EP1224169A2 - In 5-stellung substituierte indolinone und ihre verwendung als kinase und cyclin/cdk-komplexe inhibitoren - Google Patents
In 5-stellung substituierte indolinone und ihre verwendung als kinase und cyclin/cdk-komplexe inhibitorenInfo
- Publication number
- EP1224169A2 EP1224169A2 EP00966136A EP00966136A EP1224169A2 EP 1224169 A2 EP1224169 A2 EP 1224169A2 EP 00966136 A EP00966136 A EP 00966136A EP 00966136 A EP00966136 A EP 00966136A EP 1224169 A2 EP1224169 A2 EP 1224169A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- alkyl
- phenyl
- indolinone
- phenylmethylene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- -1 5-substituted indolinones Chemical class 0.000 title claims abstract description 170
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 132
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 83
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 52
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 35
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 33
- 125000003282 alkyl amino group Chemical group 0.000 claims description 32
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 32
- 239000001301 oxygen Substances 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 229910052717 sulfur Chemical group 0.000 claims description 32
- 125000004434 sulfur atom Chemical group 0.000 claims description 32
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 30
- 229910052801 chlorine Inorganic materials 0.000 claims description 30
- 239000000460 chlorine Substances 0.000 claims description 30
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 28
- 125000006842 cycloalkyleneimino group Chemical group 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 28
- 239000011737 fluorine Substances 0.000 claims description 28
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 20
- 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 claims description 18
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 15
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 14
- 229910052740 iodine Inorganic materials 0.000 claims description 14
- 125000001624 naphthyl group Chemical group 0.000 claims description 14
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 8
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 7
- 239000000651 prodrug Chemical group 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 239000007790 solid phase Substances 0.000 claims description 6
- 230000010933 acylation Effects 0.000 claims description 5
- 238000005917 acylation reaction Methods 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
- 150000003951 lactams Chemical group 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- UQLKRWKVLYXDMW-MVJHLKBCSA-N (3z)-2-oxo-n-phenyl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indole-5-sulfonamide Chemical compound O=C1NC2=CC=C(S(=O)(=O)NC=3C=CC=CC=3)C=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1CN1CCCCC1 UQLKRWKVLYXDMW-MVJHLKBCSA-N 0.000 claims description 3
- HHVBCDVRJXTJAE-KARKAFJISA-N (3z)-3-[[4-[[benzyl(methyl)amino]methyl]anilino]-phenylmethylidene]-5-diethoxyphosphoryl-1h-indol-2-one Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN(C)CC1=CC=CC=C1 HHVBCDVRJXTJAE-KARKAFJISA-N 0.000 claims description 3
- YUJQSBOMKGIIID-RQZHXJHFSA-N (3z)-5-methylsulfonyl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indol-2-one Chemical compound C12=CC(S(=O)(=O)C)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 YUJQSBOMKGIIID-RQZHXJHFSA-N 0.000 claims description 3
- LXUKTKWJGSMCAI-KTMFPKCZSA-N (3z)-n-butyl-n-methyl-2-oxo-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indole-5-sulfonamide Chemical compound C12=CC(S(=O)(=O)N(C)CCCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 LXUKTKWJGSMCAI-KTMFPKCZSA-N 0.000 claims description 3
- CXNZOTVYJUQCIA-KARKAFJISA-N (3z)-n-methyl-2-oxo-n-phenyl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indole-5-sulfonamide Chemical compound C=1C=C2NC(=O)\C(=C(/NC=3C=CC(CN4CCCCC4)=CC=3)C=3C=CC=CC=3)C2=CC=1S(=O)(=O)N(C)C1=CC=CC=C1 CXNZOTVYJUQCIA-KARKAFJISA-N 0.000 claims description 3
- XEBDWDOSVOTBRA-ZIADKAODSA-N CCC(NC(C=C1)=CC=C1N/C(\C1=CC=CC=C1)=C(/C1=CC(S(NC2=CC=CC=C2)(=O)=O)=CC=C1N1)\C1=O)=O Chemical compound CCC(NC(C=C1)=CC=C1N/C(\C1=CC=CC=C1)=C(/C1=CC(S(NC2=CC=CC=C2)(=O)=O)=CC=C1N1)\C1=O)=O XEBDWDOSVOTBRA-ZIADKAODSA-N 0.000 claims description 3
- DKSXVGISYCRBTI-ZIADKAODSA-N CN(C)CC1=CC=C(N\C(\C2=CC=CC=C2)=C\2/C(NC3=CC=C(C=C/23)S(=O)(=O)NC2=CC=CC=C2)=O)C=C1 Chemical compound CN(C)CC1=CC=C(N\C(\C2=CC=CC=C2)=C\2/C(NC3=CC=C(C=C/23)S(=O)(=O)NC2=CC=CC=C2)=O)C=C1 DKSXVGISYCRBTI-ZIADKAODSA-N 0.000 claims description 3
- QTIZYXRUEZEOMZ-FLWNBWAVSA-N CN(CCC1=CC=C(N\C(\C2=CC=CC=C2)=C\2/C(NC3=CC=C(C=C/23)S(=O)(=O)NC2=CC=CC=C2)=O)C=C1)C Chemical compound CN(CCC1=CC=C(N\C(\C2=CC=CC=C2)=C\2/C(NC3=CC=C(C=C/23)S(=O)(=O)NC2=CC=CC=C2)=O)C=C1)C QTIZYXRUEZEOMZ-FLWNBWAVSA-N 0.000 claims description 3
- 230000009435 amidation Effects 0.000 claims description 3
- 238000007112 amidation reaction Methods 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- PMDHYVHSTIGUSK-ZIADKAODSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-2-(dimethylamino)-n-methylacetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC1=CC=C(N(C)C(=O)CN(C)C)C=C1 PMDHYVHSTIGUSK-ZIADKAODSA-N 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- 238000005932 reductive alkylation reaction Methods 0.000 claims description 3
- RPVNAZNLJZJJAS-FLWNBWAVSA-N (3z)-5-diethoxyphosphoryl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indol-2-one Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 RPVNAZNLJZJJAS-FLWNBWAVSA-N 0.000 claims description 2
- GPIWFBZLTMDTGZ-RQZHXJHFSA-N (3z)-5-methylsulfinyl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indol-2-one Chemical compound C12=CC(S(=O)C)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 GPIWFBZLTMDTGZ-RQZHXJHFSA-N 0.000 claims description 2
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 2
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 2
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 2
- 230000002159 abnormal effect Effects 0.000 claims description 2
- 150000003855 acyl compounds Chemical class 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000005141 aryl amino sulfonyl group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 125000005142 aryl oxy sulfonyl group Chemical group 0.000 claims description 2
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 2
- GLYPPQKVEKBATR-ZIADKAODSA-N c12cc(P(=O)(OCC)OCC)ccc2NC(=O)\C1=C(/Nc1ccc(N(CC(=O)N(C)C)S(C)(=O)=O)cc1)c1ccccc1 Chemical compound c12cc(P(=O)(OCC)OCC)ccc2NC(=O)\C1=C(/Nc1ccc(N(CC(=O)N(C)C)S(C)(=O)=O)cc1)c1ccccc1 GLYPPQKVEKBATR-ZIADKAODSA-N 0.000 claims description 2
- 230000004663 cell proliferation Effects 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims 1
- PUICUSANCAHLEO-ZIADKAODSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-[2-(dimethylamino)ethyl]methanesulfonamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC1=CC=C(N(CCN(C)C)S(C)(=O)=O)C=C1 PUICUSANCAHLEO-ZIADKAODSA-N 0.000 claims 1
- 108050006400 Cyclin Proteins 0.000 abstract description 7
- 102000016736 Cyclin Human genes 0.000 abstract description 7
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 192
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 150
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- 229910021529 ammonia Inorganic materials 0.000 description 7
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- ZLKFTKZEQDACDZ-ZIADKAODSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-[2-(ethylamino)ethyl]methanesulfonamide Chemical compound C1=CC(N(CCNCC)S(C)(=O)=O)=CC=C1N\C(C=1C=CC=CC=1)=C/1C2=CC(P(=O)(OCC)OCC)=CC=C2NC\1=O ZLKFTKZEQDACDZ-ZIADKAODSA-N 0.000 description 1
- MHUWMDWAFZVAHC-ZIADKAODSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-[2-(methylamino)ethyl]acetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC1=CC=C(N(CCNC)C(C)=O)C=C1 MHUWMDWAFZVAHC-ZIADKAODSA-N 0.000 description 1
- BWOQIMHNVIPZCS-DQSJHHFOSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-[2-(methylamino)ethyl]methanesulfonamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC1=CC=C(N(CCNC)S(C)(=O)=O)C=C1 BWOQIMHNVIPZCS-DQSJHHFOSA-N 0.000 description 1
- ZZWOUOMBXAVYMP-KTMFPKCZSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-[3-(dimethylamino)propyl]acetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC1=CC=C(N(CCCN(C)C)C(C)=O)C=C1 ZZWOUOMBXAVYMP-KTMFPKCZSA-N 0.000 description 1
- MCXDVTSJGYISSW-FLWNBWAVSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-[3-(methylamino)propyl]acetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC1=CC=C(N(CCCNC)C(C)=O)C=C1 MCXDVTSJGYISSW-FLWNBWAVSA-N 0.000 description 1
- FDWBQDAZTADNSF-DQSJHHFOSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-methyl-2-(methylamino)acetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC1=CC=C(N(C)C(=O)CNC)C=C1 FDWBQDAZTADNSF-DQSJHHFOSA-N 0.000 description 1
- FSHSSBSMOAKWTG-KTMFPKCZSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-methyl-2-morpholin-4-ylacetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1N(C)C(=O)CN1CCOCC1 FSHSSBSMOAKWTG-KTMFPKCZSA-N 0.000 description 1
- BQINCYMIOZGSCM-KTMFPKCZSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-methyl-2-piperazin-1-ylacetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1N(C)C(=O)CN1CCNCC1 BQINCYMIOZGSCM-KTMFPKCZSA-N 0.000 description 1
- ONOFEYHAKRCPFR-MVJHLKBCSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-methyl-2-piperidin-1-ylacetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1N(C)C(=O)CN1CCCCC1 ONOFEYHAKRCPFR-MVJHLKBCSA-N 0.000 description 1
- VBEUHKJPAHKSKM-FLWNBWAVSA-N n-[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]-n-methylpiperidine-1-carboxamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1N(C)C(=O)N1CCCCC1 VBEUHKJPAHKSKM-FLWNBWAVSA-N 0.000 description 1
- SRHXRXFTZAJAGC-KNWKATPGSA-N n-[4-[[(z)-[2-oxo-5-(phenylsulfamoyl)-1h-indol-3-ylidene]-phenylmethyl]amino]phenyl]-n-(2-oxo-2-piperidin-1-ylethyl)acetamide Chemical compound C=1C=C(N\C(=C/2C3=CC(=CC=C3NC\2=O)S(=O)(=O)NC=2C=CC=CC=2)C=2C=CC=CC=2)C=CC=1N(C(=O)C)CC(=O)N1CCCCC1 SRHXRXFTZAJAGC-KNWKATPGSA-N 0.000 description 1
- KDKQADBEFDMFBR-DQSJHHFOSA-N n-[4-[[(z)-[2-oxo-5-(phenylsulfamoyl)-1h-indol-3-ylidene]-phenylmethyl]amino]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1N\C(C=1C=CC=CC=1)=C/1C2=CC(S(=O)(=O)NC=3C=CC=CC=3)=CC=C2NC\1=O KDKQADBEFDMFBR-DQSJHHFOSA-N 0.000 description 1
- YDVBJMJUIYEPSM-RQZHXJHFSA-N n-[[4-[[(z)-(5-diethoxyphosphoryl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]phenyl]methyl]acetamide Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC1=CC=C(CNC(C)=O)C=C1 YDVBJMJUIYEPSM-RQZHXJHFSA-N 0.000 description 1
- OQZNDAVFQRPOPP-ZIADKAODSA-N n-[[4-[[(z)-[2-oxo-5-(phenylsulfamoyl)-1h-indol-3-ylidene]-phenylmethyl]amino]phenyl]methyl]acetamide Chemical compound C1=CC(CNC(=O)C)=CC=C1N\C(C=1C=CC=CC=1)=C/1C2=CC(S(=O)(=O)NC=3C=CC=CC=3)=CC=C2NC\1=O OQZNDAVFQRPOPP-ZIADKAODSA-N 0.000 description 1
- YUECHZOURBGTHL-KARKAFJISA-N n-methyl-2-morpholin-4-yl-n-[4-[[(z)-[2-oxo-5-(phenylsulfamoyl)-1h-indol-3-ylidene]-phenylmethyl]amino]phenyl]acetamide Chemical compound C=1C=C(N\C(=C/2C3=CC(=CC=C3NC\2=O)S(=O)(=O)NC=2C=CC=CC=2)C=2C=CC=CC=2)C=CC=1N(C)C(=O)CN1CCOCC1 YUECHZOURBGTHL-KARKAFJISA-N 0.000 description 1
- MYKBOKGDXJCOSO-UHFFFAOYSA-N n-methyl-n-[(4-nitrophenyl)methyl]-1-phenylmethanamine Chemical compound C=1C=C([N+]([O-])=O)C=CC=1CN(C)CC1=CC=CC=C1 MYKBOKGDXJCOSO-UHFFFAOYSA-N 0.000 description 1
- ZQAZBIFGCPPZCG-KARKAFJISA-N n-methyl-n-[4-[[(z)-[2-oxo-5-(phenylsulfamoyl)-1h-indol-3-ylidene]-phenylmethyl]amino]phenyl]-2-piperazin-1-ylacetamide Chemical compound C=1C=C(N\C(=C/2C3=CC(=CC=C3NC\2=O)S(=O)(=O)NC=2C=CC=CC=2)C=2C=CC=CC=2)C=CC=1N(C)C(=O)CN1CCNCC1 ZQAZBIFGCPPZCG-KARKAFJISA-N 0.000 description 1
- WGMOBJTXHOXBII-YHZPTAEISA-N n-methyl-n-[4-[[(z)-[2-oxo-5-(phenylsulfamoyl)-1h-indol-3-ylidene]-phenylmethyl]amino]phenyl]-2-piperidin-1-ylacetamide Chemical compound C=1C=C(N\C(=C/2C3=CC(=CC=C3NC\2=O)S(=O)(=O)NC=2C=CC=CC=2)C=2C=CC=CC=2)C=CC=1N(C)C(=O)CN1CCCCC1 WGMOBJTXHOXBII-YHZPTAEISA-N 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000013034 phenoxy resin Substances 0.000 description 1
- 229920006287 phenoxy resin Polymers 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- LTEKQAPRXFBRNN-UHFFFAOYSA-N piperidin-4-ylmethanamine Chemical compound NCC1CCNCC1 LTEKQAPRXFBRNN-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- LFQCEHFDDXELDD-UHFFFAOYSA-N tetramethyl orthosilicate Chemical compound CO[Si](OC)(OC)OC LFQCEHFDDXELDD-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- CWLNAJYDRSIKJS-UHFFFAOYSA-N triethoxymethoxyethane Chemical compound CCOC(OCC)(OCC)OCC CWLNAJYDRSIKJS-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
Definitions
- the present invention relates to new 5-substituted indolinones of the general formula
- R x represents a hydrogen atom or a prodrug residue
- R x represents a hydrogen atom or a prodrug residue
- Receptor tyrosine kinases such as VEGFR2, PDGFR ⁇ , PDGFRß, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR and on the proliferation of cells, in particular tumor cells.
- the present invention thus relates to the above compounds of the general formula I, where the compounds in which R x represents a hydrogen atom or a prodrug residue have valuable pharmacological properties, the medicaments containing the pharmacologically active compounds, their use and process for their preparation.
- X is an oxygen or sulfur atom
- R x is a hydrogen atom or a prodrug residue such as a C 1-4 alkoxycarbonyl or C 2 . 4 -alkanoyl group,
- R 2 is hydroxy, C - ⁇ - alkoxy, aryloxy, phenyl-C ⁇ alkoxy, cyano, (HO) 2 PO-, (HO) (C ⁇ -alkoxy) PO-, (HO) ( Aryloxy) PO-, (HO) (benzyloxy) PO-, (C ⁇ alkoxy) 2 PO-, (aryloxy) 2 PO-, (benzyloxy) 2 PO-, (C ⁇ alkylene dioxy) PO-, H (C ⁇ alkoxy) PO-, H (aryloxy) PO-, H (benzyloxy) PO-, mercapto, C ⁇ alkylmercapto, arylmercapto, phenyl-C ⁇ alkylmercapto, C ⁇ alkylsulfinyl, arylsulfinyl -, phenyl-C ⁇ -alkylsulfinyl-, C ⁇ -alkylsulfon
- R 3 is a hydrogen atom, a C ⁇ j alkyl, C 3 . 7- cycloalkyl, trifluoromethyl or heteroaryl group, a phenyl or naphthyl group, one by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C 1-4 alkyl or C - ⁇ - alkoxy group mono- or disubstituted phenyl or naphthyl group, in the case of disubstitution the substituents can be the same or different and the abovementioned unsubstituted, mono- and disubstituted phenyl and naphthyl groups additionally
- j -alkyl group with 4 to 7 ring members each, the methylene group in position 4 in a 6 or 7-membered cycloalkyleneimino group being represented by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH or -N (C ⁇ - j -Alkyl) group can be replaced,
- R 4 is a phenyl group
- a methylene group linked to the imino group can be replaced by a carbonyl or sulfonyl group or
- the cycloalkylene part can be condensed with a phenyl ring or
- one or two hydrogen atoms each case by a C ⁇ - j -Al- kyl distr may be replaced and / or
- a sulfinyl, sulfonyl, -NH-, -N (C ⁇ alkyl) -, -N (phenyl) -, -N (C ⁇ alkylcarbonyl) - or -N (benzoyl) group can be replaced,
- one or two hydrogen atoms each through a C- L .- j alkyl, C s . 7- cycloalkyl or phenyl group can be replaced or / and
- each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by a hydroxy, carboxy, C - ⁇ - alkoxycarbonyl, aminocarbonyl, C ⁇ - j -alkylaminocarbonyl-, di- (C 1. 3 - alkyl) -aminocarbonyl-, phenyl -C ⁇ alkylamino or N- (C ⁇ alkyl) phenyl-C ⁇ alkylamino group substituted or
- a sulphinyl, sulphonyl, -NH-, -N (C 1 3 alkyl.) -, -N (phenyl) -, -N (C ⁇ alkyl-carbonyl) - or -N (benzoyl) group can be replaced,
- a 5- to 7-membered cycloalkenyleneimino group in which the double bond is isolated from the nitrogen atom by a phenylamino, N- -phenylamino-, phenyl -C ⁇ - j -alkylamino-, N- (C ⁇ alkyl) -phenyl-C 1 . 3 -alkylamino or di- (phenyl-C ⁇ -alkyl) -amino group,
- R a is a hydrogen atom or a C 1 . 3 -alkyl group
- n one of the numbers 0, 1, 2 or 3 and
- R b is an amino, C - ⁇ - alkylamino, phenylamino, N- (C - ⁇ - alkyl) phenylamino, benzylamino, N- (C 1, 4 alkyl) benzylamino or di (C - ⁇ - alkyl) amino group, a 4- to 7-membered cycloalkyleneimino group, the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group being represented by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, NH-, -N (C ⁇ -alkyl) -, -N (phenyl) -, -N (C 1, 3- alkyl-carbonyl) - or -N (benzoyl) - group can be replaced, or, if n one which represents numbers 1, 2 or 3, also denote a hydrogen atom,
- R c is a hydrogen atom, a C ⁇ alkyl group, a C ⁇ - j alkylcarbonyl, arylcarbonyl, phenyl-C ⁇ alkylcarbonyl, C ⁇ alkylsulfonyl, arylsulfonyl or phenyl-C ⁇ alky1sulfonyl group .
- R d is an amino, C ⁇ alkylamino, phenylamino, N- (C ⁇ alkyl) phenylamino, benzylamino, N- (C - ⁇ - alkyl) benzylamino or di (C- ⁇ alkyl) amino group, a 4- to 7-membered cycloalkyleneimino group, where the cycloalkylene part can be condensed with a phenyl ring or the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by an oxygen or sulfur atom, by a sulfinyl -, sulphonyl, -NH-, -N (.
- C 1 -A1- 3 alkyl) -, -N (phenyl) -, -N (C 1 3 alkyl-carbonyl.) - or -N (as benzoyl ) - Group can be replaced, a C 1 . 3 alkoxy group or a 1-position optionally by a C ⁇ pe -Alkylgrup- substituted di (C 1. 4 alkyl) amino-C j ⁇ . j denotes alkylamino group,
- R 3 is not the meaning of a hydrogen atom, one C 3 . 7- cycloalkyl or trifluoromethyl group, also has an arylsulfonylaminophenyl or N- (C 1, 3- alkyl) arylsulfonylaminophenyl group,
- R 5 is a hydrogen atom or a C 1-4 alkyl group, an existing carboxy, amino or imino group can additionally be substituted by a residue which can be split off in vivo and can thus be present in the form of a prodrug residue,
- an imino or amino group in vivo for example a hydroxyl group, an acyl group such as the benzoyl or pyridinoyl group or a C- L .- L g-alkanoyl group such as the formyl, acetyl, propionyl, Bu- tanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.
- an imino or amino group in vivo for example a hydroxyl group, an acyl group such as the benzoyl or pyridinoyl group or a C- L .- L g-alkanoyl group such as the formyl, acetyl, propionyl, Bu- tanoyl, pentanoyl or
- R e is C ⁇ a alkyl, C 5 . 7- cycloalkyl, phenyl or phenyl - C 1-4 alkyl group,
- R f is a hydrogen atom, a C ⁇ alkyl, C s . 7- cycloalkyl or phenyl group and
- R g is a hydrogen atom, a C ⁇ - j alkyl or
- R e represents CO-0- (R f CR g ) -O group in which R e to R g are defined as mentioned above,
- phthalimido group is additionally to be understood for an amino group, the ester radicals mentioned above also being able to be used as a group which can be converted into a carboxy group in vivo,
- an aryl group means one optionally by a fluorine, chlorine or bromine atom, by a Trifluoromethyl, C 1 . 3- alkyl, C 1-4 alkoxy or nitro group mono- or disubstituted phenyl or naphthyl group and
- a heteroaryl group means a monocyclic 5- or 6-membered heteroaryl group which is optionally substituted by a C 1-4 alkyl group, the 6-membered heteroaryl group having one, two or three nitrogen atoms and the 5-membered heteroaryl group one optionally having a C 1- 3 alkyl group substituted imino group, an oxygen or sulfur atom or an imino group optionally substituted by a C 1-4 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms, and also to the monocyclic heterocyclic groups mentioned above a phenyl ring may be fused on via two adjacent carbon atoms.
- saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group, etc., unless stated otherwise.
- X is an oxygen atom
- R x is a hydrogen atom, a C 1 _ 4 alkoxycarbonyl or C 2 . 4 -alkanoyl group,
- R 2 is a C ⁇ - j alkoxy, C ⁇ - j alkyl mercapto, C ⁇ alkyl sulfinyl, C 1-3 alkyl sulfonyl, cyano, (C 1-4 alkoxy) 2 P0, (C ⁇ -Alkylene-dioxy) PO-, aminosulfonyl-, C 1 . 4 alkylaminosulfonyl, di- (C x "-.
- R 3 is a phenyl or naphthyl group
- R 4 is a phenyl group
- a methylene group linked to the imino group can be replaced by a carbonyl or sulfonyl group or
- the cycloalkylene part can be condensed with a phenyl ring or
- one or two hydrogen atoms can each be replaced by a C 1-4 alkyl group or / and in each case the methylene group in position 4 bonyl- or a 6- or 7-membered cycloalkyleneimino group by a carboxy, C ⁇ alkoxycarbonyl, aminocarbonyl, C ⁇ -Alkylaminocar- aminocarbonyl group substituted di (alkyl C 1. 3,) or
- one or two hydrogen atoms each through a C 1 . 3 alkyl group can be replaced or
- the cycloalkylene with a phenyl group or an optionally by a fluorine, chlorine or bromine atom, by a C ⁇ - alkyl or C j. 1 3 -alkoxy group substituted imidazolo or pyridino group can be condensed or can be replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH or -N (C 1-3 -alkyl) group,
- R a is a hydrogen atom or a C ⁇ alkyl group
- n one of the numbers 0, 1 or 2 and
- R b is an amino, C 1-4 alkylamino, di (C ⁇ alkyl) amino, phenylamino or benzylamino group or a 5- to 6-membered cycloalkyleneimino group, the methylene group in position 4 of the piperidino group being replaced by a Oxygen or sulfur atom, can be replaced by a sulfinyl, sulfonyl, -NH or -N (C ⁇ alkyl) group, or, if n represents the number 1 or 2, also represent a hydrogen atom,
- R c is a hydrogen atom, a C 1-3 alkyl, C ⁇ - j alkylcarbonyl or C 1 _ 3 alkylsulfonyl group,
- R d is an amino, C 1-4 alkylamino, di (C 1-4 alkyl) amino, phenylamino or benzylamino group or a 5- to 6-membered cycloalkyleneimino group, the methylene group in position 4 of the piperidino group being replaced by an oxygen or sulfur atom, can be replaced by a sulfinyl, sulfonyl, -NH or -N [C _ 3 -alkyl) group, a di- (C ⁇ -alkyl) optionally substituted in the 1-position by a C ⁇ -alkyl group ) -amino-C ⁇ - j -alkylamino group or, if n represents the number 1 or 2, also denote a hydrogen atom,
- R 5 represents a hydrogen atom or a methyl group
- X is an oxygen atom
- R ⁇ is a hydrogen atom, a C ⁇ alkoxycarbonyl or C 2 . 4 -alkanoyl group,
- R 2 is a C 1 . 3 alkoxy, C ⁇ alkylmercapto, C - ⁇ - (. C 1 4 alkoxy) alkylsulfinyl, C- ⁇ j alkylsulfonyl, cyano, 2 P0, aminosulfonyl, C ⁇ alkylaminosulfonyl, di- (C 1 4 alkyl.) -aminosulfonyl-, Phe nylaminosulfonyl-, N- (C - ⁇ - alkyl) -phenylaminosulfonyl-, 3-pyridine dylaminosulfonyl- or N- (C 1 3 alkyl.) - 3-pyridylaminosulfonyl group, the phenyl radicals contained in the groups mentioned being replaced by a fluorine, chlorine or bromine atom, a C 1 . 3 -alkyl-, trifluoromethyl-,
- R 3 is a phenyl or naphthyl group, but especially the phenyl group
- R 4 is a phenyl group
- N- (phenylmethyl) -C ⁇ alkylamino group which is monosubstituted in the phenyl part by a fluorine, chlorine or bromine atom, a C ⁇ alkyl, C ⁇ - j alkoxy, trifluoromethyl or cyano group or can be disubstituted by two C 1-4 alkyl or C 1-4 alkoxy groups,
- cycloalkylene part can be condensed with a phenyl group
- R a is a C ⁇ alkyl group
- n one of the numbers 0, 1 or 2 and
- R b is an amino, C 1-4 alkylamino, di (C 1-4 alkyl) amino, pyrrolidino or piperidino group, the methylene group in position 4 of the piperidino group being represented by an oxygen or sulfur atom, by a sulfinyl , Sulfonyl, -NH or -N (C x . 3 -alkyl) group can be replaced, mean
- R c is a C 1 . 3- alkylcarbonyl or C 1-3 -alkylsulfonyl group
- R d is an amino, C 1 . 3 alkylamino, di (C 1. 4, alkyl) amino, pyrrolidino or piperidino group wherein the methylene group in position 4 of the piperidino group by an oxygen or sulfur atom, by a sulphinyl, sulphonyl, -NH- or (3 alkyl C. 1) may be replaced -N group or in the 1-position is optionally substituted by a C - ⁇ - substituted alkyl group, di- (C ⁇ j alkyl) amino-C ⁇ alkylamino group,
- R 5 represents a hydrogen atom
- the new compounds are obtained, for example, by the following processes which are known in principle from the literature:
- R 6 is a hydrogen atom or a protective group for the nitrogen atom of the lactam group, where R s can also represent a bond to a solid phase which may be formed via a spacer, and
- Z 1 represents a halogen atom, a hydroxyl, alkoxy or aryloxy group, for example a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,
- R 4 and R s are defined as mentioned at the beginning, and if necessary subsequent cleavage of a protective group used for the nitrogen atom of the lactam group or from a solid phase.
- a protective group for the nitrogen atom of the lactam group is, for example, an acetyl, benzoyl, ethoxycarbonyl, tert. - Butyloxycarbonyl or benzyloxycarbonyl group and
- a resin such as a 4- (2 ', 4' -dimethoxyphenylamino-methyl) -phenoxy resin, where the binding is advantageously carried out via the amino group, or a p-benzyloxybenzyl alcohol resin, the binding advantageously via an intermediate member such as a 2, 5-Dimethoxy-4-hydroxy-benzyl derivative is considered.
- the reaction is advantageously carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175 ° C, one protective group used can be split off simultaneously as a result of transamidation.
- a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, methylene chloride or mixtures thereof
- an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175 ° C
- one protective group used can be split off simultaneously as a result of transamidation.
- Z 1 in a compound of the general formula II denotes a halogen atom
- the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120 ° C.
- reaction is preferably carried out at temperatures between 20 and 200 ° C.
- a protective group which may be required is expediently carried out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dirnethylformamide / water, methanol or ethanol
- an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
- a solid phase used is preferably cleaved off using trifluoroacetic acid and water at temperatures between 0 and 35 ° C., preferably at room temperature.
- R 1 and R 3 to R 5 are defined as mentioned at the outset and
- R represents one of the substituted mercapto or sulfinyl groups mentioned at the outset for R 2
- the oxidation is preferably carried out in a solvent or solvent mixture, for example in water, water / pyridine, acetone, methylene chloride, acetic acid, acetic acid / acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used advantageously carried out at temperatures between -80 and 100 ° C.
- a solvent or solvent mixture for example in water, water / pyridine, acetone, methylene chloride, acetic acid, acetic acid / acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used advantageously carried out at temperatures between -80 and 100 ° C.
- the oxidation is conveniently carried out with one equivalent of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C or in acetone at 0 to 60 ° C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert , - Butyl hypochlorite in
- the oxidation is advantageously carried out with a corresponding sulfinyl compound using one or more equivalents of the oxidizing agent used or, starting from a corresponding mercapto compound, advantageously with two or more equivalents of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid / acetane hydride, trifluoroacetic acid or in formic acid at 20 to 100 ° C or in acetone at 0 to 60 ° C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid, sodium periodate or potassium perma- ganate in acetic acid, water / sulfuric acid or in
- the subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of one Alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
- an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
- one Alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
- the subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically excited hydrogen, for example from Hydrogen in the presence of Raney nickel, platinum or palladium / carbon, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminum hydride at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.
- a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide
- an acid such as hydrochloric acid
- catalytically excited hydrogen for
- the subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or diethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 ° C. and the boiling point of the solvent used.
- a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or diethylformamide
- the acylation with an appropriate acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetra-methoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus trichloride, phosphorus trichloride, phosphorus Dicyclohexylcarbodiimide, N, N '-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N' -dicyclohexylcarbodiimide / l-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3, 3- tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,
- the subsequent esterification or amidation is advantageously carried out by reacting a reactive corresponding carboxylic acid derivative with a corresponding alcohol or amine as described above.
- the subsequent reduction of a nitro group is preferably carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C. , but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
- a catalyst such as palladium / carbon or Raney nickel
- a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
- an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C. , but preferably at room temperature, and at
- any reactive groups present such as carboxy, aminosulfonyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are split off again after the reaction.
- the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group comes as a protective radical for a carboxyl group
- a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert. Butoxycarbonyl-, Benzyloxycarbonyl-, Benzyl-, Methoxy- benzyl- or 2, 4-Dimethoxybenzyl distr and for the amino group additionally the phthalyl group into consideration.
- a protective radical used takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide , Sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
- an aqueous solvent for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide , Sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
- a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C., but preferably at Room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
- a catalyst such as palladium / carbon
- a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
- an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C., but preferably at Room
- a methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
- an oxidizing agent such as cerium (IV) ammonium nitrate
- a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
- a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
- a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.
- a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methyl amine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
- chiral compounds of the general formula I obtained can be separated into their enantiomers and / or diastereomers.
- the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)
- the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separating the mixture of diastereomeric salts or derivatives obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
- an optically active substance which forms salts or derivatives such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols
- optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetyl-aspartic acid or quinic acid.
- an optically active alcohol for example (+) - or (-) menthol and the optically active acyl radical in amides, for example the (+) - or (-) menthyloxycarbonyl radical.
- the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
- Suitable acids for this are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.
- the new compounds of formula I thus obtained can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
- Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
- the new compounds of the general formula I in which R 1 represents a hydrogen atom or a prodrug residue have valuable pharmacological properties, in particular inhibitory effects on various kinases and cyclin / CDK complexes, on the proliferation of cultured human tumor Cells as well as after oral Given for the growth of tumors in nude mice infected with human tumor cells.
- High Five TM insect cells (BTI-TN-5B1-4), which were infected with a high titer of recombinant baculovirus, were used for the production of active human cyclin / CDK holoenzymes.
- a baculovirus vector that contained two promoters (polyhedrin enhancer promoter, P10 enhancer promoter), GST-tagged cyclins (eg Cyclin Dl or Cyclin D3) with the corresponding Hisg-tagged CDK subunit (eg for CDK4 or CDK6) expressed in the same cell.
- the active holoenzyme was isolated by affinity chromatography on glutathione-Sepharose.
- Recombinant GST-tagged pRB (aa 379-928) was produced in E. coli and purified by affinity chromatography on glutathione-Sepharose.
- the substrates used for the kinase assays depended on the specific kinases.
- Histone Hl Sigma was used as a substrate for Cyclin E / CDK2, Cyclin A / CDK2, Cyclin B / CDK1 and for v-Cyclin / CDK6.
- GST-tagged pRB (aa 379-928) was used as a substrate for Cyclin D1 / CDK4, Cyclin D3 / CDK4, Cyclin D1 / CDK6 and for Cyclin D3 / CDK6.
- Lysates of the insect cells infected with recombinant baculovirus or also recombinant kinases were combined with radioactively labeled ATP in the presence of a suitable substrate with various concentrations of the inhibitor in a 1% DMSO solution (dimethyl sulfoxide ) Incubated at 30 ° C for 45 minutes.
- the substrate proteins with associated radioactivity were multi-well mixed with 5% TCA (trichloroacetic acid) in hydrophobic PVDF Microtiter plates (Millipore) or precipitated with 0.5% phosphoric acid solution on Whatman P81 filters. After adding scintillation fluid, the radioactivity was measured in a Wallace 1450 Microbeta liquid scintillation counter. Double measurements were carried out per concentration of the substance; IC5 Q values for enzyme inhibition were calculated.
- SK-UT-1B obtained from the American Type Culture Collection (ATCC)
- ATCC American Type Culture Collection
- UT-IB cells were placed in Cytostar® multi-well plates (Amersham) with a density of 4000 cells per well and incubated overnight in an incubator. Different concentrations of the compounds (dissolved in DMSO; final concentration: ⁇ 1%) were added to the cells. After 48 hours of incubation, 14 C-thymidine (Amersham) was added to each well and incubation was continued for 24 hours. The amount of
- the new compounds of general formula I, their isomers and their physiologically tolerable salts are suitable for the treatment of diseases which are characterized by excessive or abnormal cell proliferation.
- Such diseases include (without claim to completeness): viral infections (eg HIV and Kaposi's sarcoma); Inflammation and autoimmune diseases (eg colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin diseases (eg psoriasis); Bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful for protecting proliferating cells (e.g. hair, intestine) tinal, blood and progenitor cells) against DNA damage from radiation, UV treatment and / or cytostatic treatment.
- viral infections eg HIV and Kaposi's sarcoma
- Inflammation and autoimmune diseases eg colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing
- bacterial, fungal and / or parasitic infections eg colitis, arthritis, Alzheimer's disease, glomerulonephriti
- the new compounds can also be used for the short-term or long-term treatment of the abovementioned diseases, if appropriate in combination with other "state-of-art” compounds such as other cytostatics.
- the dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration, and 0.1 to 100 mg / kg, preferably 0.3 to 30 mg / kg, 1 to each for oral administration 4 times a day.
- the compounds of the formula I prepared according to the invention cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, Tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional galenical preparations such as tablets, dragees, capsules, Incorporate powders, suspensions, suppositories or as solutions for injections or infusions.
- TBTU O- (benzotriazol-1-yl) -N, N, N ', N' -bis (tetramethylene) uronium hexafluorophosphate
- HOBt 1-hydroxy-1H-benzotriazole
- N- f 2 -Di methyl amino-ethyl -N-methyls l fonyl -4-ni troani 1 in 38.9 g N-methylsulfonyl-4-nitroaniline are dissolved in 2.0 1 acetone, 51.9 g l-chloro-2-dimethylamino-ethane , 77.4 g of potassium carbonate and 5.0 g of sodium iodide were added and the mixture was stirred for a total of 4 days at 50 ° C., after 12 hours a further 25.9 g of l-chloro-2-dimethylamino-ethane, 49.8 g of potassium carbonate and 5.0 g of sodium iodide in 500 ml Acetone and after 36 hours a further 26.0 g of l-chloro-2-dimethylaminoethane, 50.0 g of potassium carbonate and 5.0 g of sodium iodide in 100 ml of acetone
- N- (dimethylamomethyl-carbonyl) -N-methyl-4-nitro-ani 1 in 1.8 g of dimethylamine hydrochloride and 5.5 g of potassium carbonate are placed in 80 ml of acetone and 4.2 g of N- (2-bromomethylcarbonyl) - N- methyl-4-nitroaniline (manufactured according to Chem. Ber. 11, 2430 (1986)) added in three portions at room temperature. The mixture is stirred for 12 hours at room temperature. After this time the mixture is filtered and the filtrate is concentrated. The residue is dissolved in ethyl acetate, washed twice with water, dried over sodium sulfate and finally evaporated.
- the catalyst is filtered off and the filtrate is evaporated.
- R f value 0.4 (silica gel, methylene chloride / methanol / ammonia
- Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.
- the ready-to-use solution is dissolved with water for injections.
- (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled on a capsule filling machine into size 3 hard gelatin capsules.
- (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
- This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.
- 1 suppository contains:
- Polyethylene glycol (M.G. 1500) 600.0 mg
- the polyethylene glycol is melted together with polyethylene sorbitan monostearate.
- the milled active substance is homogeneously dispersed in the melt at 40 ° C. It gets to 38 ° C cooled and poured into weakly pre-cooled suppository molds.
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DE19949209 | 1999-10-13 | ||
PCT/EP2000/009847 WO2001027080A2 (de) | 1999-10-13 | 2000-10-07 | In 5-stellung substituierte indolinone und ihre verwendung als kinase und cyclin-cdk-komplexe inhibitoren |
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US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
US6797825B2 (en) | 2001-12-13 | 2004-09-28 | Abbott Laboratories | Protein kinase inhibitors |
AU2002360753B2 (en) | 2001-12-27 | 2008-08-21 | Theravance, Inc. | Indolinone derivatives useful as protein kinase inhibitors |
US7169936B2 (en) | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
US7514468B2 (en) | 2002-07-23 | 2009-04-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6 position, the preparation thereof and their use as pharmaceutical compositions |
DE10233500A1 (de) * | 2002-07-24 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel |
DE10237423A1 (de) | 2002-08-16 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von LCK-Inhibitoren für die Behandlung von immunologischen Erkrankungen |
US20040204458A1 (en) | 2002-08-16 | 2004-10-14 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of Lck inhibitors for treatment of immunologic diseases |
US7148249B2 (en) | 2002-09-12 | 2006-12-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinones substituted by heterocycles, the preparation thereof and their use as medicaments |
US20050043233A1 (en) | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
DE102004012070A1 (de) | 2004-03-12 | 2005-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue cycloalkyl-haltige 5-Acylindolinone, deren Herstellung und deren Verwendung als Arzneimittel |
DE102004012068A1 (de) * | 2004-03-12 | 2005-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue alkyl-haltige 5-Acylindolinone, deren Herstellung und deren Verwendung als Arzneimittel |
PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
WO2007122219A1 (en) * | 2006-04-24 | 2007-11-01 | Boehringer Ingelheim International Gmbh | 3- (aminomethyliden) 2-indolinone derivatives and their use as cell proliferation inhibitors |
US20170065529A1 (en) | 2015-09-09 | 2017-03-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical dosage form for immediate release of an indolinone derivative |
WO2020070332A1 (en) * | 2018-10-05 | 2020-04-09 | Ichnos Sciences S.A. | Oxindole compounds for use as map4k1 inhibitors |
CN111285872B (zh) * | 2018-12-06 | 2022-05-17 | 北京志健金瑞生物医药科技有限公司 | 吲哚-2-酮衍生物及其制备方法与用途 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4476307A (en) * | 1982-09-20 | 1984-10-09 | Pfizer Inc. | Heteroylidene indolone compounds |
US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
GB9718913D0 (en) * | 1997-09-05 | 1997-11-12 | Glaxo Group Ltd | Substituted oxindole derivatives |
DE19815020A1 (de) * | 1998-04-03 | 1999-10-07 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
-
1999
- 1999-10-13 DE DE19949209A patent/DE19949209A1/de not_active Withdrawn
-
2000
- 2000-10-07 AU AU76631/00A patent/AU7663100A/en not_active Abandoned
- 2000-10-07 EP EP00966136A patent/EP1224169A2/de not_active Withdrawn
- 2000-10-07 WO PCT/EP2000/009847 patent/WO2001027080A2/de active Search and Examination
- 2000-10-12 CO CO00077919A patent/CO5261507A1/es not_active Application Discontinuation
- 2000-10-13 AR ARP000105395A patent/AR026037A1/es active Pending
Non-Patent Citations (1)
Title |
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See references of WO0127080A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO2001027080A3 (de) | 2001-11-22 |
CO5261507A1 (es) | 2003-03-31 |
WO2001027080A2 (de) | 2001-04-19 |
AU7663100A (en) | 2001-04-23 |
AR026037A1 (es) | 2002-12-26 |
DE19949209A1 (de) | 2001-04-19 |
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