DE19814838A1 - Indolyl-3-glyoxylsäure-Derivate mit Antitumorwirkung - Google Patents
Indolyl-3-glyoxylsäure-Derivate mit AntitumorwirkungInfo
- Publication number
- DE19814838A1 DE19814838A1 DE19814838A DE19814838A DE19814838A1 DE 19814838 A1 DE19814838 A1 DE 19814838A1 DE 19814838 A DE19814838 A DE 19814838A DE 19814838 A DE19814838 A DE 19814838A DE 19814838 A1 DE19814838 A1 DE 19814838A1
- Authority
- DE
- Germany
- Prior art keywords
- group
- groups
- substituted
- alkyl
- acid
- 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.)
- Granted
Links
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 239000000243 solution Substances 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 8
- 239000003085 diluting agent Substances 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000000725 suspension Substances 0.000 claims abstract description 7
- 238000001802 infusion Methods 0.000 claims abstract description 4
- 239000002775 capsule Substances 0.000 claims abstract description 3
- 239000006071 cream Substances 0.000 claims abstract description 3
- 239000002674 ointment Substances 0.000 claims abstract description 3
- 239000000843 powder Substances 0.000 claims abstract description 3
- 239000000829 suppository Substances 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims abstract description 3
- 239000004480 active ingredient Substances 0.000 claims abstract 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract 3
- 239000008298 dragée Substances 0.000 claims abstract 2
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- -1 Boc Chemical group 0.000 claims description 34
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 28
- SOLIIYNRSAWTSQ-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)methyl]indol-3-yl]-2-oxo-n-pyridin-4-ylacetamide Chemical compound C1=CC(Cl)=CC=C1CN1C2=CC=CC=C2C(C(=O)C(=O)NC=2C=CN=CC=2)=C1 SOLIIYNRSAWTSQ-UHFFFAOYSA-N 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- PXZNKAFWRZAUAS-UHFFFAOYSA-N 2-[1-[(4-fluorophenyl)methyl]indol-3-yl]-2-oxo-n-pyridin-4-ylacetamide Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2C(C(=O)C(=O)NC=2C=CN=CC=2)=C1 PXZNKAFWRZAUAS-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 239000002246 antineoplastic agent Substances 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000005862 (C1-C6)alkanoyl group Chemical group 0.000 claims description 2
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims description 2
- 125000006294 amino alkylene group Chemical group 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 239000000174 gluconic acid Substances 0.000 claims description 2
- 235000012208 gluconic acid Nutrition 0.000 claims description 2
- 229940097043 glucuronic acid Drugs 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 235000021190 leftovers Nutrition 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- 239000003937 drug carrier Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000010 aprotic solvent Substances 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000002475 indoles Chemical class 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 125000004475 heteroaralkyl group Chemical group 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- AWMLDBKLOPNOAR-UHFFFAOYSA-N 2-(1h-indol-3-yl)-2-oxoacetamide Chemical class C1=CC=C2C(C(=O)C(=O)N)=CNC2=C1 AWMLDBKLOPNOAR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
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- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 239000003495 polar organic solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
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- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- IZXWCDITFDNEBY-UHFFFAOYSA-N 1-(chloromethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCl)C=C1 IZXWCDITFDNEBY-UHFFFAOYSA-N 0.000 description 2
- NNPAZBSSZIZVEI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]indole Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2C=C1 NNPAZBSSZIZVEI-UHFFFAOYSA-N 0.000 description 2
- BVRCPMXFRMVPNG-UHFFFAOYSA-N 2-(1h-indol-3-yl)-2-oxo-n-pyridin-4-ylacetamide Chemical compound C=1NC2=CC=CC=C2C=1C(=O)C(=O)NC1=CC=NC=C1 BVRCPMXFRMVPNG-UHFFFAOYSA-N 0.000 description 2
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 2
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
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- 238000011835 investigation Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
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- 238000011580 nude mouse model Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
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- 238000003756 stirring Methods 0.000 description 2
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- FPEGGKCNMYDNMW-UHFFFAOYSA-N 2-(1h-indol-3-yl)-2-oxoacetyl chloride Chemical compound C1=CC=C2C(C(=O)C(=O)Cl)=CNC2=C1 FPEGGKCNMYDNMW-UHFFFAOYSA-N 0.000 description 1
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000000587 Glycerolphosphate Dehydrogenase Human genes 0.000 description 1
- 108010041921 Glycerolphosphate Dehydrogenase Proteins 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- CAMRJRZJXQIBGQ-UHFFFAOYSA-N N-[1-[(4-fluorophenyl)methyl]-2-(4-phenylpiperazin-1-yl)indol-3-yl]-2-oxoacetamide Chemical compound C(C=O)(=O)NC1=C(N(C2=CC=CC=C12)CC1=CC=C(C=C1)F)N1CCN(CC1)C1=CC=CC=C1 CAMRJRZJXQIBGQ-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 102000005473 Secretory Phospholipases A2 Human genes 0.000 description 1
- 108010031873 Secretory Phospholipases A2 Proteins 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000050 cytotoxic potential Toxicity 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000020717 oral cavity carcinoma Diseases 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- YXJYBPXSEKMEEJ-UHFFFAOYSA-N phosphoric acid;sulfuric acid Chemical compound OP(O)(O)=O.OS(O)(=O)=O YXJYBPXSEKMEEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- CBFZWGRQXZYRRR-UHFFFAOYSA-N pyridin-4-amine;hydrochloride Chemical compound Cl.NC1=CC=NC=C1 CBFZWGRQXZYRRR-UHFFFAOYSA-N 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61K31/4164—1,3-Diazoles
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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Abstract
Description
R = Wasserstoff, (C1-C6)-Alkyl, wobei die Alkylgruppe ein- oder mehrfach durch den Phenylring substituiert sein kann und dieser Phenylring seinerseits ein- oder mehrfach durch Halogen, (C1-C6)-Alkyl, (C3-C7)-Cycloalkyl, durch Carboxylgruppen, mit C1-C6-Alkanolen veresterte Carboxylgruppen, Trifluormethylgruppen, Hydroxylgruppen, Methoxygruppen, Ethoxygruppen, Benzyloxygruppen sowie durch eine im Phenylteil ein- oder mehrfach mit (C1-C6)-Alkylgruppen, Halogenatomen oder Trifluormethylgruppen substituierte Benzylgruppe substituiert sein kann,
R steht ferner für die Benzyloxycarbonyl-Gruppe (Z-Gruppe) und für den tertiär- Butoxycarbonylrest (Boc-Rest), weiterhin für die Acetylgruppe.
R1 kann weiterhin für den Fall, daß R Wasserstoff, die Z-Gruppe, den BOC-Rest, die Acetyl- oder die Benzylgruppe bedeuten, der Säurerest einer natürlichen oder unnatürlichen Aminosäure sein, z. B. den α-Glycyl-, den α-Sarkosyl-, den α-Alanyl-, den α-Leucyl-, den α-iso-Leucyl-, den α-Seryl-, den α-Phenylalanyl-, den α-Histidyl-, den α-Prolyl-, den α-Arginyl-, den α-Lysyl-, den α-Asparagyl- und den α-Glutamyl- Rest darstellen, wobei die Aminogruppen der jeweiligen Aminosäuren ungeschützt vorliegen oder geschützt sein können. Als Schutzgruppe der Aminofunktion kommen der Carbobenzoxy-Rest (Z-Rest) und der tert.-Butoxycarbonyl-Rest (BOC-Rest) sowie die Acetylgruppe in Frage. Im Fall des für R1 beanspruchten Asparagyl- und Glutamylrestes liegt die zweite, nicht gebundene Carboxylgruppe als freie Carboxylgruppe oder in Form eines Esters mit C1-C6-Alkanolen, z. B. als Methyl-, Ethyl- bzw. als tert.-Butylester vor.
Ausbeute: 7,09 g (90% d. Th.)
Schmelzpunkt: 225-226°C
Elementaranalyse:
berechnet:
C 70,77; H 4,32; N 11,25;
gefunden:
C 71,09; H 4,36; N 11,26.
Beispiel 3, D 24834 N-(Pyridin-3-yl)-[1-(4-fluorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 4, D 24835 N-(Pyridin-3-yl)-(1-benzylindol-3-yl)-glyoxylamid
Beispiel 5, D 24836 N-(Pyridin-3-yl)-[1-(2-chlorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 6, D 24840 N-(4-Fluorphenyl)-[1-(4-fluorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 7, D 24841 N-(4-Nitrophenyl)-[1-(4-fluorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 8, D 24842 N-(2-Chlorpyridin-3-yl)-[1-(4-fluorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 9, D 24843 N-(Pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamid
Beispiel 10, D 24848 N-(Pyridin-4-yl)-[1-(3-pyridylmethyl)-indol-3-yl]-glyoxylamid
Beispiel 11, D 24849 N-(4-Fluorphenyl)-[1-(2-pyridylmethyl)-indol-3-yl]-glyoxylamid
Beispiel 12, D 24850 N-(4-Fluorphenyl)-[1-(3-pyridylmethyl)-indol-3-yl]-glyoxylamid
Beispiel 13, D 24851 N-(Pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 14, D 24852 N-(Pyridin-4-yl)-[1-(2-chlorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 15, D 24853 N-(Pyridin-2-yl)-[1-(4-fluorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 16, D 24847 N-(Pyridin-4-yl)-[1-(2-pyridylmethyl)-indol-3-yl]-glyoxylamid
Beispiel 17, D 24858 (4-Phenyl-piperazin-1-yl)-[1-(4-fluorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 18, D 24854 N-(Pyridin-2-yl)-(1-benzyl-indol-3-yl)-glyoxylamid
Beispiel 19, D 25421 N-(Pyridin-4-yl)-[1-(4-fluorbenzyl)-6-ethoxycarbonylamino-indol-3-yl]- glyoxylamid
Beispiel 20, D 25422 N-(Pyridin-4-yl)-[1-(4-fluorbenzyl)-5-ethoxycarbonylamino-indol-3-yl]- glyoxylamid
Beispiel 21, D 25423 N-(Pyridin-4-yl)-[1-(4-fluorbenzyl)-6-cyclopentyloxycarbonylamino- indol-3-yl]-glyoxylamid
Beispiel 22, D 25420 4-(Pyridin-4-yl)-piperazin-1-yl)-[1-(4-fluorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 23, D 24866 N-(3,4,5-Trimethoxybenzyl)-N-(allylaminocarbonyl-2-methyl-prop-1-yl)- [1-(4-fluorbenzyl)-indol-3-yl]-glyoxylamid
Beispiel 24 N-(Pyridin-4-yl)-[1-(4-fluorbenzyl)-5-methoxy-indol-3-yl]-glyoxylamid
Beispiel 25 N-(Pyridin-4-yl)-[1-(4-fluorbenzyl)-5-ethoxycarbonylamino-methyl indol-3-yl]-glyoxylamid.
Ausbeute: 9,8 g (43,3% d. Th.)
Fp.: ab 250°C.
Ausbeute: 41% d. Th.
Schmp.: 224-225°C
Elementaranalyse:
Berechnet:
C 70,77; H 4,32; N 11,25;
Gefunden:
C 70,98; H 4,40; N 11,49.
Die Indole besonders D-24851 und D-24241 sind zuerst im XTT-Proliferationstest-/Zytotoxizitätstest aufgefallen (Tab. 3 und Tab. 3a). In diesem Testsystem wird der Einfluß von Substanzen auf das Proliferationsverhalten von Tumorzellinien untersucht. Dabei wird das zytotoxische Potential dieser Substanzen erfaßt. Die Testmethode ist bei Scudiero et al. 1988, Cancer Res. 48, 4827 beschrieben.
Die KB-Zellinie ein epidermales Karzinom der Mundhöhle die L1210-Zellinie eine lymphatische Leukämie der Maus
die LNCAP-Zellinie ein Prostatakarzinom und
die SK-OV-3 Zellinie ein Ovarial-karzinom.
Am Dunning Tumor konnte nach Gabe von 7×100 mg/kg und 7×147 mg/kg p.o. D-24851 ein Tumorwachstumsstop, bei einigen Tieren sogar eine Tumorregression beobachtet werden.
Claims (11)
wobei die Reste R, R1, R2, R3, R4 und Z folgende Bedeutung haben:
R = Wasserstoff, (C1-C6)-Alkyl, wobei die Alkylgruppe ein- oder mehrfach durch den Phenylring substituiert sein kann und dieser Phenylring seinerseits ein- oder mehrfach durch Halogen, (C1-C6)-Alkyl, (C3-C7)-Cycloalkyl, durch Carboxylgruppen, mit C1-C6-Alkanolen veresterte Carboxylgruppen, Trifluormethylgruppen, Hydroxylgruppen, Methoxygruppen, Ethoxygruppen, Benzyloxygruppen sowie durch eine im Phenylteil ein- oder mehrfach mit (C1-C6)-Alkylgruppen, Halogenatomen oder Trifluormethylgruppen substituierte Benzylgruppe substituiert sein kann,
R steht ferner für die Benzyloxycarbonyl-Gruppe (Z-Gruppe) und für den tertiär- Butoxycarbonylrest (Boc-Rest), weiterhin für die Acetylgruppe.
R1 kann den Phenylring, der ein- oder mehrfach mit (C1-C6)-Alkyl, (C1-C6)-Alkoxy, Cyano, Halogen, Trifluormethyl, Hydroxy, Benzyloxy, Nitro, Amino, (C1-C6)- Alkylamino, (C1-C6)-Alkoxycarbonylamino und mit der Carboxylgruppe bzw. mit der mit C1-C6-Alkanolen veresterten Carboxylgruppe substituiert ist, oder ein Pyridin- Gerüst der Formel 2 und deren N-Oxid
bedeuten und dessen N-Oxid, wobei das Pyridin-Gerüst wahlweise an den Ringkohlenstoff Atomen 2, 3 und 4 gebunden ist und mit den Substituenten R5 und R6 substituiert sein kann. Die Reste R5 und R6 können gleich oder verschieden sein und die Bedeutung (C1-C6)-Alkyl sowie die Bedeutung (C3-C7)- Cycloalkyl, (C1-C6)-Alkoxy, Nitro, Amino, Hydroxy, Halogen und Trifluormethyl besitzen und ferner den Ethoxycarbonylamino-Rest sowie die Gruppe Carboxyalkyloxy darstellen, bei dem die Alkylgruppe über 1-4 C-Atome verfügen kann.
R1 kann ferner ein 2- bzw. 4-Pyrimidinyl-Heterocyclus sein, wobei der 2-Pyrimidinyl-Ring ein- oder mehrfach mit der Methylgruppe substituiert sein kann, weiterhin das mit (C1-C6)-Alkyl, Halogen, der Nitrogruppe, der Aminogruppe und dem (C1-C6)- Alkyl- amino-Rest substituierte 2-, 3-, und 4- und 8-Chinolylgerüst bedeuten, eine 2-, 3- und 4-Chinolylmethylgruppe darstellen, wobei die Ringkohlenstoffe des Pyridylmethylrestes der Chinolylgruppe und des Chinolylmethyl-Restes mit (C1-C6)- Alkyl1 (C1-C6)-Alkoxy, Nitro, Amino und (C1-C6)-Alkoxycarbonylamino substituiert sein können.
R1 kann weiterhin für den Fall, daß R = Wasserstoff, die Methyl -oder Benzylgruppe sowie den Benzyloxycarbonyl-Rest (Z-Rest), den tert.-Butoxycarbonyl-Rest (BOC- Rest) und die Acetylgruppe darstellt, die folgenden Reste bedeuten:-
R1 kann weiterhin für den Fall, daß R Wasserstoff, die Z-Gruppe, den BOC-Rest, die Acetyl- oder die Benzylgruppe bedeuten, der Säurerest einer natürlichen oder unnatürlichen Aminosäure sein, z. B. den α-Glycyl-, den α-Sarkosyl-, den α-Alanyl-, den α-Leucyl-, den α-iso-Leucyl-, den α-Seryl-, den α-Phenylalanyl-, den α-Histidyl-, den α-Prolyl-, den α-Arginyl-, den α-Lysyl-, den α-Asparagyl- und den α-Glutamyl- Rest darstellen, wobei die Aminogruppen der jeweiligen Aminosäuren ungeschützt vorliegen oder geschützt sein können. Als Schutzgruppe der Aminofunktion kommen der Carbobenzoxy-Rest (Z-Rest) und der tert.-Butoxycarbonyl-Rest (BOC-Rest) sowie die Acetylgruppe in Frage. Im Fall des für R1 beanspruchten Asparagyl- und Glutamylrestes liegt die zweite, nicht gebundene Carboxylgruppe als freie Carboxylgruppe oder in Form eines Esters mit C1-C6-Alkanolen, z. B. als Methyl-, Ethyl- bzw. als tert.-Butylester vor.
Weiterhin kann R1 die Allylaminocarbonyl-2-methyl-prop-1-yl-Gruppe bedeuten.
R und R1 können ferner zusammen mit dem Stickstoff-Atom, an das sie gebunden sind, einen Piperazinring der Formel 3 oder einen Homopiperazinring bilden, sofern R1 eine Aminoalkylengruppe darstellt, bei dem
R7 einen Alkylrest darstellt, einen Phenylring bedeutet, der ein- oder mehrfach mit (C1-C6)-Alkyl, (C1-C6)-Alkoxy, Halogen, der Nitrogruppe, der Aminofunktion und mit der (C1-C6)-Alkylaminogruppe substituiert sein kann. R7 bedeutet ferner die Benzhydryl-Gruppe und die Bis-p-fluorbenzylhydryl-Gruppe.
R2 kann Wasserstoff und die (C1-C6)-Alkyl-Gruppe bedeuten, wobei die Alkylgruppe ein- oder mehrfach durch Halogen und Phenyl substituiert ist, das seinerseits ein- oder mehrfach durch Halogen, (C1-C6)-Alkyl, (C3-C7)-Cycloalkyl, Carboxylgruppen mit C1-C6-Alkanolen veresterten Carboxylgruppen, Trifluormethylgruppen, Hydroxylgruppen, Methoxygruppen, Ethoxygruppen oder Benzyloxygruppen substituiert sein kann. Die für R2 geltende (C1-C6)-Alkyl-Gruppe kann ferner durch die 2-Chinolylgruppe und das 2-,3- und 4-Pyridyl-Gerüst substituiert sein, die beide jeweils ein- oder mehrfach durch Halogen, (C1-C4)-Alkylgruppen oder (C1-C4)- Alkoxy-gruppen substituiert sein können. R2 steht ferner für den Aroyl-Rest, wobei der diesem Rest zugrunde liegende Arylteil den Phenylring darstellt, der ein- oder mehrfach durch Halogen, (C1-C6)-Alkyl, (C3-C7)-Cycloalkyl, Carboxylgruppen mit C1-C6-Alkanolen veresterte Carboxylgruppen, Trifluormethylgruppen, Hydroxylgruppen, Methoxygruppen, Ethoxygruppen oder Benzyloxygruppen substituiert sein kann.
R3 und R4 können gleich oder verschieden sein und Wasserstoff, (C1-C6)-Alkyl, (C3-C7)- Cycloalkyl, (C1-C6)-Alkanoyl, (C1-C6)-Alkoxy, Halogen und Benzyloxy bedeuten.
Weiterhin können R3 und R4 die Nitrogruppe, die Aminogruppe, die (C1-C4)-mono- oder dialkylsubstituierte Aminogruppe, und die (C1-C6)-Alkoxy-carbonylamino- Funktion oder (C1-C6)-Alkoxycarbonylamino-(C1-C6)-alkyl-Funktion bedeuten.
Z steht für O und S.
wobei die Reste
R = Wasserstoff
R1 = 4-Pyridyl, 4-Fluorophenyl
R2 = Benzyl, 4-Chlorbenzyl, 4-Fluorbenzyl, 3-Pyridylmethyl, 4-Brombenzyl
R3 und R4 = Wasserstoff und
Z Sauerstoff bedeuten.
D 24241 N-(Pyridin-4-yl)-[1-(4-fluorbenzyl)-indol-3-yl]glyoxylamid
D 24843 N-(Pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamid
D 24850 N-(4-Fluorphenyl)-[1-(3-pyridylmethyl)-indol-3-yl]-glyoxylamid
D 24851 N-(Pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxylamid
D-25505 N-(Pyridin-4-yl)-[1-(4-fluorbenzyl)-indol-3-yl]glyoxylamid HCL.
Priority Applications (45)
Application Number | Priority Date | Filing Date | Title |
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DE19814838A DE19814838C2 (de) | 1998-04-02 | 1998-04-02 | Indolyl-3-glyoxylsäure-Derivate mit Antitumorwirkung |
TR2000/02853T TR200002853T2 (tr) | 1998-04-02 | 1999-03-22 | Antitümör etkili indolil-3-glioksilik asit türevleri |
DE59912562T DE59912562D1 (en) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylsäure-derivate mit antitumorwirkung |
PCT/EP1999/001918 WO1999051224A1 (de) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylsäure-derivate mit antitumorwirkung |
PL343525A PL192779B1 (pl) | 1998-04-02 | 1999-03-22 | Zastosowanie N-podstawionych indolo-3-glioksyloamidów |
CZ20003483A CZ302588B6 (cs) | 1998-04-02 | 1999-03-22 | Použití N-substituovaného indol-3-glyoxylamidu pro výrobu léciva |
EP99910372A EP1071420B1 (de) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylsäure-derivate mit antitumorwirkung |
HU0101530A HUP0101530A3 (en) | 1998-04-02 | 1999-03-22 | Pharmaceutical compositions containing indolyl-3-glyoxylic acid derivatives with antitumoral activity |
EEP200000581A EE04354B1 (et) | 1998-04-02 | 1999-03-22 | Indolüül-3-glüoksüülhappe derivaadid, nende kasutamine ravimite valmistamiseks ja neid sisaldavad kasvajavastase toimega ravimid |
YUP-593/00A RS49866B (sr) | 1998-04-02 | 1999-03-22 | Derivati indolil-3-glioksilne kiseline sa antitumorskom aktivnošću |
CA002326833A CA2326833C (en) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylic acid derivatives with antitumoral activity |
IDW20001988A ID26504A (id) | 1998-04-02 | 1999-03-22 | Turunan-turunan asam indolil-3-glioksilat yang memiliki aksi anti tumor |
AU29349/99A AU768510B2 (en) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylic acid derivatives with antitumoral activity |
AT99910372T ATE304352T1 (de) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylsäure-derivate mit antitumorwirkung |
SI9930851T SI1071420T1 (sl) | 1998-04-02 | 1999-03-22 | Derivati indolil-3-glioksilne kisline z antitumorskim ucinkom |
SK1430-2000A SK286393B6 (sk) | 1998-04-02 | 1999-03-22 | Použitie N-substituovaných indolyl-3-glyoxylamidov s protinádorovým účinkom |
RU2000128035/15A RU2262339C2 (ru) | 1998-04-02 | 1999-03-22 | Производные индолил-3-глиоксиловой кислоты - соединения, обладающие противоопухолевой активностью, фармацевтическая композиция, противоопухолевое средство (варианты) |
NZ507084A NZ507084A (en) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylic acid derivatives with antitumoral activity |
ES99910372T ES2249884T3 (es) | 1998-04-02 | 1999-03-22 | Derivados del acido indolil-3-glioxilico con efecto antitumoral. |
BR9909902-0A BR9909902A (pt) | 1998-04-02 | 1999-03-22 | Derivados de ácido indolil-3-glioxìlico com efeito antitumor |
UA2000116192A UA70942C2 (uk) | 1998-04-02 | 1999-03-22 | Застосування n-заміщеного індоліл-3-гліоксиламіду як протипухлинного засобу, спосіб лікування пухлинних захворювань та лікарська композиція для лікування пухлинних захворювань |
JP2000541995A JP5253696B2 (ja) | 1998-04-02 | 1999-03-22 | 抗腫瘍作用を有するインドリル−3−グリオキシル酸誘導体 |
CNB998059234A CN1148183C (zh) | 1998-04-02 | 1999-03-22 | 具有抗肿瘤作用的吲哚基-3-乙醛酸衍生物 |
DK99910372T DK1071420T3 (da) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylsyrederivater med antitumorvirkning |
IL13873799A IL138737A0 (en) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylic acid derivatives with antitumoral activity |
KR1020007010934A KR100583545B1 (ko) | 1998-04-02 | 1999-03-22 | 인돌릴-3-글리옥실산 유도체를 포함하는 약제학적 조성물 |
GEAP19995611A GEP20032967B (en) | 1998-04-02 | 1999-03-22 | Indolyl-3-Glyoxylic Acid Derivatives As an Antitumor Agent and Pharmaceutical Composition |
TW088104599A TWI230608B (en) | 1998-04-02 | 1999-03-23 | Indolyl-3-glyoxylic acid derivatives having antitumor action |
ARP990101501A AR018175A1 (es) | 1998-04-02 | 1999-03-31 | Compuestos de indol-3-glioxilamidas sustituidas, utiles como medicamentos antitumorales, composiciones farmaceuticas formuladas con dichos derivados,utilizacion de dichos derivados para la preparacion de medicamentos antitumorales y los medicamentos asi preparados. |
US09/285,058 US6232327B1 (en) | 1998-04-02 | 1999-04-02 | Indolyl-3-glyoxylic acid derivatives having antitumor action |
DE19946301A DE19946301A1 (de) | 1998-04-02 | 1999-09-28 | Indolyl-3-glyoxylsäure-Derivate mit therapeutisch wertvollen Eigenschaften |
US09/492,531 US6693119B2 (en) | 1998-04-02 | 2000-01-27 | Indolyl-3-glyoxylic acid derivatives having therapeutically valuable properties |
IS5635A IS2307B (is) | 1998-04-02 | 2000-09-22 | Indólýl-3-glýoxýlsýru afleiður með virkni gegn æxlum |
IL138737A IL138737A (en) | 1998-04-02 | 2000-09-27 | Pharmaceutical preparations with antiseptic activity containing a history of indolyl-3-glyoxylic acid |
NO20004916A NO327721B1 (no) | 1998-04-02 | 2000-09-29 | Anvendelse av indolyl-3-glyoksylsyrederivater for fremstilling av et medikament, for behandling av tumorer. |
HR20000643A HRP20000643A2 (en) | 1998-04-02 | 2000-10-02 | Indolyl-3-glyoxylic acid derivatives with antitumoral activity |
BG104849A BG64838B1 (bg) | 1998-04-02 | 2000-10-12 | Производни на индолил-3-глиоксиловата киселина с антитуморно действие |
ZA200006150A ZA200006150B (en) | 1998-04-02 | 2000-10-31 | Indolyl-3-glyoxylic acid derivatives with antitumoral activity. |
US09/810,604 US20030023093A1 (en) | 1998-04-02 | 2001-03-19 | United states patent office |
HK01107405A HK1036408A1 (en) | 1998-04-02 | 2001-10-24 | Indolyl-3-glyoxylic acid derivatives with antitumoral activity. |
US10/309,204 US7579365B2 (en) | 1998-04-02 | 2002-12-04 | Indolyl-3-glyoxylic acid derivatives having antitumor action |
US10/686,809 US7452910B2 (en) | 1998-04-02 | 2003-10-17 | Indolyl-3-glyoxylic acid derivatives having therapeutically valuable properties |
US11/894,729 US20080057124A1 (en) | 1998-04-02 | 2007-08-20 | Indolyl-3-glyoxylic acid derivatives having therapeutically valuable properties |
US11/894,591 US20080027110A1 (en) | 1998-04-02 | 2007-08-20 | Indolyl-3-glyoxylic acid derivatives having antitumor action |
JP2011053448A JP2011148809A (ja) | 1998-04-02 | 2011-03-10 | 抗腫瘍作用を有するインドリル−3−グリオキシル酸誘導体 |
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DE19814838A DE19814838C2 (de) | 1998-04-02 | 1998-04-02 | Indolyl-3-glyoxylsäure-Derivate mit Antitumorwirkung |
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DE59912562T Expired - Lifetime DE59912562D1 (en) | 1998-04-02 | 1999-03-22 | Indolyl-3-glyoxylsäure-derivate mit antitumorwirkung |
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JP (2) | JP5253696B2 (de) |
KR (1) | KR100583545B1 (de) |
CN (1) | CN1148183C (de) |
AR (1) | AR018175A1 (de) |
AT (1) | ATE304352T1 (de) |
AU (1) | AU768510B2 (de) |
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ES (1) | ES2249884T3 (de) |
GE (1) | GEP20032967B (de) |
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HR (1) | HRP20000643A2 (de) |
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ID (1) | ID26504A (de) |
IL (2) | IL138737A0 (de) |
IS (1) | IS2307B (de) |
NO (1) | NO327721B1 (de) |
NZ (1) | NZ507084A (de) |
PL (1) | PL192779B1 (de) |
RS (1) | RS49866B (de) |
RU (1) | RU2262339C2 (de) |
SK (1) | SK286393B6 (de) |
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