstract description 13
206010025323 Lymphomas Diseases 0.000 claims abstract description 12
201000003793 Myelodysplastic syndrome Diseases 0.000 claims abstract description 12
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
108091030071 RNAI Proteins 0.000 claims abstract 8
-1 hydroxy, amino Chemical group 0.000 claims description 411
125000000217 alkyl group Chemical group 0.000 claims description 145
150000007523 nucleic acids Chemical class 0.000 claims description 66
102000039446 nucleic acids Human genes 0.000 claims description 64
108020004707 nucleic acids Proteins 0.000 claims description 64
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 58
125000004432 carbon atom Chemical group C* 0.000 claims description 49
150000001875 compounds Chemical class 0.000 claims description 47
239000003112 inhibitor Substances 0.000 claims description 46
229910052739 hydrogen Inorganic materials 0.000 claims description 44
239000001257 hydrogen Substances 0.000 claims description 44
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
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 37
150000003839 salts Chemical class 0.000 claims description 35
239000004055 small Interfering RNA Substances 0.000 claims description 35
125000002252 acyl group Chemical group 0.000 claims description 33
239000005517 L01XE01 - Imatinib Substances 0.000 claims description 31
229960002411 imatinib Drugs 0.000 claims description 31
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 27
125000005037 alkyl phenyl group Chemical group 0.000 claims description 27
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
239000002773 nucleotide Substances 0.000 claims description 24
125000003729 nucleotide group Chemical group 0.000 claims description 23
125000003545 alkoxy group Chemical group 0.000 claims description 21
150000002431 hydrogen Chemical class 0.000 claims description 21
206010009944 Colon cancer Diseases 0.000 claims description 20
208000001333 Colorectal Neoplasms Diseases 0.000 claims description 20
230000000295 complement effect Effects 0.000 claims description 20
125000000623 heterocyclic group Chemical group 0.000 claims description 20
208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 20
208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 20
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
229910052760 oxygen Inorganic materials 0.000 claims description 19
239000001301 oxygen Substances 0.000 claims description 19
239000013598 vector Substances 0.000 claims description 17
125000005842 heteroatom Chemical group 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
108091027967 Small hairpin RNA Proteins 0.000 claims description 15
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
229910052736 halogen Inorganic materials 0.000 claims description 15
150000002367 halogens Chemical class 0.000 claims description 15
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 15
125000003277 amino group Chemical group 0.000 claims description 14
125000002837 carbocyclic group Chemical group 0.000 claims description 14
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
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 12
208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 11
HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical group 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
125000004093 cyano group Chemical group *C#N 0.000 claims description 10
125000001931 aliphatic group Chemical group 0.000 claims description 9
238000002360 preparation method Methods 0.000 claims description 9
125000000547 substituted alkyl group Chemical group 0.000 claims description 5
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
241000124008 Mammalia Species 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
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
201000010099 disease Diseases 0.000 abstract description 13
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239000003757 phosphotransferase inhibitor Substances 0.000 abstract description 13
238000004519 manufacturing process Methods 0.000 abstract description 11
230000036210 malignancy Effects 0.000 abstract description 8
229940121372 histone deacetylase inhibitor Drugs 0.000 abstract 1
239000003276 histone deacetylase inhibitor Substances 0.000 abstract 1
210000004027 cell Anatomy 0.000 description 158
210000003630 histaminocyte Anatomy 0.000 description 76
230000014509 gene expression Effects 0.000 description 58
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230000001613 neoplastic effect Effects 0.000 description 50
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 47
229950010895 midostaurin Drugs 0.000 description 47
150000003254 radicals Chemical class 0.000 description 45
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 44
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 44
229940079593 drug Drugs 0.000 description 40
230000000694 effects Effects 0.000 description 38
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230000000692 anti-sense effect Effects 0.000 description 36
238000012228 RNA interference-mediated gene silencing Methods 0.000 description 33
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208000000516 mast-cell leukemia Diseases 0.000 description 29
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229910052757 nitrogen Inorganic materials 0.000 description 27
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108020004414 DNA Proteins 0.000 description 26
125000001424 substituent group Chemical group 0.000 description 26
238000002474 experimental method Methods 0.000 description 23
102200076881 rs121913507 Human genes 0.000 description 22
102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 21
108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 21
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
125000003282 alkyl amino group Chemical group 0.000 description 20
239000000203 mixture Substances 0.000 description 20
102000040650 (ribonucleotides)n+m Human genes 0.000 description 19
230000004083 survival effect Effects 0.000 description 19
230000006907 apoptotic process Effects 0.000 description 17
230000001640 apoptogenic effect Effects 0.000 description 15
229920006395 saturated elastomer Polymers 0.000 description 15
230000000875 corresponding effect Effects 0.000 description 14
229910052717 sulfur Inorganic materials 0.000 description 14
125000003118 aryl group Chemical group 0.000 description 13
230000012010 growth Effects 0.000 description 13
230000035772 mutation Effects 0.000 description 13
235000018102 proteins Nutrition 0.000 description 13
102000004169 proteins and genes Human genes 0.000 description 13
241000282414 Homo sapiens Species 0.000 description 12
201000009004 Indolent systemic mastocytosis Diseases 0.000 description 12
239000005536 L01XE08 - Nilotinib Substances 0.000 description 12
229960001346 nilotinib Drugs 0.000 description 12
238000001262 western blot Methods 0.000 description 12
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 11
125000003342 alkenyl group Chemical group 0.000 description 11
210000001185 bone marrow Anatomy 0.000 description 11
230000003833 cell viability Effects 0.000 description 11
125000001183 hydrocarbyl group Chemical group 0.000 description 11
239000011593 sulfur Substances 0.000 description 11
235000001014 amino acid Nutrition 0.000 description 10
125000000539 amino acid group Chemical group 0.000 description 10
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
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239000002253 acid Substances 0.000 description 9
125000002015 acyclic group Chemical group 0.000 description 9
125000004414 alkyl thio group Chemical group 0.000 description 9
238000004458 analytical method Methods 0.000 description 9
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238000006467 substitution reaction Methods 0.000 description 9
238000001890 transfection Methods 0.000 description 9
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 8
125000005115 alkyl carbamoyl group Chemical group 0.000 description 8
125000004390 alkyl sulfonyl group Chemical group 0.000 description 8
125000003275 alpha amino acid group Chemical group 0.000 description 8
150000005840 aryl radicals Chemical class 0.000 description 8
239000003795 chemical substances by application Substances 0.000 description 8
238000009396 hybridization Methods 0.000 description 8
230000002401 inhibitory effect Effects 0.000 description 8
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
125000004433 nitrogen atom Chemical group N* 0.000 description 8
125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 7
125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 7
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 7
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 7
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 7
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 7
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 7
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108090000994 Catalytic RNA Proteins 0.000 description 7
102000053642 Catalytic RNA Human genes 0.000 description 7
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 7
125000004423 acyloxy group Chemical group 0.000 description 7
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125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 7
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238000011068 loading method Methods 0.000 description 7
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125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 7
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102000001708 Protein Isoforms Human genes 0.000 description 6
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ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
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125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 6
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125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
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ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 5
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239000002609 medium Substances 0.000 description 5
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QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
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125000004487 4-tetrahydropyranyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
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239000004215 Carbon black (E152) Substances 0.000 description 4
208000010833 Chronic myeloid leukaemia Diseases 0.000 description 4
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208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 4
HYVABZIGRDEKCD-UHFFFAOYSA-N N(6)-dimethylallyladenine Chemical compound CC(C)=CCNC1=NC=NC2=C1N=CN2 HYVABZIGRDEKCD-UHFFFAOYSA-N 0.000 description 4
238000000636 Northern blotting Methods 0.000 description 4
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238000010240 RT-PCR analysis Methods 0.000 description 4
108091081021 Sense strand Proteins 0.000 description 4
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 4
DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 4
230000002159 abnormal effect Effects 0.000 description 4
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239000004480 active ingredient Substances 0.000 description 4
125000005236 alkanoylamino group Chemical group 0.000 description 4
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230000001028 anti-proliverative effect Effects 0.000 description 4
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GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
229910052794 bromium Inorganic materials 0.000 description 4
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